Efeitos da administração diária da associação estavudina/nelfinavir sobre os fetos e placentas da rata albina / Effects of daily administration of a stavudine/nelfinavir association on the fetuses and placentas of female albino rats

OBJETIVO: avaliar o efeito da administração da associação estavudina/nelfinavir durante toda a prenhez da rata, avaliando seu peso e dos conceptos, bem como o número de implantações, fetos, placentas, reabsorções e mortalidades materna e fetal. MÉTODOS: quarenta ratas albinas EPM-1 Wistar, prenhes, foram aleatoriamente divididas em quatro grupos: GCtrl (controle do veículo) e três experimentais, ExpI, ExpII e ExpIII, que receberam, respectivamente, 1/40, 3/120 e 9/360 mg/kg por dia de estavudina/nelfinavir por via oral. As drogas e o veículo (água destilada) foram administrados por gavagem em duas tomadas diárias (12/12 horas), desde o dia 0 até o 20º dia da prenhez. No último dia do experimento, todos os animais foram anestesiados e eutanasiados. Foram avaliados a evolução do peso materno no 7º, 14º e 20º dias, número de fetos, placentas, implantações, reabsorções, óbitos intrauterinos, malformações maiores e o peso dos fetos e das placentas. A análise estatística foi realizada por análise de variância (ANOVA), complementada pelo teste de Kruskal-Wallis (p<0,05). RESULTADOS: em relação ao peso corporal das ratas, houve ganho gradual e progressivo durante o decorrer da prenhez em todos os grupos, sendo este ganho mais evidente no período final; porém não foram constatadas diferenças estatisticamente significantes entre eles. O número de fetos, placentas, implantações, assim como os pesos fetais e placentários também não mostraram diferenças estatisticamente significantes entre os grupos analisados. Não foram observadas, também nos grupos experimentais, reabsorções e malformações fetais maiores externas, no entanto, observamos entre o 8º e o 14º dias de gestação um caso de morte materna em cada grupo experimental. CONCLUSÕES: a administração da associação estavudina/nelfinavir não mostrou efeitos deletérios sobre os conceptos.

PURPOSE: to evaluate the effect of administration of a stavudine/nelfinavir combination on the rat pregnancy by assessing maternal and concepts weights, as well as the number of implantations, fetuses, placentas, resorptions and maternal and fetal mortality. METHODS: forty adult pregnant Wistar rats of the EPM-1 strain were randomly divided into four groups: control (GCtrl - drug vehicle control, n=10), and three experimental groups, which were treated with an oral solution of stavudine/nelfinavir (ExpI - 1/40 mg/kg b.w., n=10; ExpII - 3/120 mg/kg b.w., n=10; ExpIII - 9/360 mg/kg b.w., n=10) from day 0 to the 20th day of pregnancy. Maternal body weights were determined at the start of the experiment and on the 7th, 14th and the 20th day thereafter. At term (20th day) the rats were anesthetized and, upon laparotomy and hysterotomy, the number of implantations, resorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed and the concepts were examined under a stereomicroscope for possible external malformations. Statistical analysis was performed by analysis of variance (ANOVA) complemented by the Kruskal-Wallis test (p<0.05). RESULTS: there was a progressive and gradual increase in body weight during the course of pregnancy in all groups, which was more evident in the final period, but with no significant difference between groups. The mean number of fetuses, placentas, implantations, and fetal and placental weights showed no significant differences between groups. Also, no resorptions or external malformations were found in the experimental groups. However, between the 8th and 14th days of gestation, there was one case of maternal mortality in each experimental group. CONCLUSIONS: the administration of a stavudine/nelfinavir combination had no deleterious effects on the concepts.

