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PubMed1995

Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs.

A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

Animals↗
PubMed2000

Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in rabbit, mouse and human: identification of fluorine NIH shift metabolites using NMR and tandem MS.

1. The urinary metabolites of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) have been investigated in samples obtained following oral administration to rabbit, mouse and human. GW420867X underwent extensive biotransformation to form hydroxylated metabolites and glucuronide conjugates on the aromatic ring, and on the ethyl and isopropyl side-chains in all species. In rabbit urine, a minor metabolite was detected and characterized as a cysteine adduct that was not observed in mouse or man. 2. The hydroxylated metabolites and corresponding glucuronide conjugates were isolated by semi-preparative HPLC and characterized using NMR, LC-NMR and LC-MS/MS. The relative proportions of fluorine-containing metabolites were determined in animal species by 19F-NMR signal integration. 3. The fluorine atom of the aromatic ring underwent NIH shift rearrangement in the metabolites isolated and characterized in rabbit, mouse and human urine. 4. The characterization of the NIH shift metabolites in urine enabled the detection and confirmation of the presence of these metabolites in human plasma.

Animals↗
PubMed2001

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377).

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance mutations were assessed before study treatment (baseline) and at virologic failure. Zdv, ddI, and ddC mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp and 3TC mutations were detected frequently at virologic failure, and Nvp mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp and 3TC mutations plus Rtv and Nfv mutations. However, Rtv and Nfv mutations were detected at unexpectedly low rates.

Adolescent↗
PubMed2005

Non-nucleoside HIV reverse transcriptase inhibitors, Part 6[1]: synthesis and anti-HIV activity of novel 2-[(arylcarbonylmethyl)thio]-6-arylthio DABO analogues.

2-(Arylcarbonylmethyl)thio-6alpha-naphthylmethyl derivatives of dihydro-alkoxy-benzyl-oxopyrimidines (DABO) were newly found to exhibit activity against both HIV-1 and HIV-2. To further explore their structure-activity relationship, the modified S-DABO analogues (5a-g and 6e-f) with a 1-naphthylthio or phenylthio group at the C-6 position were synthesized. S-Alkylation of 5-ethyl-2-thiouracil with substituted 2-bromo-acetophenones provided crude 2-[(arylcarbonylmethyl)thio]-5-ethyl-(3H)-uracil 2a-e, which was directly subjected to toluenesulfonylation with TsCl to afford disulfonate 4a-e. Substitution of 4a-e with arylthiol afforded the desired S-DABO analogues 5a-g and 6e-f. The compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells. The IC(50) values for anti-HIV-1 activity fall into the range 0.37-29.50 microM, and the IC(50) values for anti-HIV-2 activity fall into the range 23.11-181.07 microM. The results indicated that these compounds are moderately active against HIV-1 and HIV-2.

Anti-HIV Agents↗
PubMed2002

Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation.

In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC90) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg). Monte Carlo simulation was performed, assuming a log-normal distribution for 1,000 simulated subjects for each dose, and was repeated three times. The trough concentrations were divided by 76 to account for protein binding and for the difference between EC50 and EC90. We then determined the fraction of the simulated population whose free drug trough concentrations would exceed an EC90 over a broad range of values. The target attainment for all three doses exceeded 95% out to a starting EC50 of 10 nM. For 16 viral isolates, the EC50 range encountered for GW 420867X did not exceed 8 nM, implying that the three doses could not be differentiated by effect in a clinical trial in naive patients. This prediction was shown to be correct in a randomized, double-blind trial with 1 week of monotherapy with GW 420867X.

Double-Blind Method↗
PubMed1998

Synergistic inhibition of HIV-1 by an antisense oligonucleotide and nucleoside analog reverse transcriptase inhibitors.

We have studied the effects of the gag antisense phosphorothioate oligonucleotide GEM 91 and mismatch antisense controls on the antiviral activities of ddC and other nucleoside analogs in HIV-infected MT-4 cells using a cytoprotection based assay. Under standard assay conditions, i.e. simultaneous incubation of drugs, HIV-1 IIIB and MT-4 cells, both GEM 91 and mismatch controls interacted synergistically with ddC resulting in an approximate 40-fold decrease in the IC50 value of ddC; this suggests a potent but sequence non-specific effect of GEM 91. Under post-adsorption assay conditions, i.e. pre-incubation of virus and cells and removal of excess HIV before drug addition, GEM 91 exhibited synergism with ddC, with an approximate 5-fold decrease in ddC IC50 value. This favorable interaction was not seen with any of the mismatch oligonucleotides, suggesting the involvement of a sequence-specific mechanism of action. Similar results were seen with the thymidine analogs AZT and d4T in combination with GEM 91. These data suggest a potential role for GEM 91 and future sequence-specific antisense drugs in combination with nucleoside analogs for the treatment of HIV infection. It is essential that potential interactions between new and existing classes of anti-HIV drugs are studied extensively as antiretroviral drug combinations become increasingly more complex.

