Agent Monotherapy Research Articles

Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty

BackgroundThe aim was to evaluate the analgesic efficacy and safety of the dexketoprofen/tramadol 25 mg/75 mg fixed-dose combination vs dexketoprofen (25 mg) and tramadol (100 mg) in moderate-to-severe acute pain after total hip arthroplasty. MethodsThis was a randomized, double-blind, parallel-group study in patients experiencing pain of at least moderate intensity on the day after surgery, compared with placebo at first administration to validate the pain model. The study drug was administered orally every 8 h throughout a 5 day period. Rescue medication, metamizole 500 mg, was available during the treatment period. The evaluation of efficacy was based on patient assessments of pain intensity and pain relief. The primary end point was the mean sum of the pain intensity difference values throughout the first 8 h (SPID8). ResultsOverall, 641 patients, mean age 62 (range 29–80) yr, were analysed; mean (sd) values of SPID8 were 247 (157) for dexketoprofen/tramadol, 209 (155) for dexketoprofen, 205 (146) for tramadol, and 151 (159) for placebo. The primary analysis confirmed the superiority of the combination over dexketoprofen 25 mg (P+0.019; 95% confidence interval 6.4–73) and tramadol 100 mg (P+0.012; 95% confidence interval 9.5–76). The single components were superior to placebo (P<0.05), confirming model sensitivity. Most secondary analyses supported the superiority of the combination. The incidence of adverse drug reactions was low and similar among active treatment groups. ConclusionThe efficacy results confirmed the superiority of dexketoprofen/tramadol over its single components, even at higher doses (tramadol), with a safety profile fully in line with that previously known for these agents in monotherapy. Clinical trial registrationEudraCT 2012-004548-31 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004548-31);ClinicalTrials.gov NCT01902134 (https://www.clinicaltrials.gov/ct2/show/NCT01902134?term=NCT01902134&rank=1).

Tazarotene 0.1% Cream as Monotherapy for Early-Stage Cutaneous T-Cell Lymphoma

Numerous treatments are available for cutaneous T-cell lymphoma (CTCL), including systemic retinoids. Very few data are available on topical retinoids. The aim of this study was to evaluate the safety and efficiency of tazarotene as monotherapy for early-stage CTCL. An open-label, prospective study of tazarotene as monotherapy for stages IA to IIA CTCL was conducted. Index lesions on 10 patients were followed for 6 months on treatment, plus at least 6 months off treatment. Six patients (60%) showed complete response (CR). Erythema, scaling, thickness, and lesion area decreased progressively throughout treatment. The mean time to CR was 3.8 months; CR was durable for at least 6 months in 83%. Of the 4 patients (40%) without CR, 2 (20%) had stable disease and 2 (20%) stopped the medication because of local side effects; none showed progression. This is the first Canadian trial providing evidence that topical tazarotene has excellent potential as a monotherapy agent for stages I to IIA CTCL.

PD-1/PD-L1 blockades in non-small-cell lung cancer therapy.

Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC) is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1) receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy), and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients.

To study the comparison of efficacy and side effect profile of bimatoprost 0.03% versus fixed combination timolol 0.5% and dorzolamide 2% in patients with primary open angle glaucoma or ocular hypertension

Aims: To study IOP lowering efficacy and side effect profile of bimatoprost 0.03% versus fixed combination timolol 0.5% and dorzolamide 2%. Settings and Design: Prospective, open, randomized, parallel group, comparative study, 100 patients of POAG/ocular hypertension with moderate glaucomatous damage attending the outpatient department of ophthalmology, at our institute were included. Materials and Methods: The patients were randomly assigned to one of the two treatment groups, each having a sample size of 50 patients. Group 1 instilled 1 drop of Bimatoprost 0.03%at 8 p.m. (once daily) for 12 weeks and Group 2 instilled 1 drop of fixed drug combination of timolol 0.5% and dorzolamide 2% at 8a.m. and 1 drop at 8p.m. for 12 weeks. All the patients were subjected to the detailed ocular examination following examination and tests at baseline, 4 weeks, 8 weeks and 12 weeks after starting the study treatment. Results: Both the groups showed comparable IOP reductions in the patients. There was no statistically significant difference in the mean IOP reduction among the two groups’ at all follow-up visits. The most frequently reported adverse effect was conjunctival hyperaemia in bimatoprost group and burning, stinging sensation in eyes and taste perversion in the DTFC group. Conclusion: Bimatoprost can be used as a long term monotherapy agent in the treatment of POAG and ocular hypertension providing good efficacy with an easy dosing regimen and without much side effects. Keywords: Bimatoprost, Timolol dorzolamide, Primary open angle glaucoma, Ocular hypertension

