Showing papers in "Current Clinical Pharmacology in 2012"

Polyethylenimine as a promising vector for targeted siRNA delivery.

Abstract: Recent discovery of RNA interference (RNAi) technology for gene therapy has triggered explosive research efforts towards development of small interfering RNA (siRNA) as therapeutic modality for gene silencing. Owing to its large molecular weight (~13 kDa), polyanionic nature (~40 negative phosphate groups) and rapid enzymatic degradation, delivery of siRNA remains an unresolved issue. Hence, there arises a need of an appropriate delivery vector to overcome the intrinsic, poor intracellular uptake and limited in vitro and in vivo stability. Amongst the various non-viral delivery vectors, the application of polymeric vectors such as polyethylenimine (PEI) or its derivatives has attracted much attention due to its high transfection efficiency and ease of manipulation. PEI has been extensively investigated for DNA delivery, only recently this polymer has been employed for siRNA delivery. This review will focus on studies done on PEI to deliver siRNA, with emphasis on the targeted, self-assembled polymeric nanoparticles with promising potential to evolve as therapeutic tool in gene therapy.

GLP-1 agonists exenatide and liraglutide: a review about their safety and efficacy.

Abstract: Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide- 1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide]. In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models. We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti-diabetic drugs, including the most important studies about them in the latest ten years. We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower postprandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on β-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight.

An overview of interleukin-1 receptor antagonist, anakinra, in the treatment of cutaneous diseases.

Abstract: Interleukin (IL)-1 is a pivotal proinflammatory cytokine consisting of two molecular species, IL-1 and IL-1β. Anakinra (Kineret), a recombinant human IL-1 receptor antagonist, is regarded as a biological agent which blocks the inflammatory effects of IL-1. The aim of this review was to search the literatures and summarizes in vivo, in vitro and human studies on anakinra uses in dermatological disorders. The results show that anakinra is currently used clinically for the treatment of a variety of skin conditions such as psoriasis, atopic dermatitis, photoagaing, melanoma, Schnitzler syndrome, pyoderma gangraenosum, PAPA syndrome, hidradenitis suppurativa, lamellar ichthyosis, Sweet's syndrome, panniculitis, Muckle-Wells syndrome, familial Mediterranean fever, SAPHO syndrome and other disorders. Notably, anakinra is expensive to produce and administer. Injection is the route of therapy and allergic reaction is most possible.

Bacterial Vaginosis, Atopobium vaginae and Nifuratel

Abstract: As bacterial vaginosis (BV) is a potential cause of obstetric complications and gynecological disorders, there is substantial interest in establishing the most effective treatment. Standard treatment - metronidazole or clindamycin, by either vaginal or oral route – is followed by relapses in about 30% of cases, within a month from treatment completion. This inability to prevent recurrences reflects our lack of knowledge on the origins of BV. Atopobium vaginae has been recently reported to be associated with BV in around 80% of the cases and might be involved in the therapeutic failures. This review looks at the potential benefits of nifuratel against A. vaginae compared to the standard treatments with metronidazole and clindamycin. In vitro, nifuratel is able to inhibit the growth of A. vaginae, with a MIC range of 0.125-1 µg/mL; it is active against G. vaginalis and does not affect lactobacilli. Metronidazole is active against A. vaginae only at very high concentrations (8-256 µg/mL); it is partially active against G. vaginalis and also has no effect on lactobacilli. Clindamycin acts against A. vaginae with an MIC lower than 0.125 µg/mL and is active on G. vaginalis but it also affects lactobacilli, altering the vaginal environment. These observations suggest that nifuratel is probably the most valid therapeutic agent for BV treatment.

Pharmacogenetics and Anesthetic Drugs

Abstract: The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient.

Application of Monoclonal Antibodies as Cancer Therapy in Solid Tumors

Abstract: Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.

The treatment of autoimmune hepatitis.

