A highly concentrated and taste-improved aqueous formulation of efavirenz for a more appropriate pediatric management of the anti-HIV therapy.

Pediatric HIV is scarce in developed countries; 90% of pediatric HIV patients are in developing countries. In contrast, children represent 15% of the new infections in poor countries. Approximately 90% of the HIV-positive children do not have access to antiretrovirals (ARVs). Without treatment, 50% of the patients die before the 2 years of age. Efavirenz (EFV, aqueous solubility approximately 4 microg/mL, 40-45% bioavailability), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a first-choice pediatric ARV. To assure therapeutic plasma concentrations, the low oral bioavailability demands the administration of relatively high EFV doses. Aqueous EFV irritates the oral mucosa, causing a Burning Mouth Syndrome (BMS). A triglyceride-based liquid formulation of EFV (30 mg/mL) is not commercially available worldwide, making the appropriate dose adjustment and the swallowing difficult. More importantly, clinical trials indicated that the oral bioavailability of this oily solution is lower than that of the solid one. Moreover, a relatively high inter-subject variability has been found. The present work reports the development and full characterization of a concentrated (20 mg/mL, 2%) and taste-masked aqueous formulation of EFV for a more appropriate management of the pediatric anti-HIV therapy. Formulations displayed high physicochemical stability over time under regular storage conditions. Release assays in vitro showed a burst effect (2 h) and zero-order kinetics later on (between 2 and 24 h), compatible with the oral administration route and release. Finally, taste tests performed by adult healthy volunteers indicated that the unique combination of flavors and sweeteners employed (i) reduced the intensity of the BMS and (ii) shortened its duration significantly. Overall results indicate that the cost-effective and scalable nanotechnological strategy proposed could enable the more convenient and compliant administration of lower EFV doses. Due to a better pharmacokinetic profile, this would result in similar plasma levels than higher doses administered in solid or triglyceride-soluble form. In this context, some reduction of the treatment cost can be envisioned. This could improve the access of less affluent pediatric patients to medication in poor countries.

Importance of blood pressure variability in the assessment of cardiovascular risk and benefits of antihypertensive therapy.

Although there is no doubt regarding the relationship between short-term blood pressure variability (BPV) and cardiovascular events in the hypertensive population, to date, the association between long-term BPV and target organ damage is unknown. Rothwell et al. recently published a post-hoc analysis of two large randomized trials, Anglo Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BLPA) and the Medical Research Council (MRC), aimed at demonstrating whether drug effects on short-term and long-term BPV explain the differences of antihypertensive treatment in stroke prevention. Analysis found that short-term and long-term BPV was lower in hypertensive patients treated with amlodipine with regards to atenolol. The amlodipine group showed a lower risk of stroke and coronary events with respect to subjects assigned to atenolol. Interestingly, the lower stroke risk detected in hypertensive patients treated with amlodipine was abolished after adjusting by within-individual BPV. Taking into account these findings, the authors concluded that the opposite effect of calcium channel blockers and ß-blockers on BPV explains the disparity in the risk of stroke of patients under antihypertensive treatment. Therefore, to effectively prevent cerebrovascular events, blood pressure-lowering agents need both to reduce mean blood pressure and its short-term and long-term variability.

Is urethane-chloralose anaesthesia appropriate for pharmacokinetic-pharmacodynamic assessment? Studies with carvedilol.

INTRODUCTION: The aim of the work was to establish the impact of urethane-chloralose anaesthesia on pharmacokinetic-pharmacodynamic (PK-PD) properties of carvedilol in control rats and L-NAME hypertensive animals. METHODS: Male Wistar Rats were randomly divided into: control (n=12) with tap water to drink and L-NAME rats (n=12) with L-NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of carvedilol (1 mg kg(-1), i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg(-1), i.p.) - chloralose (50 mg kg(-1), i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK-PD modeling of carvedilol was made by means of an effect compartment model. RESULTS: Neither urethane-chloralose nor L-NAME modified estimation of pharmacokinetic parameters of carvedilol. Although urethane-chloralose did not modify potency of carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L-NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to carvedilol in control rats. Whilst no differences were found in the estimated potency of carvedilol hypotensive response comparing control and L-NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of carvedilol was significantly greater in anaesthetized control and L-NAME animals in comparison to conscious rats. L-NAME rats showed a greater maximal hypotensive response comparing to control group. DISCUSSION: Urethane-chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK-PD properties of carvedilol, considering that it does not affect the potency of carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane-chloralose anaesthetized animals, regarding the impact of l-NAME treatment on PK-PD properties of carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of carvedilol in both normotensive and L-NAME hypertensive rats.