PURPOSE OF REVIEW: The costs associated with antiretroviral therapy are becoming a major concern for the treatment of HIV-infected patients in resource-limited countries. Potential risk for the increase in toxicity due to higher drug exposure among Asians is also a concern. In this article, we discuss the studies performed using low-dose antiretroviral therapy as an effective and well tolerated strategy. RECENT FINDINGS: The studies reviewed demonstrate that dose reduction of antiretroviral therapy provides adequate plasma concentrations and effective immunological and virological responses in, mainly, a Thai population compared with whites. The differences in these pharmacokinetic parameters could possibly be due to differences in body weight and composition, drug-food interactions, metabolism, environmental factors and genetic background. Moreover, dose reduction can possibly decrease toxicity and save costs for patients in low- and middle-income countries. SUMMARY: Although the use of low-dose antiretroviral drugs showed adequate plasma levels in an Asian population, in particular, careful attention has to be given to pharmacokinetic, safety and efficacy data to avoid problems of subtherapeutic levels and drug resistance. Large, phase III studies are warranted.

Erythropoietin (EPO), a glycoprotein essential for red blood cell production acts on several non-erythropoietic tissues. The EPO receptor (EPOR) is expressed in a variety of cell types including neurons, endothelial cells, and cardiomyocytes. Recently, a number of reports have indicated that EPO preserves heart function in models of cardiac ischemia-reperfusion (I/R) injury. A diverse range of cellular/physiological processes is modulated by EPO and are thought to play a role in the preservation of heart function. In vivo, reductions in infarct size, apoptosis, oxidative stress, and inflammation have been reported. More recently, increases in angiogenesis and reductions in arrhythmias have been implicated in the cardioprotective effects of EPO. In vitro, EPO reduces apoptosis, oxidative stress, and inflammation. These cardioprotective effects appear to be mediated by a receptor interaction that is distinct from that responsible for EPO's erythropoietic effects. Downstream of receptor interactions, the activation of phosphatidylinositol-3 kinase (PI3-kinase) and Akt appear to mediate many of EPO's cardioprotective effects. However, there is emerging evidence for Akt-independent mechanisms of cardioprotection including the inhibition of glycogen synthase kinase 3beta, as well as the activation of potassium channels, protein kinase C, and protein kinases such as ERK1/2. This review focuses on the effects of EPO in the heart and the molecular mechanisms by which EPO achieves its cardioprotective effects.

Genistein (CAS 446-72-0), an isoflavone and phytoestrogen predominantly found in soy, is considered a promising natural bioactive to prevent post-menopausal bone loss. geniVida (previously Bonistein), a novel product containing of min. 98.5% synthetic genistein aglycone, was investigated in 12 healthy post-menopausal women to assess the safety and tolerability as well as to obtain pharmacokinetic data after 7 days of repeated intakes. 24 h pharmacokinetic profiles were determined after the first oral dose and after 7 days repeated intakes of 30 mg of the test formulation. Plasma genistein (aglycone) and its conjugates were determined by a standardised LC/MS analytical method using D4-genistein as the internal standard. The plasma-concentration time profiles for conjugated genistein showed a fast, monophasic one-peak course until T(max)(5.9 h (first dose), 5.3 h (steady state (SS)); C(max)(456.8 ng/ml (first dose), 498.5 ng/ ml (SS)). Elimination half-lives (t1/2) were calculated to be 10.8 h (first dose) and 8.2 h (SS), respectively. Determination of AUC(0-inf.))(first dose) was good with a low percentage of extrapolation (3949.1 h ng/ ml). AUC(0-24h) at SS was 5923.3 h ng/ml. Steady state was reached after 4 to 5 days and no relevant accumulation occurred (R = 1.02). The test formulation was safe and very well tolerated.

BACKGROUND: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. METHODS: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups. RESULTS: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. CONCLUSIONS: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries.

Mifepristone is known to induce mixed passive-, active-antagonist and agonist effects via the glucocorticoid receptor (GR) pathway. Part of the antagonist effects of mifepristone are due to the repression of gene transcription mediated by the corepressor NCoR. Here we report the crystal structure of a ternary complex of the GR ligand binding domain (GR-LBD) with mifepristone and a receptor-interacting motif of NCoR. The structures of three different conformations of the GR-LBD mifepristone complex show in the oxosteroid hormone receptor family how helix 12 modulates LBD corepressor and coactivator binding. Differences in NCoR binding and in helix 12 conformation reveal how the 11-beta-substituent in mifepristone triggers the helix 12 molecular switch to reshape the coactivator site into the corepressor site. Two observed conformations exemplify the active antagonist state of GR with NCoR bound. In another conformation, helix 12 completely blocks the coregulator binding site and explains the passive antagonistic effect of mifepristone on GR.

Background Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used. Methods An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120. Results The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2)(0.8-1.1), 17%(11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22%(15%-28%) and 27%(21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19). Conclusions Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted.

OBJECTIVE: To determine the effects of graded doses of propofol on cardiovascular parameters and intraocular pressures (IOP) in normal dogs. STUDY DESIGN: Prospective, randomized, modified Latin square, cross-over experimental study. ANIMALS: Eleven adult random-source dogs weighing 20.2 +/- 5.7 kg. METHODS: There were three treatment groups: propofol 8 mg kg(-1) intravenous (i.v.) until loss of jaw tone (Group P), propofol until loss of jaw tone +20%(Group P20), and propofol until loss of jaw tone +50%(Group P50). Atracurium 0.1 mg kg(-1) i.v. was administered in all treatments immediately after the propofol. All dogs received the three treatments in a randomized order, with at least a one week interval between treatments. Direct arterial blood pressure and IOP by applanation tonometry were obtained at baseline, after 5 minutes of pre-oxygenation (before induction), before, and after intubation. Blood gas samples were obtained at baseline, after pre-oxygenation, and before intubation. RESULTS: There was no significant difference in IOP readings at any time point among groups. The IOP was significantly higher before intubation versus before induction in all three groups. There was a significantly smaller change in systolic, mean (MAP), and diastolic (DAP) arterial pressures in the P50 group compared with the P group after intubation. There was a significantly smaller change in MAP and DAP in the P50 group compared with the P20 group after intubation. The increase in CO(2) from before induction to before intubation was significantly greater in the P50 group than in the P or P20 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Graded doses of propofol did not affect the increase in IOP observed with propofol induction in normal dogs. Higher doses of propofol are of no apparent additional benefit in animals who cannot tolerate an abrupt increase in IOP but may be of benefit in dogs who cannot tolerate an abrupt increase in blood pressure accompanying orotracheal intubation.

OBJECTIVE:: To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations. METHODS:: HIV-infected patients with a high efavirenz plasma concentration (>/=4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations. RESULTS:: One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression. CONCLUSIONS:: Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.