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9e003c170aa4b269bf61e3bbb7679d71

Ra ( rate of production ) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol , a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects .

Alpha-adrenergic agonists stimulate neonatal glucose production less than beta-adrenergic agonists in the lamb. epinephrine, a catecholamine with both alpha (alpha)- and beta (beta)-adrenergic agonist effects, may produce clinical hyperglycemia in the adult by increasing glucose production and decreasing glucose clearance. However, the relative contribution of alpha v beta adrenergic agonists in control of neonatal glucose kinetics has not been defined. Twenty-three term lambs (weighing 4.4 +/- 0.2 kg, mean +/- SEM, and aged 3.8 +/- 0.4 days) were infused with 0.9% NaCl at 0.6 mL.kg-1 min-1 + 100 microCi/kg D[6-3H]-glucose by prime plus constant infusion for 210 minutes. Ra ( rate of production ) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol , a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects . All basal kinetic data were comparable. Under conditions of epinephrine infusion, the plasma glucose concentration increased from 95 +/- 10 mg/dL to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine; P less than .0001) and from 85 +/- 6 mg/dL to 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine; P less than .00001) compared with controls (96 +/- 7 mg/dL to 95 +/- 8 mg/dL). When epinephrine and propranolol were infused simultaneously, plasma glucose concentration increased from 95 +/- 10 mg/dL to 122 +/- 12 mg/dL (50 ng.kg-1 min-1 epinephrine + 1.1 micrograms.kg-1 min-1; P less than .0001) and from 78 +/- 9 mg/dL to 134 +/- 12 mg/dL (500 ng.kg-1 min-1 epinephrine + 11 micrograms.kg-1 min-1; P less than .0001) compared with controls (no epinephrine, no propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/2901659/

3d4d260b7bf8ccf63264df8f4be236e8

The ranking order of the response rate was LD ( best ) , doxorubicin , epirubicin , ED , and DD ( worst ) .

Comparisons of Cardiotoxicity and Efficacy of Anthracycline-Based Therapies in Breast Cancer: A Network Meta-Analysis of Randomized Clinical Trials. The effects of anthracycline-based chemical therapies on breast cancer are controversial and inconclusive. We undertook a network meta-analysis to assess the cardiotoxicity and effects of anthracycline therapies in breast cancer. The PubMed, Embase, and Cochrane databases up to August 2018 were reviewed. We identified 19 randomized clinical trials including 3,484 patients with breast cancer which assessed both cardiotoxicity and the effects of anthracycline-based therapies. Eligible studies included the following five treatment strategies: doxorubicin, epirubicin, liposomal doxorubicin (LD), doxorubicin + dexrazoxane (DD), and epirubicin + dexrazoxane (ED). In a direct meta-analysis, epirubicin, LD, DD, and ED had significantly superior cardioprotective effects compared with doxorubicin with odds ratios and 95% CIs of 1.64 (1.04, 2.57), 3.75 (2.46, 5.70), 2.88 (1.93, 4.29), and 3.66 (1.09, 12.33), respectively. doxorubicin showed no significant difference of response rate compared with epirubicin or LD or DD, respectively. In a network meta-analysis, the ranking order of cardiotoxicity was doxorubicin (worst), epirubicin, DD, LD, and ED (best). The ranking order of the response rate was LD ( best ) , doxorubicin , epirubicin , ED , and DD ( worst ) . The most favorable balance between benefit and risk was shown for ED (best) followed by LD, DD, epirubicin, and doxorubicin. In conclusion, LD or ED is the suitable anthracycline treatment for breast cancer in consideration of both cardiotoxicity and efficacy.

https://pubmed.ncbi.nlm.nih.gov/31104059/

fe55149b98f840d75595f19e4bd9c92e

Systemic treatment with physostigmine , an inhibitor of acetylcholinesterase , modestly reduced the acquisition and rate of heroin self-administration , and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine .

Role of acetylcholine transmission in nucleus accumbens and ventral tegmental area in heroin-seeking induced by conditioned cues. The involvement of cholinergic transmission in heroin self-administration and the reinstatement of heroin-seeking was examined in rats trained to nose-poke for i.v. heroin. Systemic treatment with physostigmine , an inhibitor of acetylcholinesterase , modestly reduced the acquisition and rate of heroin self-administration , and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine . Following 10-14 days of self-administration, rats were left in the home environment for 14 days. Subsequently, rats were evaluated for extinction of nose-pokes during the first hour after being returned to the self-administration apparatus. One hour later a conditioned stimulus (house light, light in the nose-poke hole, sound of the infusion pump) was presented to initiate cue-induced reinstatement. Physostigmine produced a dose-dependent inhibition of cue-induced reinstatement, but only the dose of 0.5 mg/kg significantly decreased nose-poke responding in the extinction test. Chronic treatment with physostigmine (0.1 mg/kg) did not impair performance during acquisition of heroin self-administration. However, during a subsequent reinstatement test conducted in the absence of physostigmine pretreatment, heroin seeking was significantly below that of rats chronically pretreated with saline. To evaluate brain regions mediating the effects of systemic drug treatment on reinstatement, physostigmine was microinjected into the nucleus accumbens (NAc) or ventral tegmental area (VTA). Microinjection of physostigmine into the NAc prior to presenting conditioned cues inhibited the reinstatement of heroin-seeking, without affecting extinction responding. In contrast, microinjection of physostigmine into the VTA augmented the reinstatement induced by conditioned cues and extinction responding. Inactivation of either NAc or VTA by microinjecting tetrodotoxin blocked both extinction responding and cue-induced reinstatement. These data demonstrate that cholinergic transmission influences heroin self-administration and reinstatement. Moreover, cue-induced reinstatement was inhibited by physostigmine in the NAc and potentiated by cholinergic stimulation in the VTA.

https://pubmed.ncbi.nlm.nih.gov/17184925/

730e94daa49737e329a573ba8ce4b419

First-line lenvatinib , which was shown to be noninferior to sorafenib , excluded patients with main portal trunk invasion .

Hepatocellular Carcinoma with Portal Vein Tumor Involvement: Best Management Strategies. Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib , which was shown to be noninferior to sorafenib , excluded patients with main portal trunk invasion . regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.

https://pubmed.ncbi.nlm.nih.gov/30041276/

283410cfc7f4ebae3f474db63d477f10

The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer .

Fast progression in non-small cell lung cancer: results from the randomized phase III OAK study evaluating second-line atezolizumab versus docetaxel. Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study. ### methods The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer . FP rates and associated baseline factors were analyzed. FP was defined as either a ≥50% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan). ### results Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a ≥50% SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), ≥3 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a ≥50% SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92)). ### conclusions FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP. ### Trial Registration Number NCT02008227.

https://pubmed.ncbi.nlm.nih.gov/33737340/

8cfd356ecefba9d73f67538b8f8d65cc

In conclusion , combined treatment with 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids .

Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars. While treatment of keloids and hypertrophic scars normally shows modest results, we found that treatment with bleomycin was more promising. The present study was divided into two parts. In the first part the aim was to show the results using a combination of bleomycin and triamcinolone acetonide per cm2 (BTA). In the second part the objective was to determine the response to both drugs in large keloids that were divided into 1 cm2 squares, treating each square with the dose previously used. In the first part of the study, the clinical response of 37 keloids ranging from 0.3 to 1.8 cm2 treated with BTA were followed up over a period of 1- 2 years. 0.375 IU bleomycin and 4 mg triamcinolone acetonide were injected every 3 months. In the second part of the study we reviewed the clinical response in six patients with large keloids. The monthly dose administered never exceeded 3 IU of bleomycin. The first study showed 36 keloids (97.29%) softening after the first dose. In the second study, 5 showed different responses (the response was complete in the four smaller keloids). The largest keloid needed 9 doses to achieve an improvement of 70%. In conclusion , combined treatment with 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids . The best results were obtained in keloids over 1 cm2 or when divided into 1 cm2 square areas. Larger series need to be performed in order to confirm these results..

https://pubmed.ncbi.nlm.nih.gov/23793202/

9b78b0873352d649f96ed2e664b478c1

A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate .

Absence status induced by lacosamide adjunctive therapy. Since lacosamide was approved as an adjuvant agent for the treatment of medically refractory focal epilepsy over ten years ago, it is becoming more widely used for the treatment of idiopathic (genetic) generalized epilepsies. Several studies have demonstrated efficacy in reducing primary generalized tonic-clonic seizures (GTCS), but efficacy is less well-characterized for myoclonic and absence seizures. A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate . While his GTCS became controlled, he was witnessed to have confusional episodes, with waxing and waning responsiveness, lasting a few days, several times a month. After eight months of adjunctive lacosamide therapy, he was admitted to the epilepsy monitoring unit, where paroxysms of generalized spike-and-wave complexes, lasting for 30-90 minutes, were recorded, interrupted only by sleep. During these periods, he demonstrated psychomotor slowing and disorientation on examination. The absence status was successfully broken by lorazepam, and lacosamide was discontinued. The patient had no further confusional episodes at the most recent follow-up visit, four months after discharge.

https://pubmed.ncbi.nlm.nih.gov/30782579/

338aafe426c99361569ae8732520a6ac

[ A randomized controlled trial of immunochemotherapy using carmofur ( HCFU ) , mitomycin C and immunopotentiators in advanced gastric cancer following noncurative resection and nonresection ] .

[ A randomized controlled trial of immunochemotherapy using carmofur ( HCFU ) , mitomycin C and immunopotentiators in advanced gastric cancer following noncurative resection and nonresection ] . The cumulative survival rate of 166 gastric cancer patients after noncurative resection and nonresection treated by combination therapy using carmofur (HCFU), mitomycin C (MMC) and immunopotentiators was investigated. A randomized controlled trial composed of MMC and immunopotentiators (group A) versus the addition of HCFU to group A (group B) was undertaken. In all patients, the survival curve of group B was superior to that of group A (g. Wilcoxon test, p = 0.078). Noncurative resection or nonresection patients presented significantly higher survival rates in group B (p less than 0.05) after analysis according to the duration of the treatment period (Z-test). Stratification of backgrounds for noncurative patients also showed significantly higher survival rates in group B (p less than 0.05) at S 3, P, stage IV. From these results, it might be suggested that HCFU therapy is useful for gastric cancer patients after noncurative resection and nonresection.

https://pubmed.ncbi.nlm.nih.gov/3088298/

0a76598f2f1316d0277e6320f68ac00a

We thus undertook an extensive longitudinal immunologic study , including phenotypic , transcriptomic , and functional analyses , on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial ( Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma ) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL .

Lenalidomide triggers T-cell effector functions in vivo in patients with follicular lymphoma. The immunomodulatory drug lenalidomide is used in patients with follicular lymphoma (FL) with the aim of stimulating T-cell antitumor immune response. However, little is known about the effects of lenalidomide on T-cell biology in vivo in patients with FL. We thus undertook an extensive longitudinal immunologic study , including phenotypic , transcriptomic , and functional analyses , on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial ( Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma ) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL . lenalidomide rapidly and transiently induced an activated T-cell phenotype, including HLA-DR, Tim-3, CD137, and programmed cell death protein 1 (PD-1) upregulation. Furthermore, sequential RNA-sequencing of sorted PD-1+ and PD-1- T-cell subsets revealed that lenalidomide triggered a strong enrichment for several gene signatures related to effector memory T-cell features, including proliferation, antigen receptor signaling, and immune synapse restoration; all were validated at the phenotypic level and with ex vivo functional assays. Correlative analyses pinpointed a negative clinical impact of high effector T-cell and regulatory T-cell percentages before and during treatment. Our findings bring new insight in lenalidomide mechanisms of action at work in vivo and will fuel a new rationale for the design of combination therapies.

https://pubmed.ncbi.nlm.nih.gov/33877296/

7eaad3968ff192fa9bd239415a2168ed

Blockade of beta-receptors by the nonselective beta-blocking agent propranolol did not modify the brachial artery diameter , whereas pindolol increased this parameter for the same degree of blood pressure reduction .

Beta-blockade and brachial artery hemodynamics in hypertension. The effect of systemic adrenergic blockade on hypertensive brachial arteries was studied in humans with pulsed Doppler flowmetry. Blockade of beta-receptors by the nonselective beta-blocking agent propranolol did not modify the brachial artery diameter , whereas pindolol increased this parameter for the same degree of blood pressure reduction . The beta1-selective blocking agents atenolol and bisoprolol caused similar decreases in blood pressure and a reduction in the diameters of the brachial artery and abdominal aorta, respectively. The combination of alpha- and beta-blockade produced a rapid drop in blood pressure but did not change the brachial arterial diameter. Thus, following beta-blockade, the arterial diameter increased, did not change, or even decreased despite an adequate blood pressure reduction. It is suggested that beta-blockade in some instances resets the pressure-diameter curve and therefore has a direct action on the arterial wall independent of the mechanical effect of blood pressure reduction.

https://pubmed.ncbi.nlm.nih.gov/11527134/

2e2c524d37b2d036f3b49ee6d6288b44

Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel ; based on this , we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC .

Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer. Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel ; based on this , we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC . ### Patients And Methods In this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m(2)) and carboplatin (area under the curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method. ### results Between July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia. ### conclusion The combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies.

https://pubmed.ncbi.nlm.nih.gov/24099649/

41d554b6fdbce2aa310be0253e6de7b9

Acute renal failure ( ARF ) occurred concomitantly with the administration of gentamicin in combination with clindamycin in three patients in whom no other known predisposing cause of ARF could be demonstrated .

Renal failure following gentamicin in combination with clindamycin. Acute renal failure ( ARF ) occurred concomitantly with the administration of gentamicin in combination with clindamycin in three patients in whom no other known predisposing cause of ARF could be demonstrated . The evidence for combined nephrotoxicity consisted of the temporal relationship between administration of the antibiotics and the development of ARF, and the prompt improvement in renal function upon cessation of therapy. Complete or partial recovery of renal function occured in all patients. Renal function should be carefully monitored in patients receiving this antibiotic combination.

https://pubmed.ncbi.nlm.nih.gov/951016/

6309c83d434bba5f9f972fcc701f6454

However , nicotinic acid , nicotinamide , and pyridoxamine are not able to reverse the effect of isoniazid .