Abstract: Autoimmune hepatitis is an immune-mediated disease targeting hepatocytes. It is more common in middleaged Caucasian females, although may affect other patient populations and age groups. The diagnosis is made according to criteria based on the alkaline phosphatase: ALT ratio, IgG, the presence of autoantibodies, liver histology, response to therapy, and the absence of a viral, alcohol or drug etiology. More recently a simplified scoring system has been proposed. In the absence of treatment, the prognosis is very poor with a 60% three year mortality. There are guidelines on the indications for treatment and some groups of patients may not require treatment. The main element of treatment is prednisolone which decreases the 3 year mortality to 10%. Prednisolone is tapered down to 5-10 mg per day, as monotherapy or in combination with azathioprine. Approximately 80% of patients will respond to therapy with prednisolone with or without azathioprine and this should be given for at least 2 years. Remission is defined as an asymptomatic patient with serum aminotransferases that are normal or less than two-fold elevated, a normal level of IgG and inactive liver histology. Relapse occurs in up to 90% of patients following drug withdrawal. The sensitivity and specificity of liver histology to predict relapse off treatment is not high. Other treatments that have been proposed include mycophenolate mofetil, budesonide, cyclosporine A, tacrolimus, 6-MP, methotrexate, ursodeoxycholic acid, rapamycin and rituximab although experience with all these agents is limited.

Antipsychotic medication adherence and satisfaction among Palestinian people with schizophrenia.

Abstract: Background: In Arab and Muslim-dominated countries, spirituality and religiosity shape the belief and practices toward chronic illnesses. No previous studies were published to assess adherence to and satisfaction with antipsychotic medications in persons with schizophrenia in the Arab world. Objective: To assess medication adherence and treatment satisfaction with antipsychotics in a sample of Palestinian people with schizophrenia. Methodology: Medication adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Psychiatric symptoms were assessed using the expanded Brief Psychiatric Rating Scale (BPRS-E). Data were entered and statistically analyzed using SPSS 16 for windows. Results: A convenience sample of 131 persons with schizophrenia was studied. Based on MMAS-8, 44 persons (33.6%) had a low rate, 58 (44.3%) had a medium rate and 29 (22.1%) had a high rate of adherence. Age was significantly correlated (P=0.028) with adherence score. However, variables like use of monotherapy or atypical or depot antipsychotics were not significantly associated with higher adherence. The means of satisfaction with regard to effectiveness, side effects, convenience and global satisfaction were 72.6 ± 20.5, 67.9 ± 31.47, 63.2 ± 14.3 and 63.1 ± 18.8 respectively. There was a significant difference in the means of effectiveness (P < 0.01), convenience (P < 0.01), global satisfaction (P < 0.01), but not side effects domains (P=0.1) among persons with different levels of adherence. Furthermore, there was a significant difference in the means of positive symptom score (P < 0.01), manic (P < 0.01) and depression (P < 0.01) but not negative symptom score (P=0.4) among persons with different levels of adherence. Conclusions: Medication nonadherence was common and was associated with low treatment satisfaction scores and poor psychiatric scores. Medication related factors had insignificant effects on adherence scores.

Structure-Activity Relationships and Drug Allergy

Abstract: Structure-activity relationships (SARs) refer to the relation between chemical structure and pharmacologic activity for a series of compounds. Since the pioneering work of Crum-Brown and Fraser in 1868, they have been increasingly used in the pharmaceutical, chemical and cosmetic industries, especially for drug and chemical design purposes. Structure-activity relationships may be based on various techniques, ranging from considerations of similarity or diversity of molecules to mathematical relationships linking chemical structures to measured activities, the latter being referred to as quantitative SAR or QSAR. This review aims at briefly reviewing the history of SARs and highlighting their interest in delayed and immediate drug allergy using selected examples from the literature. Studies of SAR are commonly conducted in the area of contact dermatitis, a delayed hypersensitivity reaction, to determine the allergenic potential of a given compound without animal testing. In immediate, immunoglobulin E-mediated drug hypersensitivity, this kind of approach remains rather confidential. It has been mainly applied to neuromuscular blocking drugs (muscle relaxants) and betalactam antibiotics (penicillins, cephalosporins). This review shows that SARs can prove useful to (i) predict the allergenic potential of a chemical or a drug, (ii) help identify putative antigenic determinants for each patient or small group of patients sharing the same cross-reactivity pattern, and (iii) predict the likelihood of adverse reactions to related molecules and select safe alternatives.