Antiretroviral agents and acid-base balance at delivery of the neonate

Limited evidence is available regarding antiretroviral (ARV) safety for uninfected infants exposed to these drugs in utero. Our objective was to determine if ARV administered to pregnant women is associated with decreasing umbilical arterial pH and base excess in uninfected infants. A prospective study was conducted on 57 neonates divided into three groups: ZDV group, born to mothers taking zidovudine (N = 20), triple therapy (TT) group, born to mothers taking zidovudine + lamivudine + nelfinavir (N = 25), and control group (N = 12), born to uninfected mothers. Umbilical cord blood was used to determine umbilical artery gases. A test was performed to calculate the sample by comparing means by the unpaired one-tailed t-test, with a = 0.05 and ß = 20 percent, indicating the need for a sample of 18 newborn infants for the study groups to detect differences higher than 20 percent. The control and ARV groups were similar in gestational age, birth weight, and Apgar scores. Values of pH, pCO2, bicarbonate, and base excess in cord arterial blood obtained at delivery from the newborns exposed to TT were 7.23, 43.2 mmHg, 19.5 mEq/L, and -8.5 nmol/L, respectively, with no significant difference compared to the control and ZDV groups. We conclude that intrauterine exposure to ARV is not associated with a pathological decrease in umbilical arterial pH or base excess. While our data are reassuring, follow-up is still limited and needs to be continued into adulthood because of the possible potential for adverse effects of triple antiretroviral agents.

Efeitos do uso crônico do nelfinavir sobre a prenhez da rata albina: ensaio biológico / Effects of chronic nelfinavir treatment on rat pregnancy: biological assay

OBJETIVO: avaliar o efeito do uso crônico do nelfinavir sobre o peso de ratas albinas prenhes e seus conceptos, bem como o número de implantações, fetos, placentas, reabsorções e mortalidade materna e fetal. MÉTODOS: 50 ratas albinas EPM-1 Wistar, prenhes, foram aleatoriamente divididas em cinco grupos: 2 controles, Contr1 (controle do estresse) e Contr2 (controle do veículo), e três experimentais, Exp40, Exp120 e Exp360, que receberam, respectivamente, 40, 120 e 360 mg/kg por dia de nelfinavir por via oral. A droga e o veículo (água destilada) foram administrados por gavagem em duas tomadas diárias (12/12 horas), desde o primeiro dia até o dia 20 da prenhez. No último dia do experimento, todos os animais foram anestesiados e sacrificados. Foram avaliados a evolução do peso, número de implantações, reabsorções, fetos, placentas, óbitos intra-uterinos, o peso dos fetos e das placentas e malformações maiores. A análise estatística foi realizada pela análise de variância (ANOVA) completada pelo teste de Kruskal-Wallis. RESULTADOS: em relação ao ganho de peso das ratas, houve ganho normal em todos os grupos, não sendo constatadas diferenças significantes entre eles. ANOVA mostrou ausência de diferenças significativas entre os grupos quanto aos parâmetros estudados. As médias do número de fetos foram: controles = 9,7±0,50; grupos tratados com nelfinavir = 9,7±0,81. Para as médias de números de placentas e implantações, controles = 9,7±0,50; grupos tratados com nelfinavir = 9,7±0,78. Quanto às médias de pesos fetais, controles = 4,04±0,50; grupos tratados com nelfinavir = 3,91±0,33 g. Finalmente, para as médias de pesos de placentas, controles = 0,64±0,02; grupos tratados com nelfinavir = 0,67±0,02 g. Além disto, não foram observadas reabsorções, mortalidade das matrizes, óbitos e malformações fetais. CONCLUSÕES: o nelfinavir, em todas as doses administradas, não influiu no ganho de peso das ratas prenhes e não mostrou efeitos deletérios sobre...

