atezolizumab

durvalumab

pembrolizumab

nivolumab

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


Metformin

Rosiglitazone

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


curcumin

docetaxel

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


propranolol

metoprolol

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


nivolumab

regorafenib

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


chenodeoxycholic

ketoconazole

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


etoposide

vincristine

mitomycin

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


cholic

chenodeoxycholic

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


vancomycin

rifampin

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


roflumilast

tiotropium

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


rituximab

cyclosporine

rituximab

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


cisplatin

doxorubicin

cyclophosphamide

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


Methotrexate

hydroxychloroquine

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


rifampin

isoniazid

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


Sorafenib

bortezomib

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


candesartan

candesartan

rofecoxib

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


cyclophosphamide

methotrexate

fluorouracil

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


everolimus

alemtuzumab

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


lisinopril

captopril

lisinopril

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


Capecitabine

oxaliplatin

fluorouracil

cisplatin

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


dexmedetomidine

butorphanol

methadone

morphine

tramadol

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


melatonin

all-trans retinoic acid

somatostatin

melatonin

Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules. melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition ; this phenomenon was associated with altered conductance through Ca²⁺ and voltage-activated K⁺ ( BK ) channels , and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling . The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer.


cytosine arabinoside

vincristine

prednisone

Treatment of adult acute lymphoblastic leukemia with cytosine arabinoside, vincristine, and prednisone. Thirteen adults with acute lymphoblastic leukemia were entered into a protocol in which cytosine arabinoside infusion was added to vincristine and prednisone as remission induction and periodic intensification therapy. Central nervous system prophylaxis consisting of cranial irradiation and intrathecal methotrexate was given, and all patients received continuous oral 6-mercaptopurine and methotrexate as maintenance treatment. Myelotoxicity was severe during induction, with prolonged granulocyte and platelet count nadirs noted. Nine of 13 patients (69%) obtained a complete remission and one (8%) obtained a partial remission. The median duration of complete remission was 38.1 weeks. It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration .


warfarin

rivaroxaban

dabigatran

apixaban

edoxaban

Proton Pump Inhibitor Co-Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulants and a Prior History of Upper Gastrointestinal Tract Bleeding. The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. ### methods Using a nationwide claims database, OAC-naïve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC ( warfarin , rivaroxaban , dabigatran , apixaban , and edoxaban ) and whether or not they received PPI co-therapy , and were followed up for incidence of major GIB . ### results Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6 years (interquartile ranges 0.2-1.7 years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. ### conclusion Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.


Celecoxib

doxorubicin

etoposide

irinotecan

vincristine

Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo. Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2-specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. ### Experimental Design Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. ### results Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin , etoposide , irinotecan or vincristine in vitro . In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. ### conclusions celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. celecoxib could also be a potential drug for treatment of minimal residual disease.


midostaurin

rituximab

Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis. An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-κB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo , midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments . Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.


