Effects of localized hydrophilic mannitol and hydrophobic nelfinavir administration targeted to olfactory epithelium on brain distribution.

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = -3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

Trough concentrations of lopinavir, nelfinavir, and nevirapine with standard dosing in human immunodeficiency virus-infected pregnant women receiving 3-drug combination regimens.

The objective of this study was to evaluate the plasma drug concentrations in human immunodeficiency virus (HIV)-infected pregnant women receiving highly active antiretroviral therapy (HAART) and to define the rate of occurrence of subtherapeutic concentrations for some commonly used antiretroviral drugs during pregnancy. We evaluated HIV-infected women (n = 68) in the third trimester of pregnancy in steady-state treatment with an HAART regimen administrated on a twice a day basis, which included 2 nucleoside reverse transcriptase inhibitors plus nelfinavir (NFV), lopinavir/ritonavir (LPV/r), or nevirapine (NVP). Blood samples were collected at predose (C(trough)). The following thresholds were used to define therapeutic drug concentrations-NFV: 0.8 microg/mL; LPV: 4.0 microg/mL/1.0 microg/mL (experienced/naive); and NVP: 3.1 microg/mL. At predose sampling, adequate drug concentrations were found in a higher proportion of women receiving NFV (70.8%) and LPV (75.0%) than NVP (55.6%). Median C(trough) plasma concentrations were 1.2 microg/mL for NFV, 5.5 microg/mL for LPV, and 3.1 microg/mL for NVP. Women receiving lopinavir/ritonavir had the lowest rates of detectable (>50 copies/mL) HIV RNA (15.4%) compared with rates of 22.2% and 41.7% among women receiving NVP and NFV, respectively. Genotypic resistance was detected in 50% of women with detectable HIV RNA for whom samples were available for testing. Subtherapeutic predose concentrations among HIV-infected pregnant women were more commonly found with NVP than with protease inhibitors. LPV administration was associated with the best viral load suppression.

Safety, tolerability, and antiretroviral effects of ritonavir-nelfinavir combination therapy administered for 48 weeks.

OBJECTIVE: To evaluate the safety, tolerability, and anti-HIV activity of ritonavir-nelfinavir (RTV-NFV). DESIGN: Single-site, open-label, nonrandomized, multiple-dose trial of RTV combined with two doses of NFV in protease inhibitor (PI)-naive, HIV-infected patients. METHODS: Mean baseline HIV RNA was 39,500 copies/ml; mean baseline CD4 count was 323 cells/mm3. All patients received RTV at a dosage of 400 mg twice daily. Cohorts I (N = 10) and II (N = 10) received NFV at a dosage of 500 mg and 750 mg twice daily, respectively, for the initial 12 weeks of the study before allowing intensification with reverse transcriptase inhibitors. RESULTS: The commonest effects of RTV-NFV therapy were study drug-related moderate-to-severe diarrhea (9 patients in cohorts I and II) and drug-related moderate-to-severe nausea (4 patients in cohorts I and II). HIV RNA was suppressed in a biphasic manner. At 48 weeks in cohort I, mean HIV RNA reduction was 2.82 log10 copies/ml (standard error [SE] =.61; p =.001; N = 4); mean CD4 cell count increase was 236 cells/mm3 (SE = 67.1; p =.006; N = 4). In cohort II, mean HIV RNA reduction at Week 48 was 2.21 log10 copies/ml (SE =.430; p =. 001; N = 8); mean CD4 cell count increase was 120 cells/mm3 (SE = 47. 5; p =.03; n = 8). In cohort I patients, 2 of 4 completing Week 48 had HIV RNA <20 copies/ml; and 3 of 4 had HIV RNA <400 copies/ml. In cohort II, 2 of 8 patients completing Week 48 had HIV RNA <20 copies/ml and 4 of 8 had HIV RNA <400 copies/ml. In addition, 3 patients in cohort I withdrew because of virologic failure not thought to be related to poor compliance. Moreover, 15 patients elected to add new reverse-transcriptase inhibitors (RTIs) after week 12. CONCLUSIONS: RTV-NFV with concomitant reverse transcriptase inhibitors is a potential dual-PI option for PI-naive patients.

Adherence, side effects and efficacy of stavudine plus lamivudine plus nelfinavir in treatment-experienced HIV-infected patients.

OBJECTIVES: To evaluate adherence, side effects and efficacy of a modality of highly active antiretroviral therapy (HAART) in HIV-infected patients. METHODS: In a cohort, prospective study, 65 previously treated patients received stavudine plus lamivudine plus nelfinavir. Fifty-three participants (81%) had a history of intravenous drug use. Patients were evaluated at 3-month intervals. The association of adherence with demographic variables, hepatitis C virus infection, number of stopped antiretroviral regimens, HIV RNA level, CD4 cell count, and adverse effects to drugs was assessed. RESULTS: After a median follow-up of 12 months, 30 participants (46%) showed adequate adherence in all visits. An association was observed between adherence and female sex: 18 of 47 men (38%) vs. 12 of 18 women (67%) presented adequate adherence in all visits (P=0. 0416). An association was also observed between adherence and low baseline HIV RNA level (P=0.0229). Discontinuation of treatment took place because of refusal to take medication in 11 participants (17%) and because of side effects in seven participants (11%). Undetectable HIV RNA level was achieved in 26 patients (40%) at 3 months and in lower percentages at months 6, 9 and 12. CONCLUSIONS: Overall adherence to the employed HAART regimen was poor. Female sex and low baseline HIV RNA were associated with better adherence. Refusal to take medications and side effects were the main reasons to stop therapy. At 3 months' follow-up, virological efficacy was achieved in 40% of patients.