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fb3968457142d3e200753ba423dd76e6

These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas .

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas .

https://pubmed.ncbi.nlm.nih.gov/19536776/

9c6dd86cf42be0dc6db7778db1fcd651

In order to investigate the effects of a realistic pharmaceutical mixture on an ecosystem , a study utilizing 15 of 12,000 L aquatic microcosms treated with eight common pharmaceuticals ( atorvastatin , acetaminophen , caffeine , sulfamethoxazole , carbamazepine , levofloxacin , sertraline , and trimethoprim ) at total ( summed ) molar concentrations of 0 , 0.044 , 0.608 , 2.664 , and 24.538 micromol/L ( n = 3 ) was conducted .

Microcosm evaluation of the effects of an eight pharmaceutical mixture to the aquatic macrophytes Lemna gibba and Myriophyllum sibiricum. Pharmaceuticals have been detected in surface waters of the US and Europe, originating largely from two sources, sewage effluent and agricultural runoff. These compounds often occur as mixtures leading to potential combined effects. In order to investigate the effects of a realistic pharmaceutical mixture on an ecosystem , a study utilizing 15 of 12,000 L aquatic microcosms treated with eight common pharmaceuticals ( atorvastatin , acetaminophen , caffeine , sulfamethoxazole , carbamazepine , levofloxacin , sertraline , and trimethoprim ) at total ( summed ) molar concentrations of 0 , 0.044 , 0.608 , 2.664 , and 24.538 micromol/L ( n = 3 ) was conducted . Phytotoxicity was assessed on a variety of somatic and pigment endpoints in rooted (Myriophyllum sibiricum) and floating (Lemna gibba) macrophytes over a 35-day period. EC10, EC25 and EC50 values were calculated for each endpoint exhibiting a concentration-dependent response. Generally, M. sibiricum and L. gibba displayed similar sensitivity to the pharmaceutical mixture, with phytotoxic injury evident in both species, which was concentration dependent. Through single compound 7-day daily static renewal toxicity tests with L. gibba, the sulfonamide antibiotic sulfamethoxazole, the fluoroquinolone antibiotic levofloxacin and the blood lipid regulator atorvastatin were found to be the only compounds to elicit phytotoxic effects in the concentration range utilized (0-1000 microg/L). atorvastatin concentration was highly correlated to decreased pigment content in L. gibba, likely inhibiting the known target enzyme HMGR, the rate-limiting enzyme in isoprenoid biosynthesis. Hazard quotients were calculated for both microcosm and laboratory studies; the highest HQ values were 0.235 (L. gibba) and 0.051 (L. gibba), which are below the threshold value of 1 for chronic risks. The microcosm data suggest that at an ecological effect size of >20%, biologically significant risks are low for L. gibba and M. sibiricum exposed to similar mixtures of pharmaceutical compounds. For M. sibiricum and L. gibba, respective minimum differences of 5 and 1%, were detectable, however, these effect sizes are not considered ecologically significant.

https://pubmed.ncbi.nlm.nih.gov/15451605/

025b8825ec9c2ac2b1b6c82763b21d3d

The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography ( CT ) with iodinated contrast material ( DSBCT ) were prospectively evaluated in 75 patients by using iothalamate meglumine , iopamidol , and iohexol ( 25 patients received each agent ) .

Hepatic dynamic sequential CT: section enhancement profiles with a bolus of ionic and nonionic contrast agents. The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography ( CT ) with iodinated contrast material ( DSBCT ) were prospectively evaluated in 75 patients by using iothalamate meglumine , iopamidol , and iohexol ( 25 patients received each agent ) . After baseline noncontrast CT was performed, DSBCT was performed with a 180-mL intravenous bolus administered at 2 mL/sec. Scanning was started 25 seconds after the bolus was initiated, by using a 3-second scan time and rapid cephalocaudal table incrementation, yielding contiguous 8-mm-thick sections at a rate of nine sections per minute. On postcontrast images, peak enhancement was 115% for iopamidol and 117% for iohexol, both of which were superior to iothalamate meglumine at 95% (P less than .05). After peaking, enhancement then decreased for all three contrast agents, although the decline was more precipitous for iothalamate meglumine. Enhancement on the more caudal sections with both iopamidol and iohexol was superior to that with iothalamate meglumine (P less than .05). The data suggest that the enhancement characteristics for the two nonionic agents may be more optimal for detection of focal hepatic lesions than the ionic agent.

https://pubmed.ncbi.nlm.nih.gov/1987614/

0576c71d7dcc9e0dea83264897cdb410

Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) .

Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. ### Patients And Methods Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. ### results Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. ### conclusion NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.

https://pubmed.ncbi.nlm.nih.gov/10764435/

11606721daca6e4dbd9d993400db75bc

The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment .

Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment . ### methods This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. ### results The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). ### conclusion Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo.

https://pubmed.ncbi.nlm.nih.gov/11394732/

b3091e36da5861d17b4bb73004c91646

Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline .

Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline. ### methods From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks. ### results Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred. ### conclusions Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline . Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.

https://pubmed.ncbi.nlm.nih.gov/23223595/

e50ad95ee57016b82dec8134f6f4b203

In the main study submitted for this application , a 2.4-month longer median overall survival time and a 30 % lower risk for death were observed for cabazitaxel , compared with mitoxantrone .

The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use. On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application , a 2.4-month longer median overall survival time and a 30 % lower risk for death were observed for cabazitaxel , compared with mitoxantrone . The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).

https://pubmed.ncbi.nlm.nih.gov/22477727/

6437f27dae4e4543db96a39e19b72d17

Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 .

[Intrascrotal rhabdomyosarcoma in adult: a case report]. The patient was a 34-year-old man presenting with the right intra-scrotal painless mass. With a diagnosis of right intrascrotal tumor, the patient underwent right high orchiectomy. The pathological diagnosis of pleomorphic rhabdomyosarcoma arisen from the right spermatic cord was made. Computed tomography revealed a single metastasis in the para-vena cava lymph node. Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 . But the chemotherapy was ineffective and a retoroperitoneal lymphadenectomy (RPLND) was therefore performed. After 3 months following RPLND, the tumor relapsed in a pelvic lymph node involved in right ureter and ileocaecal valve. Resection of the tumor with ileocaecum was performed and then intraoperative radiotherapy (15 Gy) against the tumor bed was performed to ensure the curative effects. After his recovery, he received a total of 6 courses of systemic chemotherapy consisting of vincristin, ifosphamide, etoposide (IRS-IV Regimen 47). The patient was rigorously followed up for 42 months after the final chemotherapy, with no tumor recurrence.

https://pubmed.ncbi.nlm.nih.gov/19514277/

83a0b0353d77ad8e33b43deac6ea7ec0

He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission .

Non-Hodgkin Lymphoma in a Kidney Transplant Patient: A Case Report. Post-transplant lymphoproliferative disorders are a possible complication of kidney transplant due to chronic immunosuppressive therapy, and they can elevate the mortality rate. Furthermore, the type of clinical appearance has a wide range. We describe a case of a 38-year-old male recipient who developed post-transplant lymphoproliferative disorders and received successful treatment. The recipient had received a kidney with 1 HLA-B and 1 HLA-DR match, and the deceased donor allotransplant was performed successfully on December 9, 2012. The cause of kidney failure was membranoproliferative-glomerulonephritis proved by biopsy results. The induction therapy was antithymocyte globulin; the basic immunosuppressive therapy consisted of tacrolimus, steroid, and mycophenolate mofetil. After 2 months the patient had elevated serum creatinine level, and biopsy results revealed cellular rejection (Banff grade I). We applied steroid bolus therapy. After that the graft worked properly for 5 years, and the patient had no symptoms or complaints; then he had right lower abdomen pain. After urgent procedures (laboratory diagnostics, abdominal ultrasonography, computed tomography), we operated on the patient in a short time, and after a few weeks the fluorescence in situ hybridization confirmed the translocation of region C-myc; the diagnosis was diffuse large B-cell lymphoma. With the assistance of hematologists, the patient received adequate therapy. He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission . Our case is worth presenting because immunosuppressive drugs can modify the clinical picture, complicating the diagnosis and delaying treatment.

https://pubmed.ncbi.nlm.nih.gov/31101215/

3cd851564f73006f34a5529afd713a77

The RC0.1 and RC1 cells have high cross-resistance to CPT derivatives including SN-38 and topotecan , but are not cross-resistant to the non-top1 inhibitors etoposide , doxorubicin , and vincristine .

Characterization of a novel topoisomerase I mutation from a camptothecin-resistant human prostate cancer cell line. In this study, we characterized the structure and function of topoisomerase I (top1) protein in the camptothecin (CPT)-resistant prostate cancer cell lines, DU-145/RC0.1 and DU-145/RC1 (RC0.1 and RC1, respectively). Both of the cell lines were previously selected by continuous exposure to 9-nitro-CPT. The RC0.1 and RC1 cells have high cross-resistance to CPT derivatives including SN-38 and topotecan , but are not cross-resistant to the non-top1 inhibitors etoposide , doxorubicin , and vincristine . Although the top1 protein levels were not decreased in the resistant cells compared with the parental cells, CPT-induced DNA cleavage was markedly reduced in the RC0.1 and RC1 nuclear extracts. The resistant-cell-line nuclear extracts also demonstrated top1 catalytic activity and resistance to CPT, in in vitro assays. Reverse transcription-PCR products from the resistant cell lines were sequenced, and revealed a point mutation resulting in a R364H mutation in the top1 of both RC0.1 and RC1. No wild-type top1 RNA or genomic DNA was detected in the resistant cell lines. Using a purified recombinant R364H top1, we found that the R364H mutant top1 was CPT resistant and fully active. In the published top1 crystal structure, the R364H mutation is close to the catalytic tyrosine and other well-known mutations leading to CPT resistance.

https://pubmed.ncbi.nlm.nih.gov/11280753/

36a73344b5f63d64d0393e6860b5f08a

To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood .

Nifuratel-containing initial anti-Helicobacter pylori triple therapy in children. Proton pump inhibitor-containing triple therapy with amoxicillin and metronidazole is recommended as initial treatment of Helicobacter pylori in childhood. However, eradication rate with this "classic" regimen is relatively low in Russia. ### aim To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood . ### Materials And Methods Pediatric outpatients with H. pylori-associated chronic gastritis who underwent endoscopy for dyspeptic symptoms received the combination of bismuth subcitrate (8 mg/kg/day, q.d.s.), nifuratel (30 mg/kg/day, q.d.s.), and amoxicillin (50 mg/kg/day, q.d.s.) for 10 days. H. pylori status was determined before and after the treatment (in 4-6 weeks) by modified Giemsa staining. ### results Seventy-three children (48 boys, 25 girls, age range 9-14) were entered. H. pylori was eradicated in 63 patients (86%; 95% confidence interval: 76.6-93.2; intention-to-treat and per protocol). There were no serious adverse reactions and were no withdrawals due to any side-effects. All of side-effects were self-limiting (dark stools, urine discoloration, blackening of the tongue, and others). ### conclusions The combination of nifuratel, bismuth subcitrate, and amoxicillin was an effective and tolerable regimen for H. pylori eradication.

https://pubmed.ncbi.nlm.nih.gov/17309749/

33140a176ef4e6f6be4235f20a0f447d

The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission .

Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2). We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission . At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.

https://pubmed.ncbi.nlm.nih.gov/15929101/

200b0264779d54035ddc6c2f1eaaf23e

The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration .

Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. We performed a meta-analysis of data from randomized trials to estimate the risk of all-cause mortality and bleeding (and especially gastrointestinal [GI] bleeding) in patients treated with low doses of acetylsalicylic acid (ASA) (75-325 mg/d), alone or in combination with other medications. ### methods We searched 10 electronic databases (until October 2010) and collected data on adverse events in randomized controlled studies that evaluated low doses of ASA, alone (35 trials) or in combination with anticoagulants (18 trials), clopidogrel (5 trials), or proton pump inhibitors (PPIs; 3 trials). We analyzed data using random-effects meta-analysis and meta-regression, applying Peto's odds ratio (OR) for adverse events. ### results Low doses of ASA alone decreased the risk for all-cause mortality (relative risk, 0.93, 95% confidence interval [CI], 0.87-0.99), largely because of effects in secondary prevention populations. The risk of major GI bleeding increased with low doses of ASA alone (OR, 1.55; 95% CI, 1.27-1.90), compared with inert control reagents. The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration . Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of ASA (OR, 0.34; 95% CI, 0.21-0.57). ### conclusions In a meta-analysis, low doses of ASA increased the risk for GI bleeding; risk increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs.

https://pubmed.ncbi.nlm.nih.gov/21699808/

00fed36f9da425f2e99920574f260728

Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug .

Combined Raloxifene and Letrozole for Breast Cancer Patients. Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug . However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48 h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer.

https://pubmed.ncbi.nlm.nih.gov/29229198/

3a94029adb94f341238c07809b06653f

In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate .

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate . In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. ### methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. ### results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). flutamide was not associated with enhanced benefit in patients with minimal disease. ### conclusions The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

https://pubmed.ncbi.nlm.nih.gov/9761805/

2840ea50d46d8f2b1fa1546b87a622f3

Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities .

Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities . We examined the effects of mono and polyphasic oral contraceptives containing desogestrel or levonorgestrel on serum lipoproteins, sex hormone binding globulin and post-heparin plasma lipase activities. ### design The women took either desogestrel or levonorgestrel during the first menstrual cycle on days 15-28. They then received monophasic ethinyloestradiol plus either desogestrel or levonorgestrel for three cycles. After this, the women took sequential pills containing ethinyloestradiol plus either desogestrel or levonorgestrel for the three following cycles. Fasting blood samples were drawn pretreatment and at the end of each treatment. ### patients The study group consisted of 30 apparently healthy women, aged 18-35. They were randomly divided into desogestrel and levonorgestrel groups, each consisting of 15 women. ### measurements Cholesterol, triglyceride and phospholipids were determined in whole serum and in all lipoprotein fractions (following isolation of lipoproteins by ultracentrifugation). Plasma apolipoprotein A-I concentration, post-heparin plasma lipase activities and serum sex hormone binding globulin were also measured. ### results desogestrel (150 micrograms/day) did not change serum total triglyceride concentration, whereas levonorgestrel (150 micrograms/day) decreased it. Except for monophasic ethinyloestradiol plus levonorgestrel, the oestrogen-containing combinations increased serum triglyceride level. Low density lipoprotein (LDL) cholesterol remained stable with all treatments, but the cholesterol/triglyceride ratio of LDL decreased during all combinations with ethinyloestradiol. levonorgestrel reduced total high density lipoprotein (HDL) cholesterol and both progestins reduced HDL2 cholesterol concentration. Addition of ethinyloestradiol reversed this change in the desogestrel but not in the levonorgestrel group. The polyphasic ethinyloestradiol plus levonorgestrel combination did not change total HDL cholesterol. Hepatic lipase was activated with either progestin when administered alone but its activity was suppressed below the baseline level when ethinyloestradiol was added. Conversely, both progestins suppressed sex hormone binding globulin levels, but addition of ethinyloestradiol caused marked increases above baseline. These increases were greater in women taking desogestrel than in those taking levonorgestrel. No treatment affected lipoprotein lipase activity significantly. ### conclusions Monophasic or polyphasic combinations of ethinyloestradiol and desogestrel do not have deleterious effects on serum lipoproteins. If levonorgestrel is used as the progestin component, polyphasic ethinyloestradiol plus levonorgestrel appears more favourable than monophasic ethinyloestradiol plus levonorgestrel.

https://pubmed.ncbi.nlm.nih.gov/1533186/

40c71f770fe0068228d83a69ec8659db

Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori , and susceptibility to six antibiotics ( clarithromycin , amoxicillin , gentamicin , furazolidone , metronidazole , and levofloxacin ) was tested from 2012 - 2014 .

Antibiotics resistance of Helicobacter pylori in children with upper gastrointestinal symptoms in Hangzhou, China. The decreasing eradication rate of Helicobacter pylori is mainly because of the progressive increase in its resistance to antibiotics. Studies on antimicrobial susceptibility of H. pylori in children are limited. This study aimed to investigate the resistance rates and patterns of H. pylori strains isolated from children. ### Materials And Methods Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori , and susceptibility to six antibiotics ( clarithromycin , amoxicillin , gentamicin , furazolidone , metronidazole , and levofloxacin ) was tested from 2012 - 2014 . ### results A total of 545 H. pylori strains were isolated from 1390 children recruited. The total resistance rates of H. pylori to clarithromycin, metronidazole, and levofloxacin were 20.6%, 68.8%, and 9.0%, respectively. No resistance to amoxicillin, gentamicin, and furazolidone was detected. 56.1% strains were single resistance, 19.6% were resistant to more than one antibiotic, 16.7% for double resistance, and 2.9% for triple resistance in 413 strains against any antibiotic. And the H. pylori resistance rate increased significantly from 2012-2014. There was no significant difference in the resistance rates to clarithromycin, metronidazole, and levofloxacin between different gender, age groups, and patients with peptic ulcer diseases or nonulcer diseases. ### conclusions Antibiotic resistance was indicated in H. pylori strains isolated from children in Hangzhou, and it increased significantly during the 3 years. Our data strongly support current guidelines, which recommend antibiotic susceptibility tests prior to eradication therapy.

https://pubmed.ncbi.nlm.nih.gov/29528162/

32b6dbf07fe994efe427a84515f594f4

Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively .

Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively . The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.

https://pubmed.ncbi.nlm.nih.gov/10414664/

b0f79f8deba457cab659d10899ce9bf4

The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America .

[Ewing sarcoma]. Ewing sarcoma is the second most frequent primary bone cancer affecting children or young adults. Advances in molecular biology have revealed common chromosomal translocations such as EWS-FLI 1 among Ewing sarcoma and related diseases such as primitive neuroectodermal tumor (PNET), so these are considered as Ewing sarcoma family tumor (ESFT). Although fewer than 10% of patients with ESFT survived before establishment of modern multiagent chemotherapy, the multimodal therapeutic regimens including combination chemotherapy, radiotherapy, and surgery can cure 60% of patients with localized disease, due to the collaborative research in European-American or the international trials. The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America . Meanwhile, those with metastatic disease have a much worse outcome with an approximately 10-30% 5-year event-free survival rate. New American-European collaborative trials such as EURO-E.W.I.N.G.99 are in progress for further improvement of the cure rate in localized and metastatic ESFT. In Japan, Japan Ewing Sarcoma Study Group (JESS) phase II clinical trial for localized ESFT, and some clinical trials including new drugs are ongoing and waiting for results.

https://pubmed.ncbi.nlm.nih.gov/17301523/

c3cb386de34dbea5637e93d5f9c2b7bf

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies .

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies . This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.

https://pubmed.ncbi.nlm.nih.gov/20198402/

711c51bfb251156a64c6d58f1d2d1839

Combined therapy : what does acamprosate and naltrexone combination tell us ?

Combined therapy : what does acamprosate and naltrexone combination tell us ? Relapse prevention treatment with both acamprosate and naltrexone has been shown to be efficacious in the treatment of alcoholism. Whereas both compounds act pharmacologically differently, there is up to now only limited evidence as to whether combined treatment is efficacious and pharmacologically safe. It remains to be answered whether data justify the combination of both drugs in clinical practice. ### methods Review of the three pre-clinical and four clinical studies that have been published to date on either combined tolerability or efficacy. ### results Data available up to now show no occurrence of severe adverse events during combined treatment. Diarrhoea and nausea were shown to be the most significant side-effects. Whereas pre-clinical studies regarding efficacy of combined treatment are not yet conclusive, clinical data show the superiority of combined treatment compared with both placebo and acamprosate monotherapy. The synergistic effect of combined treatment remained after 12 weeks of drug-free follow-up. ### conclusions The combination of acamprosate with naltrexone in a clinical sample seems to be efficacious and safe. Numerous alcohol dependent patients could benefit, particularly those that responded insufficiently on monotherapeutic treatment with either acamprosate or naltrexone.

https://pubmed.ncbi.nlm.nih.gov/15456690/

a0c0e90584efb59d8860e1b6f8ecfe7b

Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) .

Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM). Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) . Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.

https://pubmed.ncbi.nlm.nih.gov/33374980/

78c18c2e1184f5d132f93846c9e3f49a

TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia .

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy. In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia . Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

https://pubmed.ncbi.nlm.nih.gov/24477330/

9a5d4c5cdf2df42bbc1f3e178e565124

Almost all the isolates were resistant to Ampicillin and Tobramycin ( 99.3 % each ) .

