Critical Pronociceptive Role of Family 2 Voltage-Gated Calcium Channels in a Novel Mouse Model of HIV-Associated Sensory Neuropathy.

Some people living with HIV present painful sensory neuropathy (HIV-SN) that is pharmacoresistant, sex-associated, and a major source of morbidity. Since the specific mechanisms underlying HIV-SN are not well understood, the aim of our study was to characterize a novel model of painful HIV-SN by combining the HIV-1 gp120 protein and the antiretroviral stavudine (d4T) in mice and to investigate the pronociceptive role of the family 2 voltage-gated calcium channel (VGCC) α1 subunit (Cav2.X channels) in such a model. HIV-SN was induced in male and female C57BL/6 mice by administration of gp120 and/or d4T and detected by a battery of behavior tests and by immunohistochemistry. The role of Cav2.X channels was assessed by the treatment with selective blockers and agonists as well as by mRNA detection. Repeated administration with gp120 and/or d4T produced long-lasting touch-evoked painful-like behaviors (starting at 6 days, reaching a maximum on day 13, and lasting up to 28 days after treatment started), with a greater intensity in female mice treated with the combination of gp120 + d4T. Moreover, gp120 + d4T treatment reduced the intraepidermal nerve fibers and well-being of female mice, without altering other behaviors. Mechanistically, gp120 + d4T treatment induced Cav2.1, 2.2, and 2.3 transcriptional increases in the dorsal root ganglion and the Cav2.X agonist-induced nociception. Accordingly, intrathecal selective Cav2.2 blockade presented longer and better efficacy in reversing the hyperalgesia induced by gp120 + d4T treatment compared with Cav2.1 or Cav2.3, but also presented the worst safety (inducing side effects at effective doses). We conclude that the family 2 calcium channels (Cav2.X) exert a critical pronociceptive role in a novel mouse model of HIV-SN.

Optimization and Quest of HPMC loaded Stavudine Controlled Release Dosage Development by Central Composite Design utilizing Reduced Factorial Screening Technique

Abstract The current research focused on screening and finding the significant independent variables in stavudine loaded tablet, followed by optimizing the best formulation using central composite design. The objective of the study to develop stavudine loaded controlled release tablet utilizing reduced factorial design, followed by optimization technique as well as characterization of prepared tablets. Preliminary trial batches were prepared using different grades of hydroxypropyl methylcellulose. The resolution-IV reduced factorial design was selected to screen the significant independent variables in the dosage form design. A total number of eight runs were prepared and responses were recorded. The signified factors identified by half-normal and Pareto chart. The prepared tablets are evaluated for various physiochemical characterizations. Three dependent responses such as hardness, dissolution at 6 hour and 12 hours are considered in optimization process. Later on, drug-polymer interaction study was carried out. The principal of the study design based on finding the best formulation with prefixed set parameter values utilizing the concept of screening technique. It observed that HPMC K15M (57.18 %), HPMC K100 (66.32 %) and PVP K30 (7.97 %) as best composition in a formulation batch would fulfill the predetermined parameter with specific values.

Preenchimento facial com Polimetilmetacrilato em pacientes que vivem com a síndrome da imunodeficiência adquirida (AIDS) / Facial filling with polymethylmethacrylate in patients with acquired immunodeficiency syndrome

