Hippocampal GABAergic neurons are susceptible to amyloid-ß toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model.

The relevance of γ-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-ß (Aß) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Aß42 (between 2 and 4 months) and accumulation of insoluble Aß into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Aß42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Aß in vitro, GABAergic neurons are susceptible to Aß42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Aß load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5-2 month-old) TgCRND8 mice, it is likely that Aß toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage.

Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients.

BACKGROUND: Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options. METHODS: MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100,000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48. RESULTS: Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment. CONCLUSION: Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.

Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients.

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

Five day clarithromycin modified release versus 10 day penicillin V for group A streptococcal pharyngitis: a multi-centre, open-label, randomized study.

OBJECTIVE: A multicentre, comparative, randomized, open-label, Phase III trial evaluated the efficacy and tolerability of clarithromycin modified release (MR) versus penicillin V for pharyngitis due to group A beta-haemolytic streptococci (GABHS). METHODS: Three hundred and forty-nine patients (12-40 years) with acute pharyngotonsillitis and a positive Streptococcus A antigen immunoassay test were randomized to receive clarithromycin MR 500 mg od for 5 days or penicillin 590 mg tds for 10 days. Patients were clinically evaluated and a throat swab for culture obtained before treatment, after treatment (day 8 or 13 depending on the treatment arm) and at the follow-up visit (day 30). The main criterion for efficacy was the bacteriological cure rate after treatment. RESULTS: Three hundred and forty-nine patients were considered for the intent-to-treat analysis. After treatment, clinical cure rates were 88.1% in the clarithromycin group and 92.4% in the penicillin group, and eradication rates were 82.8% and 83.6%, respectively. There were no statistically significant differences between the two treatments. Three hundred and three (87%) patients had a positive culture before treatment, among which 29 (9.7%) were found to be clarithromycin resistant. Two hundred and thirty-nine patients were clinically and bacteriologically evaluable for per protocol analysis. After treatment, clinical cure rates were 95.2% in the clarithromycin group and 97.3% in the penicillin group, and eradication rates were 94.4% and 92%, respectively. No statistically significant difference was shown. Adverse events occurred in 46 patients of the clarithromycin group and 31 of the penicillin group (with no statistical difference). Most of them were of mild or moderate severity. CONCLUSION: Clarithromycin MR administered once daily for 5 days is as safe and effective as penicillin V administered three times a day for 10 days in the treatment of GABHS pharyngitis.