Protection of Escherichia coli from isoniazid inhibition. Inhibition of Escherichia coli by isonicotinic acid hydrazide (isoniazid) is a function of the initial cell concentration, concentration of antibiotic, and chemical composition of the medium. An initial concentration of 5 x 10(5) cells/ml in a minimal medium is inhibited by 1 mM isoniazid. The E. coli cells are protected from this inhibitory effect by a high concentration of cells in the medium. Protection is also obtained from vitamin-free Casamino Acids, methionine, or choline plus homocystine. However , nicotinic acid , nicotinamide , and pyridoxamine are not able to reverse the effect of isoniazid . Colonies arising on minimal medium supplemented with isoniazid are not due to selection of resistant mutants, because this resistance is transitory and not passed on to the daughter cells. It is hypothesized that this transitory resistance is a manifestation of the cells' ability to transfer the methyl group of methionine to either isoniazid or accumulated nicotinic acid and/or nicotinamide.

https://pubmed.ncbi.nlm.nih.gov/4599120/

c446432e28122964998c2e2d2d6286d5

To explore the role of augmenting neutrophil function in B-cell lymphoma , we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20

A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma. To explore the role of augmenting neutrophil function in B-cell lymphoma , we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20 ### Patients And Methods Twenty patients with indolent B-NHL were treated with rituximab (375 mg/m ### results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). ### conclusion The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL.

https://pubmed.ncbi.nlm.nih.gov/29233743/

18cd496eadd55ca0fd22e758dec9772b

The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept ( sequential treatment group ) in patients with diabetic macular edema ( DME ) .

Sequential Dexamethasone and Aflibercept Treatment in Patients with Diabetic Macular Edema: Structural and Functional Outcomes at 52 Weeks. The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept ( sequential treatment group ) in patients with diabetic macular edema ( DME ) . ### methods We conducted an observational retrospective study in naïve DME patients, 15 treated only with aflibercept (a monthly injection for the first 5 consecutive doses, followed by an injection every 2 months), and 15 treated with a single dexamethasone implant followed by bimonthly aflibercept. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and qualitative features as well as adverse events were assessed at baseline and at 2, 6, and 12 months. ### results BCVA increased from 70.8 ± 4.1 to 83.5 ± 2.7 letters with aflibercept and from 75.6 ± 2.7 to 86.5 ± 2.5 with sequential treatment (p = 0.551). CMT decreased from 411 ± 26.1 to 288.1 ± 10.5 with aflibercept and from 411.4 ± 24.3 to 260.8 ± 17.9 in the sequential treatment group. The differences between the 2 groups, in terms of visual gain and decreased MT, were not statistically significant (p > 0.05). Nine and 6 injections and 9 and 7 monitoring visits were performed. ### conclusion Sequential treatment in DME, starting with dexamethasone and followed by aflibercept, is a promising alternative that can reduce the treatment burden in the first year without statistically significant differences in terms of visual gain and decreased MT compared to aflibercept only.

https://pubmed.ncbi.nlm.nih.gov/29996128/

325c8adc26eb89b99972504e4cf4fbc1

Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 ( Schedule A ) or day 8 ( Schedule B ) , repeated every 21 d.

Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 ( Schedule A ) or day 8 ( Schedule B ) , repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.

https://pubmed.ncbi.nlm.nih.gov/23483678/

ffdbb009607a99d5a098d1e8645df481

Thirty-two patients with advanced breast carcinoma were randomized to receive increasing doses of paclitaxel ( 45 , 65 , 80 , 90 and 100 mg/m2 ) or docetaxel ( 30 , 35 , 40 , 45 and 50 mg/m2 ) together with the CMF agents at the same dose as that used in the conventional regimen .

Design and development of new combinations of the CMF agents with taxanes (paclitaxel or docetaxel) in advanced breast cancer: a feasibility study. We previously designed and tested combinations made up of the CMF agents, two at a time by rotation, and of doxorubicin or epirubicin. The present study was aimed to similarly test new combinations made up of the CMF agents, two at a time by rotation, and paclitaxel or docetaxel. ### methods The doses of each taxane were escalated with the objective of reaching at least a single dose level of 90 mg/m2 of paclitaxel and 45 mg/m2 of docetaxel on days 1 and 8 of each four-week cycle. Thirty-two patients with advanced breast carcinoma were randomized to receive increasing doses of paclitaxel ( 45 , 65 , 80 , 90 and 100 mg/m2 ) or docetaxel ( 30 , 35 , 40 , 45 and 50 mg/m2 ) together with the CMF agents at the same dose as that used in the conventional regimen . Each dose level was administered to a triplet of patients. No direct comparison of the two taxanes was made. ### results The fourth dose level was reached for paclitaxel and docetaxel. The most important toxicities were grade 4 neutropenia and grade 1-2 nausea/vomiting and stomatitis. The objective response rate, assessed only after the third cycle at any dose level, was 31% (95% CI, 15-47%). ### conclusions The combinations of the CMF agents (two at a time in rotation) with paclitaxel (90 mg/m2) or docetaxel (45 mg/m2) on days 1 and 8 of each four-week cycle are feasible and lead to definite signs of therapeutic activity, and the side effects are generally mild. Further studies are therefore warranted.

https://pubmed.ncbi.nlm.nih.gov/15315305/

4b5419c4e7013f2b9aa3e47ecdcbdbcb

In a 52-week , open-label , multicenter , extension study , HDL-C , TG , and LDL-C levels continued to improve , or were maintained , during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin ( atorvastatin 40 mg , rosuvastatin 20 mg , or simvastatin 40 mg ) .

Fenofibric acid: in combination therapy in the treatment of mixed dyslipidemia. fenofibric acid activates peroxisome proliferator-activated receptor alpha to modify fatty acid and lipid metabolism. fenofibric acid is the first member of the fibric acid derivatives (fibrates) class approved for use as combination therapy with HMG-CoA reductase inhibitors (statins). In three randomized, double-blind, multicenter, phase III trials in adult patients with mixed dyslipidemia, up to 12 weeks' treatment with once-daily fenofibric acid 135 mg plus a low- or moderate-dose statin (atorvastatin 20 or 40 mg, rosuvastatin 10 or 20 mg, or simvastatin 20 or 40 mg) improved high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels to a significantly greater extent than statin monotherapy, and improved low-density lipoprotein cholesterol (LDL-C) levels to a significantly greater extent than fenofibric acid monotherapy. In a 52-week , open-label , multicenter , extension study , HDL-C , TG , and LDL-C levels continued to improve , or were maintained , during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin ( atorvastatin 40 mg , rosuvastatin 20 mg , or simvastatin 40 mg ) . Once-daily fenofibric acid 135 mg plus a statin was generally as well tolerated as monotherapy with fenofibric acid 135 mg/day or the corresponding statin dosage in the three phase III trials in patients with mixed dyslipidemia. The incidence of adverse events was similar between the combination therapy group and both monotherapy groups. In the extension trial, once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg) for up to 52 weeks was generally well tolerated.

https://pubmed.ncbi.nlm.nih.gov/19929038/

5511884d05b2f45195a0c930f28abca2

To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy .

Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group. To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy . ### design Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks. ### setting Patients from 32 hospitals in Europe were enrolled throughout a 1-year period. ### patients Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced ( > or = 24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL). ### intervention Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period. ### Main Outcome Measures Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects. ### results Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P < .001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P < .001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P < .011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement. ### conclusion In zidovudine-experienced HIV-1-infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.

https://pubmed.ncbi.nlm.nih.gov/8656502/

12c2283c9ba7350e63e1dd29bcd7fb28

Bradykinin enhanced the effect of carbachol by about 10 - 15 % .

Ca(2+)-independent, Ca(2+)-dependent, and carbachol-mediated arachidonic acid release from rat brain cortex membrane. Synaptoneurosomes obtained from the cortex of rat brain prelabeled with [14C]arachidonic acid [( 14C]AA) were used as a source of substrate and enzyme in studies on the regulation of AA release. A significant amount of AA is liberated in the presence of 2 mM EGTA, independently of Ca2+, primarily from phosphatidic acid and polyphosphoinositides (poly-PI). Quinacrine, an inhibitor of phospholipase A2 (PLA2), suppressed AA release by about 60% and neomycin, a putative inhibitor of phospholipase C (PLC), reduced AA release by about 30%. An additive effect was exhibited when both inhibitors were given together. Ca2+ activated AA release. The level of Ca2+ present in the synaptoneurosomal preparation (endogenous level) and 5 microM CaCl2 enhance AA liberation by approximately 25%, whereas 2 mM CaCl2 resulted in a 50% increase in AA release relative to EGTA. The source for Ca(2+)-dependent AA release is predominantly phosphatidylinositol (PI); however, a small pool may also be liberated from neutral lipids. carbachol, an agonist of the cholinergic receptor, stimulated Ca(2+)-dependent AA release by about 17%. Bradykinin enhanced the effect of carbachol by about 10 - 15 % . This agonist-mediated AA release occurs specifically from phosphoinositides (PI + poly-PI). Quinacrine almost completely suppresses calcium-and carbachol-mediated AA release. neomycin inhibits this process by about 30% and totally suppresses the effect of bradykinin. Our results indicate that both phospholipases PLA2 and PLC with subsequent action of DAG lipase are responsible for Ca(2+)-independent AA release. Ca(2+)-dependent and carbachol-mediated AA liberation occurs mainly as the result of PLA2 action. A small pool of AA is probably also released by PLC, which seems to be exclusively responsible for the effect of bradykinin.

https://pubmed.ncbi.nlm.nih.gov/1910075/

83a954708b00b9b6e15d0d627b50420f

Here , we report that combinatorial treatment using EGFRis , such as gefitinib or erlotinib , with PI3K/AKT pathway inhibitors ( PI3K/AKTis ) demonstrated a synergistic , anti-proliferative effect in cell lines of the basal-like ( BL ) subtype , a subtype of TNBC .

Inhibition of the PI3K/AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple-negative breast cancer cells. Triple-negative breast cancers (TNBCs) are known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical trials for TNBCs using EGFR inhibitors (EGFRis) as single agents have yielded disappointing results. Here , we report that combinatorial treatment using EGFRis , such as gefitinib or erlotinib , with PI3K/AKT pathway inhibitors ( PI3K/AKTis ) demonstrated a synergistic , anti-proliferative effect in cell lines of the basal-like ( BL ) subtype , a subtype of TNBC . Western blot analysis revealed that the gefitinib/PI-103 combination significantly reduced the level of both phospho-AKT and phospho-ERK in two susceptible BL subtype cell lines, SUM149PT and MDA-MB-468, whereas it had little or no effect on the level of phospho-ERK in two non-susceptible cell lines (HS578T and MDA-MB-231) of mesenchymal stem-like (MSL) TNBC subtype. The gefitinib/PI-103 combination also significantly induced caspase-3/7-mediated PARP cleavage and reduced two anti-apoptotic proteins, XIAP and Bcl-2 in the susceptible cell lines. In addition, the level of myeloid cell leukemia 1 (Mcl-1) protein was markedly decreased by gefitinib/PI-103 combination in the BL TNBC cells, but showed no significant change by this combination in MSL subtype cells. These results suggest that pharmacological inhibition of EGFR used in combination of PI3K/AKTis is a potential therapeutic approach to treat a subtype of TNBCs.

https://pubmed.ncbi.nlm.nih.gov/23601074/

bd68176608c1e1091d907d818f76921d

Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8 , capecitabine 1300 mg/m² oral daily from day 1 to 14 , and dovitinib oral daily 5 days on and 2 days off , every 21-day cycle .

A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients. Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. ### Materials And Methods Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8 , capecitabine 1300 mg/m² oral daily from day 1 to 14 , and dovitinib oral daily 5 days on and 2 days off , every 21-day cycle . The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. ### results A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. ### conclusions dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.

https://pubmed.ncbi.nlm.nih.gov/30418178/

76cbd79e657a1ad54cf36da520ec4f51

A reduced dose of oxaliplatin 105 mg/m(2 ) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1 - 3 was well tolerated .

Oxaliplatin and Doxorubicin for relapsed or refractory high-risk neuroblastoma. Patients with relapsed or refractory neuroblastoma have poor long-term survival. New therapeutic regimens are needed. doxorubicin and cisplatin are commonly used in the treatment of high-risk neuroblastoma. oxaliplatin, a platinum compound with a 1,2-diaminocyclohexan carrier ligand, is more potent than cisplatin with less nephrotoxicity and ototoxicity. We treated seven relapsed/refractory neuroblastoma patients using oxaliplatin (105-130 mg/m(2)) and doxorubicin (60-75 mg/m(2)) together with dexrazoxane (10 mg/mg of doxorubicin) administered intravenously every three weeks. Prolonged thrombocytopenia causing treatment delay was observed when oxaliplatin was administered at 130 mg/m(2). A reduced dose of oxaliplatin 105 mg/m(2 ) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1 - 3 was well tolerated . Sensory neuropathies were mild and transient. No cardiotoxicity was noted despite all patients having a history of prior anthracycline exposure. Best responses included 1 complete response, 1 partial response, 1 mixed response, 3 stable diseases. In our cohort of heavily pretreated relapsed and refractory neuroblastoma patients, the combination of oxaliplatin and doxorubicin demonstrated anti-tumor activity and merits further investigation.

https://pubmed.ncbi.nlm.nih.gov/25551355/

f53333587fca7842b3c70bb79390b818

In terms of recurrent disease , two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication .

Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer. In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease , two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication . Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.

https://pubmed.ncbi.nlm.nih.gov/26500886/

76a47d0103d5bb645cef53e3849f296e

A total of 80 patients were randomized , including 44 to the combination group ( tamsulosin 0.4 mg and tolterodine early release 4 mg ) and 36 to the monotherapy group ( tamsulosin 0.4 mg and placebo ) .