imatinib

gefitinib

imatinib

Augmentation of multiple protein kinase activities associated with secondary imatinib resistance in gastrointestinal stromal tumors as revealed by quantitative phosphoproteome analysis. Mutations in the Kit receptor tyrosine kinase gene (KIT), which result in constitutive activation of the protein (KIT), are causally related to the development of gastrointestinal stromal tumors (GISTs). imatinib, a targeted anticancer drug, exerts a therapeutic effect against GISTs by repressing the kinase activity of KIT. Long-term administration of this drug, however, causes the emergence of imatinib-resistant GISTs. We performed quantitative phosphoproteome analysis using a cell-based GIST model system comprising an imatinib-sensitive GIST cell line (GIST882), GIST882 under treatment with imatinib (GIST882-IM), and secondary imatinib-resistant GIST882 (GIST882-R). Phosphorylated peptides were purified from each cell line using titania-based affinity chromatography or anti-phosphotyrosine immunoprecipitation, and then subjected to LC-MS/MS based quantitative phosphoproteome analysis. Using this method we identified augmentation of the kinase activities of multiple elements of the signal transduction pathway, especially KIT and EGFR. Although, these elements were up-regulated in GIST882-R, no additionally mutated KIT mRNA was found in secondary imatinib-resistant GIST cells. Treatment of GIST882-R with imatinib in combination with gefitinib , an EGFR inhibitor , partially prevented cell growth , implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST . ### Biological Significance In this study, we performed a quantitative phosphoproteome analysis using a cell culture-based GIST model system. The goal of the study was to investigate the mechanism of acquired resistance in GISTs against imatinib, a molecularly targeted drug that inhibits kinase activity of the KIT protein and that has been approved for the treatment of GISTs. In imatinib-resistant GIST cells, we observed elevated expression of KIT and restoration of its kinase activity, as well as activation of multiple proliferative signaling pathways. Our results indicate that the effects of even so-called 'molecularly targeted' drugs, are broad rather than convergent, and that the mechanisms of action of such drugs during continuous administration are extremely complex.


tamoxifen

risperidone

tamoxifen

Combination treatment of tamoxifen with risperidone in breast cancer. tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients , providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer .


Amoxicillin

erythromycin

levofloxacin

Biofilm formation by Streptococcus pneumoniae strains and effects of human serum albumin, ibuprofen, N-acetyl-l-cysteine, amoxicillin, erythromycin, and levofloxacin. Streptococcus pneumoniae ability to produce biofilms may induce persistent infections and difficulties for eradication in vivo. We investigated the ability of 11 pneumococcal strains (serotypes 3, 6B, 9V, 19F, and 23F) to form biofilms on polystyrene plates at 16 and 24 h. The extent of biofilm was greater at 24 h in 10 strains, being the highest magnitude for serotype 3 strains. Human serum albumin at 25,000 microg/mL and ibuprofen at 128 microg/mL significantly reduced biofilm formation in 7 and 5 strains, respectively. Amoxicillin , erythromycin , and levofloxacin at supra-MIC concentrations were very active against planktonic cells of 3 selected strains but lower on biofilm-associated organisms in 2 strains and null against the third . Although N-acetyl-l-cysteine had very little activity against both planktonic and biofilm-forming organisms, when combined with the 3 antibiotics, a slightly enhanced activity against biofilm-embedded organisms in 1 strain and combined with amoxicillin in another one was observed.


triprolidine

pseudoephedrine

An evaluation of triprolidine and pseudoephedrine in the treatment of allergic rhinitis.  A double-blind , parallel , placebo-controlled study was performed to assess the efficacy of a combination drug product containing the antihistamine , triprolidine , and the sympathomimetic , pseudoephedrine , in the treatment of allergic rhinitis . Allergic rhinitis was defined on the basis of coexistent nasal congestion and an aggregate symptom complex score which exceeded a pre-established value. pseudoephedrine and triprolidine were shown to make distinct and separate contributions to the treatment of allergic rhinitis defined in this manner.


epirubicin

cyclophosphamide

docetaxel

epirubicin

docetaxel

capecitabine

Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study. capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. ### Patients And Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery , 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide ( EC ; 90 and 600 mg/m(2 ) , respectively , × four cycles ) , followed by docetaxel ( 100 mg/m(2 ) × four cycles ; EC-T ) or epirubicin plus docetaxel ( ET ; 90 and 75 mg/m(2 ) , respectively , × four cycles ) , followed by capecitabine ( 1,250 mg/m(2 ) twice a day on days 1 to 14 , × four cycles ; ET-X ) ; all regimens were given every 3 weeks . The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). ### results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). ### conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.


