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4e64148cc3d63e797e29955a1e5599cd

In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures .

Mass administration of an antimalarial drug combining 4-aminoquinoline and 8-aminoquinoline in Tanganyika. For the eradication of malaria from hyperendemic regions of tropical Africa it is apparent that use may have to be made of antimalarial drugs, administered individually on a census basis, in addition to measures directed against the mosquito. The suppressive activity of existing compounds among individuals having different degrees of immunity is well established, and trials among large groups of people have been conducted with single drugs and with combination of drugs. In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures . It was found that treatment of 93% of the population at intervals of one or two weeks resulted in a reduction of the malaria indices to a very low level but such success was not obtained when the combination of drugs was administered every four weeks, although in the area concerned population coverage was less satisfactory owing to migration.

https://pubmed.ncbi.nlm.nih.gov/14021798/

995fb1567f527dad4c82bd259bd632cb

In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) .

Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Multiple myeloma accounts for approximately 10% of hematologic malignancies. ### diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). ### Risk Stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. ### Risk Adapted Initial Therapy In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) . In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). ### Maintenance Therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. ### Management Of Refractory Disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.

https://pubmed.ncbi.nlm.nih.gov/32212178/

ffe6e1e3c4c2087fd48b402e210e30e0

Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines .

Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines . To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP). ### Materials And Methods The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel. ### results GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity. ### conclusion These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.

https://pubmed.ncbi.nlm.nih.gov/18565171/

7a9e2e3120bc08702b1f8f43efe006d3

Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis .

[Efficacy of combination therapy with bosentan and sildenafil for refractory pulmonary arterial hypertension associated with fibrotic lung in systemic sclerosis]. A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis .

https://pubmed.ncbi.nlm.nih.gov/21066870/

a37b060ccdcd200503f49e6cf490f6c8

All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept , and all resided in HC-endemic regions .

Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products. ### methods The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept. ### results Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept , and all resided in HC-endemic regions . ### conclusion Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.

https://pubmed.ncbi.nlm.nih.gov/12384912/

4c12db4480499b3f103a64641ccf2593

Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months .

Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months . ### purpose To determine the efficacy of postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin in the prevention of metastasis for patients with high-risk retinoblastoma. ### methods Retrospective, nonrandomized, interventional case series of 52 eyes in 51 patients with high-risk retinoblastoma consisting of tumor invasion into the anterior segment, posterior uvea 3 mm or greater, postlaminar optic nerve, or any combination of posterior uvea and optic nerve involvement. ### results Of 51 consecutive patients with high-risk retinoblastoma, there were 30 males (59%) and 21 females (41%), with a median age of 28 months at diagnosis. All 52 eyes were classified as group E. The main histopathologic risk factors included anterior segment invasion (7 [13%]), isolated massive posterior uveal invasion of 3 mm or greater (6 [12%]), isolated postlaminar optic nerve invasion (15 [29%]), or any posterior uveal invasion with any optic nerve involvement (24 [46%]). There was additional invasion into the sclera (3 [6%]) and extrascleral structures, including the orbit (1 [2%]). A single histopathologic high-risk factor was present in 32 eyes (62%), whereas 20 eyes (38%) manifested 2 or more high-risk characteristics. Based on previously published series, untreated high-risk retinoblastoma carries at least a 24% risk for metastatic disease. In the present series, using vincristine, etoposide, and carboplatin in all cases, there was no metastasis during a mean follow-up of 66 months (median [range], 55 [12-202] months). ### conclusions Retinoblastoma with invasion into the postlaminar optic nerve and/or posterior uvea is at high risk for metastasis and death. In this study, postenucleation chemotherapy using vincristine, etoposide, and carboplatin was effective in preventing metastasis in every case (100%).

https://pubmed.ncbi.nlm.nih.gov/22084213/

5c011db3395f3d8e96b2b38ca08ad876

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation .

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation . To evaluate the clinical and cost-effectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5-fluorouracil/folinic acid (5-FU/FA) regimens. ### Data Sources Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. ### Review Methods Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5-FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. ### results The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand-foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve health-related quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at 2111 pounds and 3375 pounds, respectively, compared with the total treatment cost for the Mayo regimen of 3579 pounds. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were 3684 pounds and 6155 pounds, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be 1461 pounds and 209 pounds, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be 1353 pounds and 101 pounds, respectively, and over the inpatient de Gramont regimen were estimated to be 4123 pounds and 2870 pounds, respectively. ### conclusions The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data.

https://pubmed.ncbi.nlm.nih.gov/14604497/

c4f2d09db81566c47c4b6b76bd9ed471

All strains were susceptible to phenoxymethylpenicillin , cephalosporins , erythromycin , azithromycin , clindamycin , vancomycin , doxycycline , and ciprofloxacin but were resistant to trimethoprim-sulfamethoxazole .

Antimicrobial susceptibility of Arcanobacterium haemolyticum. The susceptibilities of 138 clinical isolates of Arcanobacterium haemolyticum to 11 antimicrobial agents were tested. All strains were susceptible to phenoxymethylpenicillin , cephalosporins , erythromycin , azithromycin , clindamycin , vancomycin , doxycycline , and ciprofloxacin but were resistant to trimethoprim-sulfamethoxazole .

https://pubmed.ncbi.nlm.nih.gov/8141569/

95afbabbb2b4898b8b0ab8854f3e5333

The inhibition by the agonist oxotremorine is comparable to that of carbachol and 1 mM pilocarpine inhibited the binding by 21 % .

Muscarinic binding sites in a catecholaminergic human neuroblastoma cell line. Tyrosine hydroxylase (TH) a characteristic enzyme activity for the catecholaminergic clonal cell line LA-N-1 and choline acetyltransferase (ChAT) a characteristic enzyme activity for the cholinergic clonal cell line LA-N-2 were previously shown to be increased in these cells exposed to 10(-5) M retinoic acid (RA) as differentiating agent. An investigation of the receptor characteristics suggests a complementarity between the two cell lines. The binding of QNB, a muscarinic ligand, was undetectable with the LA-N-2 cells but was present in the LA-N-1 cells and possessed a kD of 1.8 nM and 2.2 nM and a Bmax of 0.56 and 0.68 for control and RA grown cells respectively. There was a gradual increase in QNB binding to LA-N-1 cells from 2 days in vitro (DIV) until 6 DIV in both control and RA grown cells. An IC50 of 2.5 x 10(-8) M and 0.9 x 10(-8) M for atropine inhibition was obtained for the control and RA grown cells respectively. The corresponding values for carbachol inhibition were 7 x 10(-2) M and 3 x 10(-2) M respectively. The inhibition by the agonist oxotremorine is comparable to that of carbachol and 1 mM pilocarpine inhibited the binding by 21 % . QNB binding showed a low affinity for pirenzepine and for AF-DX-116 but was inhibited with a rather high affinity by 4-DAMP (IC50:110 microM) thus suggesting the presence of an M3 receptor. Acetylcholine (100 microM) plus eserine (50 microM) and BW284c55 (1 microM), an acetylcholinesterase inhibitor, reduced the binding of QNB by approximately 25%.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1320213/

a6f95bc857398a035571a727142fe48e

Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer .

Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer . To estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. ### methods An "an area under the curve" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. ### results Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. ### conclusions All three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.

https://pubmed.ncbi.nlm.nih.gov/23538180/

86aa3323dfc7081ec77bbad12601a64d

Limits of quantification were 0.12 , 1.09 , 1.46 , 1.47 , 5.70 , 1.32 , 1.33 µg/L for haloperidol , aripiprazole , olanzapine , quetiapine , clozapine , risperidone , and paliperidone , respectively .

Multiplexed therapeutic drug monitoring of antipsychotics in dried plasma spots by LC-MS/MS. In this work, a convenient method for the therapeutic monitoring of seven common antipsychotic drugs in "dried plasma spot" samples has been developed. It is based on the liquid chromatography tandem mass spectrometry technique, operating in multiple reaction monitoring mode, and a straightforward procedure for the simultaneous extraction of all antipsychotics in a single step, with high extraction yield. The method was fully validated with proper accuracy, precision, selectivity and sensitivity, for all the drugs. Limits of quantification were 0.12 , 1.09 , 1.46 , 1.47 , 5.70 , 1.32 , 1.33 µg/L for haloperidol , aripiprazole , olanzapine , quetiapine , clozapine , risperidone , and paliperidone , respectively . Accuracy, intra- and interday precision values were <10% for all drugs at all concentration levels examined. The method was tested in the analysis of 30 plasma samples from real patients for each drug. The proposed analytical approach, by combining practical and logistical advantages of microsampling with liquid chromatography tandem mass spectrometry analytical performance, could offer an ideal strategy for accurate and timely therapeutic drug monitoring of antipsychotic drugs in most clinical settings, even in remote centers and/or in out-patient settings, bringing so many potential improvements in psychiatric patient care.

https://pubmed.ncbi.nlm.nih.gov/32077627/

00e37a3a571029baa205896e8b8af80a

Sensitization to doxorubicin and etoposide with BPTF knockdown ( KD ) was associated with increased DNA damage , topoisomerase II ( TOP2 ) crosslinking and autophagy ; however , there was only a modest increase in apoptosis and no increase in senescence .

Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor. Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown ( KD ) was associated with increased DNA damage , topoisomerase II ( TOP2 ) crosslinking and autophagy ; however , there was only a modest increase in apoptosis and no increase in senescence . Sensitization to doxorubicin was confirmed

https://pubmed.ncbi.nlm.nih.gov/33811160/

5164a0a4ccd664fee504b3a219d45e02

This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma .

14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group. This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma . ### Patients And Methods From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. ### results All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. ### conclusion Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.

https://pubmed.ncbi.nlm.nih.gov/12721249/

b5a492e63b8d042a91334a25354a0c87

Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment .

Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment . Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. ### methods The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12 weeks after the end of treatment and safety was evaluated according to renal function. ### results Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44 mL/min/1.73 m ### conclusion daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.

https://pubmed.ncbi.nlm.nih.gov/27943523/

e0a5e104ff27dc22c4bac651946a3093

We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) .

Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients. In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) . MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.

https://pubmed.ncbi.nlm.nih.gov/3276062/

74f50f05d8872caba44cad3755e29d2a

Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms , respectively ( HR , 0.62 ; 95 % CI , 0.44 to 0.89 ; P = .009 ) .

PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS. ### Patients And Methods Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety. ### results Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms , respectively ( HR , 0.62 ; 95 % CI , 0.44 to 0.89 ; P = .009 ) . In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms. ### conclusion PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.

https://pubmed.ncbi.nlm.nih.gov/24687833/

7851400849edea591bab081dcce35070

One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) .

The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. 30 pairs of patients with complicated Plasmodium falciparum malaria (with anaemia, hyperpyrexia, jaundice or more than 5% of erythrocytes parasitized) were studied. Patients with cerebral signs and symptoms were excluded. One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) . The second group of patients was treated with quinine (10 mg/kg orally every 8 h for 7 d). All patients were admitted to hospital for 7 d and examined subsequently on days 14, 21 and 28. All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine. 2 patients treated with quinine died. There was no recrudescence in any patient of either group.

https://pubmed.ncbi.nlm.nih.gov/3075350/

79e1e6d499310e1367d0b0ff3798ad16

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer .

The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer . Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.

https://pubmed.ncbi.nlm.nih.gov/11346931/

303584137532ab3adfbf9a922097c40e

In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered .

Successful Treatment of Gastrosplenic Fistula Arising from Diffuse Large B-Cell Lymphoma with Chemotherapy: Two Case Reports. Gastrosplenic fistula (GSF) is a rare condition arising from gastric or splenic lymphomas. Surgical resection is the most common treatment, as described in previous reports. We report two cases of GSF in diffuse large B-cell lymphoma (DLBCL) patients that were successfully treated with chemotherapy and irradiation without surgical resection. Case 1 was of a 63-year-old man who had primary gastric DLBCL with a large lesion outside the stomach wall, leading to a spontaneous fistula in the spleen. Case 2 was of a 59-year-old man who had primary splenic DLBCL, which proliferated and infiltrated directly into the stomach. In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered . Case 1 had significant bleeding from the lesion of the stomach during the treatment cycle; however, endoscopic hemostasis was achieved. Case 2 developed a fistula between the stomach and the spleen following therapeutic chemotherapy; however, no complications related to the fistula were observed thereafter. In both cases, irradiation was administered, and complete remission was achieved.

https://pubmed.ncbi.nlm.nih.gov/31182954/

895f8f092802706aa4d15f7d7c46540b

Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid .

Low endoscopy bleeding risk in patients with congenital bleeding disorders. Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. ### methods We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid . Our primary outcome was the 72-hour postendoscopy bleeding rate. ### results One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). ### conclusion To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders.

https://pubmed.ncbi.nlm.nih.gov/30748066/

d9994cfb89299e8c4c4c6f0130d9189b

Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel , we suggest that physicians should consider possible predictive risk factors for overall survival , individual 's treatment priorities , and the differing safety profiles .

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. ### methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. ### findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. ### interpretation bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel , we suggest that physicians should consider possible predictive risk factors for overall survival , individual 's treatment priorities , and the differing safety profiles . ### funding Roche.

https://pubmed.ncbi.nlm.nih.gov/27501767/

90111cf0d99ec6681021ea333de19ace

The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development .

A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma. Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. ### background Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. ### methods We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m ### results The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). ### conclusion The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development . Alternative combinations with these agents could be explored in future studies.

https://pubmed.ncbi.nlm.nih.gov/28679644/

2ce0bf4cbd6f3d346eb3e1ad0fac2e63

Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology .

Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901. The role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS). ### Patients And Methods Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology . Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months. ### results A total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049). ### conclusion Maintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.

https://pubmed.ncbi.nlm.nih.gov/32727707/

d8228db05effe17e695057b6931e7251

A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy .

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). ### Data Sources Searches of main electronic databases were conducted in April and May 2005. ### Review Methods For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. ### results Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy . The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less. ### conclusions The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential.

https://pubmed.ncbi.nlm.nih.gov/17346499/

6f7f62aa1e5b1817104f828c34afc946

Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control .

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study. T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2 ### Patients And Methods Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. ### results Of 445 patients with HER2 ### conclusions Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control .

https://pubmed.ncbi.nlm.nih.gov/31735691/

a56f01a9aeaba193912053d4079ba9ad

Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide .

Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention. A 48-year-old female was admitted to our hospital presenting with a chief complaint of progressive swelling because of diabetic nephrotic syndrome. Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide . Our experience emphasizes a potential novel approach to overcoming loop diuretic resistance using this agent among some subsets of type 2 diabetic subjects complicated with severe volume accumulation. We believe that combination treatment consisting of dapagliflozin and furosemide may produce diuretic synergy via sequential nephron blockade. The accumulation of more experience with additional cases similar to ours requires continuous and careful attention.

https://pubmed.ncbi.nlm.nih.gov/26609216/

2b25d51f8c4a7f7cd32adf4f78458da5

PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients .

Combined treatment with goserelin and tamoxifen in patients with advanced chemotherapy resistant ovarian cancer. The purpose of this study was to determine the response in patients with recurrent, chemotherapy-resistant ovarian cancer to a combination of the LHRH-analog goserelin and tamoxifen. ### Patients And Methods Twenty-five patients with recurrent, chemotherapy resistant ovarian cancer received a combination of goserelin and tamoxifen until clinical or serological evidence of progression as measured by serum CA-125 levels. Suppression of LH, FSH and prolactin levels in this group were compared with a second group of ten patients treated with decapeptyl for the same indication. ### results The combination was well tolerated. The median progression free survival amounted to five (range 2-96+) months and overall survival to eight (range 3-96+) months. One of the responding patients is still alive without progression at 8 years. With this combination the median levels of LH and FSH were markedly suppressed, to respectively 2.6% and 3.7% of baseline values. With decapeptyl the LH levels were also suppressed, but the resulting FSH levels were significantly higher. PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients .

https://pubmed.ncbi.nlm.nih.gov/10629663/

7385613d0a7b2b60cf472517e778e6d6

In previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) .

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. In previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) . At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. ### Patients And Methods Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. ### results Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( ### conclusion Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.

https://pubmed.ncbi.nlm.nih.gov/32986498/

9c4c2f5c9efc3983bbdf6e974ac0c8cf

The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats .

Combination therapy of atorvastatin and amlodipine inhibits sympathetic nervous system activation and improves cognitive function in hypertensive rats. A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats . ### Methods And Results Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats. ### conclusions A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect.

https://pubmed.ncbi.nlm.nih.gov/22664571/

afcdd9616aa1ce5039d88e604c970fc4

Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients .

Is a high serum cholesterol level associated with longer survival in elderly hypertensives? The relationship between serum total cholesterol, measured at randomization, and mortality was investigated in 822 patients, who were followed for an average of 3.1 years in a double-blind trial, conducted by the European Working Party on High Blood Pressure in the Elderly. Serum cholesterol, measured at randomization, was 0.54 mmol/l higher in women than in men, and declined with increasing age in both men (0.028 mmol/l per year) and women (0.036 mmol/l per year). During follow-up on randomized treatment, cholesterol fell by a similar amount with placebo (0.11 mmol/l per year) and with active treatment (0.14 mmol/l per year). Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients . Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment. Total and non-cardiovascular mortality were also negatively correlated with haemoglobin and body weight at randomization.

https://pubmed.ncbi.nlm.nih.gov/2170516/

0f2ad9e7460bb0d985ca9e8945d14421

Eight days treatment with 15 μM clozapine increased adipogenesis by 37.4 % and 50 μM risperidone increased adipogenesis by 26.5 % during 3T3-L1 cell differentiation accompanied by increased SREBP-1 , PPARγ , C/EBPα , LDLR and Adiponectin gene expression .

Berberine inhibits SREBP-1-related clozapine and risperidone induced adipogenesis in 3T3-L1 cells. Weight gain is a common and potentially serious complication associated with the treatment of second generation antipsychotics such as clozapine and risperidone. Increased peripheral adipogenesis via the SREBP-1 pathway could be one critical mechanism responsible for antipsychotic drug-induced weight gain. berberine, a botanical alkaloid, has been shown in our previous studies to inhibit adipogenesis in cell and animal models. MTT was used to determine the cytotoxic effects of clozapine and risperidone in combination with berberine. Differentiation of 3T3-L1 cells was monitored by Oil-Red-O staining and the expression of SREBP-1 and related proteins was determined by real-time RT-PCR and western blotting. The results showed that neither clozapine nor risperidone, alone or in combination with berberine had significant effects on cell viability. Eight days treatment with 15 μM clozapine increased adipogenesis by 37.4 % and 50 μM risperidone increased adipogenesis by 26.5 % during 3T3-L1 cell differentiation accompanied by increased SREBP-1 , PPARγ , C/EBPα , LDLR and Adiponectin gene expression . More importantly, the addition of 8 μM berberine diminished the induction of adipogenesis almost completely accompanied by down-regulated mRNA and protein expression levels of SREBP-1-related proteins. These encouraging results may lead to the use of berberine as an adjuvant to prevent weight gain during second generation antipsychotic medication.

https://pubmed.ncbi.nlm.nih.gov/20564506/

11b193003411ca34e04b6ed68cb26b97

It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome .

Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions. Drug resistance acquired by Leishmania donovani (Ldv) is a major problem in the treatment and control of visceral leishmaniasis (VL). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme has been targeted as is found in other protozoan which cause diseases like sleeping sickness. GAPDH gene of Ldv (AG83 strain) was amplified, sequenced, and modeled on the basis of crystal structure of Leishmania mexicana. The model of the Ldv GAPDH exhibited NAD-binding domain with Rossmann folding. Virtual screening of different experimentally proved compounds with the crystal and the modeled structures of GAPDH of Leishmania strains revealed diverse binding affinities of different compounds. Comparison of binding affinities (based on different programs) of compounds revealed that discovery studio v2.5 (Ligandfit) was able to predict the most hit compounds, the best hit compounds against GAPDH of Leishmania strains are hydrazine, vetrazine, and benzyl carbazate. It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome .

https://pubmed.ncbi.nlm.nih.gov/22830998/

8cc0b55cf48eb3e5e082a769a6810117

If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone .

Chronic Digoxin Toxicity Precipitated by Dronedarone. To report the case of a patient who presented with chronic symptoms attributable to dronedarone-induced digoxin toxicity. A review of the literature is also provided. ### Case Summary This case report details a case of a 77-year-old male patient who presented to the hospital with multiple ambiguous symptoms that lasted several weeks. The patient was later hospitalized for symptoms of chronic digoxin toxicity, including prolonged nausea, diarrhea, weakness, and lack of appetite. The patient had a long history of digoxin use for control of his atrial fibrillation but experienced signs and symptoms of toxicity only after the addition of dronedarone. ### discussion Both the Naranjo and Drug Interaction Probability Scales indicated a "probable" relationship between the development of digoxin toxicity and dronedarone. Due to a p-glycoprotein-mediated interaction, dronedarone is able to decrease the renal clearance of digoxin, thus putting patients at risk for potentially fatal digoxin toxicity. ### conclusion This is the second case report detailing dronedarone-induced digoxin toxicity and the first to focus on chronic digoxin toxicity. The presentation, possible causes, and drug-drug interactions associated with digoxin toxicity are described. This report aims to increase clinicians' awareness of this possible complication. It is recommended that digoxin be discontinued prior to initiating dronedarone. If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone . digoxin plasma levels should be monitored closely, with frequent patient evaluation for signs and symptoms of digoxin toxicity.

https://pubmed.ncbi.nlm.nih.gov/24687541/

6ef05076decf475feae87638cf32e457

Stable isotope labelling by amino acids in cell culture ( SILAC ) coupled to high-resolution mass spectrometry ( MS ) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide .

Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture ( SILAC ) coupled to high-resolution mass spectrometry ( MS ) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide . The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer.

https://pubmed.ncbi.nlm.nih.gov/26022350/

d4e201d429bd505cd797e095cf81cb5c

All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone .

Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. ### Patients And Methods Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone . Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor-positive tumors received tamoxifen for 5 years. ### results Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. ### conclusion Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC.

https://pubmed.ncbi.nlm.nih.gov/11157012/

910846208d0afa4265c6666870b32a77

Chemotherapy consisted of ( 1 ) fluorouracil ( 5-FU ) , ( 2 ) 5-FU variations , ( 3 ) 5-FU plus oxaliplatin , ( 4 ) 5-FU plus irinotecan , or ( 5 ) oral fluoropyrimidine-based regimens .

The predictive and prognostic value of sex in early-stage colon cancer: a pooled analysis of 33,345 patients from the ACCENT database. To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received. ### methods A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of ( 1 ) fluorouracil ( 5-FU ) , ( 2 ) 5-FU variations , ( 3 ) 5-FU plus oxaliplatin , ( 4 ) 5-FU plus irinotecan , or ( 5 ) oral fluoropyrimidine-based regimens . The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors. ### results A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age ≤ 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex. ### conclusions Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients.

https://pubmed.ncbi.nlm.nih.gov/23810482/

29c3333193035b03fd398adb1e27f8b0

To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile , including lipoprotein(a ) levels , and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia ( serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl , respectively , and serum triglyceride level > 200 mg/dl ) .

Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia. To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile , including lipoprotein(a ) levels , and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia ( serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl , respectively , and serum triglyceride level > 200 mg/dl ) . ### methods This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period. ### results atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase. ### conclusion Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.

https://pubmed.ncbi.nlm.nih.gov/10353071/

e4a6ef4ca14cebe5c45a8d9177702e13

Comparison of brimonidine with latanoprost in the adjunctive treatment of glaucoma . ALPHAGAN/XALATAN Study Group .

Comparison of brimonidine with latanoprost in the adjunctive treatment of glaucoma . ALPHAGAN/XALATAN Study Group . This study compared brimonidine with latanoprost as adjunctive therapy for the treatment of open-angle glaucoma and ocular hypertension. ### background Patients with open-angle glaucoma or ocular hypertension often require >1 medication to achieve control of intraocular pressure (IOP). Both brimonidine and latanoprost effectively lower IOP, but no previously reported clinical trials have directly compared these agents as adjunctive therapy. ### methods This was a prospective, randomized, investigator-masked, multicenter, parallel-design clinical trial. Forty patients (69 study eyes) with uncontrolled IOP of < or =34 mm Hg while using a topical beta-blocker plus dorzolamide or pilocarpine were randomly assigned to receive either brimonidine 0.2% BID or latanoprost 0.005% QD over 6 months as adjunctive therapy. Tolerability was assessed by reports of adverse events, and efficacy was determined by reduction in IOP from baseline. Clinical success was defined as the achievement of a > or =15% reduction in IOP from baseline. ### results There were no significant between-group differences in any demographic variable. Most patients in each group were white, had open-angle glaucoma, and were being treated with a nonselective beta-blocker and dorzolamide. When brimonidine or latanoprost was used as an adjunctive agent with a beta-blocker and dorzolamide or pilocarpine, the rates of clinical success at month 1 were 85% (17/20 patients) with brimonidine versus 65% (13/20 patients) with latanoprost (P = 0.144). Overall mean IOP reduction at month 1 was 4.60+/-0.62 mm Hg (22.8%; P < 0.001) with brimonidine and 3.43+/-0.62 mm Hg (17.2%; P < 0.001) with latanoprost, with no significant differences between groups (P = 0.219). Among the patients with an inadequate IOP-lowering response (<15% reduction from baseline), the mean IOP reduction was 0.36+/-0.66 mm Hg with latanoprost (n = 7) and 0.50+/-2.18 mm Hg with brimonidine (n = 3). brimonidine and latanoprost had comparable IOP-lowering efficacy in patients receiving concomitant pilocarpine therapy (mean change in IOP of -4.23 mm Hg vs -3.75 mm Hg, P = 0.173). In patients concurrently treated with dorzolamide, brimonidine produced a mean change in IOP of -5.29 mm Hg, compared with a mean change of -3.21 mm Hg in the latanoprost group (P = 0.159). Both brimonidine and latanoprost were well tolerated. Few adverse events leading to discontinuation were observed with either drug regimen (n = 2 with brimonidine; n = 0 with latanoprost). ### conclusions Both brimonidine 0.2% BID and latanoprost 0.005% QD were well-tolerated and reduced IOP in most patients when used as third-line adjunctive therapy. However, clinical success was achieved by 17 of 20 patients (85%) who received brimonidine, compared with 13 of 20 patients (65%) who received latanoprost (P = 0.144). These results suggest that brimonidine 0.2% BID may be more reliable than latanoprost 0.005% QD as adjunctive therapy for glaucoma and ocular hypertension.

https://pubmed.ncbi.nlm.nih.gov/10823361/

303f2c71e88e108784acc3cd4ce0255c

Pretreatment with inhaled N(2)O can reduce the pain associated with propofol and rocuronium injection .

Effect of nitrous oxide inhalation on pain after propofol and rocuronium injection. This prospective, double-blind, placebo-controlled study was designed to determine the efficacy of nitrous oxide (N(2)O) in alleviating the pain that followed sequential injection of propofol and rocuronium. ### methods A total of 205 adult patients (age, 18-68 years) received one of the following combinations: NaCl and 100 % O(2) (group C); 0.5 mg/kg lidocaine and 100 % O(2) (group L); NaCl and a mixture of 67 % N(2)O/O(2) (group N); or 0.5 mg/kg lidocaine and a mixture of 67 % N(2)O/O(2) (group LN). Vein occlusion was released after 1 min, and 5 ml propofol was injected over 10 s. Pain was evaluated on a visually enlarged, laminated, numeric rating (0-10) scale. The remainder of the induction dose of propofol (with a 3-ml bolus of normal saline and 0.6 mg/kg rocuronium) was then injected. The response to the rocuronium injection was assessed with a four-point scale (0-3). ### results The incidence and severity of pain from the propofol injection in groups L, N, and LN were significantly lower than those in group C (P < 0.001). Frequency and intensity of the withdrawal response were significantly less in groups N and LN than in groups C and L (no response, P < 0.001; severe response, P < 0.001). ### conclusions Pretreatment with inhaled N(2)O can reduce the pain associated with propofol and rocuronium injection . Moreover, N(2)O (with or without lidocaine) is more effective than lidocaine alone in reducing rocuronium-related withdrawal reactions associated with sequential injection of propofol and rocuronium.

https://pubmed.ncbi.nlm.nih.gov/23982855/

ee8733c65a403048ff5bcc9f2ac1b28b

To further these observations , we discovered that the bromodomain PHD finger transcription factor subunit ( BPTF ) of the nucleosome remodeling factor ( NURF ) promotes resistance to doxorubicin , etoposide and paclitaxel in the 4T1 breast tumor cell line .

Autophagy Dependent Sensitization of Triple Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor. Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations , we discovered that the bromodomain PHD finger transcription factor subunit ( BPTF ) of the nucleosome remodeling factor ( NURF ) promotes resistance to doxorubicin , etoposide and paclitaxel in the 4T1 breast tumor cell line . BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (Top2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacological inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231 but not ER positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased Top2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of Top2 poisons, preventing the resolution of Top2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small molecule inhibitors to enhance the effectiveness of Top2-targeted cancer chemotherapeutic drugs. Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.

https://pubmed.ncbi.nlm.nih.gov/33811160/

ea2e6eff96dd615782bafae123dd6423

We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) .

Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity. Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma. ### methods We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) . ### results At a median follow-up of 42.5 months, the estimated 5-year overall survival for the CBV, BEAM and BEAC groups was 68.8%, 77.8% and 81.8%, respectively (P = 0.584). The estimated 5-year progression-free survival in the CBV group (43.8%) was relatively inferior to the BEAM (66.7%) and BEAC (67.5%) groups, but the differences were not significant (P = 0.403). Grade 2 or higher mucositis, diarrhea and fever were relatively more common in the BEAM group (P < 0.05). No differences were observed in the time to hematopoietic recovery and the duration of hospitalization. The amount of transfused platelet was significantly less in the CBV. ### conclusion CBV, BEAM and BEAC regimens are all optional high-dose chemotherapy before AHSCT for NHL patients.

https://pubmed.ncbi.nlm.nih.gov/28101911/

5113a643f92fbbea92632b15fc9e50a1

Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer .

Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer . The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC ≤ 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks-particularly in patients with a modest effect of ADT and poor performance status.

https://pubmed.ncbi.nlm.nih.gov/33573172/

bbc050f999f763343619808bea2a3824

Several chemotherapy drugs are active in SCCHN , most notably the platinum compounds , taxanes , fluorouracil ( 5-FU ) , methotrexate and cetuximab .

Management of recurrent head and neck cancer: recent progress and future directions. The incidence of squamous cell carcinoma of the head and neck (SCCHN) is on the rise in the US despite a drop in cigarette smoking rates. Much of this rise is due to the increasing incidence of SCCHN attributable to human papillomavirus (HPV). HPV-related SCCHN has a high cure rate, which contributes to the stable death rates despite the increased incidence. Up to half of patients with SCCHN will develop recurrence. For these patients, the first clinical decision is whether the recurrence is potentially treatable for cure, or is incurable. For those deemed potentially curable, surgical or radiation-based therapies, or both, are undertaken. For those who have incurable recurrences, the goals are palliation and possibly prolongation of life - average survivals are in the range of 6-12 months depending on the type of recurrence and other factors. Several chemotherapy drugs are active in SCCHN , most notably the platinum compounds , taxanes , fluorouracil ( 5-FU ) , methotrexate and cetuximab . Approximately 10-25% of patients will respond to treatment with one of these drugs. The response rate is higher for combinations such as a platinum plus a taxane, a platinum plus 5-FU, a combination of the three, or one of more of these drugs plus cetuximab. Combination chemotherapy has not been shown to prolong survival over single-agent therapy, with the exception of the addition of cetuximab to a platinum and 5-FU combination. A number of orally bioavailable tyrosine kinase inhibitors have been tested or are undergoing trials in SCCHN. None of these has as yet been shown to be more effective than the currently available drugs. For patients with recurrences who are undergoing active therapy, and especially for those for whom further therapy is no longer appropriate or is declined, strict attention is necessary to palliation of pain, oral and airway issues, and to nutrition, speech, and social and psychological issues.

https://pubmed.ncbi.nlm.nih.gov/21861540/

b49696c4425245043d701994c68666a9

Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma .

Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma . The authors conducted a phase II study to evaluate a new combination of chemotherapeutic drugs that includes dexamethasone, cytarabine, ifosfamide, and cisplatin as salvage therapy in non-Hodgkin lymphoma after prior exposure to both adriamycin and etoposide. All drugs were administered intravenously over 4 consecutive days. The daily dose of dexamethasone was 20 mg twice daily. The maximal daily doses of cytarabine, ifosfamide, and cisplatin were 75 mg/m2, 1,200 mg/m2, and 20 mg/m2, respectively. Cycles were repeated every 3 weeks. A total of 31 patients were entered in the trial. Thirty patients were evaluable for response. A complete response was seen in 11 patients (37%), and a partial response was noted in six patients (20%). A significantly higher complete response rate was seen in patients with relapsing non-Hodgkin lymphoma compared with those who failed to achieve a complete response with the last chemotherapy (10/14 vs. 1/16; p < 0.013). A complete response continues in two patients who received consolidation with high-dose chemotherapy for more than 49 months and more than 60 months for each patient. Median time to treatment failure and median survival were 3.3 months and 7.5 months, respectively, for the entire group and 11 months and 30 months, respectively, for complete responders. Myelosuppression was pronounced but was usually of short duration. Neutropenic fever developed in 13 patients (42%) and in 15 of 96 cycles (16%). Platelet transfusions were required in seven patients (23%). There was one drug-related death associated with myelotoxicity. Nonhematologic toxicity was not dose limiting. The authors conclude that dexamethasone, cytarabine, ifosfamide, and cisplatin is active and a relatively tolerable regime for patients with non-Hodgkin lymphoma previously treated with adriamycin and etoposide.

https://pubmed.ncbi.nlm.nih.gov/10025380/

f42c0f1b9c9ec6d9b76b4adbc90ce6b9

Cost-effectiveness of ribociclib plus letrozole

Cost-effectiveness of ribociclib plus letrozole The global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective. ### methods A model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed. ### results The total cost of treatment with ribociclib plus letrozole was USD 72,091.82 ### conclusions As demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system.

https://pubmed.ncbi.nlm.nih.gov/33948121/

76d6e9b5067c942e1d7906a02971927e

We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 .

In vitro effects of lapatinib with gemcitabine for pancreatic cancer cells. We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 . Furthermore, the changes of gemcitabine sensitivity-related genes by lapatinib treatment were examined. ### methodology The effects of lapatinib, gemcitabine, and combined treatment with both agents on cell viability were examined by methyl thiazolyl tetrazolium analysis. Synergy between lapatinib and gemcitabine was assessed by median effect analysis. The mRNA amounts of human equilibrative nucleoside transporter (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit M1 (RRM1) genes were measured by quantitative real-time polymerase chain reaction in cells exposed to lapatinib for 48 h, as compared with untreated cells. ### results No synergistic effects were observed with combined treatment in either cell line. In contrast, antagonistic effects occurred on MiaPaca-2 cells with the two agents. Specific changes in gemcitabine sensitivity-related genes induced by lapatinib were not detected in either MiaPaca-2 or PANC-1. ### conclusions lapatinib may not enhance the anti-tumor effects of gemcitabine for pancreatic cancer.

https://pubmed.ncbi.nlm.nih.gov/23933942/

7026e25992d70427b64362230b605bb3

Gal(beta1 - 3)Galbeta1-methyl ( disaccharide ) and GalNAc(beta1 - 4)GlcA(beta1 - 3)GalNAc(beta1 - 4 ) GlcA(beta1 - 3)GalNAc(pentasaccharide ) were used respectively as acceptors of [14C]GlcA from UDP-[14C]GlcA. Distributions of the two GlcA transferase activities in the sucrose-density-gradient fractions were compared with each other and with the previously reported distribution of the activities of Gal transferases ( UDP-Gal to ovalbumin , and to xylose of the proteochondroitin linkage region ) and GalNAc ( N-acetylgalactosamine ) transferase II of chondroitin polymerization .

Subcellular co-localization and potential interaction of glucuronosyltransferases with nascent proteochondroitin sulphate at Golgi sites of chondroitin synthesis. Microsomal membranes from chick embryo epiphyseal cartilage were fractionated by equilibrium sucrose-density-gradient centrifugation and assayed for GlcA (glucuronic acid) transferase I (the enzyme that transfers GlcA from UDP-GlcA to Gal-Gal-Xyl of proteochondroitin linkage region), for comparison with GlcA transferase II (the GlcA transferase of chondroitin polymerization). Gal(beta1 - 3)Galbeta1-methyl ( disaccharide ) and GalNAc(beta1 - 4)GlcA(beta1 - 3)GalNAc(beta1 - 4 ) GlcA(beta1 - 3)GalNAc(pentasaccharide ) were used respectively as acceptors of [14C]GlcA from UDP-[14C]GlcA. Distributions of the two GlcA transferase activities in the sucrose-density-gradient fractions were compared with each other and with the previously reported distribution of the activities of Gal transferases ( UDP-Gal to ovalbumin , and to xylose of the proteochondroitin linkage region ) and GalNAc ( N-acetylgalactosamine ) transferase II of chondroitin polymerization . The linkage-region GlcA transferase I had a dual Golgi distribution similar to that of chondroitin-polymerizing GlcA transferase II and distinctly different from the distribution of linkage-region Gal transferases I and II, which were found exclusively in the heavier fractions. Solubilized GlcA transferase I was partly purified by sequential use of Q-Sepharose, heparin-Sepharose and wheatgerm agglutinin-agarose and was accompanied at each step by some of the GlcA transferase II activity. Both GlcA transferase I and II bound to the Q-Sepharose as though they were highly anionic. However, treatment with chondroitin ABC lyase eliminated the binding while markedly decreasing enzyme stability. The enzyme activities could not be reconstituted by adding chondroitin or chondroitin pentasaccharide to the chondroitin ABC lyase-treated enzymes. Incubation of the partly purified enzymes with both UDP-GlcA and UDP-GalNAc resulted in a 40-fold greater incorporation than with just one sugar nucleotide, indicating the presence of bound, nascent proteochondroitin serving as the acceptor for chondroitin polymerization. These results, together with the membrane co-localization, indicate that GlcA transferase I and GlcA transferase II occur closely together with nascent proteochondroitin at the site of synthesis and that this complex with the nascent proteochondroitin stabilizes both enzymes during purification.

https://pubmed.ncbi.nlm.nih.gov/9405295/

6d427c9e01e1e8a4826839198fa2af7f

No significant changes of endothelium-independent dilation were observed with both drugs ( from 17.10+/-2.4 % to 18.14+/-3.76 % and from 18.73+/-4.07 % to 17.46+/-4.27 % during nifedipine and hydrochlorothiazide , respectively , NS ) .

Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension. off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs ( from 17.10+/-2.4 % to 18.14+/-3.76 % and from 18.73+/-4.07 % to 17.46+/-4.27 % during nifedipine and hydrochlorothiazide , respectively , NS ) . Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.

https://pubmed.ncbi.nlm.nih.gov/9931168/

7a76285b62b9c23acaeb7d96cf4c1b8d

The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing .

Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC). Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. ### Materials And Methods Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m ### results Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. ### conclusion The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. ### Implications For Practice To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing . The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.

https://pubmed.ncbi.nlm.nih.gov/30952818/

0e887d3051881c9eb2e97aff4e8b454c

Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir .

Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir. To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. ### design Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. ### methods Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. ### results Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). lopinavir levels were similar to historical data. ### conclusion Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir . This boosted double PI combination could be an effective option for patients with limited RTI options.

https://pubmed.ncbi.nlm.nih.gov/15090803/

ba57e1b08c300abc4c30ff284a79ac02

Clopidogrel administration significantly reduces the likelihood of recurrent CATE compared with aspirin in cats ; both drugs were well tolerated .

Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). To determine if clopidogrel administration is associated with a reduced likelihood of recurrent cardiogenic arterial thromboembolism (CATE) in cats compared to aspirin administration. Secondary aims were to determine if clopidogrel administration had an effect on the composite endpoint of recurrent CATE and cardiac death and to identify adverse effects of chronic clopidogrel or aspirin therapy. ### animals Seventy-five cats that survived a CATE event. ### methods Multicenter, double-blind, randomized, positive-controlled study. Cats were assigned to clopidogrel (18.75 mg/cat PO q 24 h) or aspirin (81 mg/cat PO q 72 h). Kaplan-Meier survival curves were created for each endpoint and the log rank test performed to compare treatment groups with respect to time to event and the likelihood of the event occurring. ### results The mean age of all cats was 8.0 ± 3.5 yr and 57/75 (76%) were male (p < 0.001); 62/75 (83%) were mixed breed with the remainder including Persian, Abyssinian, American Shorthair, Bengal, Birman, Himalayan, Maine Coon, Ragdoll, Snowshoe, and Sphynx breeds. Only 15% (11/75) of cats had a history of heart disease recorded prior to the CATE event. clopidogrel administration was associated with significantly reduced likelihood of recurrent CATE compared to aspirin (p = 0.024) and had a longer median time to recurrence [443 (95% CI 185-990) days vs. 192 (95% CI 62-364) days, respectively]. clopidogrel was also associated with a significantly reduced likelihood of the composite endpoint of recurrent CATE or cardiac death (p = 0.033) with a longer median time to event [346 (95% CI 146-495) days vs. 128 (95% CI 58-243) days]. ### conclusions Clopidogrel administration significantly reduces the likelihood of recurrent CATE compared with aspirin in cats ; both drugs were well tolerated .

https://pubmed.ncbi.nlm.nih.gov/26776588/

f23bcffeb3185e2f6c8931118c169096

In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib .

Sorafenib and Sunitinib for the Treatment of Metastatic Thyroid Cancer of Follicular Origin: A 7-Year Single-Centre Experience. Radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is a rare form of DTC which poses a therapeutic challenge due to the scarcity of effective treatment options. In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib . These appear to be associated with improved progression-free survival (PFS). ### objectives We aim to describe our experience with sorafenib and sunitinib in the treatment of RAI-refractory metastatic DTC and to evaluate and compare their efficacy and adverse effect profiles. ### method A total of 28 patients with RAI-refractory metastatic DTC were included - 26 had first-line treatment with sorafenib (8 subsequently switched to sunitinib, most due to disease progression) and 2 with sunitinib. We evaluated PFS and best radiological response achieved with each agent as primary endpoints. The secondary objective was to describe adverse effects and safety profile. ### results Mean PFS was 10.8 months with sorafenib and 6 months with sunitinib as a second-line treatment. Best overall response was partial remission (PR) with either agent - PR rate of 30.7% with sorafenib and 37.5% with second-line sunitinib. All treatment courses had registered adverse effects and 13.9% justified definitive treatment cessation. ### conclusions sorafenib and sunitinib appear to be effective treatment options in delaying disease progression of patients with RAI-refractory metastatic DTC, with an acceptable safety profile. Interestingly, sunitinib appears to show some efficacy even in patients who experience disease progression on sorafenib.

https://pubmed.ncbi.nlm.nih.gov/31768337/

1340b6ccb9e588be0096065a7dbffdfd

By passage 25 and thereafter , the selected cells were resistant to doxorubicin , etoposide , mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1 , MRP1 , MRP2 and breast cancer resistance protein .

A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells. U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter , the selected cells were resistant to doxorubicin , etoposide , mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1 , MRP1 , MRP2 and breast cancer resistance protein . In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.

https://pubmed.ncbi.nlm.nih.gov/11774257/

b584eb44c6c157bad2207e9da0ce15a9

The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated .

In vitro activity of zidovudine alone and in combination with ciprofloxacin against Salmonella and Escherichia coli. The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated . zidovudine showed a good activity against Escherichia coli and Salmonella (MIC range 0.5-8 micrograms/ml and 1.5-62 micrograms/ml respectively) isolated from biological samples of HIV-infected patients. These strains proved to be extremely susceptible to ciprofloxacin alone. The interaction between zidovudine and ciprofloxacin ranged from additive activity to indifference. No antagonism was observed: the FIC index for every combination resulted < or = 1.5. The addition of AZT 1 mg/l (clinically achievable plasma concentration after therapeutic doses of 1200 mg/day) did not affect the bactericidal activity of ciprofloxacin; on the contrary, in some cases we observed an increase of bactericidal effect of the quinolone. These data have to be considered in patients with AIDS who can be treated concomitantly with zidovudine and ciprofloxacin.

https://pubmed.ncbi.nlm.nih.gov/8364519/

f2861595996d83b4c3c73e885a009998

This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective .

[A case of primary antiphospholipid antibody syndrome with severe nephrotic syndrome showing remarkable endothelial cell damage in the capillary lumen]. A 25-year-old woman complained of anasarca and was admitted to Sakura National hospital on the presumptive diagnosis of nephrotic syndrome with 10.7 g of 24-hour urinary protein. At first, lupus nephritis with antiphospholipid antibody syndrome was suspected because of prolongation of APTT, existence of lupus anticoagulant and elevation of serum anticardiolipin antibody titer (IgM) in addition to positive ANA, lymphocytopenia and the biologically false positive test for syphilis (BFPTS). On day 28 of hospitalization, renal biopsy findings revealed severe endocapillary cell damage, such as swelling and proliferation of endothelial cells, fragmentation and double contour of the basement membrane walls, which were located only in the capillary lumens with a few thrombi. Immunofluorescent micrography revealed the absence of specific immunoglobulin or complement deposit. Therefore, the diagnosis of lupus nephritis was negated as these findings were suggestive of characteristic glomerulopathy due to primary antiphospholipid antibody syndrome. She was treated initially with oral prednisolone 60 mg and intravenous infusion of heparin 20,000 units daily. Moreover, cyclophosphamide 750 mg was administered intravenously as pulse therapy on day 13 as her serum level of CH50 had fallen suddenly, and hemodialysis was necessary because her renal function had deteriorated and she was suffering from cough and orthopnea with overhydratin. After the combined therapy, BFPTS disappeared and APTT returned to the normal range: dialysis treatment was not required further after the 4th hemodialysis. Thereafter, renal function improved and complete remission of nephrotic syndrome was obtained. This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective . We present this instructive case to promote understanding of the pathogenesis of primary antiphospholipid antibody syndrome.

https://pubmed.ncbi.nlm.nih.gov/9198367/

b735fb903e9b00efcf84b11b8bfce9e3

Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution .

Antibiotic prophylaxis in neurosurgery. A randomized controlled trial. A randomized trial was performed to support the contention that prophylactic antibiotics can reduce the incidence of postoperative neurosurgical wound infections. The regime outlined by Malis was followed. Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution . Patients were randomly assigned to two groups: control and treated. The infection rate in the control group was 3.5% and in the treated group 0.5%.

https://pubmed.ncbi.nlm.nih.gov/6368765/

b0e281e2e21137034cbcfb125ee8f931

We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines .

Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines. Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti-melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors. We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines . This combination of inhibitors significantly decreased Akt and Erk phosphorylation, while the drugs used independently were insufficient. Additionally, after treatment with pairs of inhibitors, cells became larger, with more pronounced stress fibers and abnormally shaped nuclei. We also noticed the appearance of polyploid cells and massive enrichment in the G2/M phase. Therefore, combination treatment was much more effective against melanoma cells than a single-targeted approach. Based on our results, we conclude that both EGFR and MET receptors might be effective targets in melanoma therapy. However, variation in their levels in patients should be taken into consideration.

https://pubmed.ncbi.nlm.nih.gov/29719603/

aff964519fe19b2506eced45b9c9d22a

Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy ( RR=0.88 , 95 % CI=0.64 - 1.21 , p=0.43 ) .

A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity. The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy ( RR=0.88 , 95 % CI=0.64 - 1.21 , p=0.43 ) . Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection.

https://pubmed.ncbi.nlm.nih.gov/26001980/

fc00a893900f4703d0e0b6f310b9f548

During the infusion protocol used in clinical practice , etoposide , cytarabine and daunorubicine were stable and compatible with the various materials present in the infusion sets and extension tubing ( polyvinyl chloride , polyethylene ) and catheters ( silicone ) .