Adherence to Antiretroviral Therapy Among Iranian HIV/AIDS Patients

Abstract: Purpose: Treatment adherence of 95% or higher is recommended for appropriate therapeutic response and improving the function of immune system in HIV positive patients. To the best of our knowledge, there was report of adherence to HAART regimen from Iran. In the present study, we have reported the HAART adherence rate of Iranian HIV positive patients. Method: In a twelve-month period, all patients older than 18 years old who referred to HIV clinic were on HAART regimen enrolled in the study. Beside demographic and clinical characteristics of Iranian HIV positive patients, Adherence to HAART was assessed by self-report and pill count methods at during the three consecutive months of the patients’ visits. Results: The mean of patients’ adherence to HAART regimen based on the self-report method was 69.4%, 64.6% and 62.8% in the first, second and third month of follow up, respectively. The mean of adherence rates in three months followup assessed by self-report (65.5%) and pill count (60.4%) methods were correlated significantly (r=0.93 and p Conclusion: Although the adherence level of Iranian HIV infected patients is acceptable compared to other countries, the available antiretroviral medications are limited in our country, therefore, encouraging patients to have higher levels of adherence is more important.

Systematic review on infusion reactions associated with chemotherapies and monoclonal antibodies for metastatic colorectal cancer.

Abstract: Objective: The objective of this systematic review is to summarize the literature to date on the rates of infusion reactions (IR) associated with chemotherapies and monoclonal antibody (mAb) drug therapies used for the treatment of metastatic colorectal cancer (mCRC) and the associated clinical and economic impact. Methods: This study searched Medline, Medline (R) In-Process, Embase and Cochrane Library databases for studies on IRs associated with chemotherapy and mAbs in mCRC patients from 2000-2011. Results: For chemotherapy, the incidence of IRs ranged from 0-71% for all grades and 0-15% for grade 3-4. Rates of all grade IRs associated with cetuximab ranged from 7.6-33% and grade 3-4 IR rates were 0-22%. Rates of all grade IRs associated with panitumumab ranged from 0-4% and rates of grade 3-4 IRs ranged from 0-1%. The overall rate of IRs associated with bevacizumab ranged from 1.6-11%, with a rate of 0-4% for grade 3-4 IRs. A range of 50-100% of patients with grade 3-4 IRs terminated chemotherapy, and 34-100% of cetuximab patients with grade 3-4 IRs discontinued cetuximab therapy. No data were reported for bevacizumab or panitumumab. Only one study evaluated the economic impact of IRs. The study compared cetuximab administrations without an IR to those with an IR requiring resource utilization and found that mean costs were $9308 and $1725 higher for those with an IR requiring an emergency room visit or hospitalization and for those with an IR requiring outpatient treatment, respectively. Conclusions: The incidence of IRs varies among different mAbs; and IRs may cause treatment disruption and require costly medical interventions.

Identification of drug-related problems: a prospective study in two general hospitals.

Abstract: Drug-related problems (DRPs) can reduce the potential clinical benefits of treatment with medicines and waste valuable resources. No previous studies were published to examine the nature and frequency of drug related problems among hospitalized patients in Palestinian hospitals. Methodology: Prospective observational study was conducted to report and record the natural and frequency of drug related problems in two general hospitals. Results: The study included 212 patients, 54.4 % female, with a mean age 62.2 (±10.6 SD). 88% of the patients were reported with one or more DRPs, with an average of 1.9 DRPs per patient were found. The most prevalent DRP was incorrect dosing regimen which was represented by (22.2%), followed by drug-drug interaction (19.4%), drugs need laboratory tests (15.2%). Ceftriaxone, warfarin, enoxapirin and dogixin were the drugs causing most frequent DRPs. The drug groups causing most DRPs were anti-infective agents, anti-thrombotic agents and non-steroidal anti-inflammatory agents. Once discovered, the majority of DRPs (71.6%) were accepted by the physicians and solved immediately, while 11.5 % of pharmacist advice was not approved. Multiple regression analysis indicated that the number of medications (RR 1.99; 95% CI 1.31-3.76) and the number of medical conditions (RR 1.81; 95% CI 1.11-3.13) independently predicted the number of DRPs. Conclusion: DRPs in general hospitals are frequent, serious and predictable. Most of the problems identified as DRPs by the pharmacists were accepted by the physicians and solved. Pharmacists in the hospital setting are well suited to identify and resolve DRPs.