Adsorption↗
PubMed2002

Metabolic activation of nucleoside and nucleotide reverse transcriptase inhibitors in dendritic and Langerhans cells.

BACKGROUND: Langerhans cells and interstitial dendritic cells are the earliest targets for HIV infection through sexual transmission of HIV. Metabolism of nucleoside analogues markedly differs in proliferating T lymphocytes and resting monocyte/macrophages, and thus their antiviral efficacy can substantially differ between both cell types. METHODS: The metabolism of radio-labelled zidovudine (ZDV), lamivudine (3TC) and tenofovir (PMPA) to their antivirally active metabolites was studied in primary cells, representative of early in vivo targets of HIV [i.e. monocyte-derived dendritic cells (MO-DC), MO-derived Langerhans cells (MO-LC), PHA/IL-2-activated T-blast cells] as well as in a laboratory T-lymphocyte (CEM) cell line. RESULTS: Whereas lamivudine metabolism to its active triphosphate derivative (3TC-TP) did not markedly differ between T-cells and MO-derived LC and DC, zidovudine was much better converted to ZDV-TP in T-cells than in MO-LC and MO-DC. In contrast, tenofovir was markedly more abundantly converted to its antivirally active diphosphate metabolite PMPApp in MO-DC and MO-LC than zidovudine and lamivudine. CONCLUSION: Our metabolic data suggest that tenofovir may be superior to zidovudine and lamivudine for inhibition of HIV replication in dendritic/Langerhans cells, the first-line cell types targeted by a primary HIV infection.

Adenine↗
PubMed2006

A high incidence of nucleoside reverse transcriptase inhibitor (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context.

OBJECTIVE: To determine the incidence of and predisposing risk factors for lactic acidosis in HIV-infected patients on antiretroviral drugs in South Africa. DESIGN: Observational case series. SETTING: Sinikithemba HIV Clinic, McCord Hospital, Durban. SUBJECTS: Eight hundred and ninety-one HIV-positive patients on highly active antiretroviral therapy (HAART) during an 18-month period commencing in January 2004. MEASUREMENTS AND RESULTS: Fourteen cases of lactic acidosis (incidence rate of 19 (95% confidence interval (CI): 9-29) cases per 1,000 person-years of treatment) were reported. All cases were female, with a median age of 36 years and a median weight of 81 kg. The median time on HAART before developing lactic acidosis was 7.5 months and the median peak lactate level was 9.3 mmol/l. All cases were on stavudine (d4T), lamivudine (3TC) and 1 non-NRTI. The case mortality rate was 29% (4 patients). CONCLUSIONS: The incidence rate is higher than reported in studies in developed countries. This may be due to d4T, which is recommended as a first-line antiretroviral drug in South Africa. This implication raises the question whether it is an appropriate drug in first-line treatment of patients with predisposing risk factors such as female gender and being overweight.

Acidosis, Lactic↗
PubMed2003

Predictive factors and selection of thymidine analogue mutations by nucleoside reverse transcriptase inhibitors according to initial regimen received.

Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219.

Anti-HIV Agents↗
PubMed1998

Evaluation of mixtures of wild-type HIV-1 and HIV-1 with resistance point mutations against reverse transcriptase inhibitors.

The presence of resistance-related mutations in 185 serial proviral DNA samples from 108 HIV-infected patients was monitored using the line probe assay (LiPA). The proportions of wild-type and mutant virus in each sample were determined. Subsequent samples from the same patient were analysed. Resistance mutations were detected in 58 of 108 patients studied (53.7%), 53 of 73 (72.6%) treated with antivirals and 5 of 35 (14.2%) untreated. The mutations were against zidovudine (51), lamivudine (1), zidovudine and lamivudine (4), zidovudine and zalcitabine (1) and zidovudine and didanosine (1). Among the 58 patients with resistant virus, 168 related mutations were observed: 161 to zidovudine (90 in codon 70, 25 in codon 41 and 46 in codon 215), 5 to lamivudine (codon 184), 1 to zalcitabine (codon 69) and 1 to didanosine (codon 74). Mixtures of wild-type and resistant mutants were detected in 76 of 90 (84.4%) mutated at codon 70, 28 of 46 (60.8%) mutated at codon 215 and in 21 of 25 (84%) mutated at codon 41. The mutations at codon 184 were mixtures of wild-type and resistant in 4 of 5 samples. The agreement between LiPA and sequencing was 96.5%. LiPA was more sensitive for the detection of mutants that were present at low frequency. The analysis of sequential samples from the same patient allowed evaluation of the dynamics of appearance of the resistant mutants.