Does Combination Therapy with Tamsulosin and Tolterodine Improve Ureteral Stent Discomfort Compared with Tamsulosin Alone? A Double-Blind, Randomized, Controlled Trial. Ureteral stent discomfort is a significant postoperative problem for many patients. Despite the use of narcotics and α-blockers patients often experience bothersome lower urinary tract symptoms and pain, which impair daily activities. We compared combination therapy with an α-blocker and an anticholinergic to monotherapy with an α-blocker. ### Materials And Methods A double-blind, randomized, controlled trial was performed from December 2012 to April 2014. A total of 80 patients were randomized , including 44 to the combination group ( tamsulosin 0.4 mg and tolterodine early release 4 mg ) and 36 to the monotherapy group ( tamsulosin 0.4 mg and placebo ) . Patients with preexisting ureteral stent placement or current anticholinergic therapy were excluded from study. Patients completed USSQ (Urinary Stent Symptom Questionnaire) before stent placement on the day of surgery, the day after stent placement, the morning of stent removal and the day after stent removal. The questionnaire included questions regarding urinary symptoms, general health, body pain, and work and sexual history. ### results A total of 80 patients (40 males and 40 females) were studied. Mean age was 51.5 vs 51.3 years (p = 0.95) and mean body mass index was 33.6 vs 31.9 kg/m(2) (p = 0.44) in monotherapy group 1 vs combination therapy group 2. Between the 2 groups there was no significant difference in urinary symptoms, body pain and activities of daily living from baseline to just before stent removal (p = 0.95, 0.40 and 0.95, respectively). Although there was no difference between the groups, both showed improvement in urinary symptoms from the time of initial stent insertion to just prior to stent removal (difference -0.50 for combination therapy and -0.40 for monotherapy). The mean stent indwelling time of 9.6 and 8.7 days in the combination and monotherapy groups, respectively, did not differ (p = 0.67). On ANOVA it had no significant impact on results (p = 0.64). ### conclusions Combination therapy with tamsulosin and tolterodine does not appear to improve urinary symptoms, bodily pain or quality of life in patients after ureteral stent placement for nephrolithiasis compared to tamsulosin alone. Both groups experienced worse urinary symptoms, pain and quality of life with a stent, suggesting that further research is necessary to improve stent discomfort.

https://pubmed.ncbi.nlm.nih.gov/26393904/

f1b0ff0b76130677d5b50ae333b2ff89

However , thiostrepton , dexamethasone , 2-methoxyestradiol , δ-tocotrienol , quercetin , and quinine sulphate were effective in pancreatic , prostate , breast , lungs , melanoma , Β-lymphocytes , and T-cells ( Jurkat : 40 % to 95 % ) compared to respective controls .

Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs. ### methods The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated. ### results Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5-20 μM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% - 92%. However , thiostrepton , dexamethasone , 2-methoxyestradiol , δ-tocotrienol , quercetin , and quinine sulphate were effective in pancreatic , prostate , breast , lungs , melanoma , Β-lymphocytes , and T-cells ( Jurkat : 40 % to 95 % ) compared to respective controls . In lung cancer cells, these compounds were effective between 5 and 40 μM. The IC ### conclusions These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

https://pubmed.ncbi.nlm.nih.gov/29606130/

b233b4e3fc9cdd13f716e884102c3d03

Of them , 47 patients started with docetaxel at cycle one due to reaction to paclitaxel ( n=32 ) , fear of NT ( n=4 ) , and other reasons ( n=11 ) , whereas 59 patients switched to docetaxel during cycle 2 - 6 due to NT ( n=32 ) , reaction to paclitaxel ( n=19 ) , and other reasons ( n=8 ) .

Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. To describe characteristics associated with neurotoxicity (NT) in advanced ovarian cancer patients treated on Gynecologic Oncology Group 218 and examine effect of substituting docetaxel for paclitaxel in these patients. ### methods The development of NT was defined as Common Toxicity Criteria grade (G)≥1. The association between substitution with docetaxel and NT improvement was explored with generalized estimating equations adjusting for treatment cycle and NT grading at previous cycle. ### results Of 1864 evaluable patients, 1329 (71%) developed G≥1 NT during the study. Nearly half appeared within the first two cycles of chemotherapy, with 31% experiencing G≥2. Older patients or those with worse quality of life (QoL) scores at baseline (p<0.05) were more likely to experience NT. One-hundred-six patients received docetaxel as substitute for paclitaxel. Of them , 47 patients started with docetaxel at cycle one due to reaction to paclitaxel ( n=32 ) , fear of NT ( n=4 ) , and other reasons ( n=11 ) , whereas 59 patients switched to docetaxel during cycle 2 - 6 due to NT ( n=32 ) , reaction to paclitaxel ( n=19 ) , and other reasons ( n=8 ) . Although the protocol instructed otherwise, the majority continued paclitaxel despite G≥2 NT symptoms. There was no evidence that substitution with docetaxel improved NT (Odds Ratio: 1.57; 95% CI 0.98-2.54; p>0.05). Of 59 patients who switched to docetaxel, only seven (12%) discontinued taxane prior to chemotherapy completion. A roughly equal chance of worsening NT was reported on paclitaxel (6%) as on docetaxel (5%). ### conclusions Age and worse QoL at baseline are associated with NT. Substitution of docetaxel did not improve NT symptoms.

https://pubmed.ncbi.nlm.nih.gov/25529832/

197fa35b97d4040fda9cd228ffe661ab

Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption , prednisolone and cyclophosphamide .

Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption , prednisolone and cyclophosphamide . Ten patients with rapidly progressive glomerulonephritis and acute renal failure were treated with extracorporeal immunoadsorption, prednisolone, and cyclophosphamide. Three patients had systemic lupus erythematosus, five had microscopic polyarteritis and two had Wegener's granulomatosis. All ten patients were dialysis-dependent prior to immunoadsorption. Nine of ten patients rapidly regained renal function and seven continue to have independent renal function between 9 and 30 months after immunoadsorption. Three patients at presentation were not dialysis dependent. Despite treatment with methylprednisolone, cyclophosphamide, and oral prednisolone, renal function continued to deteriorate and they required dialysis. Immunoadsorption was then started without alteration in baseline immunosuppression. Within a mean of 4.6 days, range 3-7 days, renal function improved and the patients no longer required dialysis. Antineutrophil cytoplasmic antibodies and double-stranded DNA antibodies were rapidly removed by immunoadsorption. Only one patient with systemic lupus erythematosus and two with microscopic polyarteritis had significant resynthesis of antibody at 1 month post-immunoadsorption. Renal biopsy before and after immunoadsorption and immunosuppressive therapy showed resolution of glomerular crescents and no evidence of active disease. Immunoadsorption coupled with prednisolone and cyclophosphamide may be of value in the treatment of rapidly progressive glomerulonephritis.

https://pubmed.ncbi.nlm.nih.gov/1956551/

9e833fe8bad3c49371b619cf31472d4f

[ Doxifluridine , medroxyprogesterone acetate and cyclophosphamide ( DMpC ) combination therapy is effective against recurrent triple negative breast cancer -- a case report ] .

[ Doxifluridine , medroxyprogesterone acetate and cyclophosphamide ( DMpC ) combination therapy is effective against recurrent triple negative breast cancer -- a case report ] . We report a postmenopausal recurrent breast cancer patient with triple negative disease who presented with right recurrent nerve palsy. Nine years previously, she had undergone a mastectomy. FDG-PET scan revealed neck lymph node metastases from the breast cancer. The recurrent nerve palsy was thus considered to have been caused by the lymph node metastases. The patient was orally administered DMpC (doxifluridine, medroxyprogesterone acetate and cyclophosphamide) combination therapy. This resulted in a remarkable response after five months, with the recurrent nerve palsy completely disappearing at six months. No side effects from the treatment were observed. The patient was well and the treatment was being continued without relapse at nine months. Oral anti-cancer treatments such as DMpC appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients with triple negative disease.

https://pubmed.ncbi.nlm.nih.gov/19098418/

61d52dccc15e2956f4223de1a92b4cba

Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir .

Pharmacokinetics of ganciclovir and valganciclovir in the adult horse. Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV-1) infection, is associated with substantial morbidity and mortality in the horse. As compared to other antiviral drugs, such as acyclovir, ganciclovir has enhanced potency against EHV-1. This study investigated the pharmacokinetics of ganciclovir and its oral prodrug, valganciclovir, in six adult horses in a randomized cross-over design. ganciclovir sodium was administered intravenously as a slow bolus at a dose of 2.5 mg/kg, and valganciclovir was administered orally at a dose of 1800 mg per horse. Intravenously administered ganciclovir disposition was best described by a three-compartment model with a prolonged terminal half-life of 72 ± 9 h. Following the oral administration of valganciclovir, the mean observed maximum serum ganciclovir concentration was 0.58 ± 0.37 μg/mL, and bioavailability of ganciclovir from oral valganciclovir was 41 ± 20%. Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir . However, superposition suggested that i.v. administration of ganciclovir at 2.5 mg/kg every 8 h for 24 h followed by maintenance dosing of 2.5 mg/kg every 12 h would maintain effective ganciclovir serum concentrations in most horses throughout the dosing interval.

https://pubmed.ncbi.nlm.nih.gov/23301502/

3ebfe9d6dea0a9a490ea2aa0454bbe73

The levels of 3 NF-kappaB transcription factors , the activating inhibitors of NF-kappaB ( IkappaB ) kinases , and the NF-kappaB target matrix metalloproteinase 9 ( MMP9 ) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel , cisplatin , and cyclophosphamide .

Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Recent work has suggested a role for nuclear factor kappaB (NF-kappaB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappaB in ovarian cancer is unknown. The authors hypothesized that the NF-kappaB pathway is over activated in aggressive ovarian cancers. ### methods The levels of 3 NF-kappaB transcription factors , the activating inhibitors of NF-kappaB ( IkappaB ) kinases , and the NF-kappaB target matrix metalloproteinase 9 ( MMP9 ) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel , cisplatin , and cyclophosphamide . Associations were made between NF-kappaB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. ### results The presence of NF-kappaB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IkappaB kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappaB machinery suggested activity of NF-kappaB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. ### conclusions The deregulation of NF-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappaB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity.

https://pubmed.ncbi.nlm.nih.gov/20564628/

6cb24a0aa6f5f1697a1eee72f33a27f2

The clonidine DV suppression was reliably reversed by yohimbine ( 1.75 micrograms ) , but by none of the other adrenoceptor antagonists or naloxone .

The role of brain norepinephrine in clonidine suppression of isolation-induced distress in the domestic chick. Distress vocalizations (DV) induced by social isolation were measured in 1-day-old domestic chicks after intracerebroventricular injections of drugs believed to exert their effects through the noradrenergic system. The alpha-adrenoreceptor agonist clonidine reliably suppressed DV rates at doses low as 0.08 micrograms. When given alone, phentolamine, phenoxybenzamine, propranolol, sotalol, and yohimbine (adrenoreceptor antagonists) did not reliably alter DV rates at doses that were not toxic. The clonidine DV suppression was reliably reversed by yohimbine ( 1.75 micrograms ) , but by none of the other adrenoceptor antagonists or naloxone . 6-Hydroxydopamine at doses as high as 120 micrograms, which essentially eliminated forebrain norepinephrine, failed to suppress DV rates reliably when given alone and, when given in combination with clonidine (0.1 micrograms) or morphine (0.05 micrograms), failed to reverse the severe DV suppression imposed by these drugs. The results suggest that clonidine suppresses DV rates in or by some means other than prejunctional alpha 2-adrenoreceptor stimulation.

https://pubmed.ncbi.nlm.nih.gov/6407049/

f65d266d877f06ce911e476b58ade05a

There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status ; the mean shrinkage was -17 % vs -25 % for sunitinib-treated patients with high vs low tumour CAIX expression , compared to -13 % vs + 9 % for sorafenib-treated patients ( P interaction , 0.05 ) .

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. ### Patients And Methods We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed. ### results There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status ; the mean shrinkage was -17 % vs -25 % for sunitinib-treated patients with high vs low tumour CAIX expression , compared to -13 % vs + 9 % for sorafenib-treated patients ( P interaction , 0.05 ) . A higher tumour clear-cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02). ### conclusions Although CAIX expression had no prognostic value in patients with clear-cell mRCC treated with VEGF-targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear-cell component in their tumours are likely to have a superior clinical benefit from VEGF-targeted therapy.

https://pubmed.ncbi.nlm.nih.gov/20230385/

373e5d7f0b58c2077b7b3e990ecd028c

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer .

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer . seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 ( ### Materials And Methods Patients with ### results One hundred twenty-nine patients received seribantumab + erlotinib ( ### conclusion The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). ### Implications For Practice The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

https://pubmed.ncbi.nlm.nih.gov/30975923/

9dbe60379e343d03771d72567b7e1952

Trabectedin in combination with pegylated liposomal doxorubicin ( PLD ) has been fully available privately in the UK since 2009 for treating patients with ROC .

Real-life experience using trabectedin plus pegylated liposomal doxorubicin combination to treat patients with relapsed ovarian cancer. The goal of recurrent ovarian cancer (ROC) treatment is no longer just palliation, but prolonging survival. This is usually through administering a new line of chemotherapy at each relapse. A novel treatment sequencing strategy to achieve this is through the intercalation of an effective non-platinum alternative, in between platinum-based therapies. Trabectedin in combination with pegylated liposomal doxorubicin ( PLD ) has been fully available privately in the UK since 2009 for treating patients with ROC . A single institution's experience with the trabectedin + PLD combination, as a non-platinum/non-taxane alternative, to intercalate between platinum-based therapies is reported here. To date 6 patients have been successfully treated with trabectedin + PLD at Broomfield Hospital, Chelmsford, Essex. Here we describe a new, practice-changing treatment approach in a real-life case study of a heavily-treated patient with advanced ROC treated with trabectedin + PLD at fourth-line and then subsequently rechallenged at seventh-line; with treatment continuing until disease progression.

https://pubmed.ncbi.nlm.nih.gov/26759528/

4301abf0739a41ba2cdbb7b62a226409

More interestingly , lumefantrine tolerance is associated with an increase in chloroquine susceptibility , raising the possibility of re-introducing chloroquine .

Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine. Coartem(®), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(®) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly , lumefantrine tolerance is associated with an increase in chloroquine susceptibility , raising the possibility of re-introducing chloroquine . In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.

https://pubmed.ncbi.nlm.nih.gov/22761327/

ae0bd2532fba1ddf22f0e68f16423f74

Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine .

Vinblastine and estramustine phosphate in metastatic renal cell carcinoma: a phase II trial of the Fox Chase Network. It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine . The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine. ### methods Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy. ### results Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks. ### conclusions Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC.

https://pubmed.ncbi.nlm.nih.gov/14584064/

c1075bb61cf549c452bcc7f9aef03755

Cohort 7 ( gemcitabine 600 mg/m/wk and carboplatin 2 AUC ) showed 4 dose limiting toxicities : 2 grade 3 esophagitis ; one grade 3 febrile neutropenia ; and one grade 4 neutropenia .