INTRODUÇÃO: Pacientes que vivem com síndrome da imunodeficiência adquirida (AIDS) em uso da Terapia Antirretroviral de Alta Potência (TARV) são suscetíveis a desenvolver síndrome lipodistrófica. O preenchimento facial com polimetilmetacrilato é opção de tratamento. O objetivo é analisar o procedimento de preenchimento facial e avaliar os pacientes em relação à percepção, incômodo, revelação do diagnóstico, expectativa quanto ao preenchimento e a satisfação e impacto em suas vidas. MÉTODOS: Análise em 63 pacientes submetidos ao preenchimento facial. Foram realizados procedimentos, analisados prontuários dos pacientes e o Protocolo do Ambulatório de Lipodistrofia do Programa Municipal de doenças sexualmente transmissíveis (DST)/AIDS e Hepatites Virais de São Bernardo do Campo, atendidos no período de janeiro a julho de 2009. RESULTADOS: Todos os 63 pacientes iniciais que concordaram em participar da pesquisa permaneceram até o término deste trabalho. Apenas seis pacientes (9,5%) eram de origem de outros municípios, enquanto 57 pacientes (90,5%) eram moradores de São Bernardo. 68,2% eram homens e 100% brancos. A média das idades foi 49,7 anos. Em média, o Vírus da Imunodeficiência Humana (HIV) foi diagnosticado há 11,5 anos, com tempo médio de uso de TARV por 10 anos e tempo médio de lipoatrofia facial de 3,8 anos. A maioria fez uso de Estavudina e/ou Efavirenz. Quem ficava mais desconfortável com as alterações na face eram os próprios pacientes. 85,7% não revelaram o diagnóstico para terceiros. 100% dos pacientes ficaram satisfeitos ou muito satisfeitos com o resultado obtido. CONCLUSÃO: 100% dos pacientes ficaram satisfeitos ou muito satisfeitos com o resultado obtido. Em 100% dos casos houve um impacto favorável na vida. Não houve efeitos adversos ao procedimento cirúrgico de preenchimento.

INTRODUCTION: Patients with acquired immunodeficiency syndrome (AIDS) who use highly active antiretroviral therapy (HAART) can develop lipodystrophy syndrome, for which facial filling with polymethylmethacrylate is a treatment option. The objective is to analyze the procedure of facial filling and evaluate patients in relation to their perception, discomfort, revelation of the diagnosis to third parties, expectation concerning facial filling, and satisfaction with the treatment outcome and its impact on their lives. METHODS: Sixty-three patients who underwent facial filling were evaluated. Procedures performed between January and July 2009 were assessed, the records of the patients were analyzed, and the outpatient lipodystrophy protocol of the STD/AIDS and Viral Hepatitis Municipal Program of São Bernardo do Campo was used. RESULTS: All the 63 patients who agreed to participate in the research completed the study. Only 6 patients (9.5%) were from other municipalities, while 57 patients (90.5%) were residents of São Bernardo. Of the patients, 68.2% were men and 100% were Caucasian. The mean age of the patients was 49.7 years. Human immunodeficiency virus was diagnosed 11.5 years prior on average, with 10-year average use of HAART and 3.8-year average time of facial lipoatrophy. Most of the patients used stavudine and/or efavirenz. The patients themselves felt more uncomfortable with facial changes. Among the patients, 85.7% did not reveal the diagnosis to third parties. CONCLUSION: All of the patients were satisfied or very satisfied with the result obtained, which had a favorable impact on their lives. The filling surgical procedure had no adverse effects.

In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs.

INTRODUCTION: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. OBJECTIVE: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. METHODS: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. RESULTS: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. CONCLUSIONS: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.

INTRODUCCIÓN: Los modelos de correlación In vitro-in vivo (IVIVC) son parte integral del proceso de investigación y desarrollo de fármacos. La capacidad de predecir con exactitud el perfil in vivo a partir de las observaciones in vitro tiene diversas aplicaciones durante el desarrollo exitoso de una formulación. OBJETIVO: Desarrollar un modelo integral para predecir la absorción in vivo de fármacos antirretrovirales con base en estudios de permeabilidad, solubilidad in vitro e in vivo y demostrar su correlación con la farmacocinética en humanos. MÉTODOS: Se desarrollaron y validaron las técnicas bioanalíticas para valorar las propiedades biofarmacéuticas de Estavudina, Lamivudina y Zidovudina. Se evaluó las cineticas de disolución, la permeabilidad en monocapas celulares Caco-2 y la farmacocinética de absorción in vivo en conejos y voluntarios sanos. RESULTADOS: Los valores de AUC acumulados en el sistema de células Caco-2, en la disolución y en el modelo animal, fueron correlacionados con los valores de AUC acumulados en el humano. Con lo anterior se demostró una relación directamente proporcional entre los resultados in vitro con respecto a los obtenidos en la fase de absorción tanto en el humano como en el modelo animal. CONCLUSIONES: Los métodos analíticos y procedimientos aplicados en la IVIVC demostraron las correspondencias directas entre sí, con altos niveles de correlación. Se proponen estos modelos IVIVC como métodos alternativos costo/efectivos para la valoración de las propiedades biofarmacéuticas que determinan la biodisponibilidad, en el desarrollo de productos, en el aseguramiento de la calidad y como pruebas de bioequivalencia en los programas de farmacovigilancia.

