A multimodal approach to management of suspected neuropathic pain in a prairie falcon (Falco mexicanus).
AZT treatment for 240 days in rats induces a modest increase in SBP, hypertrophy of the interventricular septum and modified vascular smooth muscle responsiveness. The role of mitochondria in these AZT-induced cardiovascular alterations remains to be established.
Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 microM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 microM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 microM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity.
Although 2/4-ART met the predetermined criteria for noninferiority, the percentage of patients with <350 CD4 cells/mm(3) in the C-ART arm was lower than anticipated, which makes the clinical significance of this noninferiority uncertain. In addition, 2/4-ART led to an unacceptable additional risk of selecting for drug-resistant virus. This new argument against episodic ART strategies is also a caveat against any unplanned ART interruptions in Africa, where most patients receive NNRTIs.
Negatively charged albumins (NCAs, with the prototypes Suc-HSA and Aco-HSA), modified proteins with a potent anti-HIV-1 activity in the nanomolar concentration range, were studied for several aspects of their antiviral mechanism. In addition we investigated the antiviral activity of combinations and covalent conjugates of these NCAs and the reverse transcriptase inhibitor AZT. Addition of NCAs to HIV-1-infected target cells in time-of-addition experiments could be delayed for 30 min after infection before significant loss of activity occurred. Syncytium formation of HIV-infected and uninfected T-cells was inhibited by the NCAs at concentrations of 1-4 microg/ml. The gp120-mediated virus/cell binding, however, was only inhibited by the NCAs at a 10-fold higher concentrations. The combined data are compatible with a preferential influence on virus/cell fusion. A subsynergistic activity against HIV-1 was observed with the non-covalent mixture of Aco-HSA and AZT. When AZT was covalently coupled to the NCAs, and added one hour after infection of the target cells, the anti-HIV-1 activity of NCA-AZTMP was diminished by only 2-6-fold, while this was diminished at least 120-fold for the NCAs. Furthermore the addition of NCA-AZTMP could be delayed up to at least 3 h after infection without loss of antiviral activity. It is concluded that AZT that was coupled to the NCAs significantly contributes to the overall antiviral activity of the conjugates leading to complementary effects. These results highlight the potential of using NCA-AZTMP as dual-targeting preparations against HIV-1 in which both the carrier and the coupled drug contribute to the therapeutic efficacy acting at a different level in the replication cycle.
Eighteen antiretroviral-naive pregnant women with a mean viral load of 4.2 log10 and CD4 cell count of 481/mm(3) were recruited. All patients received zidovudine and 3 (all in the UK) received lamivudine. There were no serious adverse events and no discontinuations due to adverse events. Viral load declined by 1.6 log10 at week 4 and was less than 400 copies/mL at delivery in 16/17 mothers. Sixteen live births were recorded, with two in utero deaths-one secondary to an accident and the second due to antiphospholipid syndrome. Both deaths were considered by investigators to be unrelated to study therapy. All infants were HIV negative at subsequent follow-up and no fetal abnormalities were observed. Pharmacokinetic data suggested that mothers had relatively low exposures to saquinavir despite an excellent virologic response. Saquinavir was not detected in cord blood.