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6357d2a470758a4d5aea49835ba7b900

However , we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group .

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART. The valsartan amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However , we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group . There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.

https://pubmed.ncbi.nlm.nih.gov/21993491/

3d1bf519d3d919348aa6eab2ae11a2bd

Effects of chloroquine , mefloquine and quinine on natural killer cell activity in vitro .

Effects of chloroquine , mefloquine and quinine on natural killer cell activity in vitro . Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF) or interleukin 2 (Il-2); preincubation of mononuclear cells with IF or Il-2 followed by addition of anti-malarial drugs decreased the inhibitory effects of the drugs. The drug-induced inhibition of the NK cell activity was not dependent on the presence of monocytes. Using monocyte depleted Percoll fractionated NK cell enriched populations in a single cell agarose assay, it was shown that the inhibitory effects of mefloquine, but not of chloroquine and quinine were due to an inhibition of the formation of effector/target cell conjugates.

https://pubmed.ncbi.nlm.nih.gov/2431633/

dd4bbac74556ad8a14b439a38da022bd

Fulvestrant ( intramuscular injection 250 mg month(-1 ) ) was found to be at least as effective as anastrozole ( orally 1 mg day(-1 ) ) for time to progression ( 5.5 vs 4.1 months , respectively ( hazard ratio ( HR ): 0.95 ; 95.14 % confidence interval ( CI ) , 0.82 - 1.10 ; P=0.48 ) ) and objective response 19.2 vs 16.5 % , respectively ; treatment difference 2.75 % ; 95.14 % CI , -2.27 to 9.05 % ; P=0.31 ) .

Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials. fulvestrant ('Faslodex') is a new type of endocrine treatment--an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. Early efficacy data from phase I/II trials have demonstrated fulvestrant to be effective and well tolerated. Two randomised phase III trials have compared the efficacy of fulvestrant and the aromatase inhibitor, anastrozole, in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy. Fulvestrant ( intramuscular injection 250 mg month(-1 ) ) was found to be at least as effective as anastrozole ( orally 1 mg day(-1 ) ) for time to progression ( 5.5 vs 4.1 months , respectively ( hazard ratio ( HR ): 0.95 ; 95.14 % confidence interval ( CI ) , 0.82 - 1.10 ; P=0.48 ) ) and objective response 19.2 vs 16.5 % , respectively ; treatment difference 2.75 % ; 95.14 % CI , -2.27 to 9.05 % ; P=0.31 ) . More recently, fulvestrant has also been shown to be noninferior to anastrozole in terms of overall survival, with median time to death being 26.4 months in fulvestrant-treated patients and 24.2 months in those treated with anastrozole (HR: 0.97; 95% CI, 0.78-1.21; P=0.82). In a further randomised phase III trial, fulvestrant was compared with tamoxifen as first-line therapy for advanced disease in postmenopausal women. In the overall population, efficacy differences favoured tamoxifen and noninferiority of fulvestrant could not be ruled out. In the prospectively defined subset of patients with ER-positive and/or progesterone receptor-positive disease, there was no statistically significant difference between fulvestrant and tamoxifen. This paper reviews the efficacy and tolerability results from these trials.

https://pubmed.ncbi.nlm.nih.gov/15094759/

267cd5b262efa4d0f40eeeab4d4e304c

Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p

Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients. Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. ### methods We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. ### results Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. ### conclusions Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.

https://pubmed.ncbi.nlm.nih.gov/32468335/

9b8558943abd223f38c55dac03ee9082

Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 .

Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer. This ongoing phase I study sought to establish the maximum tolerated dose of the combination of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. paclitaxel was administered as a 3-hour intravenous infusion. The carboplatin infusion was administered over 30 minutes immediately afterward. Patients were assigned sequentially to one of eight treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 185 mg/m2 and from 230 to 350 mg/m2, respectively. Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 . The combination has an excellent safety profile, with only a few, short-lasting episodes of neutropenia observed and no evidence of infection. At the doses tested, thrombocytopenia has not occurred.

https://pubmed.ncbi.nlm.nih.gov/9007129/

5af37444c8364f62af66ab7987da2456

FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML , as indicated by the following ratios of median sensitivities : the anthracyclines ( 2.6- to 3.2-fold ) , mitoxantrone ( 12.5-fold ) , etoposide ( 8.7-fold ) , and cytarabine ( 2.9-fold ) .

Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. Determining in vitro drug resistance may reveal clinically relevant information in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 children with acute myeloid leukemia (AML) and 536 children with acute lymphoblastic leukemia (ALL). The differences between 3 French-American-British (FAB) types (M1/M2, M4, and M5) were also compared. AML was significantly more resistant than ALL to the following drugs, as noted by the median resistance: glucocorticoids (greater than 85-fold), vincristine (4.4-fold), L-asparaginase (6.9-fold), anthracyclines (1.8- to 3.4-fold), mitoxantrone (2.6-fold), etoposide (4.9-fold), platinum analogues (2.4- to 3.4-fold), ifosfamide (3.5-fold), and thiotepa (3.9-fold). For cytarabine and thiopurines, the median LC50 values (the drug concentration that kills 5% of the cells) were equal. Also, busulfan, amsacrine, teniposide, and vindesine showed no significant differences, but the numbers were smaller, and the median LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs demonstrated greater cytotoxicity in AML. FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML , as indicated by the following ratios of median sensitivities : the anthracyclines ( 2.6- to 3.2-fold ) , mitoxantrone ( 12.5-fold ) , etoposide ( 8.7-fold ) , and cytarabine ( 2.9-fold ) . For etoposide and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-asparaginase and vincristine as ALL. Only 15% of the AML samples were "intermediately" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer prognosis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance profiles may be helpful in the rational design of further treatment protocols. (Blood. 2000;96:2879-2886)

https://pubmed.ncbi.nlm.nih.gov/11023525/

76f53d15b6627c4c13e14f047a241f67

[ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] .

[ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] . Fourty-two febrile episodes of 32 patients with hematologic disease during neutropenia were treated with two randomly assigned antibiotic combinations of either piperacillin plus gentamicin or piperacillin plus aztreonam. Eleven of the 22 febrile episodes treated with piperacillin plus gentamicin and 12 of the 20 febrile episodes treated with piperacillin plus aztreonam responded. Addition of cefamandole to non-responders improved the outcome in 2 of the 16 febrile episodes. Mean nadir leucocyte count, age, sex, and underlying disease were not significantly different in both groups. Side effects were tolerable in both groups, although 1 patient treated with piperacillin plus gentamicin showed severe renal impairment. piperacillin plus aztreonam is as effective as piperacillin plus gentamicin as an empiric antibiotic combination in the treatment of febrile episodes with hematologic disease during neutropenia.

https://pubmed.ncbi.nlm.nih.gov/1402071/

c8c3eefd188ec9458a1b50c453b92dfb

The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man .

Effect of salbutamol on digoxin pharmacokinetics. A single dose of the beta 2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a beta 2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man . Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 micrograms.kg-1.h-1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 micrograms.kg-1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0-6 h was 15% lower during salbutamol infusion than during saline infusion. salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/1618253/

f6650ee92d2f6ba1fb001d64344a260b

Mecamylamine reversed the effects of nicotine on SHR performance .

Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD). Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance . These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD.

https://pubmed.ncbi.nlm.nih.gov/27363925/

a2471412eb546f1cfa6a282660907512

The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis .

Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis .

https://pubmed.ncbi.nlm.nih.gov/8907592/

bd6411f1a1b7f41d6e10153cd2202962

In the metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival .

Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival . Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.

https://pubmed.ncbi.nlm.nih.gov/25824606/

53a14a119d41a911324fb13bb24c206b

Patients in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy .

Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study. We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy . Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/28002342/

09afedc0b9034c5961cc31e111f44242

In patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity .

Interaction between digoxin and propafenone. The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity .

https://pubmed.ncbi.nlm.nih.gov/2911842/

f12072676087f8e74c862655cba32504

To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC .

Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis. Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. ### objectives To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC . ### Data Sources Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. ### Review Methods A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. ### results Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant benefit in terms of overall survival. Two separate economic analyses were conducted based on the completed trials; neither LAP + AI nor TRA + AI was found to be cost-effective when compared with AI monotherapy. ### limitations Because of differences in the EGF30008 and the TAnDEM trials, the Assessment Group believes the indirect comparisons analyses conducted by the manufacturers are inappropriate and, for the same reason, chooses not to compare LAP + AI with TRA + AI in an economic evaluation. ### conclusions LAP + AI and TRA + AI appear to be clinically more effective than AI monotherapy, but neither is cost-effective compared with AIs alone. It was not possible to compare LAP + AI with TRA + AI. Future research should include research into treating mBC in the HR+/HER2+ population who are not TRA (or LAP) naive and into comparing the clinical effectiveness of AIs as monotherapy in patients with HER2+ and human epidermal growth factor 2-negative breast cancer. ### funding The National Institute for Health Research Technology Assessment programme.

https://pubmed.ncbi.nlm.nih.gov/22152751/

5291c1729be9df2b8b65f392854410de

Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance .

Combination therapy with nateglinide and vildagliptin improves postprandial metabolic derangements in Zucker fatty rats. Postprandial metabolic derangements are one of the risk factors of cardiovascular disease in humans. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial metabolic derangements. In this study, we investigated the potential utility of combination therapy with vildagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial metabolic derangements in Zucker Fatty (ZF) rats, an animal model of obesity with insulin resistance. ZF rats fed twice daily with or without high fat diet (HFD) were given vehicle, 50 mg/kg of nateglinide, 10 mg/kg of vildagliptin, or both for 6 weeks. Combination therapy with nateglinide and vildagliptin for 2 weeks ameliorated postprandial hyperglycemia, hypertriglyceridemia, and elevation of free fatty acid in ZF rats fed with HFD. 6-week treatment with nateglinide and vildagliptin not only increased hepatic levels of phosphorylated forkhead box protein 1A (FOXO1A), but also reduced triglyceride contents in the liver. Combination therapy also prevented the loss of pancreatic islet mass in ZF rats fed with HFD. These observations demonstrate that combination therapy with nateglinide and vildagliptin may improve postprandial metabolic derangements probably by ameliorating early phase of insulin secretion and hepatic insulin resistance, respectively, in ZF rats fed with HFD. Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance .

https://pubmed.ncbi.nlm.nih.gov/20625970/

e9bc93e6cd607f5ce2ab6d592ba99266

Paclitaxel , doxorubicin , tamoxifen , erlotinib , gefitinib , temozolomide , and methotrexate are among therapeutic agents whose efficacy is influenced by the expression of H19 .

The role of H19 lncRNA in conferring chemoresistance in cancer cells. H19 is an oncofetal transcript with crucial roles in the development and progression of several neoplastic cells. With anti-apoptotic, pro-proliferative, and pro-migratory functions, H19 affects the carcinogenic process from different functional points. In addition, H19 has central roles in the induction of chemoresistance in breast cancer, lung cancer, glioma, liver cancer, and other types of cancers. Induction of EMT, activation of oncogenic signaling pathways, and changes in the tumor microenvironment are among mechanisms of participation of H19 in chemoresistance. Paclitaxel , doxorubicin , tamoxifen , erlotinib , gefitinib , temozolomide , and methotrexate are among therapeutic agents whose efficacy is influenced by the expression of H19 . In the present paper, we discuss the impact of H19 in conferring resistance to chemotherapeutic agents in different cancers.

https://pubmed.ncbi.nlm.nih.gov/33667788/

a28fce0214516827c33a6acc9a87f898

Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only .

Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only . In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse.

https://pubmed.ncbi.nlm.nih.gov/2540788/

241b3b811402f79bbd36216dd0287f70

Amisulpride demonstrated a greater improvement in BPRS total scores ( P<0.05 ) and PANSS negative subscores ( P=0.0001 ) than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations .

Amisulpride: a review of its efficacy in schizophrenia. To assess the efficacy of the new atypical antipsychotic drug, amisulpride. ### method Studies comparing the efficacy of amisulpride with that of haloperidol and risperidone, respectively, are reviewed. Outcome measures were Clinical Global Impression, Brief Psychiatric Rating Scale (BPRS), and Positive And Negative Symptom Scale (PANSS) scores. ### results amisulpride was at least as effective as haloperidol and risperidone in the improvement of positive symptoms, and significantly more efficacious than haloperidol in reducing PANSS negative subscores (P=0.038) in patients with acute exacerbations. Amisulpride demonstrated a greater improvement in BPRS total scores ( P<0.05 ) and PANSS negative subscores ( P=0.0001 ) than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations . ### conclusion amisulpride can thus be considered for use as first-line treatment of acute and chronic schizophrenia.

https://pubmed.ncbi.nlm.nih.gov/10823307/

24bf61baac10caa2ceda2cdbe17c973c

In patients with acute cholecystitis , ampicillin plus tobramycin , cefoperazone and piperacillin had clinical cure rates of 85 , 95 and 95 per cent , respectively .

Antibiotics in infections of the biliary tract. The combination of a penicillin and an aminoglycoside has been recommended as the initial treatment of choice for patients with infections of the biliary tract. However, elderly, septic, patients with jaundice have a high incidence of renal problems. For this reason, amingolycoside treatment of these patients must be reevaluated as newer less nephrotoxic agents become available. We, therefore, performed a prospective, randomized trial of ampicillin plus tobramycin, cefoperazone and piperacillin in patients with biliary tract infections. During a 20 month period, 106 patients with acute cholecystitis (53) or cholangitis (53), or both, received one of these antibiotic regimens for a minimum of five days. In patients with acute cholecystitis , ampicillin plus tobramycin , cefoperazone and piperacillin had clinical cure rates of 85 , 95 and 95 per cent , respectively . In patients with cholangitis, however, cure rates for the three regimens were 85, 56 (p less than 0.05 versus ampicillin plus tobramycin) and 60 per cent (not significant versus ampicillin plus tobramycin), respectively. Moreover, 13 per cent of the patients receiving cefoperazone had an increased prothrombin time and three of 39 patients receiving this antibiotic had clinical problems with bleeding. Nephrotoxicity was greatest in patients with cholangitis receiving ampicillin plus tobramycin, 10 per cent, as compared with 3 per cent in those who did not receive an aminoglycoside. This difference, however, was not statistically significant. It was concluded that piperacillin should be considered for antibiotic management of patients with acute cholecystitis and that further studies are necessary in patients with cholangitis to determine whether or not newer agents should replace penicillin and aminoglycoside combinations.

https://pubmed.ncbi.nlm.nih.gov/3310282/

03ac9f494ca93f526d5d08ad0531741a

A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel .

An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer. pemetrexed is a novel antifolate antimetabolite that targets multiple folate-dependent enzymatic pathways and inhibits multiple enzymes involved in purine and pyrimidine synthesis. Its targets include pathways that, when amplified, are associated with reduced efficacy in conventional cytotoxic agents. As second-line treatment for advanced non-small cell lung cancer, (NSCLC) pemetrexed, when administered with folic acid and vitamin B12, has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel. A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel . Newer targeted therapies, especially the epidermal growth factor receptor inhibitors gefitinib and erlotinib, have produced conflicting results and have only been compared with best supportive care and placebo. They should be compared directly to pemetrexed as second-line therapy in large, randomised studies of patients with advanced NSCLC. For patients with advanced recurrent NSCLC and good performance status who progress after first-line chemotherapy, pemetrexed should be considered as a new standard of care.

https://pubmed.ncbi.nlm.nih.gov/16318436/

f25d84924710d85834c20bd5df3dceea

Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases .

Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases . However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections.

https://pubmed.ncbi.nlm.nih.gov/7514977/

4d7d05a563202fd48c05ee58a0d965ac

The diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy .

Human Herpesvirus Type 8-associated Large B-cell Lymphoma: A Nonserous Extracavitary Variant of Primary Effusion Lymphoma in an HIV-infected Man: A Case Report and Review of the Literature. Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma subtype primarily seen in human immunodeficiency virus (HIV)-infected individuals with low CD4(+) cell counts and elevated HIV viral loads. It has always been associated with human herpesvirus type 8 (HHV-8) and in 80% of cases has also been associated with Epstein-Barr virus (EBV). Less commonly, PEL has presented in patients with advanced age and other conditions associated with an altered immunity, including malignancy, liver cirrhosis, and immunosuppressive medications. It is a tumor of B-cell lineage; however, it shows a "null" phenotype, rarely expressing pan-B cell surface antigens. It will usually express CD45, CD30, CD38, CD138, and MUM1 and is characterized by lymphomatous effusions in body cavities but not lymphadenopathy. It is an aggressive lymphoma, with an average median survival of < 1 year. HHV-8-associated large B-cell lymphoma (HHV-8-LBL) is a second variant of PEL that is both solid and extracavitary. It has immunoblastic and/or anaplastic morphologic features and a distinct immunohistochemical staining pattern. It could also have a different clinical presentation than that of classic PEL. ### Materials And Methods We describe the case of a 57-year-old HIV-infected man who presented with a slow-growing and asymptomatic abdominal mass. Examination of an excisional biopsy specimen showed malignant large cells with prominent cytoplasm that were positive for pan-B cell antigen CD20, HHV-8, and EBV and negative for CD138, CD10, BCL-6, CD3, and CD30. The Ki-67 labeling index was 90%. The diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy . At 12 months after treatment, he was in complete remission. We also performed a Medline and Embase search to better understand the clinical findings of our patient and the unique attributes of HHV-8-LBL. Focusing our search on English language studies, we identified 83 cases of HHV-8-LBL without an effusion component. We compared these 83 cases with 118 reported cases of classic PEL. ### results The median age of the patients with HHV-8-LBL was 41 years (range, 24-77), and 96% of the cases were associated with HIV. The median age of the patients with classic PEL was 41 years (range, 26-86), and 96% of the cases were associated with HIV. Of those with HHV-8-LBL, 31 of 61 (51%) had a pre-existing diagnosis of acquired immunodeficiency syndrome (AIDS) and 47 of 63 (75%) were coinfected with EBV. In contrast, 69 of 96 patients (72%) with classic PEL had a pre-existing AIDS diagnosis and 40 of 49 (82%) were coinfected with EBV. The mean CD4(+) count of the HHV-8-LBL patients was 256 cells/μL (range, 18-1126 cells/μL) compared with 139 cells/μL (range, 2-557 cells/μL) in the classic PEL patients. The median survival time for both groups was similar at 5.5 months (range, 25 days to ≥ 25 months) for patients with HHV-8-LBL and 4 months (range, 2 days to ≥ 113 months) for those with classic PEL. More patients with HHV-8-LBL were alive at the last follow-up point (59% vs. 18%). The percentage of patients achieving complete remission was 54% (30 of 56) and 36% (32 of 89) for HHV-8-LBL and classic PEL, respectively. ### conclusion Our patient's high CD4(+) cell count, the lack of a pre-existing AIDS diagnosis, and the excellent response to chemotherapy highlights that HHV-8-LBL might have distinct clinical features and possibly a better response to chemotherapy than classic PEL. HHV-8-LBL should be included in the differential diagnosis of HIV patients with solid lesions. It is essential that patients' Centers for Disease Control and Prevention HIV clinical status and HIV viral load at the diagnosis of PEL and HHV-8-LBL be reported and that the reported clinical results include longer term follow-up data. Only then will a more complete clinical picture of this little-appreciated and little-understood PEL variant be defined.

https://pubmed.ncbi.nlm.nih.gov/27234438/

05844fac1ef40cc8323e39504e4af8e5

Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) .

A phase I study of ifosfamide and doxorubicin with recombinant human granulocyte colony-stimulating factor in stage IV breast cancer. Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) . Eighteen women with stage IV breast cancer were enrolled in a Phase I study of an escalating dose of ifosfamide (1.2 g/m2/day for 5 days-2.75 g/m2/day for 5 days) with doxorubicin 20 mg/m2/day for 3 days. Granulocyte colony-stimulating factor was used at 5 microgram/kg on day 6 until hematological recovery. Prophylactic antibiotics were also used. The maximum tolerated dose of ifosfamide in combination with doxorubicin was 2.75 g/m2/day for 5 days. The objective response rate was 83% with a complete response rate of 33% (6/18 patients); the median time to treatment failure was 11.5 months. The median survival has not been reached and will exceed 18 months. We concluded that the recommended dose of ifosfamide in combination with doxorubicin is 2.5 g/m2/day for 5 days. This combination shows promise in stage IV breast cancer.

https://pubmed.ncbi.nlm.nih.gov/9815972/

05030f04e3fe94ee28f0a39f5bb787cd

A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer .

A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer . This combined, retrospective analysis compared once-per-chemotherapy-cycle pegfilgrastim with daily filgrastim in breast cancer patients undergoing myelosuppressive chemotherapy enrolled in two similarly designed, randomized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, a single subcutaneous (SC) injection of pegfilgrastim [either 6 mg (n=77) or 100 microg/kg (n=149)] was administered, or daily filgrastim SC injections (5 microg/kg/day; n=222) were initiated and continued until either absolute neutrophil count (ANC) > or =10 x 10(9)/l after the expected nadir or for up to 14 days, whichever occurred first. Individually, each of these trials demonstrated that a single pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of filgrastim. Clinical efficacy data from the two trials were combined for analysis (n=448). The risk of febrile neutropenia (FN; absolute neutrophil count <0.5 x 10(9)/l with fever > or =38.2 degrees C) was significantly lower [11% vs 19%, respectively; relative risk = 0.56 (95% confidence interval: 0.35, 0.89)] in patients receiving pegfilgrastim than for those receiving filgrastim. Trends towards lower risks of hospitalization and intravenous anti-infective use were also observed. These observations were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. Pegfilgrastim may offer patients more effective protection against neutropenic complications of chemotherapy with fewer injections and less disruption to their lives.

https://pubmed.ncbi.nlm.nih.gov/12684649/

27c978e08bc33f86686d1c1ae90f631c

[ Nilotinib in patients with chronic myeloid leukemia without response to imatinib ] .