paclitaxel

carboplatin

trastuzumab

Association of HER-2 copy number and HER-2/CEP-17 ratio with neoadjuvant taxane-containing chemotherapy sensitivity in locally advanced breast cancer. Aneusomy 17 causes inconsistency in fluorescence in situ hybridization (FISH)-based human epidermal growth factor receptor (HER)-2 status assessment using different algorithms (copy number or the HER-2/centromere enumerator probe 17 [CEP-17] ratio). We investigated the effects of FISH-based HER-2 status assessment and aneusomy 17 on responsiveness to neoadjuvant chemotherapy (NAC). ### Patients And Methods This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab . ### results The pathologic complete remission (pCR) rate in the breast and axilla was 24.3% (95% confidence interval [CI], 17.7%-32.0%). Although HER-2 status, assessed by either HER-2/CEP-17 ratio-based FISH or copy number-based FISH, was a predictor of NAC sensitivity, ratio-assessed HER-2 status had a poorer performance in determining patients' responsiveness to NAC (p = .029). Patients who were not HER-2 amplified when assessed using the HER-2/CEP-17 ratio but were HER-2 amplified when assessed using copy number (~5%) were eventually proven to be responsive to NAC, with a pCR rate of 57% (95% CI, 18.4%-90.1%). In contrast, patients who were HER-2 amplified when assessed by the ratio but not HER-2 amplified when assessed using copy number (~3%) were completely irresponsive. Higher HER-2 copy numbers represented increasing chances of a pCR (adjusted odds ratio, 3.09; 95% CI, 1.35-7.08), with an apparent gene-dose effect (p for trend < .001). ### conclusion It is likely that HER-2 copy number but not the HER-2/CEP-17 ratio determines NAC sensitivity. Additional studies to validate our findings are warranted.


rituximab

vinorelbine

ifosfamide

mitoxantrone

prednisone

High response rate and acceptable toxicity of a combination of rituximab , vinorelbine , ifosfamide , mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study . The optimal management of relapsed diffuse large B-cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leucémies et aAutres Maladies du Sang developed a combination of vinorelbine, ifosfamide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18-75 years. Patients received rituximab 375 mg/m² day 1, ifosfamide 1000 mg/m² days 1-5, vinorelbine 25 mg/m² days 1 and 15, mitoxantrone 10 mg/m² day 1, and prednisone 1 mg/kg days 1-5, every 28 days for three cycles. Responding patients underwent autologous transplantation or received three additional R-NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non-germinal centre B immunophenotype was associated with shorter progression-free survival. in conclusion, the R-NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.


rituximab

fludarabine

cyclophosphamide

Bing and neel syndrome. Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenström's macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen ( rituximab , fludarabine , and cyclophosphamide ) . In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM.


anastrozole

tamoxifen

tamoxifen

anastrozole

Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. ### methods The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. ### results At a median duration of follow-up of 18.2 months , anastrozole was at least equivalent to tamoxifen in terms of median TTP ( 8.5 and 7.0 months , respectively ; estimated hazard ratio [ tamoxifen relative to anastrozole ] , 1.13 [ lower 95 % confidence level , 1.00 ] ) . In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. ### conclusions In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.


streptozocin

doxorubicin

dacarbazine

Endocrine tumours of the gastrointestinal tract: Chemotherapy. Malignant neuroendocrine tumours are less sensitive to chemotherapy than other epithelial malignancies. If chemotherapy is considered, tumours of pancreatic origin have a higher sensitivity than tumours from the gastrointestinal tract ('carcinoids'). Chemotherapy with streptozocin combinations and with dacarbazine should be considered in patients with progressive malignant neuroendocrine tumours of the pancreas. A favourable response to chemotherapy can be expected in up to 60 % of patients receiving a combination of streptozocin plus doxorubicin , and in up to 40 % of patients receiving dacarbazine . A survival benefit has been shown for streptozocin combinations. Treatment regimens are effective in functioning and non-functioning tumours. The response to treatment cannot be predicted. Poorly differentiated neuroendocrine tumours, independent of their origin, respond to a combination of etoposide plus cisplatin. Chemotherapy is, however, almost ineffective in patients with well-differentiated neuroendocrine tumours originating in the gastrointestinal tract ('carcinoids').