PURPOSE: to evaluate the chronic effects of nelfinavir on body weight gain of pregnant albino rats and their concepts, as well as on the number of implantations, reabsorptions, fetuses, placentae, and maternal and fetal mortality. METHODS: fifty pregnant EPM-1 Wistar albino rats were randomly divided into five groups: two controls, Contr1 (control of stress) and Contr2 (drug vehicle control), and 3 experimental groups, Exp40, Exp120, Exp360, which received 40, 120 or 360 mg/kg per day of oral solution of nelfinavir, respectively. The drug and the vehicle (distilled water) were administered twice a day (12/12 h) by gavage from the first up to the 20th day of pregnancy. After sacrifice under deep anesthesia, the following parameters were evaluated: number of implantations and reabsorptions, the weight of fetuses and placentae, and the number of intrauterine deaths as well as inspection for major malformations. Data were evaluated by ANOVA followed by the Kruskal-Wallis multiple comparison test. RESULTS: body weight gain during pregnancy was normal for all the groups, and no significant differences were detected between them. ANOVA did not reveal any significant effect of nelfinavir on the studied parameters. The means of number of fetuses were: control = 9.7±0.50; nelfinavir-treated groups = 9.7±0.81. Regarding the means of number of placentae and implantations, controls = 9.7±0.50; nelfinavir-treated groups = 9.6±0.78. The mean fetal weights were as follows: controls = 4.04±0.50; nelfinavir-treated groups = 3.91±0.33 g. Finally, control placental weights averaged 0.64±0.02; nelfinavir-treated groups = 0.67±0.02 g. CONCLUSION: nelfinavir was well tolerated at all the administered doses; no damage was produced on the fetuses.

HIV-1 genotypes related to failure of nelfinavir as the first protease inhibitor treatment

Combined antiretroviral therapy results in sustained viral suppression and a decrease in mortality and morbidity due to HIV infection. Intrinsic strength, durability and absence of cross-resistance are key factors in the selection of antiretrovirals. Failure with nelfinavir has been associated with two protease gene mutations, D30N and L90M. The D30N mutation does not result in cross-resistance with other protease inhibitors, and it decreases viral fitness. In order to check for this mutation after failure with nelfinavir, the 246 HIV-1 genotyping test was performed on virus samples from 55 patients with failure of nelfinavir as the first protease inhibitor. Most (84 percent) of the viral strains were of subtype B. Nucleosides associated with mutations (NAM) were observed in 80 percent of the tests; no INS69, complex 151, K65R and L74V mutations, which give multi-resistance to nucleoside analogue reverse transcriptase inhibitors to tenofovir and DDI, respectively, were observed. In the tests for protease gene mutations, the D30N mutation was found in 57 percent, L90M in 18 percent and the wild-type virus in 25 percent. These data are similar to published reports, showing that alternative therapies used after failure with nelfinavir may be more successful, as the D30N mutation does not cause cross-resistance to other protease inhibitors.

Estimating the length of the first antiretroviral therapy regiment durability in Säo Paulo, Brazil

Brazil was the first country to provide unrestricted, cost-free access to antiretroviral (ARV) medicine for AIDS treatment. However, there is little data about the benefits of such a policy for these patients. We evaluated the duration of benefit obtained with the introduction of ARVs, defined as the durability of the first ARV regiment. We reviewed the medical charts of patients attended from 1996-2000, at the outpatient clinics of the Federal University of Säo Paulo, Brazil. A total of 120 drug-naive HIV-1 infected patients were eligible to participate in the study. About half of the individuals (53 percent) presented with disease symptoms; 59 percent of them had CD4 count below 200 cells/mm³. Mean estimated duration of the benefit of therapy was 14.1 months. The most used regimen in this cohort was Zidovudine/3TC/Indinavir (26 percent), followed by Zidovudine/DDI (17 percent), and Zidovudine/3TC/Nelfinavir (13 percent). The most frequent cause of interruption of therapy was gastrointestinal intolerance. Use of treatment regimens with three drugs was more effective than with two drugs, but only for patients with CD4<200 cells/mm³ or CV>100,000 copies RNA/mL. However, the use of triple therapy was associated with a significantly higher probability of reaching maximum viral suppression, during a longer period (p<0.05).The patients enrolled in the study benefitted from therapy for a limited time, after the introduction of double or triple antiretroviral therapy. The incidence of adverse events was significantly associated with loss of the benefits provided by the initial therapeutic regimen.