Combination therapy for type 2 diabetes: dapagliflozin plus metformin

Introduction: Type 2 diabetes (T2D) is a chronic and multifactorial metabolic disease, which brings great threats to public health. The morbidity of T2D keeps growing, and it is estimated that the population with T2D will rise to 552 million throughout the world by 2030. Effective glycemic control in patients is crucial for the treatment of T2D. However, with progressive deterioration of disease, most patients are usually unable to achieve glycemic targets receiving antidiabetic agent monotherapy. In such cases, combination therapy with different mechanisms of antidiabetic agents is highly desired. In addition, combination therapy can provide advantages beyond better glycemic improvement such as reduced incidence of hypoglycemia and cardiovascular events.Areas covered: We reviewed all the published data regarding the fixed-dose combination therapy of dapagliflozin combined with metformin, including complementary mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety.Expert opinion: The fixed-dose combination of dapagliflozin and metformin exerts synergistic effects based on two antidiabetic agents with complementary mechanisms of action. Rational co-administration of dapagliflozin and metformin provides better glycemic control with potential weight loss and the reduced incidence of hypoglycaemia.

The Hybrid Molecule, Edo-S101, Impairs Double Strand Breaks Repair in Multiple Myeloma and Synergizes with Bortezomib and Dexamethasone

Introduction. EDO-S101 is a hybrid molecule of bendamustine plus vorinostat, new in its class. Our group has previously demonstrated that EDO-S101 is effective in vitro in MM cell lines independently of p53 state, and also in a murine plasmacytoma model where it decreases tumor growth and prolongs survival with respect to bendamustine and/or vorinostat treatment. The objective of this work was to gain further insights into the efficacy of EDO-S101, its mechanism of action and its combination with other drugs used in MM.Methods. The mechanism of action was assessed by western blot, comet assay, immunohistochemistry, and flow cytometry. Homologous recombination (HR) efficiency was calculated using chromosomally integrated green fluorescent protein reporter construct-based assay. The efficacy of different combinations was studied in vitro (HMCLs), in vivo (murine plasmacytoma model CB-17 SCID mice) and ex vivo (cells from patients).Results. In addition to the activity of EDO-S101 in MM cell lines we demonstrated that it was active ex vivo in cells isolated from 7 MM patients, with median IC50 of 5 µM (ranging from 1,8 to 8 µM), some of them previously exposed and resistant to alkylators such as melphalan. Interestingly, EDO-S101 could also overcome alkylators-resistance in vitro, as it was active in melphalan resistant cells (U266-LR7 and RPMI8226-LR5). EDO-S01 was also effective in the presence of factors that confer proliferative advantage to plasma cells, like IL-6, IGF or co-culture with mesenchimal cells hMSC-TERT.Regarding its mechanism of action, we found that the apoptosis induced by EDO-S101 was caspase-independent but calpain-dependent, since PD150606, an inhibitor of this protein could overcome EDO-S101-induced apoptosis, whereas the caspase inhibitor Z-VAD -FMK did not. This data was consistent with the finding that under treatment with EDO-S101, MM1S cells showed AIF (apoptotic inducing factor) translocation from the mitochondria into the nucleus. Interestingly, the release of this pro-apoptotic protein from the mitochondria could be mediated by calpains, as it has been described in literature.We subsequently demonstrated that EDO-S101 causes DNA damage, as revealed by the phosphorylation and subsequent activation of several components of the DNA Damage Response (DDR) such as ATM, H2AX, chk1, chk2 or p53, and the induction of DNA fragmentation, that was detected by the comet assay. EDO-S101 was also found to induce cell cycle arrest in different phases depending on the dose and cell line.It has previously been suggested that DACi may impair DNA repair by inhibiting homologous recombination (HR), a pathway related with genomic instability and progression, very active in MM. Therefore we next evaluated the efficiency of HR using a reported construct that was chromosomally integrated in two MM cell lines, JJN3 and U266. Treatment with EDO-S101 significantly reduced the efficiency of HR in both cell lines, by 50% and 20% of untreated controls respectively.Finally, we tested potential combinations with other antimyeloma agents like lenalidomide and thalidomide; and also with proteasome inhibitors (bortezomib, carfilzomib and oprozomib). EDO-S101 potentiated the activity of all these agents, but the most synergistic combination was that including Bortezomib + Dexamethasone (CI 0,4). This combination was also evaluated in vivo, where it significantly decreased tumor growth and prolonged survival compared to agents in monotherapy and in double combinations. We are currently deepening into the mechanism of action of this combination.Conclusions. EDO S101 is active ex vivo in cells isolated from patients and is able to overcome resistance to alkylators. It induces caspase-independent apoptosis, and cell cycle arrest in MM cell lines. These effects are due to the potent DNA damage which is enhanced by HR impairment induced by the hybrid molecule. Moreover, the combination with bortezomib and dexamethasone is especially attractive to be taken into the clinical setting. DisclosuresMehrling:4Mundipharma-EDO GmbH, Basel, Switzerland: Employment. Mateos:Takeda: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy.