fenfluramine

fluoxetine

Behavioural satiety sequence (BSS): separating wheat from chaff in the behavioural pharmacology of appetite. The history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use. In view of recent progress in our understanding of the multiplicity of signalling pathways involved in appetite regulation, and the resultant deluge of reports on the anorectic efficacy of novel therapies, it seems timely to stress the need to differentiate treatments that suppress intake by primary means from those that only indirectly achieve this endpoint. The current article reviews the conceptual history of the behavioural satiety sequence (BSS), also known as the behavioural sequence of satiety, post-ingestive satiety, and the postprandial satiety sequence. Early research confirmed that natural satiation, produced by a caloric load on the gut, is associated with a predictable transition from feeding through grooming to resting. Although many less naturalistic manipulations are also capable of reducing food intake, very few do so without disrupting the normal structure of this feeding cycle. Thus, while CCK and d-fenfluramine reduce intake by accelerating but otherwise maintaining the integrity of the BSS, other anorectic interventions disrupt the BSS through response competition (e.g. d-amphetamine), nausea/discomfort (e.g. lithium chloride) and/or interference with taste-mediated positive feedback (e.g. quinine adulteration of the diet). A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B ) and 5-HT(2C ) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine . Recent BSS analyses have also identified rather selective anorectic profiles for the dual noradrenaline and 5-HT reuptake inhibitor sibutramine, the orexin-1 receptor antagonist SB-334867, and the broad spectrum opioid receptor antagonist naloxone. However, similar analyses have offered little/no support for the anorectic potential of the gut peptide PYY(3-36) while the acute anorectic efficacy of cannabinoid CB1 receptor antagonist/inverse agonists appears largely to be secondary to response competition. In contrast, studies with low-dose combinations of naloxone and CB1 receptor antagonist/inverse agonists have very recently confirmed the potential of drug polytherapies not only in appetite suppression but also in attenuating/eliminating unwanted side-effects. In sum, as BSS analysis offers a reliable means of differentiating the wheat (primary anorectics) from the chaff (secondary anorectics), it should form an integral part of early phase testing in any anti-obesity drug screening programme.


Pilocarpine

carbachol

Cevimeline-induced monophasic salivation from the mouse submandibular gland: decreased Na+ content in saliva results from specific and early activation of Na+/H+ exchange. cevimeline and pilocarpine are muscarinic agonists used clinically to treat dry mouth. In this study, we explored fluid secretion from mouse submandibular glands to determine the mechanism of cevimeline, pilocarpine, and an experimentally used agent carbachol. cevimeline evoked almost the same amount of secretion at concentrations from 30 μM to 1 mM. Pilocarpine also induced secretion at a concentration as low as 1 μM and was the most powerful secretagogue at 10 μM. Secretion was induced by carbachol at 0.1 μM , with maximum secretion at 1.0 μM. cevimeline induced monophasic secretion at all concentrations tested, whereas higher concentrations of pilocarpine and carbachol induced secretion with variable kinetics, i.e., an initial transient high flow rate, followed by decreased secretion after 2 to 3 min. In the presence of an epithelial Na(+) channel blocker, amiloride, neither carbachol nor pilocarpine affected the Na(+) level of secreted saliva; however, it significantly increased the Na(+) content of cevimeline-induced saliva. The intracellular Ca(2+) response of acinar cells was almost identical among all three agents, although recovery after drug removal was slower for cevimeline and pilocarpine. A profound decrease in intracellular pH was observed during pilocarpine and carbachol treatment, whereas intracellular acidification induced by cevimeline was only seen in the presence of a Na(+)/H(+) exchange inhibitor. When external HCO(3)(-) was removed, cevimeline-induced saliva significantly decreased. These findings suggest that cevimeline specifically activates Na(+)/H(+) exchange and may promote Na(+) reabsorption by stabilizing epithelial sodium channel activity.