In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs / Modelo de correlación farmacocinético in vitro-in vivo para el aseguramiento de la calidad de medicamentos antirretrovirales

Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/ effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.

Introducción: Los modelos de correlación In vitro-in vivo (IVIVC) son parte integral del proceso de investigación y desarrollo de fármacos. La capacidad de predecir con exactitud el perfil in vivo a partir de las observaciones in vitro tiene diversas aplicaciones durante el desarrollo exitoso de una formulación. Objetivo: Desarrollar un modelo integral para predecir la absorción in vivo de fármacos antirretrovirales con base en estudios de permeabilidad, solubilidad in vitro e in vivo y demostrar su correlación con la farmacocinética en humanos. Métodos: Se desarrollaron y validaron las técnicas bioanalíticas para valorar las propiedades biofarmacéuticas de Estavudina, Lamivudina y Zidovudina. Se evaluó las cineticas de disolución, la permeabilidad en monocapas celulares Caco-2 y la farmacocinética de absorción in vivo en conejos y voluntarios sanos. Resultados: Los valores de AUC acumulados en el sistema de células Caco-2, en la disolución y en el modelo animal, fueron correlacionados con los valores de AUC acumulados en el humano. Con lo anterior se demostró una relación directamente proporcional entre los resultados in vitro con respecto a los obtenidos en la fase de absorción tanto en el humano como en el modelo animal. Conclusiones: Los métodos analíticos y procedimientos aplicados en la IVIVC demostraron las correspondencias directas entre sí, con altos niveles de correlación. Se proponen estos modelos IVIVC como métodos alternativos costo/efectivos para la valoración de las propiedades biofarmacéuticas que determinan la biodisponibilidad, en el desarrollo de productos, en el aseguramiento de la calidad y como pruebas de bioequivalencia en los programas de farmacovigilancia.

Association between antiretrovirals and thyroid diseases: a cross-sectional study.

OBJECTIVE: This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases. MATERIALS AND METHODS: A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables. RESULTS: The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059. CONCLUSION: The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases.

Association between antiretrovirals and thyroid diseases: a cross-sectional study

Objective This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases. Materials and methods A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables. Results The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059. Conclusion The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases. .

Antirretrovirais estavudina (d4t) 30mg e indinavir (idv) 400mg / Antiretroviral stavudine (d4t) 30mg and indinavir (idv) 400mg

INTRODUÇÃO: A partir da Nota Técnica nº 90/2012, de março de 2012, o Ministério da Saúde recomendou a substituição de estavudina (d4T) 30mg e indinavir (IDV) 400mg por outros antirretrovirais (ARV) da mesma classe terapêutica para todos os adultos ainda em uso destes medicamentos, e reitera a não indicação de ambos na terapia antirretroviral inicial. Após sua publicação, houve redução no número de pessoas em uso de d4T e IDV, permanecendo, entretanto, um contingente de pessoas com esquemas antirretrovirais estruturados com estes ARV. Conforme as diretrizes nacionais de tratamento antirretroviral, estes medicamentos não devem ser utilizados para estruturar o esquema antirretroviral inicial, em razão da existência de outras opções terapêuticas com melhor perfil de toxicidade. Assim, toda nova prescrição de tratamento com estavudina (d4T) e/ou indinavir (IDV) como primeiro esquema de tratamento para adultos, terá sua dispensação bloqueada pelo Sistema de Controle Logístico de Medicamento (SICLOM). Toda prescrição que mantenha d4T e/ou IDV para pacientes que já vinham em uso destes medicamentos no passado, terá que ser avaliada em relação a existência de outras opções de tratamento e aprovada pelas Câmaras Técnicas dos Estados ou pelo Ministério da Saúde. Aqueles que estão em uso destes medicamentos seu fornecimento será mantido por no máximo 6 (seis) meses após a publicação deste Relatório. Após este período, a dispensação destes medicamentos será bloqueada no SICLOM. Para pacientes que apresentam supressão viral completa (carga viral indetectável), sugere-se: a) substituir d4T por zidovudina (AZT), tenofovir (TDF), didanosina (ddI) ou abacavir (ABC); b) substituir IDV por lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) ou fosamprenavir/ritonavir (FPV/r). Esta avaliação deve ser individualizada, considerando o histórico de tratamento antirretroviral e genotipagens anteriores.Pacientes que já fazem uso de IDV ou d4T e que estão em falha terapêutica, devem realizar teste de genotipagem e ter seu esquema estruturado conforme as diretrizes expressas no documento "Recomendações para Terapia Antirretroviral em Adultos Infectados pelo HIV" vigente no País. RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC presentes na 24ª reunião do plenário realizada nos dias 09/04/2014 e 10/04/2014 recomendaram a exclusão da estavudina (d4T) 30mg e indinavir (IDV) 400mg na terapia antirretroviral inicial. DECISÃO: PORTARIA Nº 36, de 26 de setembro de 2014 - Torna pública a decisão de excluir os antirretrovirais estavudina (d4t) 30mg e indinavir (idv) 400mg no âmbito do Sistema Único de Saúde - SUS.