RTOG 0017: a phase I trial of concurrent gemcitabine/carboplatin or gemcitabine/paclitaxel and radiation therapy ("ping-pong trial") followed by adjuvant chemotherapy for patients with favorable prognosis inoperable stage IIIA/B non-small cell lung cancer. The optimal dose of gemcitabine that can be used with concurrent radiation therapy for locally advanced non-small cell lung cancer has not been well defined. This trial addresses this question in an alternating sequence "ping-pong" design trial to find the maximum tolerated dose (MTD) for gemcitabine/carboplatin (Sequence A) or gemcitabine/paclitaxel (Sequence B) and thoracic radiation therapy followed by adjuvant gemcitabine/carboplatin chemotherapy. ### Patients And Methods Thirty-five patients with histologically confirmed Stage IIIA/B non-small cell lung cancer were entered into two separate sequences, each with multiple cohorts. A dose level was considered acceptable if, of the first six eligible patients on each cohort, fewer than three experienced dose limiting toxicities. ### results Sequence B of this 2 sequence "ping-pong" trial closed early due to toxicity in cohort 2 (gemcitabine 300 mg/m/wk and paclitaxel 30 mg/m/wk). On Sequence A, the MTD was the cohort 5 dose: gemcitabine 450 mg/m/wk and carboplatin 2 area under curve (AUC) concurrently with thoracic radiation. Cohort 7 ( gemcitabine 600 mg/m/wk and carboplatin 2 AUC ) showed 4 dose limiting toxicities : 2 grade 3 esophagitis ; one grade 3 febrile neutropenia ; and one grade 4 neutropenia . ### conclusion Concurrent gemcitabine/paclitaxel chemoradiation regimen followed by adjuvant gemcitabine/carboplatin produced excessive toxicity at the lowest tested dose combination and was not suitable for further study in this trial. Meanwhile, the MTD of concurrent gemcitabine/carboplatin chemoradiation was determined to be gemcitabine 450 mg/m and carboplatin AUC-2. This combination was found to be tolerable. Although not a primary end point, survival results are summarized as well.

https://pubmed.ncbi.nlm.nih.gov/19096311/

8e05f49203e45d0f5d18bf08087c48a2

Treatment with IFN-α plus bevacizumab or standard targeted therapy ( sunitinib ) may lead to similar one-year overall mortality ( RR 0.37 , 95 % CI 0.13 to 1.08 ; 1 study ; 83 participants ; low-quality evidence ) and AEs of grade 3 or greater ( RR 1.18 , 95 % CI 0.85 to 1.62 ; 1 study ; 82 participants ; low-quality evidence ) .

Immunotherapy for metastatic renal cell carcinoma. Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. ### objectives To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. ### Search Methods We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. ### Selection Criteria We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. ### Data Collection And Analysis We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. ### Main Results We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with IFN-α plus bevacizumab or standard targeted therapy ( sunitinib ) may lead to similar one-year overall mortality ( RR 0.37 , 95 % CI 0.13 to 1.08 ; 1 study ; 83 participants ; low-quality evidence ) and AEs of grade 3 or greater ( RR 1.18 , 95 % CI 0.85 to 1.62 ; 1 study ; 82 participants ; low-quality evidence ) . QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). ### Authors Conclusions Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.

https://pubmed.ncbi.nlm.nih.gov/28504837/

35396e2be6839ef529a93eff596364a0

In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib .

Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. ### methods A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. ### results In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib . In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. ### conclusions ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. ### Clinical Trial Registration DOC-MEK (EudraCT no: 2009-018153-23).

https://pubmed.ncbi.nlm.nih.gov/31839677/

aed14eca85db89b8b0b3d86c37c2081b

Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC ( mRCC ) .

Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma. Induction of regulatory T cells (Treg) is an important mechanism leading to tolerance against tumors. Increased levels of Treg have been described in renal cell carcinoma (RCC) patients and seem to correlate with an adverse outcome. Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC ( mRCC ) . Treg were analyzed by flow cytometry in the peripheral blood (PB) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). Blood samples were taken before treatment and during the first, second, and third months of therapy. Flow cytometric analysis of PB mononuclear cells was performed using fluorochrome-labeled antibodies against CD3, CD4, CD25, and FOXp3. During the first month of therapy, patients treated with sorafenib showed a significant increase in FOXp3CD3CD4CD25 Treg (13.5 vs. 36.3% of gated cells, P=0.02, or 0.35 vs. 0.49% of total cells) and the ratio FOXp3 T cells/FOXp3 T cells (0.16 vs. 0.56 of gated cells, P=0.02). These elevated levels persisted throughout the treatment period. There was no influence of sunitinib on the frequency of Treg in our cohort of patients. sorafenib, but not sunitinib, leads to an early and sustained increase in Treg in PB of mRCC patients. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. Our study suggests that sorafenib should be avoided in such a therapeutic setting.

https://pubmed.ncbi.nlm.nih.gov/22156795/

1eab299f82afbf61906b779959587b5e

Naloxone ( 5 x 10(-7 ) mol/kg iv ) and atropine ( 0.1 mg/kg iv ) induced isolated orad contractions .

Rhythmic oscillating complex: characterization, induction, and relationship to MMC in chickens. Migrating myoelectrical complexes (MMCs) and rhythmic oscillating complexes (ROCs) have been investigated in chickens prepared for electromyography. Animals were chronically implanted with electrodes in stomach, duodenum, jejunum, ileum, ceca, and rectum. MMCs showing phases I-III were found in the jejunum and ileum both in fed and fasted states. Repetitive spike bursts were recorded in the duodenum (0.5-1/h), disrupting the gastroduodenal coordination and preceding a phase III in the jejunum. ROCs appeared spontaneously in fasted animals and in 75% of the recordings during the dark period. Four consecutive intestinal myoelectrical patterns have been described during a ROC. Briefly, they consisted in series of high-speed propagated abroad contractions of great amplitude that progressively changed into others of orad direction. In relation to the MMC, the ROC pattern appeared just after a phase III reached the distal ileum, and a pattern of duodenal repetitive spike bursts, followed by a migrating phase III in the jejunum, started at the duodenum after a ROC. No myoelectrical changes were recorded in cecorectal activity during ROC. Vagotomized animals showed the ROC pattern. Neither apomorphine (5-100 micrograms/kg iv) nor cholecystokinin (10(-9) mol/kg iv) induced ROCs. Naloxone ( 5 x 10(-7 ) mol/kg iv ) and atropine ( 0.1 mg/kg iv ) induced isolated orad contractions . Myoelectrical and functional similarities can be found between retrograde giant contractions, described in mammals, and ROCs. However, they differ in their origin and mechanism of induction.

https://pubmed.ncbi.nlm.nih.gov/8178997/

91a967a9455079d236d1c9191fe1aa68

FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model ( p=0.003 ) , with no difference in the < 75-yr model ( p>0.9 ) .

Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial. abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). ### objective To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. ### Design Setting And Participants We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). ### intervention Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. ### Outcome Measurements And Statistical Analysis To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. ### Results And Limitations In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model ( p=0.003 ) , with no difference in the < 75-yr model ( p>0.9 ) . A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. ### conclusions Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. ### Patient Summary In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.

https://pubmed.ncbi.nlm.nih.gov/30591354/

d6e707bfab45da269027b64b4534859e

The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy .

Doxorubicin in combination with verapamil in advanced colorectal cancer. A phase II trial. The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy . The treatment started with oral verapamil, which was escalated up to the individual maximum tolerable dose (defined by prolongation of P-Q in ECG, fall in blood pressure, or dizziness). The median maximum tolerable dose was 600 mg (range 320-1,440 mg). During continued verapamil administration the patients then got weekly infusions of doxorubicin, 25 mg/m2. The median number of doxorubicin courses was 8 (range 2-22). Among 21 patients evaluable for response and toxicity two partial remissions occurred but no complete remission. The study did not indicate enhanced cardiac, hematological or non-hematological toxicity from the combined treatment.

https://pubmed.ncbi.nlm.nih.gov/2009180/

516f23cdd806a08725fc0664796a5694

Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine ( 20 mg/m2 on D1 , D15 ) , followed by paclitaxel ( 175 mg/m2 on D1 ) , every 3 weeks .

Phase II study of paclitaxel combined with vinorelbine in patients with advanced breast cancer. paclitaxel and vinorelbine are two drugs active against breast cancer. A phase II study was initiated with the aim of assessing the efficacy and feasibility of the combination. Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine ( 20 mg/m2 on D1 , D15 ) , followed by paclitaxel ( 175 mg/m2 on D1 ) , every 3 weeks . A 48% (95% CI: 35-61) response rate was obtained in the 23 patients evaluable for response. vinorelbine was administered on D15, as scheduled, in 72% of cycles. The main toxicity observed was grade III to IV neutropenia in 73% of patients. Febrile neutropenia was reported in three patients. Disease-free survival was 118 days, and overall median survival was 361 days. This combination of paclitaxel and vinorelbine is feasible and effective in patients with early relapse or previously treated with first-line chemotherapy for metastatic disease.

https://pubmed.ncbi.nlm.nih.gov/15170156/

f10f68be5ebe5d09547fc181228e3653

Although monotherapy with cytotoxic agents , including docetaxel and pemetrexed , is recommended for patients with previously treated advanced non-small cell lung cancer ( NSCLC ) , its outcomes are unsatisfactory .

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer. In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. ### background Although monotherapy with cytotoxic agents , including docetaxel and pemetrexed , is recommended for patients with previously treated advanced non-small cell lung cancer ( NSCLC ) , its outcomes are unsatisfactory . S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. ### methods Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m ### results Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. ### conclusion This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.

https://pubmed.ncbi.nlm.nih.gov/31040252/

c560366d3211f10db393fbae2d29f7ca

Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine , it has not previously been reported for combination therapy that includes diltiazem .

Combination therapy with diltiazem and propranolol: precipitation of congestive heart failure. Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine , it has not previously been reported for combination therapy that includes diltiazem . The following case documents the occurrence of clinical congestive failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patients had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of diltiazem and propranolol resulted in the development of congestive heart failure. Thus, although generally well tolerated, given the suitable scenario of reduced left ventricular function, the combination of diltiazem and a beta blocker may adversely affect left ventricular performance.

https://pubmed.ncbi.nlm.nih.gov/4006348/

31a6bbc586c08e3c8ff0a066bf1a97f2

Relationships between heart rate , exercise tolerance and cardiac output in atrial fibrillation : the effects of treatment with digoxin , verapamil and diltiazem .

Relationships between heart rate , exercise tolerance and cardiac output in atrial fibrillation : the effects of treatment with digoxin , verapamil and diltiazem . Six patients with chronic atrial fibrillation (AF) took single doses of digoxin, verapamil and diltiazem, alone and in combination. Three hours after dosing, resting and post-exercise heart rate, exercise tolerance and resting and post-exercise cardiac output were measured. Post-exercise heart rates ranged from 167 bpm (after placebo) to 122 bpm (after digoxin plus diltiazem) (P less than 0.05). However, the lower ventricular rates seen after treatment with the calcium antagonists were not associated with improved exercise tolerance, which did not differ significantly between the various treatments. Reduction of the ventricular rate was associated with a small increase in stroke volume but the benefits of this were offset by a rate related reduction in cardiac output. Further reduction of the rapid ventricular rates seen in digitalized patients with AF does not appear to be of benefit in terms of improving either exercise tolerance or cardiac output.

https://pubmed.ncbi.nlm.nih.gov/3169046/

293b50fc8d6d4c34305176b415115cb6

Oxaliplatin , which is effective for colorectal cancer ( CRC ) in combination with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) , is widely used for metastatic CRC .

Scheduled prospective tri-weekly modified FOLFOX6 maintenance chemotherapy in the treatment of metastatic colorectal cancer. Oxaliplatin , which is effective for colorectal cancer ( CRC ) in combination with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) , is widely used for metastatic CRC . With the increasing use of oxaliplatin, however, serious adverse events have been experienced, including hematologic and neurologic toxicities. The aim of this study was to evaluate whether tri-weekly modified FOLFOX6 (mFOLFOX6) maintenance chemotherapy is associated with a low incidence of severe hematologic and neurologic toxicities in the treatment of patients with metastatic CRC. ### methodology We developed a new treatment regimen with mFOLFOX6 biweekly for 8-10 consecutive cycles (induction phase) followed by a 3-week rest period, after which treatment was resumed with cycles of tri-weekly mFOLFOX6 at standard doses (maintenance phase). Validity and complications were investigated retrospectively. ### results Twenty-nine patients were enrolled in this study. The median progression-free survival (PFS) and overall survival (OS) times were 9.4 months and 23 months, respectively. All patients had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 2 patients (6.9%). ### conclusions mFOLFOX6 maintenance chemotherapy was associated with a very low incidence of grade 3 hematologic and neurologic toxicities. The toxicities associated with PFS and OS were comparable to those reported in the treatment of patients with metastatic CRC. A tri-weekly mFOLFOX maintenance strategy of alternative treatment with a less-toxic regimen may reduce toxicity and maintain efficacy.

https://pubmed.ncbi.nlm.nih.gov/22234064/

67b30dffc6de839918db012062658e49

The cytotoxicity of sequential combinations of a taxoid [ paclitaxel ( TAX ) or docetaxel ( TXT ) ] with a vinca alkaloid [ vinorelbine ( NVB ) ] was compared in differentiated and undifferentiated HT29-D4 cells .

The effect of combining antitubulin agents on differentiated and undifferentiated human colon cancer cells. The cytotoxicity of sequential combinations of a taxoid [ paclitaxel ( TAX ) or docetaxel ( TXT ) ] with a vinca alkaloid [ vinorelbine ( NVB ) ] was compared in differentiated and undifferentiated HT29-D4 cells . Agents were titrated from low doses inducing no modification of microtubule network to high doses corresponding to the clinically relevant concentrations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtained synergism for low doses of both compounds [NVB (1-5 nM) and TAX (1-15 nM)], then additivity and finally antagonism when one of the compounds was at the concentration inducing mitotic block. The three patterns of results were also obtained with NVB/TXT combinations. For the synergistic combinations at the lowest concentrations, cytotoxicity occurred by apoptosis following mitosis. For differentiated cells, the most cytotoxic combinations were 1 microM TAX or TXT for 3 days followed by 1 microM NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 microM NVB for 3 days, the latter producing synergistic effects. Cytotoxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low sensitivity of differentiated cells to antitubulin agents and the difference in apoptotic pathways since mitosis is not involved in differentiated cells.

https://pubmed.ncbi.nlm.nih.gov/9625431/

2d82fb93fb6b942eb0e64bf06d08cece

Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures .

Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). ### aim To evaluate patient-reported outcomes (PROs) in this population. ### methods Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. ### results In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures . ### conclusion First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. ### Clinical Trial Registration NCT02477826.

https://pubmed.ncbi.nlm.nih.gov/31195357/

f59f33fd8ec9cbe50b31da1f0cf1ae9b

In the present study , we investigated the effect atorvastatin , celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells .

Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere-forming cells. Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study , we investigated the effect atorvastatin , celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells . The sphere-forming cells were isolated from Panc-1 cells by sphere-forming method. These sphere-forming cells showed CSC properties. The levels of CD44, CD133 and ALDH1A1 in the sphere-forming cells were increased. Moreover, Panc-1 sphere-forming cells were resistant to chemotherapeutic drug gemcitabine. Combined atorvastatin with celecoxib and tipifarnib synergistically decreased the sphere forming ability of Panc-1 cells and the drug combination also strongly inhibited cell proliferation and promoted apoptosis in the sphere-forming cells. The effects of the drug combination on the Panc-1 sphere-forming cells were associated with decreases in the levels of CD44, CD133 and ALDH1A1, and suppression of Akt and NF-κB activation. Results of the present study indicate that the combination of atorvastatin, celecoxib and tipifarnib may represent an effective approach for inhibiting pancreatic CSCs.

https://pubmed.ncbi.nlm.nih.gov/33359649/

7c401c1d411b0113dc808c946ee82227

As SD , donepezil , galantamine , rivastigmine , and memantine are now usable .

[The Use of Symptomatic Drugs for Dementia]. The treatment of Alzheimer's disease (AD) can be roughly divided into Disease-modifying Drugs (DMD) and Symptomatic Drugs (SD). Major strategies of DMD are the amyloid vaccine therapy and β/γ-secretase inhibitors, which have been developed with high expectations as fundamental treatments for AD. As SD , donepezil , galantamine , rivastigmine , and memantine are now usable . While memantine is an NMDA receptor inhibitor, the remaining three agents are cholinesterase inhibitors. The inhibitory mechanisms of the four agents exhibit some differ- ences. Although they may offer tips for proper use, the SD guidelines have so far stated that there are no significant differences among SD. The guidelines also state that no SD can stop the progression of AD and that their use for MCI should not be encouraged. There are some criticisms about the use of SD because they are not root treatments. In contrast, there are some reports that SD delay AD progression, preserve ADL, reduce the care burden and have an effect on BPSD. Therefore, in proper combination with non-drug treat- ments, the use of SD is considered to be valuable.

https://pubmed.ncbi.nlm.nih.gov/30620505/

f48415452d7b0e6ce4967eaeb91f01cf

Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen .

The pharmacokinetics of raloxifene and its interaction with apigenin in rat. Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen . As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. ### methods The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared. ### results Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the C(max) and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the C(max) and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and C(max) of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug. ### conclusions The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.

https://pubmed.ncbi.nlm.nih.gov/21088662/

6da26e74359677fd1d5ba9e66a1a400d

Recipients received the dual endothelin-1 ( ET-1 ) receptor blocker , bosentan ( 100 mg/kg ) , the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril ( 5 mg/kg ) , bosentan plus ramipril ( doses as just noted ) or vehicle .

Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. Blockade of the renin-angiotensin and the endothelin (ET) systems ameliorates fibrous airway obliteration in rat tracheal allografts. The aim of this study was to test which of these pharmacologic interventions attenuates the process more effectively, and whether combination therapy confers additional benefit. ### methods Rat tracheas were heterotopically transplanted from Brown-Norway donors into Lewis recipients. Recipients received the dual endothelin-1 ( ET-1 ) receptor blocker , bosentan ( 100 mg/kg ) , the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril ( 5 mg/kg ) , bosentan plus ramipril ( doses as just noted ) or vehicle . Grafts were harvested at Days 7 and 21 for morphometric studies and molecular analysis by real-time polymerase chain reaction (PCR). ### results At Day 21, bosentan and ramipril treatment reduced the percentage of luminal occlusion compared with vehicle to a similar extent. In animals that received the combined treatment, luminal obliteration was further reduced compared with the respective monotherapies. Furthermore, rats treated with bosentan plus ramipril showed a lower percent of epithelial necrosis. The beneficial effects of bosentan and ramipril, alone or in combination, were associated with reduced mRNA levels of transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-A in the tracheal allografts. ### conclusions Our data suggest that ET receptor blockade prevents fibrous airway obliteration to a similar extent as ACE inhibition in this model. Interruption of both pathways provides superior graft protection as compared with single-system blockade.

https://pubmed.ncbi.nlm.nih.gov/17097496/

735602428e2782a5443ff74b8692b68a

After surgery , she received a sequential chemotherapy , ie , intraabdominal injection of carboplatin ( CBDCA 300 mg/m2 ) and div administration of paclitaxel ( PTX 180 mg/m2 ) as a standard regimen for advanced ovarian cancer .

[Weekly paclitaxel administration and intraabdominal CBDCA injection possibly beneficial treatment for recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation--a case report]. A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery , she received a sequential chemotherapy , ie , intraabdominal injection of carboplatin ( CBDCA 300 mg/m2 ) and div administration of paclitaxel ( PTX 180 mg/m2 ) as a standard regimen for advanced ovarian cancer . However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.

https://pubmed.ncbi.nlm.nih.gov/15791819/

124c8b6c6bf2b30f2f78adefcf61a980

They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine .

Pharmacodynamic effects in the cardiovascular system: the modeller's view. Cardiovascular disease, and the cardiovascular side effects of drugs, are essentially multifactorial problems involving interactions between many proteins, dependent on highly organized cell, tissue and organ structures. This is one reason why the side effects of drugs are often unanticipated. It is impossible to unravel such problems without using a systems approach, i.e. focussing on processes, not just molecular components. This inevitably involves modelling as the interactions require quantitative analysis. Modelling is a tool of analysis aimed at understanding, first, and predicting, eventually. We illustrate these principles using modelling of the heart. Models of the cardiac myocyte have benefited from several decades of interaction between experimentation and simulation. They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine . With the help of cardiac modelling, we have also been able to unravel the mechanisms underlying the beneficial effect of sodium calcium exchange block for long QT syndrome (LQTS) 2 and LQTS3 patients. Detailed models of the interaction between ion channels and blocking agents provide the basis for modelling drug action from basic principles and predict changes in the inhomogeneous tissue of the heart. We demonstrate that mathematical models are beneficial for unravelling the complex interactions of pharmacodynamics in the heart. Embedding these detailed biophysical cellular scale models into anatomically correct models of the ventricle geometry will enable reconstructions of Torsades de Pointes arrhythmias and of fibrillation, providing a mechanism for linking detailed cellular scale experimental data to clinical applications.

https://pubmed.ncbi.nlm.nih.gov/20470255/

575a700b1cd7fe934b3fc3817ad38ce4

Based on clinical knowledge , we re-prioritized 30 potentially repurposable drugs against COVID-19 ( including pseudoephedrine , andrographolide , chloroquine , abacavir , and thalidomide ) .

Network bioinformatics analysis provides insight into drug repurposing for COVID-19. The COVID-19 disease caused by the SARS-CoV-2 virus is a health crisis worldwide. While developing novel drugs and vaccines is long, repurposing existing drugs against COVID-19 can yield treatments with known preclinical, pharmacokinetic, pharmacodynamic, and toxicity profiles, which can rapidly enter clinical trials. In this study, we present a novel network-based drug repurposing platform to identify candidates for the treatment of COVID-19. At the time of the initial outbreak, knowledge about SARS-CoV-2 was lacking, but based on its similarity with other viruses, we sought to identify repurposing candidates to be tested rapidly at the clinical or preclinical levels. We first analyzed the genome sequence of SARS-CoV-2 and confirmed SARS as the closest virus by genome similarity, followed by MERS and other human coronaviruses. Using text mining and database searches, we obtained 34 COVID-19-related genes to seed the construction of a molecular network where our module detection and drug prioritization algorithms identified 24 disease-related human pathways, five modules, and 78 drugs to repurpose. Based on clinical knowledge , we re-prioritized 30 potentially repurposable drugs against COVID-19 ( including pseudoephedrine , andrographolide , chloroquine , abacavir , and thalidomide ) . Our work shows how in silico repurposing analyses can yield testable candidates to accelerate the response to novel disease outbreaks.

https://pubmed.ncbi.nlm.nih.gov/33817623/

93a123749afedefac98a5460298616f9

To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein ( PBP ) 3-specific beta-lactam antibiotic cefuroxime , the aminoglycoside tobramycin , and a combination of the two , and to test the relationship between bacterial killing rate and endotoxin release .

Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release. To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein ( PBP ) 3-specific beta-lactam antibiotic cefuroxime , the aminoglycoside tobramycin , and a combination of the two , and to test the relationship between bacterial killing rate and endotoxin release . ### methods A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two. Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h. All experiments were performed in triplicate. For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used. ### results Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size. At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001). With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin. When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01). This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin. ### conclusions Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate. Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.

https://pubmed.ncbi.nlm.nih.gov/11168076/

2a359cf25849d20eccded92308b894fd

As CDK7 inhibitors are currently under clinical evaluation in patients , our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients .

Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN-amplified neuroblastoma. Patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression have very poor prognosis. The cyclin-dependent kinase 7 (CDK7)/super-enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c-Myc protein and suppresses c-Myc protein degradation. Here we screened the U.S. Food and Drug Administration-Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN-amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N-Myc protein but not N-Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N-Myc protein but not mRNA expression and decreased MYCN-amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients , our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients .

https://pubmed.ncbi.nlm.nih.gov/32086952/

964062c679d44f0b3a91577d0b30722d

An effective treatment for operable breast cancer , NCT with epirubicin plus paclitaxel results in significant downstaging or eliminating of primary tumors in breast cancer , thus expanding the indication of breast conservation therapy .

[Feasibility of breast conservation surgery after neoadjuvant chemotherapy for breast cancer]. To investigate the efficacy of neoadjuvant chemotherapy (NCT) and the feasibility of conservative breast surgery after reducing the size of a primary tumor by NCT in patients with operable breast cancer. ### methods Thirty patients with stage IIB and IIIA breast cancer underwent NCT including epirubicin 60 mg/m(2) by intravenous injection on day 1 and paclitaxel 150 mg/m(2) by 3-hour continuous infusion on day 2 with 21 days as a cycle from July 2001 to April 2003. All patients received 3 - 4 cycles of NCT. Breast conservation treatment or modified mastectomy was performed after the tumor was reduced to less than 3 cm in diameter. The nonresponders received modified mastectomy. ### results The overall response rate (ORR) was 93% (28/30) for the primary tumors of breast, Fifteen patients (50%) obtained clinical complete response (cCR), including 7 cases (23%) with pathologic complete response (pCR). Thirteen cases (43%) achieved clinical partial response (cPR), and 2 (7%) no change (NC). No case showed progression of disease. Twenty-six (87%) cases were downstaged according to the TNM system classification. The median initial tumor size was 4 cm (3 - 10 cm) before NCT and was reduced to 0.8 cm (0 - 6 cm) after NCT. All 30 patients received operation. Eighteen (60%) of them were candidates for breast conserving therapy, and actually only 11 (37%) selected such surgery. ### conclusion An effective treatment for operable breast cancer , NCT with epirubicin plus paclitaxel results in significant downstaging or eliminating of primary tumors in breast cancer , thus expanding the indication of breast conservation therapy .

https://pubmed.ncbi.nlm.nih.gov/15949385/

8df184ac811fb4494fa807e24e4a4add

Carboplatin and etoposide for recurrent malignant glioma following surgical and radiotherapy failure : A clinical study conducted at the Northern Israel Oncology Center .

Carboplatin and etoposide for recurrent malignant glioma following surgical and radiotherapy failure : A clinical study conducted at the Northern Israel Oncology Center . We conducted a phase II study using carboplatin and etoposide on patients with recurrent malignant glioma to investigate tumor response. ### methods From January 1995 to March 1997, 21 patients with recurrent malignant glioma were treated with a carboplatin (300 mg/m(2), day 1)/etoposide (100 mg/m(2), days 1-3) regimen every 3-4 weeks. The following radiologic parameters were evaluated: tumor size, central lucency, degree of contrast enhancement, and mass effect. No patient had received chemotherapy previously. Dose escalation corresponded to hematologic tolerance and to general and neurologic performance status. Most patients were treated postoperatively with involved field radiotherapy followed by a boost to the tumor area, as defined on the presurgery computed tomography scan or on magnetic resonance imaging. Mean interval to introduction of chemotherapy was 8.8 months (range, 7-36 months). Patients received a mean of four cycles [range, 2-8 cycles]. ### results Only 2 patients showed moderate radiological response, while 12 patients died of progressive disease. Mean time to progression following discontinuation of chemotherapy was 5.8 months (range, 1-11 months). The other patients survived with persistent disease and are being treated palliatively. Toxicity was manageable (1, neutropenic sepsis; 1, thrombocytopenia (45,000/mm(3)); 2, temporarily elevated transaminase level; 2, steroid-induced erosive gastritis). ### conclusions This phase II regimen proved to be ineffective in recurrent malignant glioma. Further studies incorporating innovative drug regimens and schedules are warranted. J. Surg. Oncol., 1999;71:167-170.

https://pubmed.ncbi.nlm.nih.gov/10404133/

fe6d0e16126ed7cba1f7493904ed6f98

ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib , resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27 M mutant DIPG .

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma. An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). ### objective To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. ### methods The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. ### results Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). ### conclusion ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib , resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27 M mutant DIPG .

https://pubmed.ncbi.nlm.nih.gov/31225627/

0988f1d7dca388570b1b818609c4a80e

Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain .

Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). ### Patients And Methods Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain . HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module-Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients. ### results At 6 weeks, both groups showed improvement in several HQL domains, and only physical functioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P =.009), four functioning domains, and nine symptoms (.001 < P <. 01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P <.05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P <.003). ### conclusion Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.

https://pubmed.ncbi.nlm.nih.gov/10561201/

bb5a3874cf046983e6858e0f91d42add

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase .

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase . In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.

https://pubmed.ncbi.nlm.nih.gov/12933584/

71d32890c951bfd74b4107d9656c7f86

Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine : a multicenter , phase II trial of the Swiss Group for Clinical Cancer Research .

Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine : a multicenter , phase II trial of the Swiss Group for Clinical Cancer Research . To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. ### Patients And Methods Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. ### results Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. ### conclusion Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.

https://pubmed.ncbi.nlm.nih.gov/18669455/

cbf4da62141a838ba38d27cc916b1711

as neoadjuvant chemotherapy , and two cycles of doxorubicin/cisplatin and ifosfamide , and two cycles of high-dose methotrexate ( 10 - 12 g/m(2 ) ) were given post-operatively .

Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan. From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m(2) plus cisplatin 120 mg/m(2) and ifosfamide 15 g/m(2) were given as neoadjuvant chemotherapy , and two cycles of doxorubicin/cisplatin and ifosfamide , and two cycles of high-dose methotrexate ( 10 - 12 g/m(2 ) ) were given post-operatively . All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy. With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively. The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one.

https://pubmed.ncbi.nlm.nih.gov/23433444/

0ab60b7bf70ff6b6e80353dbdd5002f9

Reported is a case of a 58-year-old female treated in the past with cytostatics and rituximab for follicular lymphoma , in whom HBV infection was detected during a follow-up of the contacts of her partner diagnosed with acute viral hepatitis B. At the beginning , the patient had a very high serum level of HBV DNA ( 4.3 × 108 IU/mL ) and therefore she was treated with combined antiviral therapy ( lamivudine and tenofovir ) .

[Viral hepatitis B in a patient with follicular lymphoma treated with biological therapy]. Reactivation, recurrence or acute infection with hepatitis B virus (HBV) represent severe complications of biological therapy. Reported is a case of a 58-year-old female treated in the past with cytostatics and rituximab for follicular lymphoma , in whom HBV infection was detected during a follow-up of the contacts of her partner diagnosed with acute viral hepatitis B. At the beginning , the patient had a very high serum level of HBV DNA ( 4.3 × 108 IU/mL ) and therefore she was treated with combined antiviral therapy ( lamivudine and tenofovir ) . After 10 months, the serum level of HBV DNA decreased significantly (3,100 IU/mL) and the combined antiviral therapy was switched to monotherapy with tenofovir. Another 5 months later, the serum level of HBV DNA was only 950 IU/mL. This case demonstrates important clinical problems connected with HBV infection in immunocompromised persons.

https://pubmed.ncbi.nlm.nih.gov/21452121/

ff12dfaf336d750698f604fab7741017

Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil- , oxaliplatin- and irinotecan-based chemotherapies were randomised ( 1:1 ) to either panitumumab plus irinotecan ( panitumumab arm ) or cetuximab plus irinotecan ( cetuximab arm ) .

Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G). cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. ### Patients And Methods Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil- , oxaliplatin- and irinotecan-based chemotherapies were randomised ( 1:1 ) to either panitumumab plus irinotecan ( panitumumab arm ) or cetuximab plus irinotecan ( cetuximab arm ) . The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. ### results From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). ### conclusion panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.

https://pubmed.ncbi.nlm.nih.gov/32526634/

bab3251cbe1fd79f43555c7668ec347a

Epirubicin , oxaliplatin , and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer ( REAL3 ):

Epirubicin , oxaliplatin , and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer ( REAL3 ): EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. ### methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. ### findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). ### interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. ### funding Amgen, UK National Institute for Health Research Biomedical Research Centre.

https://pubmed.ncbi.nlm.nih.gov/23594787/

72830b924efe02f8d02dbfad93ee887d

In 2005 , after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen , a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone ; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting ( IPCW ) are used to account for selective crossover to letrozole of patients ( n=619 ) in the tamoxifen arm .

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. ### methods BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005 , after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen , a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone ; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting ( IPCW ) are used to account for selective crossover to letrozole of patients ( n=619 ) in the tamoxifen arm . Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. ### findings 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. ### interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. ### funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

https://pubmed.ncbi.nlm.nih.gov/22018631/

01b9ba979fcff6b6cdf24f4999f38ca1

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) .

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) . To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. ### Patients And Methods CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. ### results Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. ### conclusion In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. ### Clinical Trials Number NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.

https://pubmed.ncbi.nlm.nih.gov/27234640/

5c84675aee263d1138ecdc8f62224159

The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries .

Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). ### methods The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries . Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. ### findings 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. ### interpretation Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. ### funding Pfizer.

https://pubmed.ncbi.nlm.nih.gov/21247627/

b3f4393572a850ae5b107fac5a2985ad

Patients used 2.16 ( range 0.0 - 6.3 ) formoterol and 2.34 ( range 0.1 - 7.5 ) terbutaline relief inhalations x day(-1 ) .

Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma. The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 ( range 0.0 - 6.3 ) formoterol and 2.34 ( range 0.1 - 7.5 ) terbutaline relief inhalations x day(-1 ) . No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.

https://pubmed.ncbi.nlm.nih.gov/12412676/

1495e39f848fa37e5076bf8266d3afb4

Preoperative chemotherapy with FLOT ( 5-FU , leucovorin , oxaliplatin and docetaxel ) without radiation therapy is the standard treatment in the West .

Advances in the treatment of gastric cancer: 2019. The aim of this study was to review studies published within the past year regarding management of gastric cancer. ### Recent Findings Laparoscopic gastrectomy achieves equivalent survival compared with open gastrectomy in early stage and locally advanced gastric cancer. Adjuvant chemotherapy with 6 months of S-1 and oxaliplatin was superior to 12 months of S-1, and the addition of postoperative radiation therapy did not improve survival. The FLOT regimen is the new standard for preoperative chemotherapy. In metastatic gastric cancer, the addition of docetaxel to S-1 and cisplatin failed to improve overall survival over two-drug chemotherapy. The addition of the immune checkpoint inhibitor pembrolizumab to chemotherapy failed to improve overall survival compared with chemotherapy alone. ### summary Laparoscopic gastrectomy is acceptable in early and locally advanced gastric cancer. Combination adjuvant chemotherapy is superior to S-1 monotherapy. Adjuvant radiation therapy after D2 gastrectomy for node-positive gastric cancer does not improve survival. Preoperative chemotherapy with FLOT ( 5-FU , leucovorin , oxaliplatin and docetaxel ) without radiation therapy is the standard treatment in the West . Two-drug chemotherapy is the optimal initial treatment in metastatic disease. Adding pembrolizumab to front-line chemotherapy did not improve survival, with use of immune checkpoint inhibitors reserved to treat chemotherapy refractory metastatic disease.

https://pubmed.ncbi.nlm.nih.gov/31436556/

75d2cb0cce16c32ec61e9f1bbffe1781

The third-generation aromatase inhibitors ( AIs ) , including anastrozole , exemestane and letrozole , have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer .

Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer. The third-generation aromatase inhibitors ( AIs ) , including anastrozole , exemestane and letrozole , have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer . AIs can be used in several adjuvant endocrine settings: as upfront therapy, switch to an AI after 2-3years of tamoxifen or extended therapy following 5years of tamoxifen. In the switch setting, two different types of study designs have been utilized. One is a late randomization design which randomizes patients who are disease-free after 2-3years of tamoxifen to receive an AI versus continuation of tamoxifen. In contrast, an early randomization design randomizes all patients immediately after primary treatment and prior to starting tamoxifen. Efficacy benefits with AIs have been shown in several trials evaluating the late randomization strategy, including the Intergroup exemestane Study, the Italian tamoxifen anastrozole trial and the anastrozole-Nolvadex 95 trial. Similarly, early randomization studies, including the Austrian Breast and Colorectal Cancer Study Group-8 and the Breast International Group (BIG) 1-98 trial, have demonstrated the effectiveness of receiving an AI after tamoxifen. Two trials are assessing an early switch strategy versus upfront AI therapy: the BIG 1-98 trial and the ongoing tamoxifen exemestane Adjuvant Multicentre trial are assessing switching from tamoxifen to an AI after 2-3years versus upfront AI therapy. This paper reviews studies that have investigated a switch strategy with AIs and considers the implications of these data on treatment choice for postmenopausal patients with hormone receptor-positive breast cancer.

https://pubmed.ncbi.nlm.nih.gov/19944537/

07c1063282576d4753c0c0db96239065

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway .

Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway . Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.

https://pubmed.ncbi.nlm.nih.gov/30735911/

049218fea98c023864d6458df5d2c72d

Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin .

Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1. The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis. ### methods We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay. ### results rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin . The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment. ### conclusions rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.

https://pubmed.ncbi.nlm.nih.gov/19565301/

4b95bba024fb2e67f272f90f02ed77c0

These structural motifs represent typical azoles , such as econazole , fluconazole , and metyrapone .

How do azoles inhibit cytochrome P450 enzymes? A density functional study. To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles , such as econazole , fluconazole , and metyrapone . The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH(2) distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.

https://pubmed.ncbi.nlm.nih.gov/18563875/

69b943fb5c20147ee6ba43647c87c513

The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs , including atezolizumab , durvalumab , pembrolizumab , and nivolumab as first-line treatment in patients with ES-SCLC .

Comparison of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis. In recent years, immune checkpoint inhibitors (ICIs) including atezolizumab, durvalumab, pembrolizumab, and nivolumab have reported their efficacy and safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). However, given the diverse efficacy and inconsistent safety among the ICIs, with the absence of head-to-head researches designed to evaluate the efficacy among them, it might bring with confusion on selection in clinical practice. ### objectives The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs , including atezolizumab , durvalumab , pembrolizumab , and nivolumab as first-line treatment in patients with ES-SCLC . ### design Several databases were retrieved with established criteria until June 20, 2020, with the main MeSH Terms and their similarities. Hazard ratios of overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) of disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were compared indirectly with network meta-analysis. ### Data Sources Medline, Cochrane library, and Embase. ### Eligibility Criteria Prospective, randomized, controlled clinical studies, which reported PFS, OS, and AEs. ### Data Extraction And Synthesis Clinical characteristics were extracted by the 2 authors independently. Comparisons of HRs were calculated for PFS and OS by random effect model. ORR, DCR, and AEs were presented with ORs. Based on surface under the cumulative ranking curve, and forest plots, efficacy and safety of the treatments were ranked, with predicted histogram described. ### results In total, there were 4 studies including 1547 patients who met the eligibility criteria and enrolled. For indirect comparisons, no significant difference on PFS was observed between atezolizumab and durvalumab (HR 0.96, 95% CI, 0.72-1.29), or between atezolizumab and pembrolizumab (HR 1.05, 95% CI, 0.78-1.43), or between atezolizumab and nivolumab (HR 1.18, 95% CI, 0.79-1.79), or between durvalumab and pembrolizumab (HR 1.10, 95% CI, 0.84-1.43). or between durvalumab and nivolumab (HR 1.23, 95% CI, 0.83-1.82), or between pembrolizumab and nivolumab (HR 1.12, 95% CI, 0.76-1.66), nor significant difference on OS observed between atezolizumab and durvalumab (HR 0.93, 95% CI, 0.67-1.30), or between atezolizumab and pembrolizumab (HR 0.88, 95% CI, 0.62-1.24), or between atezolizumab and nivolumab (HR 1.04, 95% CI, 0.66-1.66), or between durvalumab and pembrolizumab (HR 0.94, 95% CI, 0.70-1.25), or between durvalumab and nivolumab (HR 1.12, 95% CI, 0.73-1.71), or between pembrolizumab and nivolumab (HR 1.19, 95% CI, 0.77-1.84). However, durvalumab was shown statistical superiority on ORR when compared with atezolizumab (HR 0.79, 95% CI, 0.64-0.98), also with significantly higher risk on immune-related AEs when compared with atezolizumab (OR 0.22, 95% CI, 0.10-0.50), and pembrolizumab (OR 3.12, 95% CI, 1.27-7.64). ### conclusions Results of the study revealed that there was no statistical difference on PFS or OS among agents of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. However, durvalumab was shown superiority on ORR when compared with atezolizumab, also with significantly higher risk on immune-related AEs.

https://pubmed.ncbi.nlm.nih.gov/33847617/

2ca7b36a7e1a152d5919cdef8a7ccb46

Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone .

Effects of metformin on rosiglitazone-induced cardiac hypertrophy in mice. Thiazolidinediones (TZD) can cause adipose tissue accumulation and myocardial hypertrophy. This study aimed to determine if combined metformin (Glucophage) and rosiglitazone (Avandia) could reduce the risk of heart failure caused by rosiglitazone in BALB/c mice. BALB/c mice were treated with oral rosiglitazone/metformin twice daily for four weeks. metformin or rosiglitazone alone and non-treated mice acted as double control. Myocardial hypertrophy and associated side effects of the combined therapy were determined through isolated heart and body weights. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were applied to evaluate expression of sulfonylurea receptor 2A (SUR2A) and Kir 6.2. The activities of peroxisome proliferator activated receptor alpha (PPARalpha) in the myocardium were also observed. rosiglitazone/metformin decreased body weight gain and food intake, and inhibited an increasing adipose ratio but did not reduce myocardial hypertrophy. rosiglitazone increased Kir6.2/SUR2A, Kir6.2/SUR2B, and PPARalpha gene expression. The rosiglitazone/metformin combination further increased these gene expressions, especially PPARalpha. Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone . Whether metformin can reduce side effects of TZDs in humans warrants further study.

https://pubmed.ncbi.nlm.nih.gov/20823565/

a80ae76dc1ab83090b8ebbd9238273d1

The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients .

Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root. ### results Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, three dose-limiting toxicities were observed and two out of three patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with five PR and three SD. Some improvements as biological and clinical responses were observed in most patients. ### Patients And Methods Patients with advanced or metastatic breast cancer were eligible. docetaxel (100 mg/m(2)) was administered as a 1 h i.v. infusion every 3 w on d 1 for six cycles. curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients . Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements and assessment of objective and clinical responses to the combination therapy. ### conclusion The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 w in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

https://pubmed.ncbi.nlm.nih.gov/19901561/

5e1b7e15286c15dfdac6bb72c128fdf7

The subjects were then randomly assigned to treatment with either propranolol or metoprolol and repeated the exercise protocol after 1 week of treatment .