carboplatin

paclitaxel

bevacizumab

Phase II trial of induction chemotherapy with carboplatin and paclitaxel plus bevacizumab in patients with stage IIIA to IV nonsquamous non-small cell lung cancer. Surgery remains the best curative treatment option for non-small cell lung cancer (NSCLC), but is of benefit only to patients with localized disease. A meta-analysis showed a significant beneficial effect of induction chemotherapy on survival, but there is still no clear evidence. This phase II study was conducted to establish whether induction chemotherapy with carboplatin ( CBDCA ) and paclitaxel ( PTX ) plus bevacizumab prior to surgery reduces the risk of progression . ### methods The subjects of this study were 29 patients with treatment-naive nonsquamous NSCLC (clinical stages IIIA to IV). Patients received PTX (200 mg/m ### results The overall response rate was 72.4%. Of the 29 patients, ten underwent surgery after the induction chemotherapy and complete resection was achieved in 7 (70%). The median progression-free-survival (PFS) time and the 3-year PFS rate were 0.92 years and 16.2%, respectively. The median overall survival (OS) time and the 3-year OS rate were 1.96 years and 44.9%, respectively. ### conclusion Combined modality therapy with surgery after induction chemotherapy with CBDCA and PTX plus bevacizumab is clinically feasible and tolerable for patients with unknown or negative molecular profiles.


valproate

levetiracetam

lamotrigine

Treatment options in juvenile myoclonic epilepsy. Juvenile myoclonic epilepsy (JME) is characterized by excellent response to treatment, if diagnosed correctly. Lifestyle advice is an integral part of the treatment of JME; it should include recommendations on avoidance of common triggers such as sleep deprivation and alcohol excess and emphasis on the importance of compliance with medication. The drug of first choice in the treatment of JME is sodium valproate, which has a response rate of up to 80%. Valproate should be avoided in women of childbearing age because of significantly increased risks of fetal malformations and neurodevelopmental delay. levetiracetam or lamotrigine are alternative first-line options if valproate is contraindicated. With limited data from trials to support either of these drugs, the choice should take into account comorbidity factors and patient priorities. Because of its low side effect profile, excellent tolerability, and lack of interactions with other drugs, levetiracetam is our preferred alternative first-line agent. lamotrigine is another first-line option but may exacerbate myoclonus. The failure of valproate or failure of two first-line antiepileptic drugs suggests that combination therapy is indicated. Drug interactions and the patient's gender, age, and comorbidities need to be considered. levetiracetam, lamotrigine, and valproate are suitable adjuncts, with a synergistic effect reported from the combination of valproate and lamotrigine. clonazepam is a useful adjunct for myoclonus and can be used in combination with lamotrigine to avoid lamotrigine's myoclonic effects. In women of childbearing potential , valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage . topiramate is a cost-effective alternative monotherapy, but because of its poor tolerability, we recommend it as add-on treatment only. zonisamide should remain a second-line adjunct in the treatment of JME, owing to the lack of supportive data. Phenobarbital is the most cost-effective drug and can be used to control the seizures of JME when antiepileptic drugs are limited or too costly. carbamazepine, oxcarbazepine, and phenytoin can exacerbate absences and myoclonus and are therefore contraindicated, although they can improve control of tonic-clonic seizures when these are refractory to other medication. gabapentin, pregabalin, tiagabine, and vigabatrin are contraindicated and can worsen seizures. (tiagabine and vigabatrin have been reported to induce absence status epilepticus.) Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.


cyclophosphamide

doxorubicin

vincristine

prednisone

Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma.  Patients with clinically localized , intermediate- or high-grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) . Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. ### methods We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. ### results Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). ### conclusions Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.