Bacteriophage typing and antibiotic sensitivity pattern of Staphylococcus aureus from clinical specimen in and around Solapur (South Maharashtra). Two hundred and eighty nine strains of Staphylococcus aureus isolated from pus and wound swabs (149), blood (36), urine (28), sputum (14), stool (12), throat swab (9) and CSF (4) were subjected for bacteriophage typing and antibiotic susceptibility pattern. 113 (39.11%) strains were typable. Among the typable strains, 16 (5.53%) belonged to phage group I, 33 (11.41%) strains belonged to phages group II, 38 (13.14%) belonged to phage group III, 26 (8.99%) strains belonged to the phages which have not been allocated to any group (Miscellaneous group) 176 (60.89%) strains were untypable. Only one (0.34%) strain was sensitive to all the drugs tested. Almost all the isolates were resistant to Ampicillin and Tobramycin ( 99.3 % each ) . 286 (98.96%) strains were found to be resistant to Penicillin and erythromycin followed by kanamycin 272 (94.11%) and gentamicin 263 (91.3%). 113 (39.1%) strains were Methicillin resistant Staphylococcus aureus (MRSA). All MRSA strains were resistant to all drugs tested except vancomycin. Resistance to most of the commonly used antimicrobial agents indicates a need to replace these drugs with other agents and maintenance of surveillance to detect changing patterns of resistance.

https://pubmed.ncbi.nlm.nih.gov/15239300/

874b4041ed7349e2cad9ebb2f7c2feb5

Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal .

Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study. Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. ### methods Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. ### results Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal . Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment. ### conclusions The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.

https://pubmed.ncbi.nlm.nih.gov/22668581/

1d48843a67e7504029372f6725caf9ed

Pharmacy costs of cefazolin used as prophylaxis were more than twice the cost for cephapirin .

Use, misuse, and cost of parenteral cephalosporins at a county hospital. We reviewed total usage of parenteral cephalosporins at a county hospital during 1978 with regard to appropriateness, pattern of use, and cost. In addition, we determined the impact of replacing cephalothin with cephapirin in the hospital formulary. During the 12-month study 366 patients received 409 courses of parenteral cephalosporins: 167 received cefazolin, 160 received cephapirin, and 35 received a combination of cefazolin and cephapirin. The surgical service prescribed 87% of the cephapirin and 92% of the cefazolin. Parenteral cephalosporins were used 62% of the time for prophylaxis and 38% of the time for therapy. Usage was judged inappropriate in 47% of all courses based on our criteria; 25% of the therapeutic courses were judged inappropriate, compared to 60% of the prophylactic courses. Pharmacy costs of cefazolin used as prophylaxis were more than twice the cost for cephapirin . Cost of a mean therapeutic course for cefazolin was 43% higher than for cephapirin. Antibiotic audits and continued education combined with judicial substitution of therapeutic equivalents should limit the inappropriate use and expense of parenteral cephalosporins for large as well as small hospitals.

https://pubmed.ncbi.nlm.nih.gov/7444511/

b188617afabc590d2a58574c2988de5e

PP-6 isolated from Tibetan Plateau could ferment raffinose , lactose , sorbitol , melibiose and sucrose , and LS-5 could ferment cottonseed sugar , laetrile , rhamnose , lactose , sorbitol , xylose , arabinose , melibiose and sucrose , but the same species of commercial strains could not use these sugars .

[Effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans]. In order to detect the effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans. ### methods We used 3 isolated lactic acid bacteria with better growth at low temperatures of 10 and 15 degrees C at ensiling of Elymus nutans. Subsequently, effects of the selected lactic acid bacteria on fermentation profiles of Elymus nutans silages stored at 15 and 25 degrees C were evaluated by using the same species of commercial inoculants as the control. ### results PP-6 isolated from Tibetan Plateau could ferment raffinose , lactose , sorbitol , melibiose and sucrose , and LS-5 could ferment cottonseed sugar , laetrile , rhamnose , lactose , sorbitol , xylose , arabinose , melibiose and sucrose , but the same species of commercial strains could not use these sugars . Inoculation of these three strains into Elymus nutans at 15 and 25 degrees C ensiled for 50 d, we found that LS-5 significantly reduced silage pH, propionic acid concentration and ratio of ammonia nitrogen/total nitrogen at 15 degrees C (P < 0.05), salvaged more water-soluble carbohydrate and crude protein; Application of LP-2 and PP-6 as a combined inoculant to Elymus nutans significantly improved lactic acid concentration (P < 0.05), resulting in a lower ratio of ammonia nitrogen/total nitrogen, saved more crude protein and significantly reduced neutral detergent fiber content (P < 0.05) as compared with the commercial strains. ### conclusion The three isolated strains can improve silage quality of Elymus nutans growing on the Qinghai-Tibetan Plateau at low temperature, but these strains have no obvious advantages at 25 degrees C in comparison with the commercial inoculants.

https://pubmed.ncbi.nlm.nih.gov/26939457/

f7ab75242ec372a88c94d2f9359b2859

Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas .

Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells. Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyper-activation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients. ### methods In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro. ### results Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas . Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials. ### conclusions Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas.

https://pubmed.ncbi.nlm.nih.gov/30574020/

4ed783b2bf9c376b4f0e615621a6649a

Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful .

Cutaneous immunoblastic T-cell lymphoma. The case of a 69-year-old male patient with an unusual type of malignant lymphoma is presented. Clinically, it was at first characterized by follicular papules and erythematous patches, later, by the development of cutaneous tumors and enlarged lymph nodes, and by a severe, finally excruciating pruritus. Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful . The patient died of pneumonia 2.5 years after the onset of the first clinical symptoms. An immunoblastic infiltrate was observed histologically and electromicroscopically in the initial lesions of the skin. Therefore, the diagnosis of a cutaneous immunoblastic T-cell lymphoma was tentatively made at the beginning, which was later confirmed in numerous biopsies and laboratory investigations. Immunocytologically and enzymecytochemically, the infiltrating cells were shown to be immature T cells; in the lymph nodes, numerous immunoblasts and large Sézary cells was observed in the peripheral blood, though there were no very large Sézary cells or blast cells. In the autopsy, a systemic involvement with an atypical lymphoid infiltration was found in numerous internal organs. The special nature of this case justifies its classification as high-grade malignant lymphoma and its differentiation from normal cases of mycosis fungoides. In contrast, mycosis fungoides generally fulfils criteria typical of low-grade malignant lymphomas.

https://pubmed.ncbi.nlm.nih.gov/6984639/

5b2a3850c05cec3894d8fbf760db8885

This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1 , 2004 , through December 31 , 2014 .

Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer. Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT. ### objective To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC. ### Design Setting And Participants This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1 , 2004 , through December 31 , 2014 . Patients were stratified by tumor origin in the left vs right sides. ### interventions Treatment with SC or SC plus bevacizumab or cetuximab. ### Main Outcomes And Measures Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed. ### results A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001). ### Conclusions And Relevance Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.

https://pubmed.ncbi.nlm.nih.gov/28975237/

1754d72a3f257d2ecd67f1aec7bdb7d3

We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population .

Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial. High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population . ### methods Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on vinorelbine or gemcitabine according to the patient's preference. ### results A total of 126 cycles of vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on vinorelbine, 5 patients on gemcitabine; 12 patients (26%) had stable disease, 7 patients on vinorelbine, 5 patients on gemcitabine. Of 24 patients with progressive disease on vinorelbine, 3 patients (12.5%) responded to gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. ### conclusion This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.

https://pubmed.ncbi.nlm.nih.gov/15949597/

097865bb7793218ba27867eeb0f08c14

Apoptosis in Hep2 cells treated with etoposide and colchicine .

Apoptosis in Hep2 cells treated with etoposide and colchicine . When malignant cells undergo apoptosis, they exhibit many distinct patterns of behavior, with blebbing being one of the most spectacular and mysterious features. Despite huge advancements in our understanding of cell death, the mechanisms of apoptosis associated blebbing have not been elucidated. In order to verify the putative involvement of actin and tubulin in this process, Hep2 cells were treated with a combination of etoposide (10 microg/ml) and colchicine (0.2 microg/ml) for 24 h. Blebbing was analyzed using immunofluorescence staining of actin and tubulin, and the course of apoptosis was followed by time-lapse videomicroscopy, immunofluorescence detection of caspase-3 and cytokeratin fragment 18. The results indicate that microfilaments (actin) and not microtubules (tubulin) are involved in blebbing of Hep2 cells. Furthermore, despite the different mechanisms by which both chemicals act, their combined effects are not additive, but rather eliminate each other.

https://pubmed.ncbi.nlm.nih.gov/15225902/

c9c57db7e9477555da88ff7ea0940e62

The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) .

Phase II study of carboplatin and weekly paclitaxel combination chemotherapy in advanced non-small cell lung cancer: a Kansai Clinical Oncology Group study. The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) . Patients received paclitaxel at a dose of 70 mg/m(2) on days 1, 8, 15, and carboplatin with the target dose of area under the curve (AUC) of 6 on day 1 every 28 days. Forty-six patients were enrolled. A median of four cycles (range, 1-13) were administered. Complete response was observed in one patient (2.2%) and partial response in 23 patients (50%), yielding an overall intent-to-treat response rate of 52.2% (95% confidence interval, 37.8-66.6%). The median survival time was 395 days and 1-year survival rate was 51.4%. Toxicities were mild. Twelve patients (26%) had grade 3 and three patients (7%) had grade 4 neutropenia. Grade 3 thrombocytopenia was seen in four patients (8%). Massive hematoemesis due to duodenal ulcer was observed in one patient, but no other patients experienced grade 3 or more non-hematological toxicities. There was no treatment-related death. carboplatin and weekly paclitaxel combination chemotherapy is an efficacious and feasible regimen in patients with advanced NSCLC, and this treatment will be a reasonable alternative to the conventional triweekly regimen of paclitaxel and carboplatin.

https://pubmed.ncbi.nlm.nih.gov/15140549/

e12613f5fb6c99cf4926e0c2e73f0ce5

Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) .

A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) . G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.

https://pubmed.ncbi.nlm.nih.gov/11380402/

253ab4e2581ecbfe942bd09e125e9497

Indomethacin , naproxen and dexamethasone had no effect .

