Current Clinical Pharmacology - Volume 9, Issue 1, 2014

The Renin-Angiotensin System (RAS) is recognized as the main biological system involved in cardiovascular and hydroelectrolyte homeostasis. It is well established in literature that RAS blockers retard the progression of renal failure in type 1 [angiotensin converting enzyme (ACE) inhibitors] and in type 2 [angiotensin type 1 receptor (AT1) antagonists] diabetes mellitus and in non-diabetic chronic kidney diseases. More recently, it was shown that newer therapeutic agents, the renin inhibitors, also exert renoprotective actions. Obesity is recognized as a proinflammatory state often associated with kidney diseases. Recent publications have associated the RAS axis imbalance leading to a predominance of Angiotensin II effects with changes in adipokine levels and actions. In this context, the aim of the current review is to present current evidence on the potential role of RAS blockers in modulating the interaction between adipokines and obesity-related renal disorders.

The out-patient pharmacies in Ramallah and Bethlehem, central Palestine, were evaluated for NSAIDs utilization and pattern of prescribing and dispensing of these commonly used medications across the whole country. In our study for this area that accounts for almost 25% of the inhabitants of all Palestine (459, 761 inhabitants according to 2011 census), we analyzed the use of NSAIDs whether were prescribed for the patient or were obtained without a prescription in the period of Sept 1st to Nov. 30, 2011. The number of defined daily doses, DDD/1000 inh/day, and the percentage utilization from total were determined and analyzed using the simple ATC/DDD model which was developed by WHO for assessment of quality prescribing of medications. From these data we calculated DU 90% for the drugs described in this study. Using a scale for GI toxicity and risk determination from a meta- analysis of controlled epidemiological studies, we determined the GI risk of the drugs in the study. Ketoprofen and piroxicam were found to be associated with the highest risk, on the other hand ibuprofen and diclofenac were associated with low risk of GI toxicity. The average Price/DDD was also determined for the purpose of comparison with the prices in other European countries. Our findings were both exciting and interesting with the total consumption of NSAIDs over the period of study was 31.26 DDD/1000 inh/day comparing to 51.02 DDD/1000 inh/day in the European countries included in the study. Only 5 drugs fell within DU 90% which are respectively along with their percentage NSAIDs consumption: (ibuprofen; 26.48%, diclofenac; 23.38%, etoricoxib; 21.24%, meloxiocam; 12.19%, and celecoxib; 7.16%). The drugs were obtained mostly by prescription except for the first 2 agents (ibuprofen and diclofenac) which were almost exclusively bought without a prescription as OTC with the pharmacist greatly influence their use and dispensing. The price of purchasing for the top DU 90% agents was almost twice the price in Europe for the same drugs taking into consideration the limitations of our study in determining the equipotency or the equivalency of the DDD doses in Palestine and Europe.

This paper evaluates the current literature on non-pharmacological early interventions (behavior behavioral, developmental and educational approaches) for pre-schoolers (aged 24-71 months) with autism spectrum disorders. Although there lies a significant heterogeneity among the available studies, the present review emphasizes the importance of considering the wide range of interventions through behavioral (behavioral or developmental interventions) and educational continuum according to the suggestions of the recent literature in this field. Furthermore, the present review: 1) outlines the issues about the scientific validity of the treatment outcome studies; 2) describes the findings of different parent-mediated interventions; 3) highlights the importance to use the same outcome measures through the studies to compare findings of different literature contributions; and 4) focuses on the importance to consider pre-treatment variables to identify children who will have better outcomes. Furthermore, some evidence-based guidelines about clinical management and treatment have also been outlined and summarized in this review. Finally, the review concludes on providing a number of practical recommendations to clinicians working in the field suggesting both the presence of a specialized team and role of an active collaboration of the family to treatment as core milestones for the clinical management.

Paralleling the developments in Gram-positive bacteria, infections caused by multidrug-resistant (MDR) Gramnegative bacilli have become a growing challenge. The most important resistance problems are encountered in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp., with increasing trends observed for all major anti- Gram-negative agents (beta-lactams, fluoroquinolones and aminoglycosides). A matter of major concern is the emergence of new beta-lactamases capable of degrading the expanded-spectrum cephalosporins and/or carbapenems, such as the extended-spectrum beta-lactamases (ESBLs) and the carbapenemases (ie. KPC, NDM and other metallo-β; -lactamases). This paper reviews the evidence in the published literature of the pharmacokinetic/pharmacodynamic profile, clinical efficacy of new antimicrobial agents, against MDR- Gram-negative pathogens, such us: i-new carbapenems (doripenem, biapenem, panipenem, tonopenem, FSI-1686); ii-new cephalosporins (ceftaroline, ceftobiprole); iii-tigecycline; and iv- β- lactamases inhibitors (BLI-489, Ro 48-1220, ME 1071, aviactam [NXL104]).