olmesartan

amlodipine

Olmesartan Combined With Amlodipine on Oxidative Stress Parameters in Type 2 Diabetics, Compared With Single Therapies: A Randomized, Controlled, Clinical Trial.  To evaluate the effects of a fixed combination of olmesartan/amlodipine compared with olmesartan or amlodipine alone on some parameters of endothelial damage in diabetic , hypertensive patients .We enrolled 221 patients; 74 were randomized to olmesartan 20 mg, 72 to amlodipine 10 mg, and 75 to olmesartan/amlodipine fixed combination 20/5 mg for 12 months. We assessed blood pressure monthly; in addition, we also assessed at baseline, and after 6 and 12 months, the following parameters: lipoprotein (a), myeloperoxidase (MPO), isoprostanes, and paraoxonase-1 (PON-1). Blood pressure values obtained with fixed olmesartan/amlodipine combination were significantly lower than those reached with single monotherapies. There was a reduction of lipoprotein (a), and isoprostanes levels with olmesartan/amlodipine fixed combination, both compared with baseline, and with single monotherapies. On the other hand, there was an increase of PON-1 with fixed olmesartan/amlodipine combination, both compared with baseline, and with single drugs. All treatments reduced MPO compared with baseline; however, in group-to-group comparison, MPO reduction was greater with olmesartan/amlodipine fixed combination. Fixed combination of olmesartan/amlodipine was more effective than single monotherapies in reducing oxidative stress, especially in increasing PON-1, and reducing isoprostanes levels in diabetic and hypertensive patients.


gemcitabine

docetaxel

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study.  Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer ( NSCLC ) than that of both agents in monotherapy . ### methods This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m(2) (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. ### results Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1-6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29-59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3-4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3-4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). ### conclusion gemcitabine 1,000 mg/m(2) on days 1 and 8 in combination with docetaxel 85 mg/m(2) on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.


thiotepa

topotecan

Stem-Cell Therapy Following High-Dose Chemotherapy in Advanced Retinoblastoma: A Systematic Review. To analyze the risk and benefit of high-dose chemotherapy followed by stem cell transplantation (HDCT-SCT) treatment in patients with advanced retinoblastoma. ### design Systematic review. ### methods A comprehensive literature search from 4 online databases, including PubMed, Scopus, EBSCO, and Cochrane was done for original studies evaluating the use of HDCT followed by SCT in the treatment of patients with advanced retinoblastoma. The last search was performed on April 15, 2020. ### results A total of 35 studies consisting of 160 patients were considered suitable for inclusion. After HDCT-SCT treatment, 108/160 (67.5%) patients were alive with no evidence of disease at the last follow-up. The incidence of secondary malignancy in our data was also relatively low, which was 16/160 (10%) patients. The side effects were mainly hematological and gastrointestinal toxicities. The prognosis for metastatic cases especially the one to the central nervous system (CNS) remains poor, as shown in our data that 22 of 44 (50%) patients died due to the evidence of disease, and 12 of 44 (27%) patients acquired CNS relapse and died. ### conclusions HDCT-SCT is a promising treatment option in patients with advanced retinoblastoma. The use of HDCT-SCT in CNS metastases needs to be carefully considered , possibly by adding thiotepa or topotecan to improve tumor control . Further randomized clinical trials are needed to draw firm conclusion regarding its safety and efficacy.


Cetuximab

Panitumumab

Zalutumumab

Gefitinib

Bevacizumab

Vandetanib

Targeted therapy in head and neck cancer. Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors ( Cetuximab , Panitumumab , Zalutumumab ) , EGFR tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( Bevacizumab , Vandetanib ) , and various inhibitors of , e.g. , Src-family kinase , PARP , proteasome , mTOR , COX , and heat shock protein . Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.