Pharmacological Management of PDA: Oral Versus Intravenous Medications

Abstract: Patent ductus arteriosus is a common problem in very low birth weight infants. Prostaglandin synthesis inhibitors such as indomethacin and ibuprofen are widely used preferred medications for ductal closure but the question of which one should be preferred is controversial. There are some studies in the literature comparing their pharmacokinetics, efficacy, side effects and long-term outcomes. In this review we aimed to focus on prostaglandin synthesis inhibitors with their pharmacodynamic and pharmacokinetic in relation to oral and intravenous forms. Oral ibuprofen seems to be an effective and cheap alternative to the intravenous forms. Studies in extremely low birth weight infants that also evaluate the neurodevelopment will clarify its use.

Drug delivery systems with modified release for systemic and biophase bioavailability.

Abstract: This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

The Role of DNA Methylation in the Pathogenesis and Treatment of Cancer

Abstract: DNA methylation is a major epigenetic mechanism that leads to inhibition of gene transcription and is known to be involved in the pathogenesis of cancer. The effectors of DNA methylation are DNA methyltransferases (DNMTs) that catalyze either de novo or maintenance methylation of hemimethylated DNA after DNA replication. DNA methylation patterns in cancer are distorted, with three ways by which DNA methylation contributes to cancer: hypomethylation of the cancer genome, focal hypermethylation of the promoters of tumour suppressor genes, and direct mutagenesis. Drugs that inhibit DNMTs are proving to be useful in the treatment of cancer with a few such drugs approved for clinical use. These drugs include nucleoside inhibitors, non-nucleoside inhibitors, oligonucleotides, and noncoding RNAs that target messenger RNAs of genes encoding DNMTs. The major value of DNMT inhibitors could be that at low doses they can induce the re-expression of aberrantly silenced tumour suppressor genes, allowing cancer cells to revert to a normal phenotype and/or reacquire cellular pathways needed for cell cycle regulation and apoptosis induction. They could also be useful in combination with other anticancer drugs.

Nifedipine blocks ondansetron electrophysiological effects in rabbit purkinje fibers and decreases early after depolarization incidence.

Abstract: We hypothesized that a high concentration of nifedipine (1 μM), known to inhibit at least 75%of L-type Ca++ current, might counteract proarrhythmic dose-dependent effects of ondansetron (0.1 to 10 μM) in rabbit Purkinje fibers. Ondansetron is a 5-HT3 receptor antagonist commonly prescribed to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery but may increase the risk of developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm and recently raised FDA concerns and warnings. Neostigmine, a quaternary nitrogen agent that was also used clinically concomitant to antiemetics after anesthesia was further investigated dose-dependently (0.1 to 10 μM) and at fixed concentration (10 μM) with 0.1 to 10 μM ondansetron. The protocol included use-dependent (1 to 0.33 Hz) studies. APD durations, triangulation and early after depolarization (EAD) incidence were assessed. Ondansetron increased APD50, APD70 and APD90 (0.01 > p < 0.05) dose-dependently. APD90 averaged 102�1%of baseline to 302�49%dose-dependently (p < 0.001) and, at the highest dose, increased to 511�73%reverse use-dependently (p < 0.001). EAD were seen at top concentrations (33%) which were increased at lower rates (50%). Neostigmine induced reverse use-dependent APD changes (p < 0.05) but no EAD. In preparations treated by nifedipine and ondansetron, APD90 changes averaged 101�2%of baseline to 151�8%dose-dependently (p < 0.01) and to 193�13%reverse use-dependently (p < 0.05) and no EAD were seen. Thus nifedipine significantly shortened ondansetron-induced APD changes (p < 0.01), whereas neostigmine only slightly shortened ondansetron-induced APD changes (p < 0.05). There was a tendency for increased incidence of EAD (p < 0.06) in the ondansetron and neostigmine group vs. neostigmine alone. It is concluded that inhibition of L-type Ca++ current by high concentration nifedipine may counteract the ondansetron effects on APD changes.

Current status of CETP inhibitors in the treatment of hyperlipidemia: an update.

Abstract: Introduction The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP). Areas covered Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

Oral beclomethasone dipropionate: a critical review of its use in the management of ulcerative colitis and Crohn's disease.