Resultados de una intervencion de farmacovigilancia en pacientes con VIH/SIDA tratados con estavudina / Pharmacosurveillance regarding Colombian patients beingtreated with stavudine

Objetivos Dado que la estavudina se ha asociado a toxicidad acumulativa e irreversible, se pretendió reducir la aparición de resultados negativos asociados al uso de estavudina mediante la notificación del riesgo a diferentes responsables de la atención sanitaria de pacientes con VIH/SIDA en Colombia. Métodos A partir de la base de datos de dispensación de medicamentos de Audifarma S.A a unos 4,5 millones de personas, se identificaron todos los usuarios de estavudina, se notificó el riesgo a los prestadores del servicio de salud y se recomendó la sustitución por zidovudina o tenofovir. Resultados En 2010 se identificaron 1 410 pacientes en tratamiento antirretroviral, de los cuales 109 (7,5 %) recibían estavudina, distribuidos en 20 ciudades del país y atendidos por 19 instituciones diferentes. Tras la intervención se consiguió en 28 meses reducir su empleo en 94,6 %. El medicamento más empleado en la sustitución fue zidovudina. Discusión Se consiguió exitosamente reemplazar estavudina siguiendo las recomendaciones de la Organización Mundial de la Salud, con lo cual se puede evitar la aparición de lipodistrofia y neuropatía periférica asociada a su empleo.(AU)

Objectives Reducing the occurrence of negative stavudine use-associated outcomes by reporting such risk to doctors responsible for the care of HIV/AIDS patients in Colombia as stavudine has been associated with cumulative and irreversible toxicity. Methods All stavudine users were identified from Audifarma S.A. (drug suppliers) databases (covering about 4.5million people). The risk was then reported to health service providers and the substitution of stavudine for zidovudine or tenofovir was recommended. Results It was found that 1,410 patients registered in the afore mentioned databases were receiving antiretroviral therapy during 2010, of whom 109 (7.5 %) were receiving stavudine; these patients were living in 20 cities and being attended by 19 institutions. Stavudine use became reduced by 94.6 % during the 28 months following the intervention. Zidovudine was the most commonly used replacement drug. Discussion Stavudine was successfully replaced following World Health Organization recommendations aimed at preventing the occurrence of lipodystrophy and the peripheral neuropathy associated with its use.(AU)

Initiation of antiretroviral therapy before 6 months of age is associated with faster growth recovery in South African children perinatally infected with human immunodeficiency virus.

OBJECTIVE: To describe the effects of age at antiretroviral therapy (ART) initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation. STUDY DESIGN: This secondary analysis describes anthropometric changes in children infected with HIV in Johannesburg, South Africa who initiated ritonavir-boosted lopinavir-based ART before 24 months of age and were randomized to continue ritonavir-boosted lopinavir or to receive nevirapine after achieving and maintaining virologic suppression. Weight, height, and head circumference were measured at visits over 48 months post-ART initiation. Growth patterns including weight-for-age z-scores (WAZs), height-for-age z-scores, body mass index-for-age z-scores, and head circumference for age z-score were compared between children initiating ART<6 months, 6-12 months, and 12-24 months of age. RESULTS: A total of 195 children (mean±SD age 10.7±5.9 months), including 54 (27.7%)<6 months, 69 (35.4%) 6-12 months, and 72 (36.9%) 12-24 months of age at ART initiation, were evaluated. In the first 12 months on treatment, children<6 months of age at ART initiation experienced more rapid improvement in WAZ (1.98 vs 1.44, P=.084) and head circumference for age z-score (1.24 vs 0.45, P=.004) than children who initiated ART between 12-24 months of age. By 48 months on ART, growth outcomes were similar, regardless of age at ART initiation. WAZ approached population norms by 12 months on ART. Although improving, height-for-age z-scores remained on average 1.0 z-score below population norms at 48 months of therapy. CONCLUSIONS: Initiation of ART before 6 months of age results in more rapid growth recovery in children infected with HIV. These data provide further evidence for the importance of prompt diagnosis and early initiation of ART for infants infected with HIV.

