Hipertensión portal no cirrótica por didanosina: Un caso infrecuente / Non-cirrhotic portal hypertension due to didanosina: A rare case

El compromiso hepático es usualmente visto en pacientes con infección por el virus de inmunodeficiencia humana (VIH), sobretodo en pacientes coinfectados con el virus de la hepatitis B o C, con el abuso de alcohol, etc. Sin embargo, existe un grupo de pacientes que desarrolla compromiso hepático e hipertensión portal de causa no específica. La hipertensión portal no cirrótica (HPNC) es un desorden hepático descrito recientemente, potencialmente grave, que ha sido reportado en pacientes infectados por el VIH con terapia antirretroviral de gran actividad (TARGA), específicamente didanosina (DDI). La fisiopatología involucra al agente infeccioso (VIH) y a su tratamiento (TARGA), pues ambas generan una venulopatía prehepática portal. Además, la infección por el VIH genera un estado protrombótico por deficiencia de proteína S conllevando a la obliteración de pequeñas vénulas hepáticas. Se ha postulado a la didanosina como un cofactor en la patogénesis del HPNC. Todo ello conlleva a que en muchas de las biopsias hepáticas se evidencie una hiperplasia nodular regenerativa. Se reporta el caso de una paciente con infección del VIH y en tratamiento con DDI de larga data que debuta con hemorragia digestiva alta (HDA) y ascitis como consecuencia de la HPNC, cuyo diagnóstico fue corroborado por biopsia. No existe reporte de casos del tema en nuestro país

Liver involvement is usually seen in patients infected with the human immunodeficiency virus (HIV), especially in patients coinfected with hepatitis B or C, in alcohol abuse, etc. However, there is a group of patients who develop liver involvement and portal hypertension of unspecified cause. Non-cirrhotic portal hypertension (NCPH) is a liver disorder recently described, but potentially serious. It has been reported in HIV-infected patients with highly active antiretroviral therapy (HAART), specifically didanosine (DDI). The pathophysiology involves the infectious agent (HIV) and its treatment (HAART), since both generate a pre-hepatic portal venulopathy. Similarly, HIV infection produces a prothrombotic state by protein S deficiency leading to the obliteration of small hepatic venules. It has been postulated that DDI as a cofactor in the pathogenesis of NCPH. All this leads that many of the liver biopsies show nodular regenerative hyperplasia. We present the case of a HIV-infected patient who was treated with a longstanding DDI. She developed upper gastrointestinal bleeding (UGB) and ascites due to NCPH, whose diagnosis was confirmed by biopsy. However, there is no similar study in our country

Solubility evaluation of didanosine: a comparison between the equilibrium method and intrinsic dissolution for biopharmaceutics classification purposes

ABSTRACT BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) were proposed as tools for classifying drugs into four categories. Both systems consider the solubility as an important characteristic for the classification of compounds in drug development and in vivo disposition prediction. Although some results of drug solubility can be found in the literature, the aforementioned characteristic is not entirely clear when considering didanosine (ddI). Based on that, the solubility of ddI was evaluated using equilibrium and intrinsic dissolution methods. For the equilibrium method, excess amount of ddI was added to each media until obtaining a supersaturated solution and the mixture was submitted to agitation at 37 °C. For the intrinsic dissolution method, the drug was compressed into the Wood's apparatus matrix and subjected to dissolution in each media with agitation at 37 °C. The results obtained from the equilibrium method indicated that it was necessary 139.37 mL of pH 1.2 media, 87.72 mL of pH 4.5 media, 12.54 mL of pH 6.8 media, 5.03 mL of pH 7.5 media and 7.65 mL of purified water for drug solubilization. Furthermore, a very fast intrinsic dissolution rate (IDR) was obtained for each media: 0.1 mg/min/cm² (pH 1.2), 0.2 mg/min/cm² (pH 4.5), 0.2 mg/min/cm² (pH 6.8), 0.1 mg/min/cm² (pH 7.5) and 0.1 mg/min/cm² (purified water). Based on these results, ddI can be considered as a highly soluble drug for both equilibrium and intrinsic dissolution methods.