Stability and compatibility of a mixture of the anti-cancer drugs etoposide, cytarabine and daunorubicine for infusion. We evaluated (i) the stability of a mixture of the three anti-cancer agents used for the treatment of leukemia, namely etoposide, cytarabine and daunorubicine, in 5% glucose, and (ii) its compatibility towards various materials during an infusion protocol as performed for therapeutic purposes in hospital practice. etoposide and cytarabine were assayed by high-performance liquid chromatography with a C18 type column and UV detection. daunorubicine was assayed by visible spectrophotometry. The stability study showed all three anti-cancer drugs to be stable in 5% glucose solution, both alone and mixed. Best conservation was obtained by keeping bottles containing the mixture in the dark at room temperature. During the infusion protocol used in clinical practice , etoposide , cytarabine and daunorubicine were stable and compatible with the various materials present in the infusion sets and extension tubing ( polyvinyl chloride , polyethylene ) and catheters ( silicone ) . Observed variations in concentration did not exceed 10% of initial concentrations of each drug, though we would advocate changing infusion sets and extension tubing daily.

https://pubmed.ncbi.nlm.nih.gov/7651971/

9b61fc81ffb14fa9cd2564d54a1b505a

Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control .

Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma. Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance. ### methods We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo. ### results First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control . Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo. ### conclusion Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.

https://pubmed.ncbi.nlm.nih.gov/28814318/

52ecae189b7c12c1e7263aef53247fc4

Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality .

[Correction of baroreflex sensitivity impairment and efficacy of prevention of sudden arrhythmic death in patients with postinfarction left ventricular dysfunction]. Baroreflex sensitivity was assessed in 287 patients with history of myocardial infarction and left ventricular ejection fraction < or =40% by phenylephrine test and was found to be depressed (4.44+/-0.38 ms/mm Hg). Repeat study in 3, 6 and 12 months revealed substantial improvement of baroreflex sensitivity in patients treated with perindopril especially when it was combined with amiodarone, metoprolol, bisoprolol and carvedilol but not with atenolol. Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality . Superiority of combination of amiodarone with lipophilic beta-adrenoblocker over monotherapy had been anticipate but was not confirmed in any of large prospective studies.

https://pubmed.ncbi.nlm.nih.gov/15477784/

4b882f10fc1a53ea41c3d37160f7c40a

Efficacy of paclitaxel , carboplatin , and bevacizumab for cervical cancer : A protocol for systematic review and meta-analysis .

Efficacy of paclitaxel , carboplatin , and bevacizumab for cervical cancer : A protocol for systematic review and meta-analysis . Cervical cancer (CC) is a very common and malignant tumor in female population. Although a variety of single medications are reported to treat this condition, they all have limited efficacy. Previous studies have reported the combination of paclitaxel, carboplatin, and bevacizumab (PCB) can be used for the treatment of patients with CC effectively. However, no systematic review has explored its efficacy and safety. This study will address its efficacy and safety systematically and comprehensively. ### methods The following electronic databases will be retrieved from their inceptions to the January 1, 2020 to identify all potential associated studies: MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Google scholar, and Chinese Biomedical Literature Database. We will include randomized controlled trials (RCTs) of adult women (≥18 years) with CC globally. Eligible interventions will target any forms of PCB. The study methodological quality of all included studies will be appraised using Cochrane risk of bias tool. Statistical analysis will be undertaken using RevMan 5.3 software. In addition, we will perform a narrative synthesis to describe quality and content of the evidence. ### results This study will summarize recent evidence and provide quality evidence for the efficacy and safety of PCB on CC. ### conclusion The findings of this study will seek to identify the efficacy and safety of PCB and suggest future directions for research efforts targeting CC among this population. ### Systematic Review Registration INPLASY202040195.

https://pubmed.ncbi.nlm.nih.gov/32541479/

21c7c9267a761f7e54194cae09a35820

The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96 % with one persistent case , and 100 % in the doxycycline group .

Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. One hundred and twenty male patients with signs and symptoms compatible with non-gonococcal urethritis were enrolled in a prospective-randomized study to compare the efficacy and safety of a single oral-dose of 1 g azithromycin and a seven-day course of 100 mg doxycycline twice-daily. Clinical examination and culture samples for Chlamydia trachomatis were performed before and approximately 8, 15 and 35 days after starting treatment. Both treatment groups were comprised of 30 chlamydia-positive patients evaluable for efficacy. The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96 % with one persistent case , and 100 % in the doxycycline group . After about two weeks, there were two re-occurrences in the azithromycin group, resulting in a cumulative eradication rate of 90% with three culture-positive cases. The corresponding figure in the doxycycline group was still 100%, but there were leucocytes present in the urethral smear of two patients who later proved to be true culture-positive re-occurrences. After about five weeks, there was an additional re-occurrence in the azithromycin group leading to a cumulative eradication rate of 87%, while two re-occurrences in the doxycycline group gave a cumulative eradication rate of 93%. There was no statistically significant difference in efficacy between the single-dose azithromycin and seven-day course of doxycycline in the treatment of patients with chlamydial urethritis.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/8396091/

c47d83d7eec4a7d07750de608807d10e

For example , the overall objective response rate of 9.5 % with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients , but toxicity , notably fatigue , lead to discontinuation in 38 % of patients .

Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example , the overall objective response rate of 9.5 % with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients , but toxicity , notably fatigue , lead to discontinuation in 38 % of patients . Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.

https://pubmed.ncbi.nlm.nih.gov/17634832/

00169f308f6bab3a5793ce3491c6817f

Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone .

Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. ### Patients And Methods Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone . Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. ### results Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. ### conclusions These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.

https://pubmed.ncbi.nlm.nih.gov/29110854/

11e266d33694244478184960a4f5ca71

In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment .

Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. ### Areas Covered A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. ### Expert Opinion In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment . Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.

https://pubmed.ncbi.nlm.nih.gov/25988772/

a552828060f67274a59cce5e784f3492

The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial .

Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active in previously untreated patients with small cell lung cancer (SCLC). We evaluated the toxicity and efficacy of a 1-hour infusion of paclitaxel added to a combination regimen of carboplatin and etoposide in a phase II trial for the treatment of patients with SCLC. Thirty-eight patients with previously untreated SCLC were treated with paclitaxel 135 mg/m2 (1-hour intravenous infusion), day 1; carboplatin at area under the concentration-time curve of 5, day 1; and oral etoposide 100 and 50 mg (alternating days), days 1 to 10. Treatment cycles were repeated every 21 days for a total of four courses. Patients with limited-stage disease received radiation therapy (4,500 cGy in 25 fractions) concurrently with the last two courses of chemotherapy. This outpatient combination was easily tolerated. Grade 3 or 4 leukopenia was experienced in only 8% of courses; grades 3 and 4 thrombocytopenia and anemia were also infrequent. Nonhematologic toxicity was uncommon, with the exception of transient esophagitis, which occurred in six of 15 patients (grade 3 in five patients, grade 4 in one) receiving concurrent chemoradiotherapy. Of 35 evaluable patients, 29 (83%) achieved a response to treatment. The complete response rate was 29% (40% in patients with limited-stage disease). Median survival was 7 months for patients with extensive-stage disease and 17 months in limited-stage patients. Prophylactic whole brain irradiation was not used, and seven patients developed brain metastases as their initial site of relapse. The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial . This treatment was highly active and the results are comparable to other standard regimens. Increased doses of both paclitaxel and carboplatin could probably be tolerated and are currently being evaluated. Precise definition of the role of paclitaxel in the treatment of SCLC will require randomized studies.

https://pubmed.ncbi.nlm.nih.gov/9007113/

17f4d7217cc41ed7afdf6e8ca2189f9d

In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) .

Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment. Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) . Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.

https://pubmed.ncbi.nlm.nih.gov/25968494/

ec8c0a2aee1447c50afd5943b55779e9

After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved .

An 11-year-old boy with Plasmodium falciparum malaria and dengue co-infection. Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites of Plasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved . However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications.

https://pubmed.ncbi.nlm.nih.gov/24692379/

997f3bcc47d7e8eb59d59b8932623751

For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors .

Update on malignant ovarian germ cell tumors. The evolution of therapy for malignant ovarian germ cell tumors has been one of the true success stories in oncology. This article reviews the major advances in this field, with emphasis on more recent developments. During the past two decades, the nomenclature and histologic criteria for the major histologic subtypes have been standardized. Although the role of secondary debulking is uncertain, it probably has merit in selected patients. The use of second-look laparotomy should be limited as much as possible. Chemotherapeutic regimens have evolved to the current "gold standard"--the combination of bleomycin, etoposide, and cisplatin, with overall disease-free survival rates of greater than 95%. For patients with metastatic dysgerminoma, chemotherapy has replaced radiation therapy as the treatment of choice. For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors . For those with platinum-resistant tumors, dose intensification with autologous bone marrow rescue or Phase II drugs are being investigated. Studies on the late effects of treatment reveal that reproductive potential can be preserved in most young patients. In summary, although the progress in this field has been phenomenal, small incremental advances will continue to occur during the 1990s.

https://pubmed.ncbi.nlm.nih.gov/8381708/

24ae80413b3dd00b228c2faee29db136

Antibiotic treatment was changed to imipenem/cilastatin , piperacillin , gentamicin , clarithromycin , erythromycin , and minocycline .