[Pharmacosurveillance regarding Colombian patients being treated with stavudine]. / Resultados de una intervencion de farmacovigilancia en pacientes con VIH/SIDA tratados con estavudina.

OBJECTIVES: Reducing the occurrence of negative stavudine use-associated outcomes by reporting such risk to doctors responsible for the care of HIV/AIDS patients in Colombia as stavudine has been associated with cumulative and irreversible toxicity. METHODS: All stavudine users were identified from Audifarma S.A. (drug suppliers) databases (covering about 4.5 million people). The risk was then reported to health service providers and the substitution of stavudine for zidovudine or tenofovir was recommended. RESULTS: It was found that 1,410 patients registered in the afore mentioned databases were receiving antiretroviral therapy during 2010, of whom 109 (7.5 %) were receiving stavudine; these patients were living in 20 cities and being attended by 19 institutions. Stavudine use became reduced by 94.6 % during the 28 months following the intervention. Zidovudine was the most commonly used replacement drug. DISCUSSION: Stavudine was successfully replaced following World Health Organization recommendations aimed at preventing the occurrence of lipodystrophy and the peripheral neuropathy associated with its use.

Effects of daily intake of zidovudine-stavudine on rat pregnancy outcome: biological essay.

PURPOSE: To evaluate the effects at term of a highly active antiretroviral drug association when administered for the whole period of rat pregnancy. METHODS: Forty pregnant rats weighing about 200 g were randomly divided into four groups: a control group (Ctr = drug vehicle control, n=10) and three experimental groups, which were treated with an oral solution of zidovudine-stavudine (Explx = 10/1 mg/kg b.w., n=10; Exp3x = 30/3 mg/kg b.w., n=10; Exp9x = 90/9 mg/kg b.w., n=10) from "day 0" up to the 20th day of pregnancy. Maternal body weights were recorded at the start of the experiment and on the 7th, 14th and 20th day thereafter. At term (20th day) the rats were anesthetized and submitted to hysterotomy. Implantations, reabsorptions, living fetuses, placentae and intrauterine deaths were looked for and recorded. The collected fetuses and placentae were weighed and the concepts were examined by a stereoscopic microscope looking for external malformations. RESULTS: No significant alterations due to the antiretroviral drug treatment could be detected regarding the number of implantations, fetuses, placentae, absorptions and malformations nor regarding maternal and fetal mortality. CONCLUSIONS: Administration of the association zidovudine/stavudine for the whole period of rat pregnancy did not interfere with the maternal, fetal and placental weight gain as well as abnormalities detectable by the employed methodology.

Biowaiver monographs for immediate-release solid oral dosage forms: stavudine.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing stavudine (d4T) are reviewed. According to Biopharmaceutics Classification System (BCS), d4T can be assigned to BCS class I. No problems with BE of IR d4T formulations containing different excipients and produced by different manufacturing methods have been reported and, hence, the risk of bioinequivalence caused by these factors appears to be low. Furthermore, d4T has a wide therapeutic index. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing d4T as the single active pharmaceutical ingredient (API) provided that (a) the test product contains only excipients present in the IR d4T drug products that have been approved in a number of countries for the same dosage form, and (b) both test product and its comparator are either "very rapidly dissolving" or "rapidly dissolving" with similarity of dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8.

Antiretroviral therapy-associated dyslipidemia in patients from a reference center in Brazil.