Dynamic exercise leads to an increase in circulating ICAM-1: further evidence for adrenergic modulation of cell adhesion. Acute mental and physical stress lead to a marked lymphocytosis, with circulating natural killer cell numbers showing the most prominent increase. Many studies have linked these acute stress effects on lymphocytes with an increase in catecholamine levels. However, the molecular mechanisms which mediate this redistribution of lymphocytes from lymphocyte reservoirs into the circulation remain unknown. We hypothesized that this form of lymphocytosis was in part due to shedding of cell adhesion molecules from the cell surface and a subsequent detachment of lymphocytes adhering to the vascular endothelium in lymphocyte reservoirs. In this study, healthy human volunteers (n = 12) were exercised on a treadmill until exhaustion. The circulating levels of the soluble cell adhesion molecules ICAM-1 and E-Selectin were determined by ELISA. The subjects were then randomly assigned to treatment with either propranolol or metoprolol and repeated the exercise protocol after 1 week of treatment . Prior to drug treatment, soluble ICAM-1 levels rose from 258 +/- 19 to 321 +/- 28 ng/ml following exercise and returned to approximate baseline levels of 263 +/- 22 ng/ml after 1 h of rest. This highly significant effect of exercise on circulating ICAM-1 levels (p < .005) was mitigated after treatment with the beta-adrenergic antagonists. Soluble E-Selectin levels were not significantly affected by exercise. These results suggest that dynamic exercise leads to shedding of the cell adhesion molecule ICAM-1 via adrenergic mechanisms. We believe that these findings will contribute to the understanding of how physical and mental stress modulate lymphocyte migration and adhesion.

https://pubmed.ncbi.nlm.nih.gov/9512820/

8a1fe940f1378e72f4fdad3f9fe48547

This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs .

Nivolumab plus regorafenib in patients with small bowel adenocarcinoma: A case report. Small bowel adenocarcinomas (SBAs) are rare cancers that have a distinct clinical characteristic and genetic profile. The only potentially curative treatment for localized SBAs is surgery, and treatment options are limited for patients in the advanced stage of disease. ### Patient Concerns A 39-year-old woman presented in October 2015 with a complaint of persistent vomiting for 8 months. ### diagnosis The patient had obstruction caused by a 3 × 2 cm mass at the ascending part of the duodenum and suspected metastasis in the right adnexal region. Postoperative pathology showed a moderately differentiated adenocarcinoma with serosal invasion. The diagnosis was stage IV duodenum adenocarcinoma with right adnexal metastasis. ### interventions After the failure of multi-line treatment with chemotherapy and targeted therapy, she was treated with the immune checkpoint inhibitor nivolumab plus regorafenib. ### outcomes Disease control lasted for 15 months with markedly improved symptoms. ### conclusion To the best of our knowledge, this is the first case of small bowel adenocarcinoma that has been treated with nivolumab combined with regorafenib. This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs .

https://pubmed.ncbi.nlm.nih.gov/33530218/

54ea32b020e5101565fb894aa10d6e16

Of the substances tested for inhibition of 11beta-HSD-I and -II , chenodeoxycholic acid was the only one that selectively inhibited 11beta-HSD-I ( IC(50 ) for reduction : 2.8x10(-6)mol/l , IC(50 ) for oxidation : 4.4x10(-6)mol/l ) , whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11beta-HSD-II .

In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Selective inhibitors of 11beta-hydroxysteroid-dehydrogenase type I may be of therapeutical interest for two reasons: i) 9alpha-Fluorinated 11-dehydrosteroids like 11-dehydro-dexamethasone (DH-D) are rapidly activated by human kidney 11beta-hydroxysteroid-dehydrogenase type II (11beta-HSD-II) to dexamethasone (D). If the same reaction by hepatic 11beta-HSD-I could be selectively inhibited, DH-D could be used for selective renal immunosuppressive therapy. ii) Reduction of cortisone to cortisol in the liver may increase insulin resistance in type 2 diabetes mellitus, and inhibition of the enzyme may lead to a decrease in gluconeogenesis. Therefore, we characterized the metabolism of DH-D by human hepatic 11beta-HSD-I and tried to find a selective inhibitor of this isoenzyme. ### methods For kinetic analysis of 11beta-HSD-I, we used microsomes prepared from unaffected parts of liver segments, resected because of hepatocarcinoma or metastatic disease. For inhibition experiments, we also tested 11beta-HSD-II activity with human kidney cortex microsomes. The inhibitory potency of several compounds was evaluated for oxidation and reduction in concentrations from 10(-9) to 10(-5)mol/l. ### results Whereas D was not oxidized by human liver microsomes at all, cortisol was oxidized to cortisone with a maximum velocity (V(max)) of 95pmol/mg per min. The reduction of DH-D to D (V(max)=742pmol/mg per min, Michaelis--Menten constant (K(m))=1.6 micromol/l) was faster than that of cortisone to cortisol (V(max)=187pmol/mg per min). All reactions tested in liver microsomes showed the characteristics of 11beta-HSD-I: K(m) values in the micromolar range, preferred cosubstrate NADP(H), no product inhibition. Of the substances tested for inhibition of 11beta-HSD-I and -II , chenodeoxycholic acid was the only one that selectively inhibited 11beta-HSD-I ( IC(50 ) for reduction : 2.8x10(-6)mol/l , IC(50 ) for oxidation : 4.4x10(-6)mol/l ) , whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11beta-HSD-II . metyrapone, which is reduced to metyrapol by hepatic 11beta-HSD-I, inhibited steroid reductase activity of 11beta-HSD-I and -II and oxidative activity of 11beta-HSD-II. These findings can be explained by substrate competition for reductase reactions and by product inhibition of the oxidation, which is a well-known characteristic of 11beta-HSD-II. ### conclusions Our in vitro results may offer a new concept for renal glucocorticoid targeting. Oral administration of small amounts of DH-D (low substrate affinity for 11beta-HSD-I) in combination with chenodeoxycholic acid (selective inhibition of 11beta-HSD-I) may prevent hepatic first pass reduction of DH-D, thus allowing selective activation of DH-D to D by the high affinity 11beta-HSD-II in the kidney. Moreover, selective inhibitors of the hepatic 11beta-HSD-I, like chenodeoxycholic acid, may become useful in the therapy of patients with hepatic insulin resistance including diabetes mellitus type II, because cortisol enhances gluconeogenesis.

https://pubmed.ncbi.nlm.nih.gov/10664531/

afd43fc146bb1d69bc9616348b7c3f1e

Anti-tumor effects of etoposide ( VP-16 ) , vincristine and mitomycin C were evaluated with four human neuroblastoma xenograft , according to Battelle Columbus Laboratories protocol .

[In vivo assessment on the therapeutic effects of etoposide, vincristine and mitomycin C against human neuroblastoma]. Anti-tumor effects of etoposide ( VP-16 ) , vincristine and mitomycin C were evaluated with four human neuroblastoma xenograft , according to Battelle Columbus Laboratories protocol . etoposide is one of the agents which has been reported to be effective against advanced neuroblastoma clinically, if combined with other agents. While vincristine was effective against 1 out 4 neuroblastoma xenografts, TS-N-2, with 58.1% maximum inhibition rate, etoposide was assessed ineffective as a single agent in all of the 3 xenografts used. Since etoposide had no effect on the weight gain in nude mice in this xenograft experiment, the dose of etoposide was increased two-fold against 2 xenografts, but found ineffective also in the increased dose. mitomycin C, which has not been used in childhood malignant tumors, was effective against 2 out of 4 xenografts, TNB-9 and SK-N-AS, with 72.0% and 78.4% maximum inhibition rates, respectively.

https://pubmed.ncbi.nlm.nih.gov/1905121/

2f516285ce6b6a692159675b6e1271f4

Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid , with the former predominating .

The effect of alfalfa-corn diets on cholesterol metabolism and gallstones in prairie dogs. Cholesterol gallstones were present in prairie dogs fed alfalfa plus corn with and without exogenous cholesterol (0.4%). The diets fed to the animals for eight weeks contained alfalfa plus corn in fixed proportions of 50:50, 85:15 and 15:85 (w/w). At sacrifice, all animals were healthy but had not gained weight; no deaths occurred during the experiment. Cholesterol gallstones were present in all groups. In the absence of exogenous cholesterol, the highest stone incidence was found in the animals which received the lowest fiber (highest corn) diets (alfalfa plus corn, 50:50, 67%; alfalfa plus corn, 15:85, 83%). Cholesterol gallstone incidence was 100% when exogenous cholesterol was added to the alfalfa plus corn diets (50:50 and 15:85). No pigment gallstones were detected in any animal. Liver and plasma cholesterol concentrations were highest in the animals receiving alfalfa plus corn (15:85) plus 0.4% cholesterol (4.29 mg/g, and 356 mg/dl, respectively). These values were lowest in animals receiving 85% alfalfa plus 15% corn without cholesterol (2.19 mg/g and 88 mg/dl, respectively). Lithogenic indices were below 1.00 in all groups. Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid , with the former predominating . Thus, gallstones can be formed in prairie dogs in the absence of exogenous cholesterol; gallstone incidence is reduced by dietary fiber.

https://pubmed.ncbi.nlm.nih.gov/2159098/

ccca9b4d3e16d02c960609c678d74fb6

Cutaneous T-cell lymphoma-like drug eruption in an HIV-positive patient taking vancomycin and rifampin .

Cutaneous T-cell lymphoma-like drug eruption in an HIV-positive patient taking vancomycin and rifampin . Cutaneous T-cell pseudolymphoma (CTPL) is a benign reactive T-cell lymphoproliferative subtype of pseudolymphoma. Some variants of CTPL can resemble the plaques of mycosis fungoides (MF). The vast majority of drug-induced cases have been associated with anticonvulsants. There is only one report in the literature documenting a case of vancomycin-induced CTPL. ### methods We report a cutaneous T-cell lymphoma-like eruption in a human immunodeficiency virus (HIV)-positive patient recently started on vancomycin and rifampin. ### results A skin biopsy showed several histologic features of MF with immunohistochemical and T-cell receptor gene rearrangement studies suggestive of CTPL. This atypical T-cell reaction mimicking MF completely resolved on cessation of rifampin followed by vancomycin. ### conclusion Considering drug-induced causes of MF-like histologic changes is crucial to prevent unnecessary treatment for MF.

https://pubmed.ncbi.nlm.nih.gov/24138984/

44b24b773d5f20565a08318a21a3249e

Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy , even in combination with tiotropium .

Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment. ### methods For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. ### findings Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753-1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740-0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group. ### interpretation Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy , even in combination with tiotropium . ### funding Takeda.

https://pubmed.ncbi.nlm.nih.gov/25684586/

02aa33a2d0f251d72f00e97592096cd3

This academic , matched-cohort study , compared 2-year outcomes of 11 consecutive IMN patients who received second-line rituximab therapy for NS persisting or relapsing after previous treatment with steroids alone or combined with alkylating agents , cyclosporine , or immunoglobulin G , with those of 11 age- ( ± 5 years ) , gender- and proteinuria- ( ± 1 g/24h ) matched reference patients given first-line rituximab therapy .

Efficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study. First-line immunosuppression with the B-cell depleting antibody rituximab reduced proteinuria and induced remission of the disease in patients with nephrotic syndrome (NS) secondary to idiopathic membranous nephropathy (IMN). Here we evaluated whether rituximab is equally effective in patients who failed to respond to previous immunosuppressive treatment. ### methods This academic , matched-cohort study , compared 2-year outcomes of 11 consecutive IMN patients who received second-line rituximab therapy for NS persisting or relapsing after previous treatment with steroids alone or combined with alkylating agents , cyclosporine , or immunoglobulin G , with those of 11 age- ( ± 5 years ) , gender- and proteinuria- ( ± 1 g/24h ) matched reference patients given first-line rituximab therapy . ### results Patients' and reference patients' baseline characteristics were similar. Compared to baseline, 24-hour proteinuria similarly declined at 1 and 2 years post-rituximab (by 50.5 ± 25.1% and 60.9 ± 17.4% in patients and by 52.7 ± 31.5% and 69.4 ± 40.4% in reference patients, respectively; p < 0.01 for all comparisons vs. baseline). 8 patients and 7 reference patients achieved full (3 vs. 2) or partial (5 per cohort) proteinuria remission. Hypoalbuminemia and hyperlipidemia normalized in both groups. Self-limited infusion-related reactions occurred in 1 subject per cohort. ### conclusion rituximab reduced proteinuria in IMN patients with no or only transient response to unselective immunosuppression as effectively and safely as in patients without previous immunosuppression.

https://pubmed.ncbi.nlm.nih.gov/21508634/

df4bd424152b18eedfbc2d6ed15dbd0b

Induction chemotherapy with cisplatin , doxorubicin , and cyclophosphamide ( CAP ) in a combined modality approach for locally advanced and inflammatory breast cancer .

Induction chemotherapy with cisplatin , doxorubicin , and cyclophosphamide ( CAP ) in a combined modality approach for locally advanced and inflammatory breast cancer . Thirty-one patients with locally advanced and inflammatory breast carcinoma (stage IIIA and IIIB) were treated with a combined modality approach between 1985 and 1989. All patients received as induction chemotherapy a combination of cisplatin, doxorubicin, and cyclophosphamide (CAP). Responsive patients and patients with operable stable disease underwent modified radical mastectomy followed by concurrent radiotherapy and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) adjuvant chemotherapy. Thirty patients were evaluable for response to CAP. The rate of objective response to induction chemotherapy was 76.7% with 2 patients (6.7%) obtaining a complete response and 21 patients (70%) a partial response. Twenty-five patients were rendered disease-free after induction chemotherapy and surgery. Only 2 of these had pathological complete response (8%). The median overall survival was 48.7 months, the median time to progression was 22.4 months and the median disease-free survival was 29.1 months. The patients with noninflammatory breast tumor had a significantly better overall survival, disease-free survival, and time to progression. The overall survival and the time to progression were statistically superior in patients with primary tumor size < or = 8 cm. At a median follow-up of 6 years, 29% (95% CI, 13.05 to 45.01) of patients were alive and 28% (95% CI, 10.4 to 45.6) were disease-free. This combined modality treatment seems feasible with quite acceptable toxicity; the CAP combination is an effective alternative to the other standard chemotherapeutic regimens. Our results, although encouraging, are still poor, and new drugs and strategies are required to improve the long-term outcome.

https://pubmed.ncbi.nlm.nih.gov/8554028/

be42ba6d693a48f4e534e93d9d0226b7

Methotrexate was efficient in one patient , hydroxychloroquine showed benefit in only 1 out of 3 patients .