[Legionella pneumonia successfully treated despite late diagnosis]. Status asthmaticus developed in a 72-year-old man who was being treated with oral prednisolone for severe persistent asthma. The dosage of prednisolone was increased, and amikacin was injected to treat pneumonia that had developed in the right lung. Progressive pulmonary infiltrates, respiratory compromise, and hypoxemia developed, and the patient eventually required mechanical ventilation. Antibiotic treatment was changed to imipenem/cilastatin , piperacillin , gentamicin , clarithromycin , erythromycin , and minocycline . Liver injury developed. More than one month after the patient was admitted, Legionella pneumonia was diagnosed. levofloxacin (400 mg/day) was then given orally, in combination with injected imipenem/cilastatin. Liver function did not deteriorate, and the pneumonia resolved. Most diagnoses of Legionnaires' disease are made retrospectively by examination of serum. In this case, antibiotics active against Legionella pneumophila had been used before the diagnosis was established, which probably contributed to the patient's recovery. When aminoglycosides or beta-lactam antibiotics are ineffective, administration of agents effective against Legionnaires' disease should be considered.

https://pubmed.ncbi.nlm.nih.gov/9234637/

62665fef62b1b254a8c360ec1c84a862

Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) .

Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection. Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. ### methods Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) . ### results A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. ### conclusions vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.

https://pubmed.ncbi.nlm.nih.gov/26986978/

dfc6b9441ddfd8b86ebcd3331ee8783d

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer .

Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer . To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. ### Materials And Methods Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). ### results The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. ### conclusion The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

https://pubmed.ncbi.nlm.nih.gov/7595707/

d404a0a64aefa9b15e1c76f398b14335

Eighteen patients received chemotherapy including etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( n = 13 ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( n = 2 ) .

HIV-associated plasmablastic lymphoma in the era of HAART: a single-center experience of 21 patients. Patients with HIV infection have an increased risk of developing plasmablastic lymphoma (PBL). In this study, we reviewed the clinicopathologic features of PBL in HIV+ patients in the era of HAART from a single health center. ### design Retrospective study. ### methods The morphologic, immunophenotypic, and clinical features were reviewed in these HIV+ patients with PBL and univariate analysis was employed to determine the survival prognosis. ### results During the interval of 1 January 2008 to 30 December 2018, we identified 95 HIV+ patients with aggressive non-Hodgkin B-cell lymphomas. Among these patients, there were 21 (22%) patients with PBL (19 men and two women; median age: 45 years). Seven patients had PBL at their initial HIV diagnosis and 14 developed PBL after a median interval of 7.7 months of HIV diagnosis. Lymph nodes (n = 10), oral cavity/sinonasal mass (n = 6), and rectal masses (n = 5) were the common involved sites, and five of 15 (33%) had bone marrow involvement. Lymphoma cells were immunoreactive for MUM-1/IRF4 (100%), CD138 (90%), CD45 (63%), CD79a (47%), and CD30 (25%). Proliferation rate assessed by Ki67 was at least 90% in 18 of 20 cases. Eighteen patients received chemotherapy including etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( n = 13 ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( n = 2 ) . With a median follow-up time of 19 months, nine out of 17 patients died. Bone marrow involvement was associated with a poorer overall survival (median: 4.7 months, P = 0.015). ### conclusion PBL is the second most common type of aggressive lymphoma and often presents in lymph nodes of patients with poorly controlled HIV infection. Bone marrow involvement is associated with a poorer outcome.

https://pubmed.ncbi.nlm.nih.gov/32889849/

e0bf205b5f4f7b0aef116d39aeca8d51

The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin .

Inhibitory effects of a calcium antagonist on ornithine decarboxylase induction in pancreatic cancer cell lines. The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin . Because of our interest in polyamine biosynthesis and metabolism and the known involvement of calcium in the induction of ornithine decarboxylase (ODC) by serum refeeding of cultured cells, the effects of verapamil on the serum-stimulated ODC activity in two hamster pancreatic adenocarcinoma cell lines were examined. In plateau phase well-differentiated (WD) PaCa and poorly differentiated (PD) PaCa cells, a dose-dependent inhibition of the 4-h serum induction of ODC was seen at concentrations of 1, 5, and 10 microM verapamil. At the higher concentrations of verapamil, the inhibition of ODC induction was comparable to that achieved with 5 mM alpha-difluoromethylornithine (DFMO, a specific enzyme inhibitor of ODC) and greater than that seen with 2 mM EGTA plus calcium-depleted serum. Log phase PD PaCa cells, included for comparison, showed less ODC induction with serum and lesser degrees of inhibition of the response to serum refeeding with verapamil, DFMO, and calcium depletion. No direct inhibition of the ODC enzyme was found when verapamil was added at the time the activity was measured. Based on our present data, a possible influence of intracellular calcium pools in the verapamil effect on ODC activity is unclear. Nevertheless, the present findings suggest that verapamil's effects on cytotoxicity may be mediated (at least in part) by inhibition of the serum-mediated induction of ODC.

https://pubmed.ncbi.nlm.nih.gov/1780323/

243ff1340b156e1ef82da5cce81b3564

The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients .

Current status of second-line therapy for metastatic colorectal cancer. Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients . The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC.

https://pubmed.ncbi.nlm.nih.gov/15212701/

4cc8adfb245b330491b730ea1b5e7855

Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide .

Direct fetal administration of adenosine for the termination of incessant supraventricular tachycardia. Adenosine terminates supraventricular reentry tachycardia safely and effectively in the pediatric age group. ### case The recurrence of pretreated incessant tachycardia led to severe hydrops in a 28-week-old fetus. The tachycardia was terminated instantly with direct fetal administration of adenosine via the umbilical vein. Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide . ### conclusion Direct fetal adenosine administration might be helpful in the treatment of fetal reentry tachycardias if the sinus rhythm achieved quickly can be preserved by long-acting antiarrhythmic drugs. Such a combined therapeutic approach might be especially advantageous in hydropic fetuses.

https://pubmed.ncbi.nlm.nih.gov/7724143/

524028001d20085596cb36bbd3d78092

A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer .

A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer . The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. ### Patients And Methods One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. ### results The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. ### conclusions irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.

https://pubmed.ncbi.nlm.nih.gov/15939714/

087b5adc35235f9ed99914b77d097379

The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime .

Incidence of Nephrotoxicity Among Pediatric Patients Receiving Vancomycin With Either Piperacillin-Tazobactam or Cefepime: A Cohort Study. Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime . ### methods We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group. ### results Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results. ### conclusion Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime.

https://pubmed.ncbi.nlm.nih.gov/29590376/

2ebb8341a08c839141f8b65e95691777

In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option .

Adrenocortical carcinoma: current treatment options. In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). ### Recent Findings Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20 mg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option . temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. ### summary ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.

https://pubmed.ncbi.nlm.nih.gov/33186181/

a73e44b782d98aba7c53f394543442eb

We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect .

Effects of regional anesthesia with ropivacaine on arterial pressure and heart rate in healthy subjects. The anesthetic, ropivacaine, has been used extensively in clinical practice, but few studies have evaluated this long-acting local anesthetic in dentistry. In this study we evaluated the effects of ropivacaine alone and ropivacaine + vasoconstrictor on the cardiovascular system when used as a dental anesthetic in volunteers. Thirty-two healthy subjects received two consecutive infiltrations of 1.8 ml of either 0.75% ropivacaine or ropivacaine + epinephrine into the pterygomandibular region. Pain sensation, numbness of the lip, arterial pressure, heart rate, and electrocardiogram changes were monitored for 2 h. The onset of anesthesia was 10 min after the injection and lasted for more than 2 h, and numbness of the lip lasted for approximately 8 h. ropivacaine alone did not cause significant changes in the cardiovascular parameters, but ropivacaine + epinephrine caused a transient increase in arterial pressure and heart rate 2 min postinjection. We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect . This finding may be relevant to dentists endeavoring to find an anesthetic of minimal cardiovascular risk to produce regional anesthesia for long-lasting procedures without the need of a vasoconstrictor.

https://pubmed.ncbi.nlm.nih.gov/16460338/

f2416fdc4c1df1164e8dae3932989427

The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol .

Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs? The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and d-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to d-cycloserine. The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol . Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria.

https://pubmed.ncbi.nlm.nih.gov/1303690/

d920c61f16550899ca4f42c2889ece9a

Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer .

Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer . The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). ### Methods And Patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. ### results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. ### conclusions capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.

https://pubmed.ncbi.nlm.nih.gov/18208793/

e8983bc29117201dac2cf3304550dfe5

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma .

Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma . Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. ### methods We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. ### results The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%). ### conclusions In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

https://pubmed.ncbi.nlm.nih.gov/29590547/

72408996cbbac6460db21f6e3b784e67

The chloroethylating nitrosoureas ( lomustine , fotemustine , cystemustine ( BCNU ) and methylating agents temozolomide ( TMZ ) , dacarbazine ( DTIC ) , procarbazine ) have documented activity in metastatic malignant melanoma with single agent response rates of 15 - 25 % .

New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. The chloroethylating nitrosoureas ( lomustine , fotemustine , cystemustine ( BCNU ) and methylating agents temozolomide ( TMZ ) , dacarbazine ( DTIC ) , procarbazine ) have documented activity in metastatic malignant melanoma with single agent response rates of 15 - 25 % . Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.

https://pubmed.ncbi.nlm.nih.gov/11007934/

e3d4c7e46a39af27f2f034cd9243dfe4

The population growth rate was adversely influenced by exposure to chlortetracycline , sulfamethazine , or sulfathiazole in water fleas , but reduction in population size was not expected .

Risk assessment of chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin in aquatic environment: are the current environmental concentrations safe? To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). In general, D. magna exhibited greater sensitivity than M. macrocopa, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline , sulfamethazine , or sulfathiazole in water fleas , but reduction in population size was not expected . In O. latipes, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by Daphnia and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation.

https://pubmed.ncbi.nlm.nih.gov/22711548/

f7fbf1b752fc2876bf34e69b16299d34

A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 .

Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients. The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 . The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.

https://pubmed.ncbi.nlm.nih.gov/11488525/

836dfe1a21ffa42a19c4d829208f22f1

Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor .

The antiplatelet effects of ticlopidine and clopidogrel. Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor . ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. clopidogrel was recently approved by the U.S. Food and Drug Administration for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease (incidence, 5.32% per year compared with 5.83% per year for aspirin; P = 0.043) with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the utility of clopidogrel in other patient populations and in stenting, requires further study. ticlopidine and clopidogrel seem to have beneficial effects compared with aspirin (the current standard) in a broad range of patients. These observations highlight the importance of antiplatelet therapy in cardiovascular disease.

https://pubmed.ncbi.nlm.nih.gov/9735068/

cceb9a88a83ca29198d7e218b0ba2623

Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer .

Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer . This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. ### Patients And Methods Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. ### results Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). ### conclusion irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

https://pubmed.ncbi.nlm.nih.gov/11870159/

b157235272b3fb888e30df30a0f83408

The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis .

Lymphomatoid granulomatosis. Successful treatment with CHOP combination chemotherapy. A patient with lymphomatoid granulomatosis is reported. The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis . She obtained a complete remission and remains free of disease 3 1/2 years from the time of diagnosis. The favorable outcome in this patient may be related to her initial limited disease or to the use of initial intensive chemotherapy; nonetheless, the generally unfavorable prognosis of this disease appears to mandate early trials of intensive therapy in most patients.

https://pubmed.ncbi.nlm.nih.gov/6546471/

690144b77124fc39135f75139b0a789f

To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature .

Serotonin syndrome due to co-administration of linezolid and methadone. Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature .

https://pubmed.ncbi.nlm.nih.gov/28956544/

ef60ba55b695c1599db590f25a7eabc7

Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene .

Vemurafenib for the treatment of melanoma. Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene . ### Areas Covered The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma. ### Expert Opinion vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.

https://pubmed.ncbi.nlm.nih.gov/23094782/

9946a786a927a415bf77bbafa138aa28

Anesthetized rats received a single intravenous injection of epinephrine ( 25 , 50 , or 100 mcg/kg ) ; matched cohorts were pretreated with phentolamine ( 100 mcg/kg ) ; n = 5 for each of the six treatment groups .

Epinephrine induces rapid deterioration in pulmonary oxygen exchange in intact, anesthetized rats: a flow and pulmonary capillary pressure-dependent phenomenon. Previous studies indicate epinephrine adversely affects arterial oxygenation when administered in a rat model of local anesthetic overdose. The authors tested whether epinephrine alone exerts similar effects in the intact animal. ### methods Anesthetized rats received a single intravenous injection of epinephrine ( 25 , 50 , or 100 mcg/kg ) ; matched cohorts were pretreated with phentolamine ( 100 mcg/kg ) ; n = 5 for each of the six treatment groups . Arterial pressure and blood gases were measured at baseline, 1 and 10 min after epinephrine administration. Pulmonary capillary pressures during epinephrine infusion with normal and increased flows were measured in an isolated lung preparation. ### results epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg. Rate pressure product was decreased by 10 min after 100 mcg/kg epinephrine. Pretreatment with phentolamine attenuated these effects except at 100 mcg/kg epinephrine. In the isolated lung preparation, epinephrine in combination with increased pulmonary flow increased pulmonary capillary pressure and lung water. ### conclusions Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. Effects were blunted by α-adrenergic receptor blockade. Edema occurred in the isolated lung above a threshold pulmonary capillary pressure when epinephrine treatment was coupled with an increase in pulmonary flow. These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.

https://pubmed.ncbi.nlm.nih.gov/22902967/

422758913c79dd8028aaaa6c7e96e8fd

Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy .

Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): ipilimumab, tremelimumab, nivolumab, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy . Four interventions were superior to chemotherapy in CR and PR (all OR > 1): nivolumab, pembrolizumab 10 mg/kg, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. However, the other seven interventions were associated with an increased risk of pruritus compared to chemotherapy (all OR > 1). ipilimumab, tremelimumab, ipilimumab + nivolumab and ipilimumab + Chemotherapy might result in a higher risk of diarrhea compared to chemotherapy (all OR > 1). Immune checkpoint therapy or combined interventions might be more effective than chemotherapy for managing melanoma patients. However, chemotherapy appears to be more tolerable than these combined strategies with respect to adverse events.

https://pubmed.ncbi.nlm.nih.gov/27764796/

438f02449febdb538919b85102dab9ea

The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel .

Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants. To determine the accuracy with which Medicare claims data measure chemotherapy use in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We compared gold-standard clinical trial data for 175 elderly cancer patients treated in two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., 45 from trial 9344 and 130 from trial 9730) with contemporaneous ambulatory and in-patient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel . The lung trial participants studied were those elderly enrolled between 1998 and 2000 and treated with paclitaxel and carboplatin or paclitaxel alone. Comparing CALGB data with Medicare claims, we found the crude sensitivity for chemotherapy administration was 93% (95% confidence interval [CI] = 88% to 96%). Individual chemotherapy agents had similarly high sensitivities, ranging from 81% (95% CI = 70% to 89%) for carboplatin to 91% (95% CI = 79% to 98%) for cyclophosphamide. Agent-specific specificities were 100%. CMS data reliably captured repeat administration of chemotherapy to within one cycle. Administrative Medicare claims data appear to be a valid source of information for chemotherapy administered to elderly Medicare beneficiaries with cancer.

https://pubmed.ncbi.nlm.nih.gov/16030306/

ae2ba8df041969a9a318e41ab57be3d2

The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities .

PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities . Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. ### methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m ### findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). ### interpretation The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. ### funding Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

https://pubmed.ncbi.nlm.nih.gov/29061295/

c63002cc4497bdfb032257bcd9cf54cc

Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .

Interventions for mycosis fungoides. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. ### objectives To assess the effects of interventions for mycosis fungoides in all stages of the disease. ### Search Methods We searched the following databases up to January 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also checked reference lists of included studies for further references to relevant RCTs. We searched online trials registries for further references to unpublished trials and undertook a separate search for adverse effects of interventions for mycosis fungoides in non-RCTs in MEDLINE in May 2011. ### Selection Criteria Randomised controlled trials (RCTs) of interventions for mycosis fungoides in people with any stage of the disease. At least 90% of participants in the trials must have been diagnosed with mycosis fungoides (Alibert-Bazin-type). ### Data Collection And Analysis Two authors independently assessed eligibility and methodological quality for each study and carried out data extraction. We resolved any disagreement by discussion. Primary outcomes were the impact on quality of life and the safety of interventions. When available, we reported on our secondary outcomes, which were the improvement or clearance of skin lesions, disease-free intervals, survival rates, relapse rates, and rare adverse effects. When possible, we combined homogeneous studies for meta-analysis. We used The Cochrane Collaboration's 'Risk of bias' tool to assess the internal validity of all included studies in six different domains. ### Main Results The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only (please see Table 1 for definitions of these stages).Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis.Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-α (IFN-α). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs.Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-α and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. ### Authors Conclusions This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.

https://pubmed.ncbi.nlm.nih.gov/22972128/

cb3f244bc027dd4d8edb28f71cbb3533

The incident number of the infected mice was significantly different among groups with different drugs and doses : 2/60 , 16/60 , 10/60 and 10/60 in the groups of Changqing capsule , spiramycin , pyrimethamine and azithromycin respectively ( P < 0.05 ) .

[In vitro effect of combined traditional Chinese medicine (Changqing capsule) on the tachyzoites of Toxoplasma gondii]. To detect the in vitro effect of the traditional Chinese medicine on the tachyzoites of Toxoplasma gondii. ### methods Supernatant (1.5 ml) of different doses of the traditional Chinese medicine (Changqing capsule) was collected by normal saline immersion and 2.5 x 10(4) Toxoplasma gondii tachyzoites were added in each paste well for 8 hours. spiramycin, pyrimethamine and azithromycin in different doses were used as controls. Normal saline was used as negative control. Mice were inoculated with drug-treated tachyzoites intraperitoneally or intragastrically. The normal mice were subcultured after 8 days for 3 generations. ### results The incident number of the infected mice was significantly different among groups with different drugs and doses : 2/60 , 16/60 , 10/60 and 10/60 in the groups of Changqing capsule , spiramycin , pyrimethamine and azithromycin respectively ( P < 0.05 ) . No mice were found incident in groups of high and medium dose Changqing capsule while 2 out of 20 found sick in the low dose group (P < 0.05). The subculture observation showed that 2 and 1 mice in the first generation of the low dose Changqing capsule group inoculated intraperitonelly and intragastrically were found infected respectively. 2 mice of the second generation in low dose spiramycin group and 1 mouse of the third generation in low dose pyrimethamine group were also found infected. ### conclusion The in vitro killing effect of the Changqing capsule on the tachyzoites of Toxoplasma gondii is better than the current clinical drugs and shows a positive correlation with the dosages.

https://pubmed.ncbi.nlm.nih.gov/16866146/

c4282f342c8740913c7239c8d24b0a85

In total , seven different interventions ( Chloroquine , Mefloquine , Mefloquine artesunate , Proguanil , Pyrimethamine , Sulfadoxine-pyrimethamine , Sulfadoxine-pyrimethamine amodiaquine ) were evaluated in 912 children with SCD .

Safety and effectiveness of antimalarial therapy in sickle cell disease: a systematic review and network meta-analysis. About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients. ### methods We searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square. ### results Six qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total , seven different interventions ( Chloroquine , Mefloquine , Mefloquine artesunate , Proguanil , Pyrimethamine , Sulfadoxine-pyrimethamine , Sulfadoxine-pyrimethamine amodiaquine ) were evaluated in 912 children with SCD . Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR = 0.72, 95% CI = 0.267-1.959; I ### conclusion The data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients. ### Systematic Review Registration PROSPERO (CRD42016052514).

https://pubmed.ncbi.nlm.nih.gov/30541465/

566beddae5f4a864547e3dd6650f5e85

We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib , carfilzomib , or ixazomib .

Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors. While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib , carfilzomib , or ixazomib . Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM.

https://pubmed.ncbi.nlm.nih.gov/27782060/