Anti-HIV Agents↗
PubMed2006

Design, synthesis, biological evaluation, and molecular modeling studies of TIBO-like cyclic sulfones as non-nucleoside HIV-1 reverse transcriptase inhibitors.

TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell-based assays (EC50=0.07 microM, CC50>200 microM, SI>2857). It was twofold less potent than R82913, but more selective. An X-ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1-3 were proven to target HIV-1 RT. In fact, representative derivatives inhibited recombinant HIV-1 RT in vitro at concentrations similar to those active in cell-based assays. 3D QSAR studies and docking simulations were developed on TIBO- and TBO-like sulfone derivatives to rationalize their anti-HIV-1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor-based alignment by docking of TIBO- and TBO-like derivatives into the NNBS of RT.

Cell Line↗
PubMed2005

5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family.

2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.

Alkylation↗
PubMed2005

Resistance of human hepatitis B virus to reverse transcriptase inhibitors: from genotypic to phenotypic testing.

The treatment of HBV infected patients with analogues of nucleos(t)ides, including lamivudine and adefovir dipivoxil, has significantly increased the rate of anti-HBe seroconversion and therefore reduced the impact of chronic hepatitis B (CHB) on liver disease. Altogether, these antivirals have offered novel options for the treatment of patients who did not respond to previous therapy with interferon alpha, the only available treatment against CHB until 1998. However, therapies using analogues of nucleos(t)ides have been confronted with viral resistances which are often associated to with worsening of liver disease. Drug resistance is conferred by the appearance of one or several mutations within the HBV polymerase gene. These mutations confer to the mutant viral population a phenotypic advantage over the wild-type pretherapeutic viral quasispecies, as they induce a reduction of drug susceptibility of mutant strains in vivo. This reduction of drug susceptibility can be as well measured in vitro, i.e in cell culture, using phenotypic assays. The detection of these mutations has become of crucial importance to better adapt clinical option to the virological status of the patient. Genotypic and more recently phenotypic assays have been developed and both assays can be used for drug resistance testing. Genotypic assay gives information about already characterized mutations associated with viral resistance, while phenotypic testing measures the overall drug susceptibility of patient-derived viral strains in cell culture. These assays are described and their potential use in the clinical setting is discussed.

Drug Resistance, Viral↗
PubMed1999

Prediction of the binding free energies of new TIBO-like HIV-1 reverse transcriptase inhibitors using a combination of PROFEC, PB/SA, CMC/MD, and free energy calculations.

We have ranked 13 different TIBO derivatives with respect to their relative free energies of binding using two approximate computational methods: adaptive chemical Monte Carlo/molecular dynamics (CMC/MD) and Poisson-Boltzmann/solvent accessibility (PB/SA) calculations. Eight of these derivatives have experimentally determined binding affinities. The remaining new derivatives were constructed based on contour maps around R86183 (8Cl-TIBO), generated with the program PROFEC (pictorial representation of free energy changes). The rank order among the derivatives with known binding affinity was in good agreement with experimental results for both methods, with average errors in the binding free energies of 1. 0 kcal/mol for CMC/MD and 1.3 kcal/mol for the PB/SA method. With both methods, we found that one of the new derivatives was predicted to bind 1-2 kcal/mol better than R86183, which is the hitherto most tightly binding derivative. This result was subsequently supported by the most rigorous free energy computational methods: free energy perturbation (FEP) and thermodynamic integration (TI). The strategy we have used here should be generally useful in structure-based drug optimization. An initial ligand is derivatized based on PROFEC suggestions, and the derivatives are ranked with CMC/MD and PB/SA to identify promising compounds. Since these two methods rely on different sets of approximations, they serve as a good complement to each other. Predictions of the improved affinity can be reinforced with FEP or TI and the best compounds synthesized and tested. Such a computational strategy would allow many different derivatives to be tested in a reasonable time, focusing synthetic efforts on the most promising modifications.

Algorithms↗
PubMed2005

Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue.

