Current Clinical Pharmacology - Volume 7, Issue 2, 2012

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.

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.

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.

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<0.001). Living with family members, changing the HAART regimen and stage of disease had a significant relationship with adherence rates. 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.

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.

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.

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.

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.