Abstract: Crohn's disease and ulcerative colitis are inflammatory bowel diseases characterised by a chronic relapsing course. Corticosteroids represent the mainstay of medical treatment of inflammatory bowel disease for the induction of remission. Despite the high efficacy of systemic steroids, their use is limited by the high incidence of potentially serious adverse effects. The topically acting steroids are synthetic compounds characterised by high anti-inflammatory activity and low systemic effects by virtue of efficient first-pass hepatic inactivation. Budesonide and Beclomethasone Dipropionate are the two most studied topically acting steroids in inflammatory bowel disease. Oral Budesonide has been extensively studied in the treatment of mild to moderate ileo-caecal Crohn’s disease but few data are available concerning oral Beclomethasone Dipropionate. This review focuses on the available evidence of efficacy and safety of oral Beclomethasone Dipropionate in the management of ulcerative colitis and Crohn's disease and a possible role of this steroid in clinical practice is suggested.

Quality assessment of clinical practice guidelines for the prescription of antidepressant drugs during pregnancy.

Abstract: Antidepressant use during the gestational period remains a controversial issue. The objective of this study was to appraise the quality of the available clinical practice guidelines (CPGs) that includes recommendations for antidepressant use during pregnancy. We systematically searched for documents published between January 2000 and September 2010 in MEDLINE / TRIP database and on clearinghouses and main scientific societies websites. Four appraisers evaluated each guideline using the Appraisal of Guidelines for Research and Evaluation tool (AGREE II). Intra-class correlation coefficients (ICC) with 95% confidence intervals (CI) were calculated as an overall indicator of agreement. Twelve CPGs were included from a total of 539 references. Only two guidelines were specifically addressed to pregnant women. The overall agreement among reviewers was high (ICC: 0.94, 95% CI: 0.86-0.98). The mean scores and standard deviation (SD) for each of the AGREE II domains were: scope and purpose: 84.4% (12); stakeholder involvement: 67.4% (29.8); rigor of development: 68.6% (19.8); clarity and presentation: 83.4% (17.4); applicability: 44% (37.3); and editorial independence: 62.1% (30.4). After standardizing the scores of the 12 guidelines, 5 were considered as being “recommended”, 5 as “recommended with modifications, and 2 as “not recommended”. Among the five recommended guidelines, two were specifically conceived to the gestational period. CPGs containing recommendations for antidepressant use during pregnancy were of moderate to high quality. Future guidelines should take into account the observed drawbacks in some domains, and specifically focus a more in depth approach of depression during pregnancy.

Medical treatment of overactive bladder: an overview.

Abstract: UNLABELLED: The overactive bladder is a common and distressing condition that has a significant impact on the quality of life of millions of people worldwide. Despite its high prevalence, it is a disorder poorly known and not usually tackled in daily clinical practice. The underlying pathophysiology that leads to OAB syndrome is, as yet, incompletely characterized. Non-pharmacological intervention is the foundation of treatment for overactive bladder. Traditional non-pharmacological tools and lifestyle modification should be provided consistently as part of a balanced program for improving target symptom control. In the past, the entire pharmacotherapeutic scenario of OAB had been dependent on modulation of muscarinic receptors. These receptors, although important to intrinsic detrusor function, do not appear to be completely responsible for OAB, given the incomplete therapeutic responses obtained with current agents. Anti-muscarinics remain the first line in pharmacotherapy. However, these agents produce variable efficacy and/or are often associated with considerable adverse effects resulting in treatment failure. Thus, there is a need for more effective treatments. Prospective therapies aimed at novel targets with novel mechanisms of action are currently at different stages of clinical development. With the exception of botulinum toxin, however, few newer therapies have emerged showing clinical benefits. OBJECTIVE: The aim of this review is to provide an overview of the various drug therapies available for the management of OAB. Non pharmacological therapies are being outlined briefly. METHODS: MEDLINE, Medscape, and Google scholar databases were searched using the relevant terms. Full text articles in English regarding the current literature on the management of OAB with major emphasis on pharmacotherapy were selected for reference.

Ciclesonide--a novel corticosteroid for the management of asthma.