[ Nilotinib in patients with chronic myeloid leukemia without response to imatinib ] . Resistance and intolerance to imatinib in patients with chronic myeloid leukemia requires alternative therapies. nilotinib provides a choice as a second-line treatment. The objective of this report was to show the results of a group of patients with chronic myeloid leukemia who received nilotinib as a second-line treatment. ### methods The medical records of 16 patients of both sexes, of any age, diagnosed with chronic myeloid leukemia, who received nilotinib as a second-line treatment, were reviewed. All of them had received imatinib prior as first-line treatment; the causes to switch to nilotinib were intolerance, resistance and clinical progression of leukemia. ### results The sample was of 16 patients, who achieved at least a hematologic response; 10 were males (62.5%). The age range was 24 to 75 years. Two patients received nilotinib due to intolerance to imatinib; seven due to resistance to imatinib and seven due to lack of response. There was response in the two patients who received nilotinib due to intolerance. One patient died five months after starting nilotinib due to progression of leukemia; four patients achieved major molecular response, two patients had reduced expression of BCR-ABL gene. Six patients continued with high expression of BCR-ABL gene; two of them carrying M244V mutation, and one with a complex karyotype with numerical and structural alterations. ### conclusions nilotinib is an option for patients with intolerance or resistance to imatinib.

https://pubmed.ncbi.nlm.nih.gov/24878095/

139b9e118c7845a3bd7efe0ae45009ca

At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response .

Dabrafenib plus trametinib rechallenge in four melanoma patients who previously progressed on this combination. In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response . Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach.

https://pubmed.ncbi.nlm.nih.gov/28252479/

464a6b634dbfb4dee12d8d282b9d21f3

We performed this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research .

[Thermo-chemotherapy of GP or TP for advanced non-small cell lung cancer: a systematic review]. Advanced non-small cell lung cancer (NSCLC) is characterized by poor treatment efficacy and short survival time. Clinical trials have shown that the combination of chemotherapy with thermotherapy exhibits strong efficacy. We performed this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research . ### methods We searched international (Cochrane Library, PubMed, and EMBASE) and Chinese (CBM, CNKI, VIP and Wanfang) databases for relevant articles and imported other retrievable sources, such as tracing-related references. We also corresponded with other authors to obtain certain inaccessible information. Data from all relevant randomized controlled trials (RCT) were collected to compare GP or TP thermochemotherapy with GP or TP chemotherapy alone. The quality of the included studies was assessed by adequate outcome-based standards and clinical circumstances. The meta-analysis was conducted using RevMan 5.1. ### results Fifteen RCTs involving 952 patients were included in this meta-analysis. The results showed that the thermochemotherapy group had higher rates of improvement in quality of life (OR=3.84, 95%CI: 2.61-5.64), survival at 1 year (HR=1.94, 95%CI: 1.21-3.12), and survival at 2 years (HR=2.05, 95%CI: 1.18-3.58) compared with the chemotherapy group, with the differences between them being significant. However, these groups did not differ in other indicators of treatment effectiveness, such as myelosuppression, alimentary canal reactions, hepatic lesions, and diarrhea. ### conclusions Compared with chemotherapy alone, thermochemotherapy can improve survival rates and curative effects, ameliorate symptoms, and enhance the quality of life of patients with advanced NSCLC, and it has an acceptable safety profile. The results of this meta-analysis warrant further investigation with a larger sample size and using a high-quality RCT design.

https://pubmed.ncbi.nlm.nih.gov/22901992/

ae18029f5969f526554b85821e622d76

The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor .

Pharmacodynamic effects during the transition between cangrelor and ticagrelor. This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor. ### background cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents. ### methods Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 μmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. ### results During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity. ### conclusions ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.

https://pubmed.ncbi.nlm.nih.gov/24656538/

f7d9cb2254b2543d60803eb573a9e7b4

A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response .

Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report. Homologous recombination deficiency is a marker of response to poly(ADP-ribose) polymerase inhibitors in different cancer types including ovary, prostate, and pancreatic cancer. To date, no report about poly(ADP-ribose) polymerase inhibitors has been published on cervical cancer. ### Case Presentation Here we present the case of a patient with cervical cancer treated in this setting. A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response . Because of a family history of cancers, the patient was tested and found positive for a pathogenic BRCA1 germline and somatic mutation, which motivated bevacizumab plus olaparib maintenance treatment. A simple hysterectomy was performed after 2 years stable disease; pathological report showed complete pathological response, and 12 months follow-up showed no recurrence. ### conclusion Poly(ADP-ribose) polymerase inhibitors could be an alternative maintenance treatment for patients with persistent advanced cervical cancer previously treated with platinum, especially when familial history of cancers is reported. Clinical trials using poly(ADP-ribose) polymerase inhibitors for advanced cervical cancer are warranted.

https://pubmed.ncbi.nlm.nih.gov/33888155/

73f773b02a672dc89e8413a7261f4848

Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years .

SEOM clinical guidelines for the treatment of metastatic prostate cancer. Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years . Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required.

https://pubmed.ncbi.nlm.nih.gov/25319721/

61f05d751c64820a8d80f60bfc98c237

Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC .

A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Platinum-based combination chemotherapy has become the standard treatment for good performance patients with stage IIIb and IV non-small cell lung cancer (NSCLC). However, newer agents such as gemcitabine and paclitaxel appear to have superior single agent activity and are more easily tolerated in comparison to the older platinum compounds. Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC . gemcitabine was given at 1,000 mg/m(2) intravenously over 30 min followed by paclitaxel at 110 mg/m(2) intravenously over 1 h on days 1, 8 and 15 every 28 days for a maximum of 6 cycles. Between April 1998 and June 1999, 40 of 42 patients entered were eligible and received chemotherapy. Data was available on 39 patients. Toxicities included Grade 3/4 neutropenia in 43% of patients, while thrombocytopenia (13%) and anemia (7%) were less frequent. Five (12.5%) patients developed neutropenic fever. Four (10%) patients developed bilateral interstitial shadows with hypoxia suggestive of a drug-induced pneumonitis. There were 4 treatment-related deaths (1 from pneumonitis, 3 from neutropenic complications). Five patients were not evaluable due to early death. Therefore, 34 patients were evaluable with 12 (35.3%) achieving a partial remission and 1 achieving a complete remission for an overall response rate of 38.2% (32.5% on an intention-to-treat basis). The median progression free survival was 107 days (range, 14-391), median survival was 148 days (range, 12-495) and 1-year survival was 26%. In conclusion, weekly gemcitabine with paclitaxel in patients with advanced NSCLC is an active regimen; however, toxicity and poor survival precludes the use of this regimen as an experimental arm on a future phase III study.

https://pubmed.ncbi.nlm.nih.gov/12367796/

bfc82b1e67e91b99aeeb487bebe450c3

Two of these antibodies , cetuximab ( Erbitux ) und bevacizumab ( Avastin ) , directed against the epidermal growth factor receptor ( EGFR ) and the vascular epithelial growth factor ( VEGF ) , respectively , have recently been approved for use in metastatic colorectal cancer .

[Antibody treatment in colorectal cancer--what the surgeon needs to know]. Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies , cetuximab ( Erbitux ) und bevacizumab ( Avastin ) , directed against the epidermal growth factor receptor ( EGFR ) and the vascular epithelial growth factor ( VEGF ) , respectively , have recently been approved for use in metastatic colorectal cancer . The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.

https://pubmed.ncbi.nlm.nih.gov/18415895/

9f0667d430098de87e37d3fd2f9d7e1b

Physically cross-linked beta-lactoglobulin ( BLG ) protein gels containing theophylline and sulfamethoxazole low molecular weight drugs were prepared in 50 % ethanol solution at pH 8 and two protein concentrations ( 6 and 7 % ( w/v ) ) .