Oral involvement in sarcoidosis: report of 12 cases. To assess the clinical features, treatment and outcome of oral sarcoidosis and to determine whether oral involvement is associated with a particular clinical phenotype of sarcoidosis. ### design Multicentric retrospective study. ### methods Retrospective chart review. Each patient was matched with four controls. ### results Twelve patients (9 women, 3 men) were identified. Their median age at sarcoidosis diagnosis was 38 years. Oral involvement was the first clinical evidence of sarcoidosis in seven cases and was a relapse symptom in five cases. Clinical presentations were nodules (n = 7) or ulcers (n = 5) and were mostly solitary. The tongue was the commonest site affected (n = 4), followed by lips (n = 3), oral mucosa (n = 2), palate (n = 2) and gingiva (n = 1). Patients with oral sarcoidosis were significantly younger and had more frequent lacrimal or salivary glands and upper airway tract clinical involvement than the controls; increased angiotensin-converting enzyme was less frequent in oral sarcoidosis. Multiple treatments of oral sarcoidosis were used: no treatment (n = 3), surgery (n = 2), corticosteroids (n = 7), hydroxychloroquine (n = 3), methotrexate (n = 2), doxycycline (n = 1). Methotrexate was efficient in one patient , hydroxychloroquine showed benefit in only 1 out of 3 patients . Three patients presented oral relapses. After a mean follow-up of 6 years, 10 patients experienced a complete (n = 7) or partial (n = 3) remission of oral sarcoidosis; stability was observed in the remaining two cases. ### conclusion Although oral manifestations of sarcoidosis are unusual, physicians should be aware that this specific localization is frequently the first manifestation of the disease. Treatment modalities range from observation in asymptomatic patients to immunosuppressants for severe involvement.

https://pubmed.ncbi.nlm.nih.gov/22422021/

33f8e5c6071fe4aee2ffdb4316c19bad

Our results show high rates of DR-TB in Nigerian HIV-infected individuals ( 7.0 % for rifampin [ RIF ] and 9.3 % for RIF or isoniazid [ INH ] ) .

Genetic determinants of drug-resistant tuberculosis among HIV-infected patients in Nigeria. Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients and the emergence of drug-resistant tuberculosis (DR-TB) is a growing problem in resource-limited settings. Adequate infrastructure for testing drug sensitivity and sufficient evidence of first-line resistance are currently unavailable in Nigeria. We collected sputum samples from HIV-infected patients enrolled in the Harvard PEPFAR/APIN Plus program over 12 months at two PEPFAR antiretroviral therapy (ART) clinics in the southwest and north central regions in Nigeria. Smear-positive sputum samples were submitted for GenoType MTBDRplus testing (n = 415); mutations were confirmed through sequencing. Our results show high rates of DR-TB in Nigerian HIV-infected individuals ( 7.0 % for rifampin [ RIF ] and 9.3 % for RIF or isoniazid [ INH ] ) . Total RIF resistance indicative of MDR-TB in treatment-naive patients was 5.52%, far exceeding the World Health Organization predictions (0 to 4.3%). RIF resistance was found in 6/213 (2.8%) cases, INH resistance was found in 3/215 (1.4%) cases, and MDR-TB was found in 8/223 (3.6%) cases. We found significantly different amounts of DR-TB by location (18.18% in the south of the country versus 3.91% in the north central region [P < 0.01]). Furthermore, RIF resistance was genetically distinct, suggesting possible location-specific strains are responsible for the transmission of drug resistance (P < 0.04). Finally, GenoType MTBDRplus correctly identified the drug-resistant samples compared to sequencing in 96.8% of cases. We found that total DR-TB in HIV-infection is high and that transmission of drug-resistant TB in HIV-infected patients in Nigeria is higher than predicted.

https://pubmed.ncbi.nlm.nih.gov/22740709/

bc93f89378df2b51229fcc631b7c9712

Sorafenib is an orally active multikinase inhibitor , and bortezomib is a proteasome inhibitor that affects multiple signaling pathways .

Phase II study of sorafenib and bortezomib for first-line treatment of metastatic or unresectable renal cell carcinoma. Sorafenib is an orally active multikinase inhibitor , and bortezomib is a proteasome inhibitor that affects multiple signaling pathways . sorafenib has clinical activity in renal cell carcinoma (RCC), whereas bortezomib has demonstrated activity against RCC cell lines in vitro, with in vitro studies showing synergism between the two agents in the induction of apoptosis in neoplastic cell lines. In this phase II study, we explored the efficacy and toxicity of this regimen. ### methods Adult patients with cytologically confirmed clear cell RCC with no prior chemotherapy, Zubrod performance status of 0-1, serum creatinine <1.5 mg/dL, and normal liver function tests were treated with sorafenib 200 mg orally b.i.d. with bortezomib 1 mg/m(2) intravenously on days 1, 4, 8, and 11 every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was median progression-free survival (PFS) of at least 70 weeks. ### results Seventeen patients were enrolled between April 2011 and January 2013. Median age was 62 years (range: 44-75 years). Four of 17 patients had known brain metastasis on enrollment. Median number of cycles was 4 (range: 1 to ≥45). No patient had complete response, 1 had partial response, 12 had stable disease, and 4 had progressive disease (response rate of 6%; 95% confidence interval: 0%-29%) with treatment. Median PFS was 13.7 weeks, and median overall survival was 110 weeks. The study was halted for futility. ### conclusion The combination of sorafenib and bortezomib was well tolerated; however, response rate and PFS were comparable to sorafenib monotherapy. This regimen is not recommended for further development.

https://pubmed.ncbi.nlm.nih.gov/25777345/

292d2c6c3937d1ce8478261c453a595e

Hypertensive rats in separate groups were treated with either candesartan ( 1 mg/kg body weight ) alone or a combination of candesartan ( 1 mg/kg body weight ) and rofecoxib ( 10 mg/kg body weight ) orally and daily for 6 weeks .

Effect of rofecoxib on antihypertensive effects of candesartan in experimental models of hypertension. Given the high prevalence of hypertension, concomitant use of nonsteroidal anti-inflammatory drugs and antihypertensive medications is commonly encountered in clinical practice. The present study was designed to study the effect of indomethacin, nimesulide, and rofecoxib on blood pressure (BP) in normotensive and hypertensive rats and also to investigate the effect of rofecoxib on BP control in candesartan-treated hypertensive rats. Male Wistar rats weighing 150-200 g were divided into three groups: control, DOCA-hypertensive, and L-NAME-hypertensive rats. All the rats were given indomethacin (15 mg/kg body weight), nimesulide (20 mg/kg body weight), rofecoxib (10 mg/kg body weight), or vehicle orally and daily for 6 weeks. Hypertensive rats in separate groups were treated with either candesartan ( 1 mg/kg body weight ) alone or a combination of candesartan ( 1 mg/kg body weight ) and rofecoxib ( 10 mg/kg body weight ) orally and daily for 6 weeks . BP measurements were performed using tail cuff method at baseline and 1-week intervals throughout the treatment period. All the three COX inhibitors resulted in increase in BP, but mean change in BP was the highest with rofecoxib. rofecoxib-treated L-NAME-hypertensive rats exhibited a significant increase in mean arterial pressure at 6 weeks (168.3+/-5.7 mmHg) as compared with DOCA-hypertensive rats (128.818+/-7.2 mmHg). Administration of rofecoxib L-NAME-hypertensive rats treated with candesartan resulted in a significant increase in BP. Systolic BP at 0 week (107.0+/-4.2 mmHg) rose to 141.6+/-2.0 mmHg at 6 weeks. Systolic BP at 2, 4, and 6 weeks was significantly higher as compared with (L-NAME+candesartan)- and (rofecoxib+candesartan)-treated group. In conclusion, concomitant use of rofecoxib resulted in poor BP control by candesartan in L-NAME-hypertensive rats.

https://pubmed.ncbi.nlm.nih.gov/15834454/

e8f82836baaf9e71816fa84fd14e9a87

The highest weight gain in the cyclophosphamide , methotrexate and fluorouracil group was 2·9 kg ( 5 % ) vs. 0·9 kg ( 1 % ) in the anthracycline-based group .

Weight change trajectory in women with breast cancer receiving chemotherapy and the effect of different regimens. To investigate the trajectory of weight change in Taiwanese women with breast cancer after starting chemotherapy and the impact of chemotherapy regimens on weight change while controlling for age, menopausal status, body mass index, lymph node involvement and changes in habits of dietary fat intake and exercise. ### background Weight gain after adjuvant chemotherapy in women with breast cancer has negative impact on health outcomes. ### design Longitudinal, clinical observational study. ### methods Weights were repeatedly measured in 147 women with breast cancer stages I-III. Hierarchical linear modelling was used to analyse these longitudinal data. ### results The overall pattern of weight change was a cubic form beginning with a mean of 56·9 kg before chemotherapy. It gradually increased to 59·4 kg at 8·5 months after the first chemotherapy followed by a decrease to 58·5 kg at 21·5 months. During the last 2·5 months, weight increased slightly and never returned to the initial level. After controlling for confounders, steeper weight change was observed among women receiving cyclophosphamide, methotrexate and fluorouracil. The highest weight gain in the cyclophosphamide , methotrexate and fluorouracil group was 2·9 kg ( 5 % ) vs. 0·9 kg ( 1 % ) in the anthracycline-based group . ### conclusion The trajectory of body weight change within two years after chemotherapy shows a trend of gradual ascent, followed by a small decline and a slight increase in the last 2·5 months. The chemotherapy regimen can predict the trend after controlling for other confounders; women on cyclophosphamide, methotrexate and fluorouracil have a steeper weight change. ### Relevance To Clinical Practice Nurses can inform women with breast cancer about the expected changes in body weight after chemotherapy to reduce their uncertainty. Future studies on effective interventions to minimise chemotherapy-induced weight gain are needed.

https://pubmed.ncbi.nlm.nih.gov/24393441/

402f6227835ed4a8c7deaebb01994c3f

Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus ( RAD001 ) and alemtuzumab : a Phase I/II study .

Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus ( RAD001 ) and alemtuzumab : a Phase I/II study . Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5 mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen.

https://pubmed.ncbi.nlm.nih.gov/26699397/

93fc84fbededb827039793d81948c432

Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde , these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma , albeit by different mechanisms .

Captopril and lisinopril decrease acetaldehyde effects upon the prothrombin time. captopril, a thiol-containing antihypertensive drug, and lisinopril, an amino-containing antihypertensive drug, will both prolong the prothrombin time (PT) of Level I plasma. Acetaldehyde, a product of ethanol metabolism, also prolongs PT. In a study to examine the interrelationship between hypertension, hemostasis, and alcoholism, an examination of the impact of acetaldehyde on the effects of captopril and lisinopril upon PT was undertaken. It was observed that the pre-mixing of 7.7 x 10(-3) M captopril with 40.6 mM acetaldehyde for 30 min at R.T. prior to the addition to plasma results in a prolongation of PT which is less than that caused by acetaldehyde alone. Successive additions of captopril and acetaldehyde to plasma also yield a PT which is less than that of acetaldehyde alone. These data suggest that captopril may partially inactivate and detoxify the acetaldehyde effect on hemostasis upon interaction to form a thiohemiacetal. captopril may prolong PT by the reduction of the S-S bridges in the coagulation factors. lisinopril behaves similarly to captopril, prolonging PT. Successive additions of lisinopril and acetaldehyde, or pre-mixtures thereof, to plasma result in a lesser prolongation of clotting time relative to acetaldehyde alone. Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde , these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma , albeit by different mechanisms .

https://pubmed.ncbi.nlm.nih.gov/17932766/

bffb465b1cdd2b90e26ec5367aab27ab

Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin , respectively .

Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma. At present, there is no standard regimen for the treatment of gastroesophageal cancer. docetaxel, cisplatin and fluorouracil (DCF) has been shown to be an effective regimen; however, toxicity is an area of concern in the palliative case setting. Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin , respectively . To reduce the toxicity of DCF while maintaining efficacy, we conducted this study to evaluate the efficacy of docetaxel, oxaliplatin and capecitabine (DOX) combination in advanced gastroesophageal cancer. ### methods Patients with histologically confirmed metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction received docetaxel 25 mg/m2 and oxaliplatin 50 mg/m2 on days 1 and 8 with capecitabine 625 mg/m2 twice daily from day 1-14, in 21-day cycles. The primary endpoint was overall response rate (ORR). ### results Of 21 patients, there were 16 males and 5 females with a median age of 57 years, range 37-80 years. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease. Grade 3/4 toxicities included diarrhea (24%), hand-foot syndrome (5%) and febrile neutropenia (5%). The ORR was 29%. The median survival was 8.4 months. At the time of analysis, 5 of the 21 patients (24%) were alive. ### conclusions The DOX combination is tolerable, active and a promising day-care regimen for advanced gastroesophageal cancer.

https://pubmed.ncbi.nlm.nih.gov/20543537/

fa3bc4b5c7d75d4fc07add3b08193775

To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol , methadone , morphine or tramadol in healthy sheep .

Behavioral and cardiopulmonary effects of dexmedetomidine alone and in combination with butorphanol, methadone, morphine or tramadol in conscious sheep. To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol , methadone , morphine or tramadol in healthy sheep . ### Study Design Randomized crossover study. ### animals Six Santa Inês sheep, five females, one male, aged 12-28 months and weighing 40.1 ± 6.2 kg. ### methods Sheep were assigned treatments of dexmedetomidine (0.005 mg kg(-1) ; D); D and butorphanol (0.15 mg kg(-1) ; DB); D and methadone (0.5 mg kg(-1) ; DM); D and morphine (0.5 mg kg(-1) ; DMO); or D and tramadol (5.0 mg kg(-1) ; DT). All drugs were administered intravenously with at least 7 days between each treatment. Rectal temperature, heart rate (HR), respiratory rate (fR ), invasive arterial pressure, blood gases and electrolytes were measured prior to administration of drugs (baseline, T0) and every 15 minutes following drug administration for 120 minutes (T15-T120). Sedation was scored by three observers blinded to treatment. ### results HR decreased in all treatments and fR decreased in DM at T30 and DMO at T30 and T45. PaCO2 was increased in D, DB and DM compared with baseline, and PaO2 decreased in D at T15 and T45; in DB at T15 to T75; in DM at T15 to T60; in DMO at T15; and in DT at T15, T30 and T75. There was a decrease in temperature in D, DB and DM. An increased pH was measured in D at all time points and in DT at T30-T120. HCO3- and base excess were increased in all treatments compared with baseline. There were no statistical differences in sedation scores. ### Conclusions And Clinical Relevance The combination of dexmedetomidine with butorphanol, methadone, morphine or tramadol resulted in similar changes in cardiopulmonary function and did not improve sedation when compared with dexmedetomidine alone.

https://pubmed.ncbi.nlm.nih.gov/26848935/