Induction of Cancer Testis Antigen Expression in Circulating Acute Myeloid Leukemia Blasts Following Hypomethylating Agent Monotherapy

Background: The development of immunotherapeutic strategies for the treatment of leukemia has shown considerable promise but targeting suitable myeloid leukemia antigens remains a significant challenge. Cancer testis antigens (CTA) have been identified as promising targets for immunotherapy in solid tumors, but dense promoter methylation silences their expression in acute myeloid leukemia, limiting their potential as targets. Patients with acute myeloid leukemia are frequently treated with hypomethylating agents (HMAs) and previous studies have established that exposure of leukemia cell lines to HMAs induces expression of CTAs. In this study, we tested the hypothesis that patients receiving HMAs exhibit increased expression of CTAs.Methods: AML patients receiving decitabine were enrolled under an IRB-approved protocol (Roswell Park) or with approval of the Ethics Committee (University of Freiburg). Peripheral blood samples were serially collected prior to decitabine treatment and two to four times per week during their first cycle of decitabine therapy (20 mg/m2 per day for 10 days).Results: We analyzed expression and demethylation of CTA genes in peripheral blood samples serially isolated from AML patients (n = 5) during and following their first cycle of decitabine therapy (20 mg/m2 per day for 10 days). These patients demonstrated induction of MAGEA1 (1/5 patients), XAGE1 (3/5), MAGEA3/A6 (3/5), and NY-ESO-1 (5/5). Western blot analysis demonstrated increased expression of NY-ESO-1 protein following decitabine treatment. The induction of NY-ESO1 mRNA was confirmed in an independent group of AML patients (5/7, treated at University of Freiburg) receiving decitabine. Since NY-ESO-1 is an established cancer immunotherapy target with clinically translatable vaccines in development, we further examined induced NY-ESO-1 expression in a larger cohort of AML patients. We performed sodium bisulfite pyrosequencing to quantify changes in NY-ESO-1 promoter methylation pre-decitabine to the post-decitabine nadir time point for each patient (n = 22). There was a statistically significant decrease in NY-ESO-1 promoter methylation (p < 0.001). Prior to decitabine treatment, 18% (4/22) of samples exhibited detectable levels of NY-ESO-1 mRNA as measured by quantitative PCR. Following decitabine therapy, 78% (17/22) of samples had detectable levels of NY-ESO-1 mRNA. Treatment with decitabine was associated with a significant increase in NY-ESO-1 expression when comparing pre-treatment expression to the maximum expression at any time interval post decitabine (p < 0.0001). We then tested whether levels of NY-ESO-1 induction were different in patients who demonstrated a clinical response compared with those who did not. Overall, 7/22 patients (32%) demonstrated a clinical response to decitabine. 6/7 patients who clinically responded to decitabine demonstrated a significant increase in NY-ESO-1 mRNA (p < 0.03). Crucially, NY-ESO-1 mRNA levels were also significantly increased in 11 out of the 15 patients that did not demonstrate a response to decitabine (p = 0.001). To test whether AML blasts expressing NY-ESO-1 could induce a T-cell response, we stimulated HLA compatible NY-ESO-1- specific CD8+ T cells with AML blasts isolated from HLA-A*0201+ AML patients before and after decitabine treatment. T-cell responses were determined by intracellular cytokine staining (IFN-γ, TNF-α and IL-2) and the expression of CD107a/b, a marker for T-cell degranulation. Co-culture of AML blasts harvested post-decitabine, resulted in increased levels of IFN-γ, TNF-α, IL-2, and CD107a/b in HLA-A*0201/NY-ESO-1157-165 tetramer+ CD8+ T-cells in three of the four patients studied, compared to T-cells co-cultured with AML blasts from the same four patients obtained prior to decitabine exposure.Conclusion: We observed enhanced expression of NY-ESO-1 in AML patients receiving decitabine and this induction was sufficient to produce a cytotoxic response in HLA-compatible antigen specific T-cells. A majority of patients who did not respond to decitabine still exhibited an increase NY-ESO-1 mRNA, suggesting that immunotherapies that target NY-ESO-1 have the potential to be effective even in patients who have not demonstrated a prior response to decitabine. These data support the combination of decitabine with immunotherapeutic approaches targeting NY-ESO-1 and other CTAs in myeloid cancer. DisclosuresGriffiths:Alexion Pharmaceuticals: Honoraria; Astex: Research Funding; Celgene: Honoraria. Off Label Use: Decitabine is in routine clinical use in the United States for the management of unfit/elderly patients with AML. Patients received decitabine as standard of care off label in the hospital per Bloom et al PNAS 2010.