Swelling behavior and controlled release of theophylline and sulfamethoxazole drugs in beta-lactoglobulin protein gels obtained by phase separation in water/ethanol mixture. Physically cross-linked beta-lactoglobulin ( BLG ) protein gels containing theophylline and sulfamethoxazole low molecular weight drugs were prepared in 50 % ethanol solution at pH 8 and two protein concentrations ( 6 and 7 % ( w/v ) ) . Swelling behavior of cylindrical gels showed that, irrespective of the hydrated or dehydrated state of the gel, the rate of swelling was the highest in water. When the gels were exposed to water, they first showed a swelling phase in which their weight increased 3 and 30 times for hydrated and dehydrated gels, respectively, due to absorption of water, followed by a dissolution phase. The absorption of solvent was however considerably reduced when the gels were exposed to aqueous buffer solutions. The release behavior of both theophylline and sulfamethoxazole drugs from BLG gels was achieved in a time window ranging from 6 to 24 h. The drug release depended mainly on the solubility of the drugs and the physical state of the gel (hydrated or dry form). Analysis of drug release profiles using the model of Peppas showed that diffusion through hydrated gels was governed by a Fickian process whereas diffusion through dehydrated gels was governed partly by the swelling capacities of the gel but also by the structural rearrangements inside the network occurring during dehydration step. By a judicious selection of protein concentration, hydrated or dehydrated gel state, drug release may be modulated to be engineered suitable for pharmaceutical as well as cosmetics and food applications.

https://pubmed.ncbi.nlm.nih.gov/16398532/

f4921173486b31b67a10b151e4371b72

Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given .

Infection prevention in autologous bone marrow transplantation and the role of protective isolation. The efficacy of an antimicrobial regimen for prevention of infections was prospectively evaluated in 113 patients undergoing autologous bone marrow transplantation (BMT). Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given . In addition all patients received streptococcal prophylaxis for 10 days after BMT. Documented infections occurred in 39% (44 of 113) of patients and unexplained fever in 27% (30 of 113). The efficacy of this regimen was reflected in a low mortality rate (3.5%) from infections and in the low need for intravenous amphotericin B (7%). No benefit of protective isolation was found in 59 patients compared with 54 patients treated without isolation measures.

https://pubmed.ncbi.nlm.nih.gov/7951125/

f7706f7238a4a6e6e1f27615c9d55119

In some recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) .

A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial). In some recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) . The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions. ### Patients And Methods From January 2011 to December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. The key eligibility criteria were age ≥ 20 years and resistance or intolerance to irinotecan, fluoropyrimidine, and oxaliplatin. All patients received 6 mg/kg of panitumumab and 150 mg/m ### results Of the 43 patients, the median age was 62 years (range, 32-75 years), 58% were male, and the Eastern Cooperative Oncology Group performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3), and the confirmed response rate was 18.6% (95% CI, 8.4-33.4). The median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4 months) and 13.6 months (95% CI, 10.8-16.5 months), respectively. The most frequent grade 3/4 toxicities were anorexia (12%), leukopenia (9%), and neutropenia (9%). Nine patients did not reach the 15-minute infusion, primarily because of disease progression. No infusion-related reactions were observed. ### conclusion The short 15-minute panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatin- and irinotecan-refractory mCRC.

https://pubmed.ncbi.nlm.nih.gov/29169974/

80434a6ceced9fc5c41ba573025ff686

A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation .

A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation . Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. ### Patients And Methods In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). ### results Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6-18.4 months) and a median overall survival of 31.0 months (range: 19.8-42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0-8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. ### conclusion Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. ### Trial Registration The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.

https://pubmed.ncbi.nlm.nih.gov/33407577/

d89f39f61c1b2844588da47a1cd3c612

Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma .

Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma . On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. ### methods Adult patients with mRCC who had received ≤ 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. ### results Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. ### conclusions In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity.

https://pubmed.ncbi.nlm.nih.gov/20922784/

ce24fba138e6c7a35f02adab371a88f2

A working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) .

Recurrent and persistent otitis media. Recurrent acute otitis media occurs during the first several years of life in approximately 20 to 30% of the pediatric population. A clinical challenge closely related to recurrent otitis media is persistent otitis media, manifested by persistence during antimicrobial therapy of symptoms and signs of middle ear infection (treatment failure) and/or relapse of acute otitis media within 1 month of completion of antibiotic therapy. Recurrent and persistent otitis media infections are early childhood problems with identifiable risk factors. Differentiation of these infections from otitis media with effusion is important in avoiding misdiagnosis and overtreatment with antibiotics. The predominant pathogens of recurrent and persistent acute otitis media are antibiotic-resistant Streptococcus pneumoniae and beta-lactamase-producing Haemophilus influenzae. A working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) . Other antibiotics were considered suboptimal or had accumulated insufficient data upon which to base a judgment. Conclusions. Optimal management of recurrent and persistent acute otitis media is a clinical challenge. Accurate diagnosis of acute otitis media is the first step in optimal management. Selection of appropriate antibiotic therapy should take into account the major pathogens (S. pneumoniae, H. influenzae and Moraxella catarrhalis) and the occurrence of antibiotic resistance.

https://pubmed.ncbi.nlm.nih.gov/11001126/

f0cfa9cab940e4dec4741dc4b6e5231d

On the basis of the estimated costs of infective complications , cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery .

A cost-effectiveness evaluation of 3 antimicrobial regimens for the prevention of infective complications after abdominal surgery. To measure the cost and effectiveness of 3 established antimicrobial regimens for the prevention of infective complications after abdominal surgery. ### design A prospective randomized trial was performed involving a total of 1070 patients undergoing abdominal surgery. ### Setting And Patients All patients having upper gastrointestinal tract, colorectal, appendiceal, or biliary surgery at a major teaching hospital in Melbourne, Australia, were considered for entry into the study. ### interventions Patients were randomized prior to surgery to receive a single dose of cefotaxime sodium (1 g), ticarcillin plus clavulanic acid (3.1 g), or ceftriaxone sodium, (1 g). All drugs were given intravenously at the start of anesthesia. ### Main Outcome Measures Rates of major wound infections, minor wound infections, other wound problems, and other infective complications. The acquisition and administrative costs of the drugs used and the costs of the infective complications were measured. ### results A Total of 1070 patients were entered into the study. Major wound infections occurred in 21 patients (2.0%). Twenty-five patients (2.3%) developed a minor wound infection. Other infective complications developed in 107 patients. There were significantly fewer minor wound infections in the ceftriaxone-treated group as compared with the other 2 groups. There was no differences in the frequency of major wound infections, other wound problems, or other infective complications. The acquisition costs of cefotaxime and ticarcillin plus clavulanic acid were less than those of ceftriaxone. The estimated cost of treating the infective complications in the group of patients who received ticarcillin plus clavulanic acid ($128,039) was greater than the cost associated with the groups being treated with cefotaxime ($91,243) or ceftriaxone ($96,095). ### conclusions The study indicates that each of the 3 regimens was associated with highly satisfactory control of postoperative infective complications after abdominal surgery. On the basis of the estimated costs of infective complications , cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery . Acquisition costs for cefotaxime were lower and it is recommended as the preferred agent on this basis.

https://pubmed.ncbi.nlm.nih.gov/8678775/

f05493b65f3c5290a97f09afd7ff253b

The epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR TKIs ) like erlotinib and gefitinib have been extensively studied .

The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer. The epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR TKIs ) like erlotinib and gefitinib have been extensively studied . Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.

https://pubmed.ncbi.nlm.nih.gov/22263036/

47520d58ca9f3c5271cd5e1b8f17c8d3

Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) ≤2 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met .

Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer. This randomised controlled phase 2 study compared pemetrexed and erlotinib in combination with either agent alone in terms of efficacy and safety as second-line treatment in a clinically selected population of never-smokers with non-squamous non-small cell lung cancer (NSCLC). ### methods Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) ≤2 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met . The primary endpoint, progression-free survival (PFS), was analysed using a multivariate Cox model. Firstly, a global comparison across the three arms was performed. If the global null hypothesis was rejected at a two-sided 0.2 significance level, pairwise comparisons of pemetrexed-erlotinib versus erlotinib or pemetrexed were then conducted using the same model. Statistical significance was claimed only if both global and pairwise null hypotheses were rejected at a two-sided 0.05 significance level. ### findings A total of 240 patients (male, 35%; East Asian, 55%; ECOG PS 0-1, 93%) were included. A statistically significant difference in PFS was found across the three arms (global p=0.003), with pemetrexed-erlotinib significantly better than either single agent: HR=0.57, 95% confidence interval (CI): 0.40-0.81, p=0.002 versus erlotinib; HR=0.58, 95% CI: 0.39-0.85, p=0.005 versus pemetrexed. Median PFS (95% CI) was 7.4 (4.4, 12.9) months in pemetrexed-erlotinib, 3.8 (2.7, 6.3) months in erlotinib and 4.4 (3.0, 6.0) months in pemetrexed. Safety analyses showed a higher incidence of drug-related grade 3/4 toxicity in pemetrexed-erlotinib (60.0%) than in pemetrexed (28.9%) or erlotinib (12.0%); the majority being neutropenia, anaemia, rash and diarrhoea. ### interpretation pemetrexed-erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable.

https://pubmed.ncbi.nlm.nih.gov/23890768/

099683c01fbf5f8bc5d641f38273f33e

This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle .

The feasibility of using glycosylated recombinant human granulocyte colony-stimulating factor (G-CSF) to increase the planned dose intensity of doxorubicin, cyclophosphamide and etoposide (ACE) in the treatment of small cell lung cancer. Medical Research Council Lung Cancer Working Party. This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle . 20 patients with small cell lung cancer (SCLC) were prescribed six cycles of 2-weekly ACE, with G-CSF on the intermediate days. 3 patients died during the treatment period and a further 5 had ACE terminated, 3 for toxicity and 2 for progressive disease. Of the 71 intervals between cycles, 42 (59%) were of the prescribed 14 days, 9 (13%) of 15-20 days, 15 (21%) of 21 days and five (7%) longer, but during the first four cycles, 36 (77%) of 47 intervals were of 14 days. The main reason for delay was haematological toxicity. All 20 patients experienced WHO grade 3 or 4 neutropenia, but at 2 weeks after a cycle only 3 had grade 4 and 1 grade 3. 17 patients required blood transfusion and 12 platelet transfusion. The only potentially serious adverse reaction to G-CSF was an episode of rash with facial oedema. Adding G-CSF allows ACE chemotherapy to be intensified by reducing the interval between cycles.

https://pubmed.ncbi.nlm.nih.gov/7536433/

7f838123add04a29b53b03e5253caefe

The rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) .

Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. ### methods We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. ### results The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) . The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). ### conclusions Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin.

https://pubmed.ncbi.nlm.nih.gov/23275643/

ad15c6b2de06399a133cb0989bdd489b

The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 .

The Role of Local Bupivacaine Irrigation in Postoperative Pain Control After Augmentation Mammoplasty: A Systematic Review and Meta-Analysis. The objective of this study is to analyze the efficacy of local bupivacaine irrigation after augmentation mammoplasty for the control of postoperative pain. ### methods A systematic review and meta-analysis was conducted including all randomized controlled trials (RCTs) that compared the irrigation of bupivacaine (±ketorolac) versus normal saline or no irrigation for pain control after breast augmentation. The primary outcome was postoperative pain measured by visual analog scale. The study protocol was established a priori according to the recommendations of the Cochrane Collaboration. A bibliographical search was conducted in September 2015 in the following Cochrane Library databases: CENTRAL, MEDLINE, EMBASE, and Scielo. The strategy used for the search was ((augmentation AND ("mammoplasty"[MeSH Terms] OR "mammoplasty")) OR (("breast"[MeSH Terms] OR "breast") AND augmentation)) AND (("pain, postoperative"[MeSH Terms])). ### results Four RCTs with a total of 264 participants were included. Two trials compared bupivacaine alone versus placebo (normal saline or no irrigation) and 3 trials compared bupivacaine plus ketorolac versus placebo. The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 . The irrigation with bupivacaine compared with placebo significantly reduced pain assessed on postoperative day 4. ### conclusion The irrigation of bupivacaine with or without ketorolac was associated with a reduction of postoperative pain compared with control groups for the first 5 postoperative days. Due to the few number of trials included, these results should be correlated further clinically.

https://pubmed.ncbi.nlm.nih.gov/29026810/

f1d7687091bcc14f1eeb6fad5e6f4ea6

In group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) .

Latamoxef versus carbenicillin plus gentamicin or carbenicillin plus mecillinam in leukopenic, febrile patients with solid tumors. Sixty-six febrile episodes associated with leukopenia were observed in 56 patients with solid tumors, WBC less than 1.5 X 10(9)/l and temperature greater than or equal to 38.5 degrees C. Stratification to antibiotic treatment regimen was made with regard to prior cis-dichlorodiamineplatinum (cis-platinum) treatment or not. Patients who had received no cis-platinum were randomized between carbenicillin 10 g every 8 h plus gentamicin 80 mg every 8 h or latamoxef 2 g every 8 h (group I). Patients having received cis-platinum were treated with carbenicillin 10 g every 8 h plus mecillinam 800 mg every 8 h or latamoxef 2 g every 8 h (group II). The first dose of latamoxef was preceded by 10 mg of vitamin K i.v. In group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) . In group II, 6 of 14 febrile episodes treated with carbenicillin plus mecillinam responded (42.9%) while 11 of 19 (57.9%) responded to latamoxef (p greater than 0.05). No bleeding due to antibiotic treatment was observed. No statistical difference between standard antibiotic therapy and latamoxef was seen in this subset of patients.

https://pubmed.ncbi.nlm.nih.gov/3535399/

a719f348c8f180930525ce7b90846d21

Following lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) .

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade. Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. ### methods A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. ### results A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) . Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01). ### conclusions Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

https://pubmed.ncbi.nlm.nih.gov/31037288/

b99eae8266e0ae323ef5089dd410ba9a

A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model .

A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model . Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPARγ), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21

https://pubmed.ncbi.nlm.nih.gov/29932104/

ba713428f331bd17d48949c1628f5dc4

Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest .

Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest . Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard first‑line therapies for patients with advanced non‑small cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wild‑type EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wild‑type NSCLC cells as single treatments or in combination with fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcription‑quantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wild‑type EGFR, by sensitizing NSCLC cells to TKIs.

https://pubmed.ncbi.nlm.nih.gov/31059070/

fc993366438427f4d6964fa73e800a2e

To compare levels of apoptosis in granulosa cells from women treated with the gonadotropin-releasing hormone ( GnRH ) agonist triptorelin or the GnRH antagonist cetrorelix .

Levels of apoptosis in human granulosa cells seem to be comparable after therapy with a gonadotropin-releasing hormone agonist or antagonist. To compare levels of apoptosis in granulosa cells from women treated with the gonadotropin-releasing hormone ( GnRH ) agonist triptorelin or the GnRH antagonist cetrorelix . ### design Randomized, prospective study. ### setting University hospital. ### Patient S Thirty-two women undergoing assisted reproduction techniques after ovulation induction with recombinant follicle-stimulating hormone (FSH) plus GnRH agonist or antagonist. ### Intervention S Granulosa cells were isolated from follicular aspirates after oocyte removal. ### Main Outcome Measure S Apoptosis was assessed with Annexin V binding assay, terminal deoxynucleotidyl transferase (TdT)-mediated nick-end labeling (TUNEL) assay, flow cytometric analysis of DNA, and ultrastructural analysis of cell morphology in transmission electron microscopy. Serum and follicular hormonal levels were also determined. ### Result S Annexin V binding and TUNEL assays revealed comparable percentages of apoptosis in the two groups under investigation. Analysis of DNA histograms revealed a similar cell cycle distribution in the two groups. Ultrastructural analysis only occasionally displayed patterns of chromatin margination in apoptotic cells. The mean concentrations of all the follicular fluid steroid hormones evaluated (E2, T, and P) were significantly lower in the GnRH antagonist-treated group. ### Conclusion S Therapy with a GnRH agonist or antagonist is associated with comparable levels of apoptosis in granulosa cells.

https://pubmed.ncbi.nlm.nih.gov/16595220/

20b68079241cd6dc54411493468becf5

In vitro effects of racemates , separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes .

In vitro effects of racemates , separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes . 1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine. The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.

https://pubmed.ncbi.nlm.nih.gov/10426558/

5e79090b1a2a1eb6907f90235c5dfb3a

Other studies are evaluating the use of capecitabine , oxaliplatin , and the anti-epidermal growth factor receptor agent cetuximab with RT in this malignancy .

Current management of anal canal cancer. Squamous cell carcinoma of the anal canal historically has been treated with abdominoperineal resection, resulting in high rates of morbidity and local recurrence. Pioneering work led to the finding that radiation therapy (RT) combined with 5-fluorouracil (5-FU) and mitomycin results in high rates of local control and disease-free and colostomy-free survival without surgery. Prospective randomized trials from Europe and the United States have shown the superiority of RT, 5-FU, and mitomycin over 1) RT alone, 2) RT with 5-FU, and 3) neoadjuvant cisplatin/5-FU with concurrent radiation, cisplatin, and 5-FU. At present, RT with 5-FU and mitomycin is the standard of care for anal cancer patients. Recent advances include the integration of positron emission tomography into staging, radiation treatment planning and monitoring, and the use of intensity modulated RT. European randomized trials are further evaluating the role of cisplatin in the neoadjuvant, concurrent, and adjuvant settings, as well as radiation dose escalation. Other studies are evaluating the use of capecitabine , oxaliplatin , and the anti-epidermal growth factor receptor agent cetuximab with RT in this malignancy .

https://pubmed.ncbi.nlm.nih.gov/19336010/

c6a3421ac22d4334dd98a5c5dd81e616

Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable .

Effects of intravitreal moxifloxacin and dexamethasone in experimental Staphylococcus aureus endophthalmitis. To evaluate the effects of intravitreal moxifloxacin and moxifloxacin and dexamethasone combination in an experimental rabbit model of Staphylococcus aureus endophthalmitis. ### methods The right eyes of 24 rabbits weighing 2 to 3 kg were used. Ten thousand colony-forming units (CFU) of S. aureus in 0.1 ml saline solution were inoculated into the vitreous cavity. The eyes were randomly assigned to one of the four groups equally. Twenty-four hours after the inoculation of S. aureus, group 1 received 50 microg moxifloxacin, group 2 received 50 microg moxifloxacin plus 400 microg dexamethasone, and group 3 received 1 mg vancomycin intravitreally. No treatment was given to group 4. Clinical examination scores were recorded. Vitreous aspirates were obtained for microbiological analysis just before sacrifice, and the eyes were enucleated for histopathologic examination. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. ### results In all treatment groups, mean number of CFU and histopathologic score were significantly lower compared with control group (p<0.05), and the difference between treatment groups was not statistically significant (p>0.05). The clinical score was not significantly different between groups (p>0.05). ### conclusions Intravitreal injection of 50 microg moxifloxacin was effective in the treatment of S. aureus endophthalmitis. Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable . Intravitreal moxifloxacin may be an option in the treatment of S. aureus endophthalmitis.

https://pubmed.ncbi.nlm.nih.gov/17453955/

d0abfbca5b519e0900c805ecc3a10c4f

Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P≤0.005 ) decrease in MPC and MPC/MIC ratio .

Mutant prevention concentration and mutant selection window for 10 antimicrobial agents against Rhodococcus equi. The objectives of this study were to determine the mutant prevention concentration (MPC), time above the MPC and mutant selection window for 10 antimicrobial agents against Rhodococcus equi and to determine if the combination of a macrolide with rifampin would decrease emergence of resistant mutants. Antimicrobial agents investigated (erythromycin, clarithromycin, azithromycin, rifampin, amikacin, gentamicin, enrofloxacin, vancomycin, imipenem, and doxycycline) were selected based on in vitro activity and frequency of use in foals or people infected with R. equi. Each antimicrobial agent or combination of agents was evaluated against four virulent strains of R. equi. MPC were determined using an agar plate assay. Pharmacodynamic parameters were calculated using published plasma and pulmonary pharmacokinetic variables. There was a significant (P<0.001) effect of the type of antimicrobial agent on the MPC. The MPC of clarithromycin (1.0 μg/ml) was significantly lower and the MPC of rifampin and amikacin (512 and 384 μg/ml, respectively) were significantly higher than that of all other antimicrobial agents tested. Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P≤0.005 ) decrease in MPC and MPC/MIC ratio . When MIC and MPC were combined with pharmacokinetic variables, only gentamicin and vancomycin were predicted to achieve plasma concentrations above the MPC for any given periods of time. Only clarithromycin and the combination clarithromycin-rifampin were predicted to achieve concentrations in bronchoalveolar cells and pulmonary epithelial lining fluid above the MPC for the entire dosing interval. In conclusion, the combination of a macrolide with rifampin considerably decreases the emergence of resistant mutants of R. equi.

https://pubmed.ncbi.nlm.nih.gov/23915992/

54964251ce7e6cabed1272f0799d82eb

This was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance .

Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity. The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line. ### methods Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses. ### results Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance . The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment. ### conclusion We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development.

https://pubmed.ncbi.nlm.nih.gov/29695239/

17ce67b32a1c7321276f9a838007b4ce

Artemether , artesunate , praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis : a comparative in vivo study .

Artemether , artesunate , praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis : a comparative in vivo study . We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40-50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages. Rats were dissected 2-4 weeks post-treatment and C. sinensis trematodes were removed from the liver and bile ducts and counted. We used a negative binomial regression model to test the effect of drug and dosage in terms of worm burden reduction. Single 150 mg/kg oral doses of artesunate, artemether, tribendimidine and praziquantel, administered to rats infected with adult C. sinensis, resulted in mean worm burden reductions of 100, 100, 89.5 and 80.7%, respectively (all P<0.001). Halving the dose to 75 mg/kg still resulted in highly significant worm burden reductions for artesunate, artemether and tribendimidine (71.4-100%), but not for praziquantel (20.7%). In the juvenile infection model, a single 150 mg/kg oral dose of tribendimidine and praziquantel resulted in mean worm burden reductions of 99.1 and 90.0%, respectively, whereas considerably lower reductions were observed for artemether (59.2%) and artesunate (57.6%) when used at the same single dose. The in vivo results presented here with the artemisinins and tribendimidine provide further data for clinical investigations to assess the safety and efficacy of these drugs in clonorchiasis patients.

https://pubmed.ncbi.nlm.nih.gov/18308285/

9fb1ec9eb7a2348ed2fbd8b3bd74a3a0

The agents studied include : propranolol , timolol , metoprolol , practolol , atenolol and the combined alpha and beta adrenoceptor blocking agent , labetalol .

Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers. Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A1. The agents studied include : propranolol , timolol , metoprolol , practolol , atenolol and the combined alpha and beta adrenoceptor blocking agent , labetalol . The drugs varied by two logs in their abilities to inhibit phospholipase A1 activity. The relative inhibitory potencies were propranolol greater than labetalol much greater than timolol greater than metoprolol much greater than practolol greater than atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A1 inhibition. A strong negative correlation was noted between the octanol/water partition coefficients and IC50 for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A1 was identical for the d, l and the d and l stereoisomers.

https://pubmed.ncbi.nlm.nih.gov/2857566/

35618f6c493f9bdf1494b7d89163d65b

Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets .

Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets . Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.

https://pubmed.ncbi.nlm.nih.gov/33408297/

e05d747dfa790c1c8bd20db1d9e43d53

Idasanutlin was tolerable alone and in combination with cytarabine .

Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆. The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine . The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.

https://pubmed.ncbi.nlm.nih.gov/33302031/

276d55d879d554f558d58f254164d21e

Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies .

Fludarabine and cladribine induce changes in surface proteins on human B-lymphoid cell lines involved with apoptosis, cell survival, and antitumor immunity. fludarabine and cladribine are purine analogues used to treat hematological malignancies. Alone or in combination with therapeutic antibodies, they are effective in treating patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, the mechanisms of action of these drugs are not well understood. Plasma membrane proteins perform a variety of essential functions that can be affected by malignancy and perturbed by chemotherapy. Analysis of surface proteins may contribute to an understanding of the mechanisms of action of purine analogues and identify biomarkers for targeted therapy. The surface of human cells is rich in N-linked glycoproteins, enabling use of a hydrazide-coupling technique to enrich for glycoproteins, with iTRAQ labeling for quantitative comparison. A number of plasma membrane proteins on human leukemia and lymphoma cells were affected by treatment with a purine analogue, including decreases in CD22 (an adhesion and signaling molecule) and increases in CD205 (a "damaged cell marker") and CD80 and CD50 (T-cell interaction molecules). Purine analogues may affect B-cell receptor (BCR) signaling and costimulatory molecules, leading to multiple signals for apoptosis and cell clearance. fludarabine and cladribine induce differential effects, with some cell survival proteins (ECE-1 and CD100) more abundant after fludarabine treatment. Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies .

https://pubmed.ncbi.nlm.nih.gov/22839105/

642c1582627371fac3aa51763b0b0fcc

After seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum .

Intestinal perforation in colorectal cancers treated with bevacizumab (Avastin). bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), and it has shown promise as a clinical agent against metastatic colorectal cancer, and particularly in combination with chemotherapy. Bowel perforation is a known risk that's associated with bevacizumab use, but the etiology is unknown. Here we report on two cases of metastatic colorectal cancer in which the patients suffered from intestinal perforation after chemotherapy with bevacizumab. For the first case, a 47 year-old man had rectal cancer with concurrent liver and lung metastasis. He underwent chemotherapy with 5-fluorouracil, irinotecan and bevacizumab. Fever and abdominal pain developed seven days later, and rectal perforation was identified upon exploration 13 days later. For the second case, a 48 year-old woman had sigmoid colon cancer with peritoneal and ovary metastases. After seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum .

https://pubmed.ncbi.nlm.nih.gov/19688063/

b7a74b8f49372a2cf52016dee22d48bd

Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group .

Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. The Ondansetron and Granisetron Emesis Study Group. This is the first international, multi-centre, double-blind, randomised, parallel group study to directly compare the efficacy and safety profile of a single intravenous dose of ondansetron (8 or 32 mg) with granisetron (3 mg) in the control of cisplatin-induced acute emesis. A total of 496 patients were randomised to receive one of three anti-emetic treatments prior to cisplatin chemotherapy (> or = 50 mg/m2). Of these, 165 and 162 patients received 8 and 32 mg of ondansetron, respectively, and 169 patients received 3 mg of granisetron. Complete control of emesis (0 emetic episodes) over 24 h was reported in 59% of patients in the 8-mg ondansetron group, 51% of patients in the 32-mg ondansetron group and 56% of patients in the granisetron group. Complete or major control (< or = 2 emetic episodes) was achieved in 76 and 74% of patients in the 8- and 32-mg ondansetron group, respectively, compared with 78% of patients in the granisetron group. Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group . There were no significant differences between the treatment groups when global satisfaction scores were compared. Logistic regression models were fitted to assess any interaction between treatments and prognostic factors (age, gender, alcohol use, cisplatin dose or concomitant chemotherapy) on complete or major response, but there was no evidence of interaction for any factor. All three anti-emetic treatments were well tolerated and no severe or unexpected drug-related adverse events were observed with ondansetron or granisetron. Headache, the most reported drug-related adverse event for all three treatment groups, occurred in 9% of all patients. In summary, no significant difference was observed between any of the treatment groups with respect to emesis, nausea or drug-related adverse events.

https://pubmed.ncbi.nlm.nih.gov/8265095/

8797191a6cfcfc6747d63887c0100779

Relatively recent studies have shown that dexmedetomidine is able to decrease circulating plasma norepinephrine and epinephrine concentration in approximately 50 % , decreases brain blood flow by directly acting on post-synaptic alpha 2 receptors , decreases CSF pressure without ischemic suffering and effectively decrease brain metabolism and intracranial pressure and also , able to decrease injury caused by focal ischemia .

Prospective, randomized study to assess the role of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. Preliminary data on the perioperative use of dexmedetomidine in patients undergoing craniotomy for brain tumor under general anaesthesia indicate that the intraoperative administration of dexmedetomidine is opioid-sparing, results in less need for antihypertensive medication, and may offer greater hemodynamic stability at incision and emergence. Dexmedetomidine, alpha 2 adrenoceptor agonist used as adjuvant to anaesthetic agents. Relatively recent studies have shown that dexmedetomidine is able to decrease circulating plasma norepinephrine and epinephrine concentration in approximately 50 % , decreases brain blood flow by directly acting on post-synaptic alpha 2 receptors , decreases CSF pressure without ischemic suffering and effectively decrease brain metabolism and intracranial pressure and also , able to decrease injury caused by focal ischemia . ### purpose This prospective, randomized, double-blind study was designed to assess the perioperative effect of intraoperative infusion of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. ### methods Forty patients with CT- scanning proof of supratentorial tumors. The patients were classified equally into 2 groups (twenty patients in each group). Group A:--The dexmedetomidine was given as a bolus dose of 1 microg/kg in 20 minutes before induction of anaesthesia, followed by a maintenance infusion of 0.4 microg/kg/hr. The infusion was discontinued when surgery ended. Group B:--The patients received similar volumes of saline. ### results The heart rate and mean arterial blood pressure, decreased in patients of group A (dexmedetomidine group) more than group B (placebo group) with significant statistical difference between the two groups (P-value <0.05). No significant statistical difference between the two groups regarding the central venous pressure and arterial partial pressure of Carbon Dioxide (P-value >0.05). The intraoperative end-tidal sevoflurane (%) in patients of group A less than in patients of group B (P-value <0.05).The intracranial pressure decreased in patients of Group A more than group B (P-value <0.05). The Glasgow coma scale (GCS) improved in patients of group A and deteriorated in patients of Group B with significant statistical difference between the two groups (P-value <0.05). The total fentanyl requirements from induction to extubation of patients increased in patients of group B more than in patients of group A (P-value <0.05). The total postoperative patients' requirements for antiemetic drugs within the 2 hours after extubation decreased in patients of group A more than group B (P-value <0.05). The postoperative duration from the end of surgery to extubation decreased significantly in patients of group A more than group B (P-value <0.05). The total urine output during the duration from drug administration to extubation of patients increased in patients of group A more than group B (P-value <0.05). ### conclusions Continuous intraoperative infusion of dexmedetomidine during craniotomy for supratentorial tumors under general anaesthesia maintained the haemodynamic stability, reduced sevoflurane and fentanyl requirements, decreased intracranial pressure, and improved significantly the outcomes.

https://pubmed.ncbi.nlm.nih.gov/22428485/