Abstract: Ciclesonide (CIC) is a novel inhaled corticosteroid (ICS) approved by US Food and Drug Administration for the treatment of persistent asthma, available as a pressurized metered-dose inhaler in two strengths, 80 mcg/activation and 160 mcg/activation. Ciclesonide is a corticosteroid with unique pharmacological profile including a high degree of serum protein binding, a low oral bioavailability and rapid systemic elimination. Ciclesonide is a prodrug metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. It has shown to improve pulmonary functions, reduce the need for oral corticosteroids (OCSs) and cause lesser suppression of the hypothalamic-pituitary-adrenal axis in asthmatic patients. Clinical efficacy studies suggest that Ciclesonide is superior to placebo and is at least as effective as several active comparators with an improved therapeutic margin thereby improving the therapeutic outcome in patients of asthma.

Novel direct factor IIa and Xa inhibitors: mechanisms of action and preclinical studies.

Abstract: The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the "ideal anticoagulant", an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development.

Clinical pharmacology of current and future drugs for the acute treatment of migraine: a review and an update.

Abstract: Migraine is a common disorder with a female prevalence of 17% and a male prevalence of 9%. Migraine is most often disabling and the patients need treatment of the attacks. The introduction of triptans has been a revolution for many migraine patients but only a minority of patients use these specific drugs. The pharmacokinetics and efficacy and tolerability of triptans are reviewed. The triptans can most likely with advantage be combined with NSAIDs and prokinetic drugs. Among future drugs, CGRP receptor antagonists are the most promising. These drugs have shown excellent tolerability with no more adverse events than placebo, but only one quarter of migraine patients have been pain-free after 2 hours in phase III studies. The development of current CGRP antagonists has been stopped.

Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations

Abstract: Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.

Prevention and treatment of venous thromboembolism and pulmonary embolism: the role of novel oral anticoagulants

Abstract: Venous thromboembolism, encompassing deep vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke. Clinicians are often summoned to make challenging decisions for the prevention and treatment of high risk patients with an unpredicted outcome, often relying on data that are less than definitive. During the last decades, heparins (unfractionated and low molecular weight heparins) as well as vitamin K antagonists, such as warfarin, and indirect Xa inhibitors, such as fontaparinux, are the cornerstone for the prevention and treatment of patients with venous thromboembolism. However, the traditionally used anticoagulants have several drawbacks that may limit their efficacy and use in every day clinical practise. The newly developed oral anticoagulants, belonging to the categories of direct thrombin inhibitors (DTIs) and direct Xa inhibitors, have emerged as promising agents with remarkable efficacy, concentrating many parameters of an ideal anticoagulant. Rivaroxaban, dabigatran and apixaban are the most studied agents, while a plethora of others are investigated in clinical trials of different phases and are expected to reach the market in the following years. The purpose of this review is to summarize the so far acquired knowledge on these agents, to report briefly some of their pharmacodynamic and pharmacokinetic properties and to focus on their role in the treatment and prevention of venous thromboembolism.

An Aggressive Medical Approach for Inflammatory Bowel Disease: Clinical Challenges and Therapeutic Profiles in a Retrospective Hospitalbased Series

Abstract: Background: We studied the toxicity of cyclosporin (CsA), azathioprine, and mesalamine in 94 patients with inflammatory bowel disease (IBD). Methods: 63 treatments with CsA (2mg/kg intravenously or 5 mg/kg orally); 57 with azathioprine (2 mg/kg); and 44 with mesalamine (3.2-4.8 gr) were included. After induction, oral CsA was continued for 6 months, azathioprine for a median of 14 months (range 1-201 mos), mesalamine until tolerated. Results: CsA toxicity frequency 25%: withdrawal and colectomy in 3 cases. AZA toxicity rate: 43% with an overall timeto- onset of a median of 6 months (range 1-60 mos); withdrawal and colectomy in 7 cases; 62% of the events were other than leukopenia. Mesalamine toxicity rates: (13.6%) with one colectomy. Conclusion: Toxicity-related withdrawal of conventional IBD treatments is significant and leads to colectomy in ulcerative colitis. 50% of the thiopurine toxicities outrange the predicting power of the available pharmacogenomic assays; mesalamine often causes allergic lung dysfunction. Efforts are warranted to optimize this conventional treatment of IBD.