Effects of certain antiarthritic agents on the synthesis of type II collagen and glycosaminoglycans in rat chondrosarcoma cultures. Cartilage destruction is a characteristic feature of osteoarthritis. Treatment with certain nonsteroidal anti-inflammatory drugs could exacerbate cartilage destruction by impairing the synthesis of cartilage matrix proteins, type II collagen and proteoglycan. In order to monitor the changes occurring in cartilage collagen synthesis, we developed a type II collagen specific ELISA. The effects of antiarthritic agents on type II collagen and glycosaminoglycan synthesis were examined in rat chondrosarcoma cultures. Drugs were added to the monolayer cultures and 4 days later the total type II collagen, as determined by the type II collagen ELISA, and glycosaminoglycan content, as measured by dimethyl-methylene blue dye binding assay, was measured. All drugs except tiaprofenic acid decreased type II collagen synthesis by at least 40% at 100 micrograms/ml. tiaprofenic acid at 1 microgram/ml increased type II collagen content by 54% of the controls. Glycosaminoglycan synthesis was decreased by acetylsalicylic acid, diclofenac and tiaprofenac acid, at 50 micrograms/ml or above. Indomethacin , naproxen and dexamethasone had no effect . Interestingly, tenidap stimulated the glycosaminoglycan synthesis by 32% at 100 micrograms/ml. We show that the combination of chondrosarcoma cultures, type II collagen specific ELISA and dimethylmethylene blue dye binding assay serves as a useful model for screening the effects of agents capable of modulating type II collagen and glycosaminoglycan synthesis.

https://pubmed.ncbi.nlm.nih.gov/7942329/

0570fa2975ebf592e8936069e10116c6

In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal .

Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. ### Experimental Design EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal . The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. ### results lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. ### conclusion Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.

https://pubmed.ncbi.nlm.nih.gov/20179222/

ee5d4e0c327fe92e840628a4a703ed85

To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide ( HCTZ ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis , we utilized Xpa-knockout mice , which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice .

Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice. voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide ( HCTZ ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis , we utilized Xpa-knockout mice , which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice . Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8-dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole-metabolite during UV exposure. The data suggest that voriconazole plus UVB-induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis.

https://pubmed.ncbi.nlm.nih.gov/29968917/

dcb788b79b119fb6cb54c5eb6c0dae0e

Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising .

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials. To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. ### methods An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. ### results Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising . ### conclusion At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.

https://pubmed.ncbi.nlm.nih.gov/27579253/

0b19218cd66509b9ec7b8b74faa776fa

This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet .

Current status of taxane and platinum-based chemotherapy in ovarian cancer. Before 1993, the standard of care for the chemotherapeutic management of advanced ovarian cancer was cisplatin or carboplatin combined with a classic alkylating agent (typically cyclophosphamide). Studies in the 1990s have changed this standard to one of the platinum-containing agents combined with a taxane, paclitaxel, or docetaxel. This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet . A separate article discusses the docetaxel-platinum doublet and how that might be considered an appropriate option for first-line therapy in patients with advanced, newly diagnosed ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/12743128/

84e5e11c5f53a9a86f14e90f0656d9b6

The results indicate that neomycin only inhibits the growth of susceptible bacteria ( E. coli , Staph . aureus ) which , conversely , are poor lactitol fermenters .

[Lactitol and neomycin: monotherapy or combined therapy in the prevention and treatment of hepatic encephalopathy?]. The beneficial effect of disaccharides, lactulose and lactitol, in prevention and treatment of hepatic encephalopathy is well established but their use in combination with neomycin is still controversial. We studied in vitro the fecal bacterial growth, acid and gas formation in presence of lactitol (beta-galactoside-sorbitol) and neomycin alone or in combination. The results indicate that neomycin only inhibits the growth of susceptible bacteria ( E. coli , Staph . aureus ) which , conversely , are poor lactitol fermenters . The resistant organisms (Lactobacillus acidophilus, Clostridium perfringens) that are efficient disaccharide fermenters continue to metabolize lactitol still when antibiotic is added. Addition of lactitol 10% increased the inhibitory effect of neomycin on bacterial growth by 25-50% within 60-70 min. These preliminary data suggest that lactitol and neomycin may have additional or synergistic effects in vivo when used together in presence of favourable intestinal microbial environment.

https://pubmed.ncbi.nlm.nih.gov/2525995/

d819bb23ae7e300013cb210830b30285

Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) .

[Effects of hyperthermia combined platinum-based drugs on ovarian cancer cell lines SKOV3]. To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. ### methods SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 microg/mL) at a temperature of 42 degrees C for hyperthermia or 37 degrees C for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. ### results DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner (P < 0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) . The half inhibitory concentration (IC50) values of DDP, CBP and OXA were (7.271 +/- 0.096) microg/mL, (37.609 +/- 0.779) microg/mL and (28.328 +/- 0.698) microg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were (2.075 +/- 0.244) microg/mL, (19.591 +/- 0.453) microg/mL, (19.089 +/- 0.424) microg/mL (P < 0.05). The increased sensitivity index was 2.075 +/- 0.244 for cis-platinum, 1.92 +/- 0.044 for carboplatin, 1.484 +/- 0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P < 0.05). ### conclusion Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression.

https://pubmed.ncbi.nlm.nih.gov/25286685/

ca87164dd56862679e6812be7a454c3f

A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution .

Quality of Life Outcomes From a Phase 2 Trial of Short-Course Radiation Therapy Followed by FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer. A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution . We present here the patient-reported quality of life (QOL) outcomes from this trial. ### Methods And Materials Eighty patients with cT3/T4, any N, any M rectal adenocarcinoma planned for resection were enrolled between 2009 and 2012. The QOL data were obtained prospectively using the Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire before RT, before surgery, and 1 year after surgery. The previously validated minimally importance difference (MID) method was used to measure clinically significant QOL changes in FACT-C scores for each patient across time points. We examined the role of ostomy on QOL. We also compared QOL with disease outcomes and physician-reported toxicity. ### results The FACT-C questionnaire was completed by 97% of patients before RT, 85% immediately before surgery, and 62% 1 year after surgery. There was no statistically significant change in mean FACT-C scores from before treatment to after treatment. The majority of patients had either no change or an increase in QOL 1 year after treatment using the MID method. There were significant changes in QOL between patients with ostomy versus no ostomy 1 year after treatment for functional well-being (FWB) (14.81 vs 20.52, P=.018) and the colorectal cancer subscale (CCS) using the MID method (P=.004). Patients without ostomy reported stable changes in bowel control 1 year after surgery. There was no statistically significant correlation between QOL and disease recurrence, pathologic complete response, pathologic T stage downstaging, or acute/late toxicity. ### conclusions SC-RT and sequential mFOLFOX6 as preoperative therapy for rectal cancer results in stable patient-reported QOL outcomes 1 year after treatment. These findings in conjunction with previously reported oncologic outcomes support further evaluation of this regimen in a phase 3 setting.

https://pubmed.ncbi.nlm.nih.gov/27209506/

ca50ee6dc69f527347fc782c655a97d4

[ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] .

[ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] . We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1.

https://pubmed.ncbi.nlm.nih.gov/25731506/

e596e3a511575d9d61a15039a7fb1f62

Sulpiride plus hydroxyzine decrease tinnitus perception .

Sulpiride plus hydroxyzine decrease tinnitus perception . The aim of the study is to confirm the effectiveness of sulpiride and hydroxyzine in tinnitus patients. The administration of sulpiride, a D2 antagonist of dopamine receptors, together with hydroxyzine, a subcortical sedative, covers the areas of tinnitus perception. ### methods A prospective, randomized, single blinded, placebo-control study was done in general otorhinolaryngology consultations for 2002-2004 in Seville and Zaragoza (Spain). One hundred and fifty patients consulted for subjective tinnitus. They were included randomly in three groups of 50. A group took sulpiride (50 mg/8 h) alone, other the same dose of sulpiride plus hydroxyzine (25 mg/12 h), and the third placebo (lactose), for 1 month. One hundred and twenty-two patients completed the study. Clinical history, tonal audiometry, tympanometry, and tinnitometry were done in the beginning and end of the study. Subjective Grading of Tinnitus Perception and visual analogical scale (0-10) were done for result evaluation. ### results Based on the Subjective Grading of Tinnitus Perception, tinnitus perception diminished by 56% in patients treated with sulpiride and by 81% in patients treated with sulpiride plus hydroxyzine. Based on the visual analogical scale, tinnitus perception diminished from 7.8 to 6.3 in the patients treated with sulpiride, and from 7.8 to 5.1 in those treated with sulpiride plus hydroxyzine. ### conclusions sulpiride plus hydroxyzine decreases tinnitus perception. Tinnitus auditolimbic dopaminergic pathway opens wide therapeutical implications.

https://pubmed.ncbi.nlm.nih.gov/17118597/

5e2553a4549f2caeca0fb06f63927535

' Arimidex ' ( anastrozole ) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer -- efficacy overview .

' Arimidex ' ( anastrozole ) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer -- efficacy overview . ATAC, a randomized, double-blind trial, compared tamoxifen (20 mg) with anastrozole ('Arimidex') (1 mg) alone, and the combination of anastrozole plus tamoxifen (combination), as adjuvant endocrine treatment for postmenopausal patients with early breast cancer. Patients with operable invasive breast cancer following completion of primary therapy, who were candidates to receive adjuvant endocrine therapy, were eligible for this study. Primary endpoints were disease-free survival (DFS) and tolerability. Other endpoints included time to recurrence (TTR: censoring non-breast cancer deaths before recurrence) and the incidence of contralateral breast cancer. A total of 9366 patients were included in this study (N=3125, 3116 and 3125 for anastrozole, tamoxifen and the combination, respectively). Median duration of therapy was 30.7 months and median follow-up was 33.3 months. The total numbers of events were 317, 379 and 383 for anastrozole, tamoxifen and the combination, respectively. DFS was significantly improved in the overall population for anastrozole versus tamoxifen (hazard ratio (HR)=0.81, 95% confidence interval (CI) (0.71-0.96), P=0.013). anastrozole showed improved TTR compared with tamoxifen (HR=0.79, CI (0.67-0.94), P=0.008), which improved even further in the ER+ and/or PR+ subgroup (HR=0.73, CI (0.59-0.90), P=0.003). The incidences of hot flushes, thromboembolic events, ischaemic cerebrovascular events, vaginal bleeding/discharge and endometrial cancer were significantly reduced with anastrozole compared with tamoxifen (P<0.03 for all). Musculoskeletal disorders and fractures were significantly reduced in patients receiving tamoxifen compared with those on anastrozole (P<0.03 for both). No increase in hip fractures was seen for anastrozole versus tamoxifen (11 versus 13, respectively). Combination treatment was equivalent to tamoxifen in terms of both efficacy and tolerability. anastrozole showed superior efficacy to tamoxifen for DFS, TTR and contralateral breast cancer. Early findings show anastrozole to be an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with early breast cancer. For the first time a choice now exists for adjuvant endocrine treatment for postmenopausal women with hormone responsive tumours. Longer follow-up will further define the benefit/risk of anastrozole adjuvant therapy.

https://pubmed.ncbi.nlm.nih.gov/14623537/

18fa86029153d65989d1c18f32f0b497

We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively .

Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1. A 15-month-old boy with severe aplastic anemia developed veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT), in which the preparative regimen included 50 mg/kg/day cyclophosphamide and anti-lymphocyte globulin for 4 consecutive days. The diagnosis was made based on clinical symptoms and data including, hepatomegaly, right upper quadrant abdominal pain, jaundice, ascites, coagulopathy and thrombocytopenia which was refractory to transfusions of platelet concentrate. We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively . Clinical and biochemical improvement was steady and dramatic. We suggest that tPA following continuous heparin and PGE1 infusion may be useful in the treatment of VOD even in infantile cases.

https://pubmed.ncbi.nlm.nih.gov/7637394/

878a3f80aefe1a6b4ea10ef54550325b

Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells .

Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells . We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors.

https://pubmed.ncbi.nlm.nih.gov/10660084/

5156321f12ef5608480d7417f89f7022

The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine .

Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up. The most commonly used regimen for the treatment of advanced Hodgkin's disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity. The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine . ### Patients And Methods A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients. ### results EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3-48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity. ### conclusions The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA.

https://pubmed.ncbi.nlm.nih.gov/12562654/

b8d214801f19a5a385cb42d7e6e2c611

The treatment of advanced non-small-cell lung cancer ( NSCLC is based on the combination of platin and one of the following agents : taxanes , gemcitabine , vinorelbine or irinotecan .

Chemoresistance in non-small cell lung cancer. The treatment of advanced non-small-cell lung cancer ( NSCLC is based on the combination of platin and one of the following agents : taxanes , gemcitabine , vinorelbine or irinotecan . There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.

https://pubmed.ncbi.nlm.nih.gov/15720263/

ea8744d49ad7af4806734b7bb3efc835

Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume .

Carvedilol in glioma treatment alone and with imatinib in vitro. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume . carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.

https://pubmed.ncbi.nlm.nih.gov/20198329/

b4f45f2f8481bf448aa604026f442c37

The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 .

A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. sorafenib is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a phase I/II study of the combination of sorafenib with cytarabine in older patients with AML or high-risk MDS who were unsuitable for intensive chemotherapy. FLT3 mutational status was determined in all patients. Twenty-one patients were enrolled (four MDS, 17 AML) with a median age of 77 years. The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 . Dose-limiting toxicities were fatigue, sepsis and skin rash. Of 15 evaluable patients treated at the RP2D, two patients responded. The overall response rate for eligible patients was 10%. FLT3 mutations were found in only three patients. We conclude that this combination of sorafenib and cytarabine has limited activity in this unselected cohort of elderly patients with AML/MDS in which FLT3 mutations seemed underrepresented.

https://pubmed.ncbi.nlm.nih.gov/23061485/

6a73d9185688e57d42aa5600c5e0d2dd

We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab .

Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab . ### Patients And Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. ### results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. ### conclusions panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

https://pubmed.ncbi.nlm.nih.gov/22210091/

fa64a98ecdeacda0be884781ff6a5743

Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) .

Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) . In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

https://pubmed.ncbi.nlm.nih.gov/25708713/

25229a6b02806782fe134bb4bcd9e577

In this study a new GC-MS method has been developed for direct analysis of five major steroid estrogens ( estrone , 17beta-estradiol , 17alpha-ethinylestradiol , dienestrol , and diethylstilbestrol ) in river sediments .

Novel approaches to the analysis of steroid estrogens in river sediments. A wide range of estrogenic contaminants has been detected in the aquatic environment. Among these, natural and synthetic steroid estrogens, typically present in municipal sewage-treatment plant (STP) effluents, are the most potent. In this study a new GC-MS method has been developed for direct analysis of five major steroid estrogens ( estrone , 17beta-estradiol , 17alpha-ethinylestradiol , dienestrol , and diethylstilbestrol ) in river sediments . Four GC-MS systems used for analysis of underivatized analytes in purified extracts were compared. Relatively low detection limits (1.5-5 ng g(-1) dried sediment) and good repeatability of GC splitless injection (RSD 1-2%) were achieved by use of a system combining low-pressure gas chromatography with a single-quadrupole mass analyzer (LP-GC-MS). Use of orthogonal gas chromatography (GCxGC) hyphenated with high-speed time-of-flight mass spectrometry (HSTOF-MS) enabled not only significantly better resolution of target analytes, and their unequivocal identification, but also further improvement (decrease) of their detection limits. In addition to these outcomes, use of this unique GCxGC-TOF-MS system enabled identification of several other non-target chemicals, including pharmaceutical steroids, present in purified sediment extracts.

https://pubmed.ncbi.nlm.nih.gov/17219098/

5754680328c8f57824b1c0bcf7861612

A series of derivatives , like dihydroartemisinin , artesunate , artemether , artether , had the same core chemical structure , and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure .

[Research progress of effect of artemisinin family drugs on T lymphocytes immunomodulation]. artemisinin was isolated from traditional Chinese herb Artemisia annua for treating malaria. A series of derivatives , like dihydroartemisinin , artesunate , artemether , artether , had the same core chemical structure , and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure . Besides anti-malaria,artemisinin family drugs were found to ameliorate many different diseases,which have attracted wide attention in recent years. Among different diseases,artemisinin family drugs were found to have T lymphocytes immunomodulation effects,including activation,proliferation,differentiation,apoptosis and subsets function. Because T cell immunologic response is the key point of many diseases,and impact the pathogenic process,therapeutic effect and prognosis,the drug studies with it as the target have become hotspots in recent years. Studies of artemisinin family drug on T cell immunomodulation were still at the initial stage and involved in different disease; furthermore,T cell immune process involves complicated molecular mechanism,it is imperative to summarize the advance of current studies for further systematic explanation and exploration of their characteristics and mechanisms. This article will summarize the research progress of artemisinin family drugs for malaria,autoimmune disease,hypersensitivity reaction,tumor,schistosomiasis and AIDS relating to T cell immune modulation,so as to provide basic and professional reference for related research and application.

https://pubmed.ncbi.nlm.nih.gov/31872610/

df454d29e767c740e64ec045b436fe31

Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion .

Effect of dipyridamole and aspirin on vein graft patency after coronary bypass operations. Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion . Early (less than or equal to 1 month) and late (1 year) occlusions were reduced both on a per patient and a per distal anastomosis basis. Bleeding complications were not increased. Graft occlusion in high-risk situations (low-flow grafts and endarterectomy) was reduced, but not eliminated, by this antiplatelet regimen. The authors recommend this combination of dipyridamole before surgery, adding aspirin after surgery, to prevent coronary artery bypass graft occlusion.

https://pubmed.ncbi.nlm.nih.gov/2082487/

f694219846d032815ad1116286eee7a7

Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil .

Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil . The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.

https://pubmed.ncbi.nlm.nih.gov/2019458/

fd5eb234c4cfd6cd435a7699e6d13175

All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) .

Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO). lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25-82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) . Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1-40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6-10 months), with a median overall survival (OS) of 15 months (95% CI: 12-18 months). The most common side effects were hand-foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3-4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3-4 toxicity.

https://pubmed.ncbi.nlm.nih.gov/24112786/

6e04b97d5214d34a963c8d2d3d179adb

The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine , pyrilamine ( an antagonist of histamine H(1 ) receptors ) , ranitidine ( an antagonist of histamine H(2 ) receptors ) , morphine ( an opioid receptor agonist ) and naloxone ( an opioid receptor antagonist ) in separate and combined treatments .

Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats. The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine , pyrilamine ( an antagonist of histamine H(1 ) receptors ) , ranitidine ( an antagonist of histamine H(2 ) receptors ) , morphine ( an opioid receptor agonist ) and naloxone ( an opioid receptor antagonist ) in separate and combined treatments . Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 μl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. naloxone alone non-significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia.

https://pubmed.ncbi.nlm.nih.gov/21602597/

fd048d555776da144bf762fba2d83daa

Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore .

Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore . ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer..

https://pubmed.ncbi.nlm.nih.gov/33773562/

4ce332ca0989680dc6d5e790292fba13

It is well established that several of the older AEDs ( carbamazepine , phenytoin and phenobarbital ) , are strong inducers of the hepatic cytochrome P450 ( CYP ) 3A4 enzyme system , and are associated with increased the risk of contraceptive failure .

Pharmacokinetic interactions between contraceptives and antiepileptic drugs. The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs ( carbamazepine , phenytoin and phenobarbital ) , are strong inducers of the hepatic cytochrome P450 ( CYP ) 3A4 enzyme system , and are associated with increased the risk of contraceptive failure . In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.

https://pubmed.ncbi.nlm.nih.gov/18206393/

fadec01e4bb1d93acce4d2143b9068ec

Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose .

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients. Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose . ### methods In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m ### results The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent ### conclusions olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. ### Trial Registration Number NCT01650376.

https://pubmed.ncbi.nlm.nih.gov/30700568/

f21c5b821b9ba475c2e345f4770ecb35

Abiraterone acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , CYP17 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency .

Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer. Abiraterone acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , CYP17 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency . In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.

https://pubmed.ncbi.nlm.nih.gov/20465382/

119edb8f6876404fc0cb6313e179e307

There was no significant correlation between the response to ferrochloroquine and those to mefloquine , halofantrine , primaquine , atovaquone or artesunate .

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine , halofantrine , primaquine , atovaquone or artesunate . Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

https://pubmed.ncbi.nlm.nih.gov/11481286/

fdd6c7c9a225a1bd5e1e673f57088495

All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) .

Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML. ### Experimental Design All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) . ### results Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%. ### conclusion D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).

https://pubmed.ncbi.nlm.nih.gov/25749041/

577dd5441437d2c79fec8349bdb8eb43

In chronic musculoskeletal conditions with assessments over 6 to 12 weeks , topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis , as did topical high-concentration capsaicin in postherpetic neuralgia .

Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews. Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic, typically osteoarthritis of hand or knee, or neuropathic pain. ### objectives To provide an overview of the analgesic efficacy and associated adverse events of topical analgesics (primarily nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate rubefacients, capsaicin, and lidocaine) applied to intact skin for the treatment of acute and chronic pain in adults. ### methods We identified systematic reviews in acute and chronic pain published to February 2017 in the Cochrane Database of Systematic Reviews (the Cochrane Library). The primary outcome was at least 50% pain relief (participant-reported) at an appropriate duration. We extracted the number needed to treat for one additional beneficial outcome (NNT) for efficacy outcomes for each topical analgesic or formulation, and the number needed to treat for one additional harmful outcome (NNH) for adverse events. We also extracted information on withdrawals due to lack of efficacy or adverse events, systemic and local adverse events, and serious adverse events. We required information from at least 200 participants, in at least two studies. We judged that there was potential for publication bias if the addition of four studies of typical size (400 participants) with zero effect increased NNT compared with placebo to 10 (minimal clinical utility). We extracted GRADE assessment in the original papers, and made our own GRADE assessment. ### Main Results Thirteen Cochrane Reviews (206 studies with around 30,700 participants) assessed the efficacy and harms from a range of topical analgesics applied to intact skin in a number of acute and chronic painful conditions. Reviews were overseen by several Review Groups, and concentrated on evidence comparing topical analgesic with topical placebo; comparisons of topical and oral analgesics were rare.For at least 50% pain relief, we considered evidence was moderate or high quality for several therapies, based on the underlying quality of studies and susceptibility to publication bias.In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high-concentration capsaicin had moderate-quality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).We judged evidence of efficacy for other therapies as low or very low quality. Limited evidence of efficacy, potentially subject to publication bias, existed for topical preparations of ibuprofen gels and creams, unspecified diclofenac formulations and diclofenac gel other than Emulgel, indomethacin, and ketoprofen plaster in acute pain conditions, and for salicylate rubefacients for chronic pain conditions. Evidence for other interventions (other topical NSAIDs, topical salicylate in acute pain conditions, low concentration capsaicin, lidocaine, clonidine for neuropathic pain, and herbal remedies for any condition) was very low quality and typically limited to single studies or comparisons with sparse data.We assessed the evidence on withdrawals as moderate or very low quality, because of small numbers of events. In chronic pain conditions lack of efficacy withdrawals were lower with topical diclofenac (6%) than placebo (9%) (11 studies, 3455 participants, number needed to treat to prevent (NNTp) 26, moderate-quality evidence), and topical salicylate (2% vs 7% for placebo) (5 studies, 501 participants, NNTp 21, very low-quality evidence). Adverse event withdrawals were higher with topical capsaicin low-concentration (15%) than placebo (3%) (4 studies, 477 participants, NNH 8, very low-quality evidence), topical salicylate (5% vs 1% for placebo) (7 studies, 735 participants, NNH 26, very low-quality evidence), and topical diclofenac (5% vs 4% for placebo) (12 studies, 3552 participants, NNH 51, very low-quality evidence).In acute pain, systemic or local adverse event rates with topical NSAIDs (4.3%) were no greater than with topical placebo (4.6%) (42 studies, 6740 participants, high quality evidence). In chronic pain local adverse events with topical capsaicin low concentration (63%) were higher than topical placebo (5 studies, 557 participants, number needed to treat for harm (NNH) 2.6), high quality evidence. Moderate-quality evidence indicated more local adverse events than placebo in chronic pain conditions with topical diclofenac (NNH 16) and local pain with topical capsaicin high-concentration (NNH 16). There was moderate-quality evidence of no additional local adverse events with topical ketoprofen over topical placebo in chronic pain. Serious adverse events were rare (very low-quality evidence).GRADE assessments of moderate or low quality in some of the reviews were considered by us to be very low because of small numbers of participants and events. ### Authors Conclusions There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions. In chronic musculoskeletal conditions with assessments over 6 to 12 weeks , topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis , as did topical high-concentration capsaicin in postherpetic neuralgia . Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.Use of GRADE in Cochrane Reviews with small numbers of participants and events requires attention.

https://pubmed.ncbi.nlm.nih.gov/28497473/

b2070e475af07a4614d17d8e754452af

Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease .

Pertuzumab in breast cancer: a systematic review. pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2(+) breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease . This approval has been based on data from a phase III Clinical Evaluation of pertuzumab and trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+). Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future.

https://pubmed.ncbi.nlm.nih.gov/23810292/

8c541ab8655b0d5cf13cf2688cab9063

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma .

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma . Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. ### methods We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. ### results Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. ### conclusions Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.

https://pubmed.ncbi.nlm.nih.gov/33197087/

1337e5873ab749cedb2aa9980a3e455a

The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials .

Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection. The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials . There is only limited data regarding the safety and efficacy in a "real-life" cohort. ### methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. ### results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE. ### conclusions The frequency of SVR in a "real-life" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.

https://pubmed.ncbi.nlm.nih.gov/24884400/

94639dcf9dbc2232915cc56197ae2ca4

In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone .

Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study. Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. ### methods Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. ### results Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1 mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone . Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. ### conclusion Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice.

https://pubmed.ncbi.nlm.nih.gov/28971491/

988d030989c289f7e661a4d25c09a2c2

The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients .

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy. The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients . The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. ### Patients And Methods Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m ### results Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in ### conclusion venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

https://pubmed.ncbi.nlm.nih.gov/32687450/

72cb047193f8acd0c8cbdc92c42cd17b

Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers .

Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers . Thirty-three patients with a histologically confirmed diagnosis of advanced squamous cell carcinoma of the head and neck were treated with a combination of vincristine, methotrexate, and bleomycin. The regimen was as follows: Day 1, vincristine (2 mg iv) and methotrexate (200 mg/m2 iv over 24 hours); Day 2, bleomycin (15 mg/day by iv infusion for 48 hours). Folinic acid rescue began 36 hours after the start of methotrexate. The regimen was repeated at intervals of 3 weeks. Toxicity was minimal but the overall response rate was only 24% (three complete responses and five partial responses) and the median duration of remission was only 16 weeks overall. The combination of vincristine, methotrexate, and bleomycin in this dosage schedule has a response rate lower than that reported with single-agent treatment of advanced head and neck cancers.

https://pubmed.ncbi.nlm.nih.gov/93514/

78463449815401119d838bb799893921

Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure .

Effectiveness of long-acting nifedipine in pheochromocytoma. In the present study, we report a case of pheochromocytoma whose high blood pressure was well controlled by single-agent therapy with long-acting nifedipine, in spite of the failure of the combination of labetalol and prazosin in lowering blood pressure satisfactorily. A 48 year old female was first noted to have hypertension (160/100 mmHg) at 45 years of age. Hypertension was not controlled by conventional antihypertensive drugs. She was admitted to Fukui Prefectural Hospital in September, 1985. Her blood pressure on admission was 210/110 mmHg. Extraction of the left adrenal gland containing a pheochromocytoma (30 x 37 x 10 mm) was performed in November, 1985. Her hypertension and abnormally high plasma noradrenaline (NA) concentration (1,760 pg/ml, normal value 40-350 pg/ml) were sustained even after operation. Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure . Furthermore, single therapy with long-acting nifedipine was effective. No reduction of urinary NA excretion was observed in our patient during long-acting nifedipine therapy, suggesting that the decrease in blood pressure was not caused by suppression of NA release from pheochromocytoma tissue.

https://pubmed.ncbi.nlm.nih.gov/2614935/

416a6d9375f6c9b30592a8c095d439f3

The monoclonal antibodies Ipilimumab , Pembrolizumab and Nivolumab , designed to interfere with T-cell inhibitory signals to activate immune responses against tumours , were originally approved as monotherapy .

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: treatment of melanoma and immune mechanisms of action. Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies Ipilimumab , Pembrolizumab and Nivolumab , designed to interfere with T-cell inhibitory signals to activate immune responses against tumours , were originally approved as monotherapy . Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune related adverse events. In this review we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use. This article is protected by copyright. All rights reserved.

https://pubmed.ncbi.nlm.nih.gov/33450785/

1d2dab74d65b4ba99e22aac2286ee71c

Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI .

Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI . This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole. ### Patients And Methods Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed. ### results Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study. ### conclusion The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.

https://pubmed.ncbi.nlm.nih.gov/22802308/

e412b8e2c69930c30c2634235d41b7fe

It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity .

Clinical and experimental keratitis due to Curvularia lunata (Wakker) Boedijn var. aeria (Batista, Lima and Vasconcelos) Ellis. A case of mycotic keratitis due to Curvularia lunata var. aeria is reported for the first time from India. Direct microscopic examination of the corneal scrapings in KOH (50 g1(-1)), stained with lactophenol cotton blue, revealed brown septate hyphae and the cultures were found positive for fungus. It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity . Lactones were least active and tolciclate and arnebins and inactive. The fungus produced experimental keratomycosis in the rabbit cornea and the infection severity as well as histopathological changes were more pronounced in rabbits that received penicillin, streptomycin and cortisone.

https://pubmed.ncbi.nlm.nih.gov/6890237/

25386eeed3d1ac4d4c3dcdcc1f1a7528

Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC .

Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first-line treatment of metastatic colorectal cancer. Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3-4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89-99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC . Further studies are warranted in PTEN deficiency.

https://pubmed.ncbi.nlm.nih.gov/30302599/

fe47fe1a70f1d97f8051d2f8e7e98202

Physician Utilization Patterns for VEGF-Inhibitor Drugs in the 2012 United States Medicare Population : Bevacizumab , Ranibizumab , and Aflibercept .

Physician Utilization Patterns for VEGF-Inhibitor Drugs in the 2012 United States Medicare Population : Bevacizumab , Ranibizumab , and Aflibercept . To evaluate variation in physician use of vascular endothelial growth factor (VEGF) inhibitors. ### Patients And Methods Population-based analysis of comprehensive, publicly available 2012 Medicare claims, aggregated by physician specialty and service type - including intravitreal injections of bevacizumab (Avastin; Genentech, South San Francisco, CA), ranibizumab (Lucentis; Genetech, South San Francisco, CA), and aflibercept (Eylea; Regeneron, Tarrytown, NY). Physicians were characterized by total patients treated, proportion treated with each drug, total intravitreal injection payments, and proportion of total payments for each drug. ### results The authors identified 2,869 ophthalmologists. On average, each treated 203 patients with VEGF-inhibitors, 75.9% of which were treated with bevacizumab. Using all three agents was the most common practice (1,121 physicians), closely followed by using bevacizumab only (1,061 physicians). ranibizumab accounted for most payments, but bevacizumab was the largest payment source for a sizeable proportion of physicians who used only/mostly bevacizumab. ### conclusion Most ophthalmologists use multiple VEGF inhibitors, but vary in their relative use. A subset of ophthalmologists predominantly use ranibizumab, but ophthalmologists overall use more bevacizumab despite financial incentives favoring ranibizumab. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:555-562.].

https://pubmed.ncbi.nlm.nih.gov/27327285/

a1de37ff2e4c46ad4bbbd914ca5be3dd

Antimicrobials that can be used with confidence to treat NG infection currently in China include ceftriaxone and spectinomycin , but not penicillin , tetracycline , ciprofloxacin , and cefixime .