phenylephrine

vasopressin

epinephrine

Vasopressor use and effect on blood pressure after severe adult traumatic brain injury. We describe institutional vasopressor usage, and examine the effect of vasopressors on hemodynamics: heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation (PbtO(2)), and jugular venous oximetry (SjVO(2)) in adults with severe traumatic brain injury (TBI). ### methods We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors ( phenylephrine , norepinephrine , dopamine , vasopressin or epinephrine ) to increase blood pressure ### results phenylephrine was the most commonly used vasopressor (43%), followed by norepinephrine (30%), dopamine (22%), and vasopressin (5%). Adjusted for age, gender, injury severity score, vasopressor dose, baseline blood pressure, fluid administration, propofol sedation, and hypertonic saline infusion, phenylephrine use was associated with 8 mmHg higher mean arterial pressure (MAP) than dopamine (P = 0.03), and 12 mmHg higher cerebral perfusion pressure (CPP) than norepinephrine (P = 0.02) during the 3 h after vasopressor start. There was no difference in ICP between the drug groups, either at baseline or after vasopressor treatment. ### conclusions Most severe TBI patients received phenylephrine. Patients who received phenylephrine had higher MAP and CPP than patients who received dopamine and norepinephrine, respectively.


irinotecan

oxaliplatin

FOLFOX/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy.  While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20 % , the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival . However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.


dacarbazine

carboplatin

temozolomide

Organ- and treatment-specific local response rates to systemic and local treatment modalities in stage IV melanoma. Metastatic melanoma shows different local response rates in organs to systemic or local treatment modalities. Whereas skin, soft tissue, lymph node and lung metastases seem to have better local response rates, the local response of metastases localized in the liver, brain and bone seems to be low. ### objectives The organ-specific response rate, local response rate of each therapeutic measure and survival of 68 patients with stage IV disease were evaluated. ### methods Four hundred and ten treatment periods (1-18 per patient) in 17 different organs of 43 men and 25 women (mean age 55 years, range 19-79) with measurable, widespread, surgically incurable disease were analysed. Chemotherapy was given in 405 of 410 treatment periods with dacarbazine , fotemustine , vindesine , carboplatin and temozolomide in different schedules . Local treatment modalities comprising radiotherapy, gamma knife radiosurgery and local hyperthermia were given in 71 of 410 treatment periods. ### results Local response (complete or partial local remission) was achieved in 52 treatment periods (12.7%). When local treatment modalities, either combined with systemic therapy or not, were compared with systemic therapeutic modalities alone, a local response of 24% was achieved with local measures, compared with 10% in systemic treatment only (P = 0.003). When a spontaneous remission rate of less than 5% is considered, however, local as well as systemic treatments had a significant effect (P < 0.001). Organ-specific response rates to local therapies showed no statistically significant differences between the various organs involved. When systemic treatments without local measures were taken into account, lung metastases, cutaneous/subcutaneous metastases and adrenal metastases performed significantly better than liver metastases. When different treatment modalities were considered, there was no significant difference between the three local measures applied (radiotherapy, gamma knife radiosurgery and hyperthermia). Among the systemic therapies, dacarbazine high dose and carboplatin monochemotherapy were superior to combined regimens using fotemustine. A local response, irrespective of the mode of therapy, was significantly associated with longer survival (median 16 months) compared with no local response or local progressive disease (median 7 months; P < 0.0001). When the first treatment period of each patient was considered, local response was no longer a significant predictor. ### conclusions The study shows that local therapeutic measures are superior in inducing a local response than systemic therapies alone. Induction of remission may be associated with longer survival. Chemotherapy, despite limited local response rates, is still statistically superior to an estimated spontaneous remission rate.


nedaplatin

leucovorin

[ Effect of nedaplatin , 5-FU , and leucovorin combined with radiation therapy in unresectable esophageal carcinoma ] . A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.