Novel oral anticoagulants in the treatment of acute coronary syndromes: is there any room for new anticoagulants?

Abstract: Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.

Non-infectious complications of immunosuppressant medications in renal transplant patients.

Abstract: Over the years Renal Transplant has become increasingly successful and fairly routine in terms of availability to prospective patients. More effective and better tolerated medications have led to decreased adverse immunologic events after transplant leading to improved graft survival. Moreover, since the last few years renal transplant is being offered to a wider range of patients with variety of comorbidities, thus making the surveillance of long term complications of immunosuppression (IS) medications critical for both graft and patient survival. As the use of newer and more potent medications becomes more wide spread, their adverse effects, interactions amongst themselves as well as with other medications, are necessary to recognize and follow closely specially in patients with other comorbidities. Although infections resulting from IS are common; other noninfectious complications cause significant problems in a transplant patient. Post-transplant, several preexisting risk factors like hypertension (HTN), dyslipidemia and hyperglycemia usually get exacerbated resulting in accelerated atherosclerosis causing cardiovascular disease which is the most common cause of death in transplant patients. Some IS medications have been implicated as a cause for certain malignancies and their close surveillance and timely intervention is an important aspect of care for these patients. Therefore an understanding of these medications and their adverse effects is of paramount importance for the successful medical management of these patients. In this manuscript we review the transplant IS and systematically outline their various noninfectious adverse effects.

Breakthrough Pain-Novel Analgesics

Abstract: Breakthrough pain (BTP) is a transitory exacerbation of pain that occurs on a background of otherwise controlled pain. It is associated in conjunction with severe chronic pain and may result in impaired physical and psychological functioning, reduced effectiveness to opioids and also, increased financial burden. It manifests commonly in malignant pain, as manifested by well managed round the clock regular opioid medication but associated with intermittent sharp pain symptoms that are not controlled by the regular medication. It is a significant clinical problem and should be independently assessed and treated. The most common approach being used is 'rescue' medication--a short acting opioid in combination with the fixed-schedule opioid regimen. The lag time between peak pain intensity during an episode of BPT and onset of analgesia of most short-acting opioids is approximately 30-60 minutes. This suggests that the effectiveness of supplemental medications for BTP might be improved with analgesic agents that have a more rapid onset of action. Traditionally the rapid onset analgesia for breakthrough pain has been achieved by administering potent opioids through sublingual route bypassing the first pass metabolism. However with recent advances in drug delivery systems, transmucosal and buccal routes have gained popularity. Pharmacokinetic studies have demonstrated a high early systemic exposure to opioids well over their therapeutic dose range resulting in management of the breakthrough pain. This article proposes to review the evidence base on the effectiveness of these novel opioid delivery systems in managing the breakthrough pain.

Confounding issues in estimation of patient-specific pharmacokinetic parameters and dosage individualization of aminoglycosides.

Abstract: Aminoglycoside antibiotics are usually administered by multiple short intravenous infusions at fixed intervals. Today, equations reported 35 years ago by Sawchuk and Zaske are still the cornerstone of methods used for determination of patient-specific pharmacokinetic parameters of aminoglycosides and individualization of drug dosage regimens in many clinical settings. Additionally, these methods are included in many clinical pharmacology curricula in pharmacy and other related fields. However, there are a few issues with regard to the application and/or modification of this method in clinical settings, which may result in some confusion among novice clinicians. For example, serum samples collected from different intervals at steady state, instead of samples obtained during the same interval, require special manipulation of sampling time before they can be used for estimation of pharmacokinetic parameters. Furthermore, there are various ways that the original equations are modified or simplified, which can result in some degree of error in the estimates of pharmacokinetic parameters and ensuing dosage regimen calculations. Simulation data presented here indicate that in some cases, these errors may be substantial, depending on the length of short infusion, half life of the drug, and the dosage interval. For instance, using equations developed for intravenous bolus mode of administration, ignoring the short infusion, may result in ≥ 25% error for a typical patient and dosing scenario. Although experts may use modified equations, understanding their error ramifications, these modifications may be confusing to the novice clinicians. Therefore, it is recommended that exact equations developed specifically for multiple intravenous infusions be used without any modification, particularly in settings where clinicians are being trained.