An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, and pharmacokinetics in dogs were determined. The 50% effective concentration (EC(50)) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 microM compared to an EC(50) of 5 microM for the parent drug, tenofovir. The (L)-alaninyl analog (GS 7340) was >1,000-fold more active than the (D)-alaninyl analog. GS 7340 has a half-life of 90 min in human plasma at 37 degrees C and a half-life of 28.3 min in an MT-2 cell extract at 37 degrees C. The antiviral activity (>10 x the EC(50)) and the metabolic stability in MT-2 cell extracts (>35 x) and plasma (>2.5 x) were also sensitive to the stereochemistry at the phosphorus. After a single oral dose of GS 7340 (10 mg-eq/kg tenofovir) to male beagle dogs, the plasma bioavailability of tenofovir compared to an intravenous dose of tenofovir was 17%. The total intracellular concentration of all tenofovir species in isolated peripheral blood mononuclear cells at 24 h was 63 microg-eq/ml compared to 0.2 microg-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread).

Adenine↗
PubMed2000

Characterization of novel glutathione adducts of a non-nucleoside reverse transcriptase inhibitor, (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3, 4-dihydro-2(1H)-quinazolinone (DPC 961), in rats. Possible formation of an oxirene metabolic intermediate from a disubstituted alkyne.

The postulated formation of oxirene-derived metabolites from rats treated with a disubstituted alkyne, (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3, 4-dihydro-2(1H)-quinazolinone (DPC 961), is described. The reactivity of this postulated oxirene intermediate led to the formation of novel glutathione adducts whose structures were confirmed by LC/MS and by two-dimensional NMR experiments. These metabolites were either excreted in rat bile or degraded to mercapturic acid conjugates and eliminated in urine. To demonstrate the oxidation of the triple bond, an analogue of DPC 961 was synthesized, whereby the two carbons of the alkyne moiety were replaced with (13)C stable isotope labels. Rats were orally administered [(13)C]DPC 961 and glutathione adducts isolated from bile. The presence of an oxygen atom on one of the (13)C labels of the alkyne was demonstrated unequivocally by NMR experiments. Administration of (14)C-labeled DPC 961 showed that biliary elimination was the major route of excretion with the 8-OH glucuronide conjugate (M1) accounting for greater than 90% of the eliminated radioactivity. On the basis of radiochemical profiling, the glutathione-derived metabolites were minor in comparison to the glucuronide conjugate. Studies with cDNA-expressed rat enzymes, polyclonal antibodies, and chemical inhibitors pointed to the involvement of P450 3A1 and P450 1A2 in the formation of the postulated oxirene intermediate. The proposed mechanism shown in Scheme 1 begins with P450-catalyzed formation of an oxirene, rearrangement to a reactive cyclobutenyl ketone, and a 1,4-Michael addition with endogenous glutathione to produce two isomeric adducts, GS-1 and GS-2. The glutathione adducts were subsequently catabolized via the mercapturic acid pathway to cysteinylglycine, cysteine, and N-acetylcysteine adducts. The transient existence of the alpha,beta-unsaturated cyclobutenyl ketone was demonstrated by incubating the glutathione adduct in the presence of N-acetylcysteine and monitoring the formation of N-acetylcysteine adducts by LC/MS. Epimerization of GS-1 to GS-2 was also observed when N-acetylcysteine was omitted from the incubation.

Animals↗
PubMed1999

Biotransformation of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, in mice, rats, rabbits, dogs, monkeys, and chimpanzees.

The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by beta-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.

Animals↗
PubMed1999

Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children.

OBJECTIVE: In an intent-to-treat study increase in CD4 cell count, reduction of viral load, clinical benefit and adverse reactions were examined in HIV-infected previously treatment-naive children taking triple therapy. METHODS: sixteen HIV-infected children in category A or B on antiretroviral triple therapy were followed-up for a period of 12 months. In group I eight patients received zidovudine, lamivudine and nelfinavir; in group II eight patients received stavudine, didanosine and nelfinavir. Viral load and CD4 cell count were measured every 4-8 weeks. Plasma nelfinavir levels were assessed once in all patients at baseline and monitored in patients with increasing viral load. RESULTS: No significant differences were observed between treatment groups in terms of CD4 cell counts and viral load. A median viral load reduction of 2.8 log10 (range, 1.4-4.2 log10) was achieved over a period of 12 months in both groups. Viral load < 500 copies/ml was found in 69% of patients and viral load < 50 copies/ml in 44% of patients after 12 months. Median CD4 cell count increased from 656 x 10(6) to 850 x 10(6) cells/l after 3 months and was maintained at 813 x 10(6) cells/l after 12 months of treatment. Main side-effects were diarrhoea, rash and hyperlipidaemia. Except for application problems, both regimens were well tolerated. Appropriate formula and individual counselling must be performed during the first weeks of treatment in order to achieve good compliance in paediatric patients. CONCLUSION: Triple antiretroviral therapy shows a stronger and more sustained reduction of viral load in HIV-infected children compared with studies combining two nucleoside analogues.

Anti-HIV Agents↗