Pharmacotherapy for the treatment of obesity

The recognition of the complex counter-regulatory hormonal, metabolic and neurochemical mechanisms that promote weight regain following weight loss and the conceptualisation of obesity as a chronic disease requiring long-term management has led to increasing focus on the role of adjunctive therapies for obesity, particularly pharmacotherapy.Currently available pharmacotherapy achieves a weight loss intermediate between that commonly attained by lifestyle intervention and bariatric surgery, however its accessibility, compared to bariatric surgery increases its appeal.Despite the poor history of obesity pharmacotherapy, novel agents that are in development appear to have several advantages over predecessors. They are generally more selective in their mechanism of action, thereby potentially minimising adverse sequelae and improving the risk-benefit ratio of pharmacotherapy. Another approach has been to use combined pharmacotherapy to better counteract the multiple counter-regulatory neuroendocrine mechanisms which promote weight regain, as well as allowing lower constituent doses of the combined monotherapy agents, which improves the safety and tolerability of these agents that are usually required long-term for chronic weight maintenance.This review will provide an overview of past, present and future pharmacotherapy for obesity. The efficacy and safety profile of currently available pharmacotherapy will be discussed in the setting of stringent regulatory review processes now in place given the fraught history of pharmacological interventions for obesity. Potential novel therapies that seek to better target the multiple complex counter-regulatory mechanisms promoting weight regain while improving the efficacy/safety profile, will also be examined.