Despite their widespread use, long acting antipsychotics, are often regarded with prejudice, due to fears of punishment, control and insufficient evolution towards psychosocial development of psychotic patients raised by their improper utilization. Another major shortcoming of long-acting antipsychotics is the impossibility of altering their dosage if side-effects appear. However, long-acting antipsychotics proved effective in schizophrenia and other severe psychotic disorders as a consequence of stable dose administration, leading to reduction of relapses and increased treatment adherence. Therapeutic opportunities have also risen after introduction of newer long acting second generation antipsychotics in recent years. Newer long-acting antipsychotics were developed to tackle the need for pharmacotherapy enhancing adherence in integrated rehabilitation programmes. This review is an outline of the development and introduction of older and newer long-acting antipsychotics in the treatment of schizophrenia and other psychoses, with considerations on past and present pharmacological and therapeutic issues.

The widespread use of biologics has paved way for newer options in therapeutics for once incurable illnesses. Their large and complex protein structure, post-translational modifications, elaborate manufacturing/production process and risk for immunogenicity adds to the uniqueness of a biologic product. Patent expiration of innovator biologics has led to the development of biosimilars; biologics similar/comparable to the reference product in terms of quality, safety and efficacy. We discuss the clinical safety and regulatory requirements for biosimilars in various countries across the world. Future holds promise for biosimilars to provide affordable, efficacious and safe treatment to a vast majority of patients with significant cost savings to the nation.

Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates.

The essential characteristic of impulse disorders is the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others. Clearly, impulse control disorders can occur without an induction of any drugs, and they may lead to very problematic situations that affect the adjustment of the patient and need to be treated immediately. However, the subject of the present review is impulsivity induced by a variety of drugs. In this context, the most frequently established agents are dopaminergic agonists that may affect the mesolimbic dopaminergic pathway, such as cocaine and methamphetamine. In Parkinson’s disease, the triggering effect of levodopa on pounding has been known since the first description of the condition by Friedman. In this paper, we reviewed the role of a variety of psychopharmacological agents, including dopaminergic ones on the occurrence of impulse control disorders, by searching the PubMed database for relevant articles published in the period between 1980 and 2012 August in detail.

Anticoagulants have a key role in the management of venous and arterial thromboembolic disorders. Traditional anticoagulants, such as unfractionated heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are effective but have limitations that make the management of thromboembolic disorders difficult. There is a clear need for new anticoagulants that are at least as effective as traditional agents but without their drawbacks. This review discusses the mechanism of action, pharmacokinetics, and pharmacodynamics of one of these newer agents – the direct Factor Xa inhibitor rivaroxaban – and provides an overview of the results of phase III clinical studies. Based on these results, rivaroxaban has gained approval for the prevention and treatment of several thromboembolic disorders in adult patients. Rivaroxaban, which has a rapid onset of action, targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It reaches maximal plasma concentration 2–4 hours after administration and has a high bioavailability (80–100%). Rivaroxaban has several advantages over traditional anticoagulants. It does not require dose adjustment for age, sex, body weight, or ethnicity, and there is no requirement for routine coagulation monitoring because it has been shown to have predictable pharmacokinetics and pharmacodynamics. Furthermore, rivaroxaban has minimal food and drug interactions. The introduction of newer oral anticoagulants, such as rivaroxaban, that are convenient to administer and have predictable pharmacokinetic and pharmacodynamic profiles, could ultimately simplify patient management in clinical practice and may improve clinical outcomes across a broad range of thromboembolic disorders.

Even though the exact amount of the increased risk is not known, patients with Ulcerative Colitis (UC) are more likely to develop colonic malignancy compared with the general population. 5-aminosalicilic acid (5-ASA) compounds are the mainstay therapy for mild-moderate UC, and their use for chemoprevention of colorectal cancer has been proposed, but the evidences are not univocal. Aim of the present work is to critically revise the available data on 5- ASA utilization for cancer chemoprevention, as well as the possible impact in the management of UC patients. In clinical practice, in fact, the best means to measure the dimension of a therapeutic effect is the number needed to treat (NNT). In our study, we show how different basal risk of colorectal cancer reported in studies coming from Europe and USA can affect the NNT, making the strategy “cost-effective” or not. Since prospective randomized controlled trials to address the chemopreventive effect of 5-ASA are not feasible, evidence relays upon observational studies that may imply several biases. Therefore, the heterogeneity of the data is mainly consequent to the different methodological approach of the published studies, in terms of study design, data collection, definitions of regular use of medication and measures of therapeutic efficacy. In addition, two meta-analyses are available with apparently conflicting results. Nonetheless, 5-ASA represents an ideal chemopreventive agent for its anti-inflammatory property, safety, acceptability and inexpensiveness, and even ECCO guidelines recommend 5-ASA long term use, as these compounds may decrease the incidence of CRC.