Current Clinical Pharmacology - Volume 9, Issue 2, 2014

Influenza A is a viral disease of global dimension, presenting with high morbidity and mortality in annual epidemics, and in pandemics which are of infrequent occurrence but which have very high attack rates. Influenza vaccines of the future must be directed toward use of conserved group-specific viral antigens, such as are present in transitional proteins which are exposed during the fusion of virus to the host cell. Influenza probes revealed a continuing battle for survival between host and parasite in which the host population updates the specificity of its pool of humoral immunity by contact with and response to infection with the most recent viruses which possess altered antigenic specificity in their hemagglutinin (HA) ligand. It is well known that the HA protein is found on the surface of the influenza virus particle and is responsible for binding to receptors on host cells and initiating infection. Polymorphonuclear neutrophils (PMN) have been reported to be involved in the initial host response to influenza A virus (IAV). Early after IAV infection, neutrophils infiltrate the airway probably due to release of chemokines that attract PMN. Clearly, severe IAV infection is characterized by increased neutrophil influx into the lung or upper respiratory tract. Carnosine (β-alanyl-L-histidine) and anserine (N-β-alanyl-1-methyl-L-histidine) are found in skeletal muscle of most vertebrates, including those used for food; for example, 100 g of chicken breast contains 400 mg (17.6 mmol/L) of carnosine and 1020 mg (33.6 mmol/l) of anserine. Carnosine-stimulated respiratory burst in neutrophils is a universal biological mechanism of influenza virus destruction. Our own studies revealed previously unappreciated functional effects of carnosine and related histidine containing compounds as a natural biological prevention and barrier against Influenza virus infection, expand public understanding of the antiviral properties of imidazole-containing dipeptide based compounds, and suggest important interactions between neutrophills and carnosine related compounds in the host response to viruses and bacteria. Carnosine and anserine were also found to reduce apoptosis of human neutrophils. In this way these histidine-containing compounds can modulate the Influenza virus release from neutrophills and reduce virus dissemination through the body of the organism. This review points the ability of therapeutic control of Influenza viral infections associated with modulation by oral nonhydrolized forms of carnosine and related histidine-containg compounds of PMN apoptosis which may be involved at least in part in the pathophysiology of the disease in animals and humans. The data presented in this article, overall, may have implications for global influenza surveillance and planning for pandemic influenza therapeutic prevention with oral forms of non-hydrolized natural L-carnosine as a suitable alternative to the conventional vaccination for various flu ailments.

The goal of this review is to address the medical implications of placebos and placebo effects in future medical practice. The applications of placebos have become increasingly relevant due to a recent abundance of clinical research that has been conducted on the mechanisms under which a placebo response is formed. With current research on placebo, the thoughts of using placebo effects as an effective form of co-treatment for patients with disorders such as pain, depression or Parkinson's disease might become a feasible proposition. This review focuses on crucial studies that have been done in this area of research with regard to the physiological and psychological mechanisms that are associated with the formation of a placebo effect, as well as emphasizing the patient-clinician relationship and the importance of this relationship for a successful treatment regimen.

Background: We sought to determine whether sustained-release bupropion (bupropion-SR) reduces smoking and promotes smoking cessation among alcohol-dependent (AD) smokers while they are in early recovery from alcohol. Methods: We conducted an open-label, naturalistic study among AD smokers enrolled in an outpatient treatment program. The treatment group (n=58) was offered bupropion-SR and brief smoking cessation counseling. A control group (n=57) was matched to the treatment group by age, sex, ethnicity, cigarette use, and years of alcohol dependence. The controls received no smoking cessation intervention. We collected tobacco and alcohol abstinence data for 6 months after enrollment. Results: Participants in the treatment group were more likely to abstain from smoking than controls, at any of the followup time points. The treatment group smoked less cigarettes per day (CPD) at baseline, 30 days and 180 days post-baseline, compared to controls. These findings persisted after adjusting for possible covariates. Conclusion: Bupropion-SR may be helpful to quit or reduce smoking for recently abstinent AD individuals.

Background: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. Purpose: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. Methods: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. Results: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. Conclusion: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

Introduction: Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer. Materials and Methods: Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9. Results: Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 – 32). The overall response rate in evaluable patients was 42% (95% CI: 23 – 63) and the median overall survival was 12.2 months (8.4 – 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9. Conclusion: Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.