Abstract 1856: Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer

Abstract Targeting signal molecules with single agent monotherapy is met with limited or transient clinical benefits. Therefore, establishing effective rational combinatorial treatment strategies provides a better option for achieving improved clinical outcomes. The AKT/PI3K and MAPK signaling pathways have been identified as key compensatory signal transduction pathways in prostate cancer. We have used genetically engineered mouse models of prostate cancer to show the treatment efficacy of monotherapy with the AKT inhibitor AZD5363 and the MAP/ERK kinase (MEK) inhibitor selumetinib (AZD6244, ARRY142886). We hypothesized that a rational combinatorial approach utilizing both of these inhibitors would improve treatment efficacy compared to single agent monotherapy. To test this hypothesis, we evaluated the treatment effects of AZD5363 and selumetinib in preclinical models of prostate cancer. In vitro experiments were carried out using a panel of human prostate cancer cell lines, and mouse prostate cancer cell lines, derived from PTEN-deficient castration-naïve prostate cancer (CNPC) and castration-resistant prostate cancer (CRPC). Treatments with AZD5363 and selumetinib demonstrated a synergistic combination effect in both human and mouse prostate cancer cell lines. We evaluated the antitumor effects in vivo by comparing the effects of AZD5363 and selumetinib alone or in combination in PTEN-deficient mice. Our studies show that combination therapy of AZD5363/selumetinib was well-tolerated by the mice and demonstrated significantly improved inhibition of tumor growth compared to single agent therapy. In the CNPC model, mice showed 16.7, 10.0 and 24.9% reductions in tumor burden after treatments with AZD5363, selumetinib and AZD5363/selumetinib, respectively (P&amp;lt;0.001). In the CRPC model, mice showed 15.8, 3.8 and 27.0% reductions in tumor burden after treatments with AZD5363, selumetinib and AZD5363/selumetinib, respectively (P&amp;lt;0.001). Target validation studies confirmed the inhibition of downstream targets. Overall, our findings suggest a potential role for targeting the PI3K/AKT and MAPK signaling pathways with AZD5363 and selumetinib for treatment of PTEN-deficient prostate cancer. Citation Format: Marco A. De Velasco, Yutaka Yamamoto, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry Davies, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2015-1856

4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype

4-Acetylantroquinonol B (4-AAQB), closely related to the better known antroquinonol, is a bioactive isolate of the mycelia of Antrodia camphorata, a Taiwanese mushroom with documented anti-inflammatory, hypoglycemic, vasorelaxative, and recently demonstrated, antiproliferative activity. Based on its traditional use, we hypothesized that 4-AAQB may play an active role in the suppression of cellular transformation, tumor aggression and progression, as well as chemoresistance in colorectal carcinoma (CRC). In this study, we investigated the antiproliferative role of 4-AAQB and its underlying molecular mechanism. We also compared its anticancer therapeutic potential with that of antroquinonol and the CRC combination chemotherapy of choice — folinic acid, fluorouracil and oxaliplatin (FOLFOX). Our results showed that 4-AAQB was most effective in inhibiting tumor proliferation, suppressing tumor growth and attenuating stemness-related chemoresistance. 4-AAQB negatively regulates vital oncogenic and stem cell maintenance signal transduction pathways, including the Lgr5/Wnt/β-catenin, JAK–STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, as well as inducing a dose-dependent downregulation of ALDH and other stemness related factors. These results were validated in vivo, with animal studies showing 4-AAQB possessed comparable tumor-shrinking ability as FOLFOX and potentiates ability of the later to reduce tumor size. Thus, 4-AAQB, a novel small molecule, projects as a potent therapeutic agent for monotherapy or as a component of standard combination chemotherapy.

Trends in Antihypertensive Medication Use and Blood Pressure Control Among Adults With Hypertension in Germany.

Hypertension is a major risk factor for morbidity and mortality, therefore its control is of great importance. In this study we compare the use of antihypertensive medication among adults with hypertension in Germany 1998 and 2008-2011 and determine factors associated with use and control. Data from German Health Examination Surveys (GNHIES98 1998, n = 7,124 and DEGS1 2008-2011 n = 7,988, age 18-79 years) including standardized blood pressure (BP) measurements and Anatomical Therapeutic Chemical (ATC) medication codes were analyzed. The use of antihypertensive medication among adults with hypertension in Germany increased from 54% to 72% in 1 decade. In 2008-2011, 67% of users were treated with polytherapy. The most commonly used antihypertensive class in 1998 was diuretics (43%) and in 2008-2011 beta-blockers (54%). Ramipril and metoprolol are currently the most commonly used monotherapy agents, while ramipril in combination with hydrochlorothiazide is the most frequent polytherapy. Being a woman, older age, having statutory health insurance, diabetes, coronary heart disease (CHD), stroke, and obesity were positively associated with antihypertensive use. The control rate among treated increased from 42% to 72%. Young women (18-54 years) had better control compared to older women or to men. Having CHD or stroke was positively associated with BP control. Increased and improved antihypertensive use might be a main contributor to the decrease in BP observed in Germany in the last decade. However, there are still socio-demographic and health disparities in hypertension treatment and control.