Antimicrobial Susceptibility Evaluation and Multiple-Locus Variable Number Tandem Repeat Analysis of Neisseria gonorrhoeae Isolates in China in 2012. This study aimed to gain information on the antimicrobial susceptibility and molecular epidemiological typing of Neisseria gonorrhoeae (NG) isolates in China in 2012. ### methods A total of 244 NG isolates were consecutively recovered from patients with uncomplicated gonorrhea attending sexually transmitted disease clinics in 3 Chinese cities-Guangzhou, Nanjing, and Tianjin-in 2012. Neisseria gonorrhoeae susceptibilities to penicillin and tetracycline were examined by detecting penicillinase-producing NG (PPNG) and high-level tetracycline-resistant NG, and NG susceptibilities to ciprofloxacin, spectinomycin, ceftriaxone, and cefixime were determined using an agar dilution method. Neisseria gonorrhoeae isolates were typed by multiple-locus variable number tandem repeat analysis. We conducted a χ analysis to compare clusters with Bonferroni correction and Kruskal-Wallis test. ### results Neisseria gonorrhoeae isolates gathered from the 3 cities differed significantly in the prevalence of tetracycline-resistant NG (P < 0.001) and NG treated with ceftriaxone with a minimum inhibitory concentration of 0.125 mg/L or higher (P < 0.001). The analysis of the combination of the 7 variable number of tandem repeats loci for all of the 244 isolates yielded 110 multiple-locus variable number tandem repeat analysis types falling into 5 clusters. Cluster III was associated with PPNG, whereas cluster II was associated with non-PPNG (P < 0.05) and NG treated with ceftriaxone with a minimum inhibitory concentration of 0.125 mg/L or higher (P < 0.05). ### conclusions Antimicrobials that can be used with confidence to treat NG infection currently in China include ceftriaxone and spectinomycin , but not penicillin , tetracycline , ciprofloxacin , and cefixime . Moreover, some of the resulting clusters were associated with PPNG and NG with decreased ceftriaxone susceptibility.

https://pubmed.ncbi.nlm.nih.gov/28282644/

e32aef4112b7d8f12296ed7e7c257710

A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise , with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET .

Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise , with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET .

https://pubmed.ncbi.nlm.nih.gov/21672194/

354bb4d160b5a92cbae23b489a5a84a4

We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) .

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study). We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) . The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. ### Methods And Materials Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). ### results Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. ### conclusions Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.

https://pubmed.ncbi.nlm.nih.gov/10863062/

f2d6a8abff8a039a68a209d7406b262c

A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours .

A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours . pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.

https://pubmed.ncbi.nlm.nih.gov/18000498/

22da74305c60249c0d19f42ca0802851

These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells .

Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors. Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. ### methods We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. ### results vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. ### conclusion These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells . L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs.

https://pubmed.ncbi.nlm.nih.gov/27504186/

b1f01aa95f676b3db6a8efa07177bf39

Based on encouraging results of previous combination regimens , we used a combination of VM26 , ifosfamide , methyl GAG , mitoxantrone ( or adriamycin ) , high-dose ( HD ) methotrexate and HD Ara C to treat 18 patients with relapsed or refractory NHL .

VIM3-ARA C: an effective salvage regimen in refractory or recurrent aggressive non Hodgkin's lymphoma. A report on 18 cases. Based on encouraging results of previous combination regimens , we used a combination of VM26 , ifosfamide , methyl GAG , mitoxantrone ( or adriamycin ) , high-dose ( HD ) methotrexate and HD Ara C to treat 18 patients with relapsed or refractory NHL . Front-line therapy had been in most of them a reinforced CHOP regimen. Twelve patients (67 per cent) responded: there were nine (50 per cent) partial responses (PR) and three (17 per cent) complete remissions (CR). Nine of these 12 responders were grafted (eight autologous, one allogeneic transplants), one relapsed before autograft could be performed and the two remaining patients were excluded from autograft because of positive bone marrow. Five of nine patients remained free of disease after 11+ to 27+ months. Response rate was higher in patients who relapsed 'off' therapy (2/3), but CR was also obtained in two refractory NHL and persisted for 11+ and 26+ months, suggesting that VIM3-ARA C was, at least partially, non-cross-resistant with front-line adriamycin-containing regimens.

https://pubmed.ncbi.nlm.nih.gov/1743628/

a64fa34c261376602b678d6653cbfc87

We treated this patient with six cycles of CHOEP ( Cyclophosphamide , Doxorubicin , Vincristine , Etoposide , and Prednisone ) chemotherapy .

ALK-positive anaplastic large cell lymphoma presenting multiple lymphomatous polyposis: A case report and literature review. Anaplastic large cell lymphoma (ALCL) is a type of T-cell lymphoma that can be divided into two categories: anaplastic lymphoma kinase-positive (ALK+) and ALK-negative. Gastrointestinal ALK+ ALCL is rare. Multiple lymphomatous polyposis (MLP) is thought to be a representative form of gastrointestinal lesion in mantle cell lymphoma, and T-cell lymphomas seldom show this feature. Here, we report the first known case of ALK+ ALCL with gastroduodenal involvement to present with MLP. ### Case Summary The patient was a 43-year-old man who was complained of a mass in the left inguinal area and was performed open biopsy. ALK+ ALCL was diagnosed pathologically. Computed tomography scan demonstrated multiple lymph node lesions in the abdomen - pelvis/inguinal region, and scattered nodular lesions in both lung fields. He did not complain of gastrointestinal symptoms. While, esophagogastroduodenoscopy identified MLP lesions from the antrum of the stomach to the descending portion of the duodenum and mild thickened folds on the corpus of the stomach, and biopsy showed invasion of ALK+ ALCL. We treated this patient with six cycles of CHOEP ( Cyclophosphamide , Doxorubicin , Vincristine , Etoposide , and Prednisone ) chemotherapy . At the conclusion of treatment, there was complete remission. Numerous white scars were found on the stomach, endoscopically consistent with a remission image of lymphoma. The endoscopic features of this case were thought to be similar to those of MCL. ### conclusion The macroscopic/endoscopic features of gastrointestinal ALK+ ALCL may be more similar to those of B-cell lymphomas rather than T-cell lymphomas.

https://pubmed.ncbi.nlm.nih.gov/31423437/

d0b9720d23cd33576ee3ef84353999bb

One study evaluated gemcitabine with gemcitabine and pertuzumab .

Gemcitabine for recurrent ovarian cancer - a systematic review and meta-analysis. More than 80 % of women with advanced ovarian cancer relapse either during or after adjuvant therapy. Platinum-sensitive women are rechallenged with a platinum-combination therapy and platinum-resistant women are challenged with non-platinum drugs. gemcitabine is one of many treatments that can be used both as single-agent or as combination therapy for the treatment of recurrent ovarian cancer. ### methods We included all randomised controlled trials investigating patients treated with gemcitabine for recurrent ovarian cancer and reporting data on overall survival, progression-free survival and toxicity. CENTRAL, EMBASE and MEDLINE were searched on the 31 ### results We included six randomised controlled trials that evaluated gemcitabine either alone or as combination therapy. Two studies compared gemcitabine to pegylated liposomal doxorubicin in women with platinum-resistant recurrent ovarian cancer. Difference in overall and progression-free survival was non-significant. gemcitabine treatment was associated with significantly more neutropenia, whereas pegylated liposomal doxorubicin was associated with significantly more hand-foot syndrome. One study evaluated carboplatin and gemcitabine to carboplatin. Difference in overall survival was non-significant, but progression-free survival was longer with gemcitabine and carboplatin (HR: 0.72, 95% CI 0.58-0.9). One study evaluated gemcitabine with gemcitabine and pertuzumab . Overall survival and progression-free survival was similar between the two arms. One study compared gemcitabine and carboplatin to gemcitabine, carboplatin and bevacizumab. Overall survival was similar in the two arms. Progression-free survival was significantly better in the bevacizumab arm (HR 0.48 95% CI 0.39-0.61). One study compared etoposide and gemcitabine to etoposide. The study showed similar overall survival and progression-free survival. ### discussion The results show that gemcitabine is an active and safe agent in the treatment of both platinum-sensitive and resistant recurrent ovarian cancer but might highlight the need of new randomised studies in heavily pre-treated patients.

https://pubmed.ncbi.nlm.nih.gov/31604664/

d202522f84cf3c5b0747be8be67b851e

Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein ( MRP ) .

Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH3 cells. Okadaic acid as well as other, structurally different, inhibitors of serine/threonine phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells. Incubation with stepwise raised concentrations of okadaic acid resulted in the isolation of cells that were increasingly less sensitive to the cytotoxic effect of this agent. After about 18 months cells were selected that survived at 300 nM okadaic acid, which is about 30 times the initially lethal concentration. This study revealed that a major pharmacokinetic mechanism underlying cell survival was the development of a P-glycoprotein-mediated multidrug resistance (MDR) phenotype. The increase in mRNA levels of the mdr1b P-glycoprotein isoform correlated with the extent of drug resistance. Functional assays revealed that increasing drug resistance was paralleled by a decreased accumulation of rhodamine 123, a fluorescent dye which is a substrate of mdr1-mediated efflux activity. Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein ( MRP ) . Okadaic acid resistance included cross-resistance to other cytotoxic agents that are substrates of mdr1-type P-glycoproteins, like doxorubicin and actinomycin D, but not to non-substrates of mdr1, e.g. cytosine arabinoside. Thus, functional as well as biochemical features support the conclusion that okadaic acid is a substrate of the mdr1-mediated efflux activity in rat pituitary GH3 cells. Maintenance of resistance after withdrawal of okadaic acid as well as metaphase spreads of 100 nM okadaic acid-resistant cells suggested a stable MDR genotype without indications for the occurrence of extrachromosomal amplifications, e.g. double minute chromosomes.

https://pubmed.ncbi.nlm.nih.gov/10494879/

922f735090a2604374e6743893bd2a15

We conclude that the combination of thiotepa , 5FU , and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer .

Phase II trial of 5-fluorouracil, folinic acid, and N,N1,N11-triethylenethiophosphoramide (thiotepa) in patients with advanced breast cancer. A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34-67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant; nadir WBC count: < 1,000/mm3 (10 patients); 1,000-1,999/mm (13 patients); nadir platelet count: < 20,000/mm3 (8 patients): 20,000-49,000/mm3 (8 patients); 50,000-99,000/mm3 (10 patients). We conclude that the combination of thiotepa , 5FU , and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer .

https://pubmed.ncbi.nlm.nih.gov/7572752/

362de315475f7a6a9eb10761b7406f1f

Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin ( 20 mg/m2/d continuous infusion [ CI ] ) , fluorouracil ( 800 mg/m2/d CI ) , and leucovorin ( 500 mg/m2/d CI ; PFL ) for 4 days followed by concurrent therapy with cisplatin ( 100 mg/m2/d on days 1 and 22 ) and approximately 70 Gy of external-beam radiotherapy .

Cisplatin, fluorouracil, and leucovorin induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: long-term follow-up. The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. ### Patients And Methods Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin ( 20 mg/m2/d continuous infusion [ CI ] ) , fluorouracil ( 800 mg/m2/d CI ) , and leucovorin ( 500 mg/m2/d CI ; PFL ) for 4 days followed by concurrent therapy with cisplatin ( 100 mg/m2/d on days 1 and 22 ) and approximately 70 Gy of external-beam radiotherapy . ### results Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. ### conclusion Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

https://pubmed.ncbi.nlm.nih.gov/15284256/

9c5365a40b4985db2716f6a1bcce365b

The saliva is shown to inhibit human platelet aggregation induced by thrombin , collagen , adenosine diphosphate ( ADP ) , epinephrine , platelet activating factor ( 1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [ PAF ] ) , and arachidonic acid .

Platelet aggregation and coagulation inhibitors in leech saliva and their roles in leech therapy. Prolonged bleeding by the host after the leech ceases to feed and several reports that the use of leeches restores blood flow in the microcirculation after plastic surgery led us to search for inhibitors of platelet aggregation in Hirudo medicinalis saliva. Dilute leech saliva was collected by phagostimulating starved leeches with a solution of arginine in saline. The saliva is shown to inhibit human platelet aggregation induced by thrombin , collagen , adenosine diphosphate ( ADP ) , epinephrine , platelet activating factor ( 1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [ PAF ] ) , and arachidonic acid . We have isolated the PAF inhibitor and found it to be an amphipathic phosphoglyceride. We have also purified apyrase adenosine triphosphate ([ATP] diphosphohydrolase), which inhibits ADP-induced platelet aggregation, and have described collagenase. Besides well-known hirudin, Hirudo saliva contains a potent inhibitor of coagulation factor Xa. We also report antiaggregant and anticoagulant activities in the crop content of the closely related Nile leech, Limnatis nilotica. Anticoagulants of hematophagous species are surveyed. We have used medicinal leeches in plastic surgery for decompression of skin flaps and in patients with postphlebitic syndrome and peripheral arterial occlusions. Preliminary results indicate certain beneficial effects of leech therapy.

https://pubmed.ncbi.nlm.nih.gov/8836013/

4fe6d3a7529d53292ae55a225e485bef

This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy .

Randomized phase II clinical trial and biomarker analysis of paclitaxel plus epirubicin versus vinorelbine plus epirubicin as neoadjuvant chemotherapy in locally advanced HER2-negative breast cancer with TEKT4 variations. Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy . ### methods In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. ### results 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). ### conclusions Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.

https://pubmed.ncbi.nlm.nih.gov/32975708/

16f4c299a62155543b6089073a1917bc

Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight ?

Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial. This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. ### Study Question Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight ? ### Study Design We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18-65 years of age without diabetes and with the body mass index (BMI) of 30-45 kg/m2. ### Measures And Outcomes The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. ### results Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were -1.99%, -1.69%, and -1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). ### conclusions Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30-39.9 kg/m2, especially participants with hyperinsulinemia.

https://pubmed.ncbi.nlm.nih.gov/33369909/

4e1fd1d1db4d8bba13b1e7ac24a90361

Combinatory activity of linezolid and levofloxacin with antituberculosis drugs in Mycobacterium tuberculosis .

Combinatory activity of linezolid and levofloxacin with antituberculosis drugs in Mycobacterium tuberculosis . The increase of multidrug and extensively drug resistant Mycobacterium tuberculosis strains turns the search for new tuberculosis (TB) treatment options of paramount importance. ### objective In this sense, the present study evaluates the in vitro activity of isoniazid (INH)/rifampicin (RIF)/levofloxacin (LVX) and INH/RIF/linezolid (LNZ) combinations in resistant M. tuberculosis. ### design The activities of the combinations were evaluated with M. tuberculosis H ### results MIC ranged from 0.03 - 6.25 μg/mL for INH, 0.008-100 μg/mL for RIF, 0.12-0.25 μg/mL for LVX and 0.25-0.5 μg/mL for LNZ in the H ### conclusion The present study calls attention for the potential use of INH/RIF/LVX and INH/RIF/LNZ combinations in the treatment of resistant TB.

https://pubmed.ncbi.nlm.nih.gov/30029913/

636111941b260acfe7cf2c70fa38a62c

Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume .

Cost analysis of fixed-dose combination of dutasteride and tamsulosin compared with concomitant dutasteride and tamsulosin monotherapy in patients with benign prostatic hyperplasia in Canada. We estimate the lifetime cost of treatment for moderate/severe symptoms associated with benign prostatic hyperplasia (BPH) in a cohort of Canadian men aged 50 to 59, and we evaluate the costs of 2 daily bioequivalent treatment options: fixed-dose combination (FDC) of dutasteride (0.5 mg) and tamsulosin (0.4 mg), or concomitant administration of dutasteride (0.5 mg) and tamsulosin (0.4 mg) monotherapies. ### methods The expected lifetime costs were estimated by modelling the incidence of acute urinary retention (AUR), BPH-related surgery and clinical progression over a patient's lifetime (up to 25 years). A model was developed to simulate clinical events over time, based on a discrete Markov process with 6 mutually exclusive health states and annual cycle length. ### results The estimated lifetime budget cost for the cohort of 374 110 men aged 50 to 59 in Canada is between $6.35 billion and $7.60 billion, equivalent to between $16 979 and $20 315 per patient with moderate/severe symptoms associated with BPH. Costs are lower for FDC treatment, with the net difference in lifetime budget impact between the 2 treatment regimens at $1.25 billion. In this analysis, the true costs of BPH in Canada are underestimated for 2 main reasons: (1) to make the analysis tractable, it is restricted to a cohort aged 50 to 59, whereas BPH can affect all men; and (2) a closed cohort approach does not include the costs of new (incident) cases. ### conclusion Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume . This analysis, using a representational patient group, suggests that the FDC is a more cost-effective treatment option for BPH.

https://pubmed.ncbi.nlm.nih.gov/24454593/

1e2154eeedba947f07269a6b40e09f81

The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor ( perindopril ) and of the diuretic indapamide in spontaneously hypertensive rats ( SHR ) .

Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects. The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor ( perindopril ) and of the diuretic indapamide in spontaneously hypertensive rats ( SHR ) . ### methods Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. ### results The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. ### conclusion These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.

https://pubmed.ncbi.nlm.nih.gov/8986928/

2197c51f733605c3f8260a584aed73ec

A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia .

A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia . Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). ### methods Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. ### results The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). ### conclusions FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.

https://pubmed.ncbi.nlm.nih.gov/33626197/

f933973c4ea22c3f3c27201921adcf04

Five other treatments closely followed ( dabrafenib [ HR PFS : 0.30 ] , nivolumab plus ipilimumab [ HR PFS : 0.34 ] , vemurafenib [ HR PFS : 0.38 ] , nivolumab [ HR PFS : 0.42 ] and pembrolizumab [ HR PFS : 0.46 ] ) .

A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. ### methods A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. ### results The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed ( dabrafenib [ HR PFS : 0.30 ] , nivolumab plus ipilimumab [ HR PFS : 0.34 ] , vemurafenib [ HR PFS : 0.38 ] , nivolumab [ HR PFS : 0.42 ] and pembrolizumab [ HR PFS : 0.46 ] ) . In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). ### conclusions Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.

https://pubmed.ncbi.nlm.nih.gov/31670077/

94f63b0823dca4159b120ef7a33e61d3

IGROV-1/APL resistant cell line shows the typical MDR phenotype : ( 1 ) increased expression of membrane-associated P-glycoprotein , ( 2 ) cross-resistance to drugs like etoposide , doxorubicin , vinblastine , vincristine , taxol , colchicin and the novel anticancer drug Yondelis ( ET-743 ) .

Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype : ( 1 ) increased expression of membrane-associated P-glycoprotein , ( 2 ) cross-resistance to drugs like etoposide , doxorubicin , vinblastine , vincristine , taxol , colchicin and the novel anticancer drug Yondelis ( ET-743 ) . The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.

https://pubmed.ncbi.nlm.nih.gov/16258264/

0ad86118b39b724723eb97299cbb1378

Patients with newly diagnosed , locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin ( area under the curve , 1.5 ) and paclitaxel ( 45 mg/m(2 ) ) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks ( every day for 18 days , twice a day for 12 days ) ( grading determined according to the TNM staging system ) .

Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer. A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). ### methods Patients with newly diagnosed , locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin ( area under the curve , 1.5 ) and paclitaxel ( 45 mg/m(2 ) ) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks ( every day for 18 days , twice a day for 12 days ) ( grading determined according to the TNM staging system ) . All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks. ### results Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy-dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted. ### conclusions Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen.

https://pubmed.ncbi.nlm.nih.gov/19634161/

20e450bb899c2d7d5613cd92168ae214

Phase 1b trial of docetaxel , prednisone , and pazopanib in men with metastatic castration-resistant prostate cancer .

Phase 1b trial of docetaxel , prednisone , and pazopanib in men with metastatic castration-resistant prostate cancer . docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. ### methods This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. ### results Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m ### conclusions The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

https://pubmed.ncbi.nlm.nih.gov/31497882/