Background: Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. Methods: This manuscript provides an overview of the drug-drug interaction potential of retigabine with other AEDs, using data collated from both in vitro work and clinical studies, either previously published or from relevant information collated during the development of retigabine. Results: Retigabine is not a substrate for the major CYP enzymes and at clinically relevant concentrations there is little or no potential for retigabine to inhibit or induce the CYP enzymes or to inhibit the major renal drug transporters. The addition of retigabine to a range of existing AEDs showed little or no effect on the AED trough concentrations apart from a 20% decrease in lamotrigine concentrations. Results from a small phase II study showed that co-administration of valproic acid and topiramate had no impact on the PK of retigabine whereas carbamazepine and phenytoin increased the clearance of retigabine by approximately 27% and 36%, respectively. Conversely, a population PK analysis of combined data from phase I, II and III studies showed that none of the coadministered AEDs affected retigabine clearance apart from lamotrigine which lowered retigabine clearance by 6.7%. Conclusion: Retigabine is not metabolized by CYP isozymes and does not induce or inhibit these isozymes at clinically relevant concentrations. Therefore, retigabine is associated with a low potential for PK interactions with other drugs via CYP450. Overall, there was little or no potential for retigabine to interact with other available AEDs. Although some PK interactions were observed with lamotrigine, these are unlikely to be clinically relevant.

CD26 is a widely expressed transmembrane glycoprotein with peptidase activity in its extracellular domain and which regulates multiple biological processes. It acts mainly as catabolic enzyme for a number of circulating proteins involved in common pathological conditions such as diabetes and cardiovascular disease and may represent a target to modulate bioavailability of crucial substrates. The aim of the present review is to summarize data regarding CD26-based pharmacological interventions. Four main subtopics were identified:1) CD26 as the target of pharmacological inhibitors to increase bioavailability of glucagon-like petide-1 (GLP-1) and hence to enhance GLP-1 glucose-lowering activity in diabetic patients; 2) role of CD26 in the physiology and pathology of the cardiovascular system; 3) the adverse prognostic value of CD26 expression on cancer cells; 4) CD26 down-regulation on lymphocytes as a mechanism of TGF-beta immunomodulation.

Valproic acid (VPA) is an anti-epileptic and mood-stabilizing compound successfully used in the clinics since many decades. During the last few years, research on VPA revitalized. VPA has profound impact on nuclear chromatin structure in target cells by impinging on epigenetic mechanisms such as inhibition of histone deacetylase HDAC1, with implications for HIV and cancer treatment, and for the direct reprogramming in generation of induced pluripotent stem (iPS) cells. VPA can thus act at multiple levels and in several cellular systems. In addition to its established applications for the treatment of neurological and psychiatric disorders, and its newly discovered epigenetic mechanisms of action, the peripheral metabolic effects of VPA administration, in particular impinging on the heart and on the liver, are now starting to be understood. These have important consequences for the management of therapy and also for investigation purposes. The aim of this article is on one hand to summarize the emerging knowledge on the role of VPA during the occurrence of cardio-metabolic dysfunctions and on the other hand to describe concisely the VPA-induced epigenetic modifications in target cells.

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life, and death. Primary sarcopenia is considered to be age-related when no other cause is evident, other than ageing itself. Secondary sarcopenia should be considered when one or more other causes are evident, such as activity-, disease-, or nutrition-related sarcopenia. In this narrative review that focused on human studies, we summarize the pharmaceutical therapies (testosterone, dehydroepiandrosterone, estrogen, growth hormone, ghrelin, vitamin D, angiotensin converting enzyme inhibitor, and eicosapentaenoic acid) and nonpharmaceutical therapies (resistance training, protein and amino acid supplementation, and non-smoking) for counteracting primary sarcopenia. Testosterone and growth hormone improve muscle mass and muscle strength, but have several side effects. Although there are some intriguing pharmaceutical therapies to combat sarcopenia, resistance training combined with supplements containing amino acids are the most effective for preventing and treating age-related muscle wasting and weakness. The etiology of sarcopenia in the elderly is multi-factorial. Patients with disuse syndrome and deconditioning often complicate the diagnosis, of not only activity-related sarcopenia, but also age-, disease-, and nutrition-related sarcopenia. In these cases a comprehensive approach to sarcopenia treatment should include pharmaceutical therapies for age-related sarcopenia and comorbid chronic diseases, resistance training, early ambulation, nutrition management, protein and amino acid supplementation, and non-smoking. The effect of pharmaceutical therapies for sarcopenia can be enhanced by this comprehensive approach. Future research on pharmaceutical therapies for counteracting sarcopenia should consider non-pharmaceutical therapies and also the causes of sarcopenia.