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2 years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

A cross-sectional retrospective study to assess the pattern of prescribing for inpatient hypertensive cases in a tertiary hospital and to find out the possible avenues for betterment of hypertension management

Objective: The primary objective of this study was to characterize the prescribing pattern of antihypertensive agents in the tertiary care teaching hospital. The secondary objective of this study was to assess the appropriateness of the prescribing pattern of antihypertensive drugs as per the seventh report of the Joint National Committee (JNC-7) guidelines. Materials and Methods: A cross-sectional, retrospective study for the period of 7 months (June 2012 to January 2013) was conducted. Only inpatient hypertensive cases suffering from essential hypertension with or without other comorbid conditions were included in the study. Results: A total of 261 hypertensive patients on treatment, of which 57.9% were females and 42.1% males, were included. Hypertension alone was present in 26.8% of the patient whereas diabetes mellitus was the most common comorbid condition in 18.8% of the cases. Of the 261 patients studied, 47.1% were on monotherapy and 52.8% on combination therapy. The commonest monotherapy agents being prescribed were calcium channel blockers (CCBs) (26.8%), followed by diuretic (9.6%), angiotensin-converting enzyme inhibitor (ACEI) (5%), beta blockers (BBs) (3.8%) and angiotensin receptor blockers (ARBs) (1.9%). The commonest two drug therapy was with CCB and diuretic (15.7%), followed by CCB and BB (7.3%), CCB and ACEI (4.2%), ACEI and diuretic (3.4%), ARBs and diuretic (2.7%), BBs and diuretic (1.9%). The commonest three drug therapy was with CCBs, BBs, and diuretic (4.2%). Conclusion: The most favored class of antihypertensive drugs, either as monotherapy or combination therapy in hypertensive patients with or without comorbidities was CCBs. There was underutilization of thiazide diuretics, ACEIs and BBs in this study. Overall the general pattern of antihypertensive prescribing in this study is only partly in accordance with the guidelines of JNC-7.

Oxidatively induced DNA damage and its repair in cancer.

Oxidatively induced DNA damage is caused in living organisms by endogenous and exogenous reactive species. DNA lesions resulting from this type of damage are mutagenic and cytotoxic and, if not repaired, can cause genetic instability that may lead to disease processes including carcinogenesis. Living organisms possess DNA repair mechanisms that include a variety of pathways to repair multiple DNA lesions. Mutations and polymorphisms also occur in DNA repair genes adversely affecting DNA repair systems. Cancer tissues overexpress DNA repair proteins and thus develop greater DNA repair capacity than normal tissues. Increased DNA repair in tumors that removes DNA lesions before they become toxic is a major mechanism for development of resistance to therapy, affecting patient survival. Accumulated evidence suggests that DNA repair capacity may be a predictive biomarker for patient response to therapy. Thus, knowledge of DNA protein expressions in normal and cancerous tissues may help predict and guide development of treatments and yield the best therapeutic response. DNA repair proteins constitute targets for inhibitors to overcome the resistance of tumors to therapy. Inhibitors of DNA repair for combination therapy or as single agents for monotherapy may help selectively kill tumors, potentially leading to personalized therapy. Numerous inhibitors have been developed and are being tested in clinical trials. The efficacy of some inhibitors in therapy has been demonstrated in patients. Further development of inhibitors of DNA repair proteins is globally underway to help eradicate cancer.

Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.

Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.

EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation.

Therapeutics that target the epidermal growth factor receptor (EGFR) can enhance the cytotoxic effects of ionizing radiation (IR). However, predictive genomic biomarkers of this radiosensitization have remained elusive. By screening 40 non-small cell lung cancer cell (NSCLC) lines, we established a surprising positive correlation between the presence of a KRAS mutation and radiosensitization by the EGFR inhibitors erlotinib and cetuximab. EGFR signaling in KRAS-mutant NSCLC cells promotes chromatin condensation in vitro and in vivo, thereby restricting the number of DNA double-strand breaks (DSB) produced by a given dose of IR. Chromatin condensation in interphase cells is characterized by an unexpected mitosis-like colocalization of serine 10 phosphorylation and lysine 9 trimethylation on histone H3. Aurora B promotes this process in a manner that is codependent upon EGFR and protein kinase C α (PKCα). PKCα, in addition to MEK/ERK signaling, is required for the suppression of DSB-inducible premature senescence by EGFR. Blockade of autophagy results in a mutant KRAS-dependent senescence-to-apoptosis switch in cancer cells treated with IR and erlotinib. In conclusion, we identify EGFR as a molecular target to overcome a novel mechanism of radioresistance in KRAS-mutant tumor cells, which stands in contrast to the unresponsiveness of KRAS-mutant cancers to EGFR-directed agents in monotherapy. Our findings may reposition EGFR-targeted agents for combination with DSB-inducing therapies in KRAS-mutant NSCLC.