The aim of this study was to determine the impact of antiretroviral therapy on the lipid profile of human immunodeficiency virus (HIV) patients before and after the initiation of highly active antiretroviral therapy (HAART). This was a cross-sectional analysis of patients receiving HAART at a reference center in Belo Horizonte, Brazil, on the basis of medical records from 2002 to 2006. Patients were included if they had at least one lipid test or a clinical or laboratory diagnosis of dyslipidemia/lipodystrophy. Among the 692 patients, 620 met the eligibility criteria. The majority were males (66.5%), middle age (average 39 years), had a low educational level (60.4%), and low income (51.0%). HAART duration ranged from 11 days to 4.6 years, with a mean of 28.6 months (SD = ± 470.19 days). The prevalence of dyslipidemia/lipodystrophy nearly tripled (11.3% pre- and 32.4% post-HAART). Dyslipidemia was associated with older age (P = 0.007), nucleoside reverse transcriptase inhibitor (NRTI) + protease inhibitor (PI) regimens (P = 0.04), NRTI + non-NRTI (NNRTI) regimens (P = 0.026), the use of stavudine (d4T) in any regimen (P = 0.002) or in NRTI-based regimens (P = 0.006), and longer exposure to HAART (P < 0.000). In addition, there was no correlation between dyslipidemia and gender (P = 0.084). Only 2.0% of the patients received treatment for dyslipidemia during the trial. These results show a need for continuous monitoring of patients under antiretroviral therapy, particularly those using NRTI-based regimens, especially when combined with d4T and PIs. Secondly, interventions should be developed to correct metabolic changes.

Antiretroviral therapy-associated dyslipidemia in patients from a reference center in Brazil

The aim of this study was to determine the impact of antiretroviral therapy on the lipid profile of human immunodeficiency virus (HIV) patients before and after the initiation of highly active antiretroviral therapy (HAART). This was a cross-sectional analysis of patients receiving HAART at a reference center in Belo Horizonte, Brazil, on the basis of medical records from 2002 to 2006. Patients were included if they had at least one lipid test or a clinical or laboratory diagnosis of dyslipidemia/lipodystrophy. Among the 692 patients, 620 met the eligibility criteria. The majority were males (66.5 percent), middle age (average 39 years), had a low educational level (60.4 percent), and low income (51.0 percent). HAART duration ranged from 11 days to 4.6 years, with a mean of 28.6 months (SD = ± 470.19 days). The prevalence of dyslipidemia/lipodystrophy nearly tripled (11.3 percent pre- and 32.4 percent post-HAART). Dyslipidemia was associated with older age (P = 0.007), nucleoside reverse transcriptase inhibitor (NRTI) + protease inhibitor (PI) regimens (P = 0.04), NRTI + non-NRTI (NNRTI) regimens (P = 0.026), the use of stavudine (d4T) in any regimen (P = 0.002) or in NRTI-based regimens (P = 0.006), and longer exposure to HAART (P < 0.000). In addition, there was no correlation between dyslipidemia and gender (P = 0.084). Only 2.0 percent of the patients received treatment for dyslipidemia during the trial. These results show a need for continuous monitoring of patients under antiretroviral therapy, particularly those using NRTI-based regimens, especially when combined with d4T and PIs. Secondly, interventions should be developed to correct metabolic changes.

Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease seldom included in the differential diagnosis of leukoencephalopathy in HIV-positive patients. METHODS: We describe the clinical findings and laboratory results of a 43-year-old male with HIV infection and MS, and reviewed 11 more cases reported in the literature. RESULTS: The first episode of MS occurred either during or after the recognition of the HIV infection except in the few cases reported in 1989. There has been a very strong male predominance. Age at onset was between 30 and 40 years old. The most common clinical course was relapsing and remitting. Most of the cases had a normal CD4+ cell count, usually exceeding 500 cells/mm(3). Despite that CD4+ cell counts were invariable high, all the patients had multiple tests to rule out opportunistic infections and HIV-associated illness. The clinical suspicion of MS was only considered after ruling out other opportunistic infections and was supported with brain imaging showing multiple white matter evanescent lesions, the presence of black holes, and a high myelin basic protein titer in the CSF. CONCLUSIONS: MS is usually considered late in patients with HIV. A typical MS course with suggestive MRI lesions and absence of severe immune suppression should suggest the diagnosis. It is possible that as with other MS patients, earlier initiation of specific treatments for MS will prevent the high burden of the disease and disability in these patients, but stronger evidence for specific recommendations remains to be obtained.