etanercept

adalimumab

infliximab

Psoriatic arthritis treated by anti-TNFs: a monocentric trial of 102 cases in Auvergne, France. While several registries have already evaluated the retention of anti-TNF therapy in psoriatic arthritis (PsA), they sometimes reach divergent conclusions. Our study therefore sought to assess therapeutic retention rates and predictive factors of response in a patient cohort from Auvergne, France, followed up in routine clinical practice. ### methods Medical records of all PsA patients treated from 2002 to May 2015 were analysed. PsA diagnosis was established based on the CASPAR criteria. ### results In total, 102 patients were analysed, comprising 62 men (44.6±12.6 years) and 40 women (37.8±13.4). Mean PsA evolution was 2.7 years (0.8-11.2). The most common forms were peripheral (47/102, 45.1%) and mixed (46/102, 46.1%) PsA. The anti-TNF treatment initiated was etanercept in 47 cases (45.2%), adalimumab in 29 (27.9%), infliximab in 20 (19.2%), and golimumab in six [5.8%]. In 28 cases (27.4%), anti-TNF was associated with methotrexate (MTX). Overall, the median duration of anti-TNF retention was 76.5 months. The hazard ratios (HR) for treatment cessation did not significantly differ between the etanercept and monoclonal antibody groups (HR=1.35[0.96-1.93], p=0.08). After 5 years , approximately 30.8 % of etanercept patients and 68.8 % of monoclonal antibody patients ( adalimumab 71.2 % ; infliximab 67.2 % ) were still being treated . Combining with MTX did not prolong the overall retention rate (HR=0.85[0.37-1.96], p=0.71). Tobacco use was predictive of discontinuation (p=0.03). ### conclusions Our study demonstrates good anti-TNF treatment retention in PsA patients, as well as confirming the deleterious effect of smoking while providing no argument in favour of combined treatment with MTX to improve maintenance.


metformin

rosiglitazone

Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial. To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. ### design Prospective randomized controlled trail. ### setting Tertiary teaching hospital. ### Patient S Obese Chinese women (body mass index [BMI] ≥25 kg/m ### Intervention S In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone ( 4 mg/day ) ; in group 3 , 69 patients administered metformin ( 1,000 mg/day ) and rosiglitazone ( 4 mg/day ) for 6 months , all with the same diet and regular exercise lifestyle recommendation. ### Main Outcome Measure S Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. ### Result S The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. ### Conclusion S Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. ### Clinical Trial Registration Number ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).


tenecteplase

alteplase

Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Background and Purpose- Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods- The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results- The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2-6). In the intention-to-treat analysis , 57 % of patients that received tenecteplase and 53 % of patients that received alteplase reached good functional outcome ( modified Rankin Scale score of 0 - 1 ) at 3 months ( odds ratio , 1.19 ; 95 % CI , 0.68 - 2.10 ) . The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26-2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65-2.37). Conclusions- tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.


dexamethasone

ethinyl

Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman. This is the first report of congenital adrenal hyperplasia (CAH) due to combined 17α-hydroxylase/17,20 lyase deficiency in an Omani patient who was initially treated for many years as a case of hypertension. CAH is an uncommon disorder that results from a defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and the types of accumulated steroid precursors. A 22-year-old woman who was diagnosed to have hypertension since the age of 10 years who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study were performed and the diagnosis was confirmed by molecular mutation study. Laboratory investigations revealed adrenal steroids and pituitary hormones profile in addition to 46XY karyotype that are consistent with the diagnosis of CAH due to 17α-hydroxylase deficiency. Extensive laboratory workup revealed low levels of serum cortisol (and its precursors 17α-hydroxyprogesterone and 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone sulfate and androstenedione), and estrogen (estradiol); and high levels of mineralocorticoids precursors (11-deoxycorticosterone and corticosterone) with high levels of ACTH, FSH and LH. Mutation analysis revealed CYP17A1-homozygous mutation (c.287G>A p.Arg96Gln) resulting in the complete absence of 17α-hydroxylase/17,20-lyase activity. The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy . A review of the literature was conducted to identify previous studies related to this subtype of CAH. This is the first biochemically and genetically proven case of CAH due to 17α-hydroxylase/17,20-lyase deficiency in Oman and in the Arab World described in the literature.