Restoration of positive mood states in major depression as a potential drug development target.

Restoration of positive mood, in addition to reducing negative mood, is an important treatment goal in the management of depression. The need to restore positive mood states in depressed patients is not adequately addressed by available treatments for major depressive disorder (MDD), suggesting that this mood dimension could be a useful target for drug development. However, for positive mood restoration to become a valid target for antidepressant drug development certain questions should be answered: are symptoms of decreased positive mood phenomenologically distinct from other symptoms of MDD? Should they be considered a distinct aspect of MDD in the diagnostic nomenclature? Is there evidence for differential responsiveness to treatment? Is the underlying pathophysiology understood and different from that of other MDD symptoms? Is low positive mood specific to depression or does it contribute to psychopathology in other disorders? Beyond these basic questions, this review identifies a number of design issues that need to be considered when conducting studies that target improving positive mood. These design issues include (1) what population to study, (2) what line of treatment to target, (3) the appropriateness and validation of methods and measures to evaluate positive mood and its restoration, (4) the role of functional outcome measures in determining success of the treatment, and (5) optimal designs for add-on therapy versus monotherapy agents.

Biological agents in monotherapy for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%-40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.

Rituximab, alkylating agents or combination therapy for gastric mucosa‐associated lymphoid tissue lymphoma: a monocentric non‐randomised observational study

There is no consensus on the standard treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori-negative patients and for patients with persistent disease despite H. pylori eradication. To evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination. In this monocentric retrospective study, which included 106 patients who had not been previously treated with anti-cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n=48), rituximab monotherapy (n=28) and the therapy combining both drugs (n=30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2years (W104). After a median follow-up period of 4.9years (range 0.4-17.2years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5-year progression-free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P=0.05 and P<0.001). No toxicity-related death was reported. The use of anti-cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents.

Evaluation of Prescribing Pattern Of Antihypertensives Against The Clinical Condition

Background :The prescribing pattern of antihypertensives by different physicians is not in compliance with that of the standard guidelines given by WHO/JNC-7.The patient factors associated with hypertension like age,sex,the presence or absence of co-morbid diseases along with hypertension will also play a major role in prescribing a particular class of antihypertensive drug. If the standard guidelines and the patient factors are not taken into consideration while prescribing the drugs then the final BP control remains unsatisfactory. Objective:The purpose of this study was to evaluate the prescribing pattern,to determine the factors associated with the treatment of the disease. Methods: It is an observational,prospective,non-interventional study in which prescriptions were collected during July-2013 to January – 2014 (for a duration of 7 months) in a tertiary care hospital to comprise a study population of 400 hypertensive patients. Results: As monotherapy ACE-Inhibitors (38.25%) were the most commonly prescribed antihypertensives followed by calcium channel blockers(19.25%), Diuretics (13.25%) ranked third in the prescribing pattern.combination treatment usually consisted of 2 antihypertensive drugs as a coformulation.the most common combination was a ACE-Inh+CCB(5%), followed by Beta-blocker+CCB( 3.5%).patients gender,age and comobidities significantly influenced which treatment was prescribed. Limitations: The main limitation of this study was that all the prescriptions were collected from inpatient from a single hospital and it may not be a representative of prescribing pattern across the city. Conclusion: In this study it was observed that the ACE-Inhibitors are the most commonly prescribed monotherapy agents (38.25%) and their prescribing pattern was in consistent with the global trends.Thiazides and the combination drugs were underutilized in this study,despite robust evidence to support their use.