Noncirrhotic portal hypertension in a human immunodeficiency virus (HIV) infected adolescent / Hipertensão portal não cirrótica em adolescente infectado pelo vírus da imunodeficiência humana (HIV)

OBJECTIVE: To alert the pediatrician who is following up HIV-infected patients about the possibility of non-cirrhotic portal hypertension (NCPH) in this period of life, in order to avoid the catastrophic consequences of this disease as bleeding esophageal varices. CASE DESCRIPTION: A 13 years old HIV-infected patient by vertical route was receiving didanosine (ddI) for 12 years. Although the HIV viral load had been undetectable for 12 years, this patient showed gradual decrease of CD4+ T cells, prolonged thrombocytopenia and high alkaline phosphatase. Physical examination detected splenomegaly, which triggered the investigation that led to the diagnosis of severe liver fibrosis by transient elastography, probably due to hepatic toxicity by prolonged use of ddI. COMMENTS: This is the first case of NCPH in HIV-infected adolescent described in Brazil. Although, the NCPH is a rare disease entity in seropositive patients in the pediatric age group, it should be investigated in patients on long-term ddI or presenting clinical and laboratories indicators of portal hypertension, as splenomegaly, thrombocytopenia and increased alkaline phosphatase.

OBJETIVO: Alertar o pediatra sobre a ocorrência de hipertensão portal não cirrótica (HPNC) na faixa etária pediátrica, no sentido de evitar as consequências catastróficas dessa doença, como o sangramento de varizes de esôfago. DESCRIÇÃO DO CASO: Paciente de 13 anos, infectado pelo HIV por via vertical, recebia esquema antirretroviral com didanosina (ddI) havia 12 anos. Apesar do controle adequado da replicação viral, com carga viral do HIV indetectável havia 12 anos, passou a apresentar diminuição gradativa dos linfócitos TCD4+, trombocitopenia prolongada e fosfatase alcalina elevada. O exame físico detectou esplenomegalia, que desencadeou o processo de investigação e culminou no diagnóstico de fibrose hepática acentuada pela elastografia, por provável toxicidade hepática devido ao uso prolongado de ddI. COMENTÁRIOS: Este é o primeiro caso de HPNC em adolescente infectado pelo HIV descrito no Brasil. Embora seja entidade mórbida rara em pacientes soropositivos para o HIV na faixa etária pediátrica, deve ser investigada nos pacientes em uso prolongado de ddI ou que apresentem indicadores clínicos e/ou laboratoriais de hipertensão portal, como esplenomegalia, trombocitopenia e aumento de fosfatase alcalina.

Analysis of in vivo absorption of didanosine tablets in male adult dogs by HPLC / 药物分析学报

Didanosine is an effective antiviral drug in untreated and antiretroviral therapy-experienced patients with Human Immunodeficiency Virus (HIV).An automated system using on-line solid extraction and High performance Liquid Chromatography (HPLC) with ultraviolet (UV) detection was developed and validated for pharmacokinetic analysis of didanosiae in dog plasma.Modifications were introduced on a previous methodology for simultaneous analysis of antiretroviral drugs in human plasma.Extraction was carried out on C18 cartridges,with high extraction yield as stationary phase,whereas mobile phase consisted of a mixture of 0.02 M potassium phosphate buffer,acetonitrile (KH2PO4:acetonitrile:96∶4,v/v) and 0.5％ (w/v) of heptane sulphonic acid.The pH was adjusted to 6.5 with triethylamine.All samples and standard solutions were chromatographed at 28℃.For an isocratic run,the flux was 1.0 mL/min,detection was at 250nm and injected volume was 20μL.The method was selective and linear for concentrations between 50 and 5000 ng/mL.Drug stability data ranged from 96％ to 98％,and limit of quantification was 25 ng/mL.Extraction yield was up to 95％.Drug stability in dog plasma was kept frozen at -20℃ for one month after thee freeze-thaw cycles,and for 24 h after processing in the auto sampler.Assay was successfully applied to measure didanosine concentrations in plasma dogs.

Preparation of gastro-resistant pellets containing chitosan microspheres for improvement of oral didanosine bioavailability / 药物分析学报

The purpose of this work was to introduce a new concept of coated pellets containing chitosan microspheres loaded with didadosine for oral administration,aiming at reducing the frequency of administration and improving the bioavailability by a suitable release profile.Chitosan microspheres were produced under fluidized bed,followed by extrusion and spheronization to obtain pellets with a mean diameter of about 1 mm.The pellets were then coated with Kollidon(R) VA64 and Kollicoat(R) MAE100P in water dispersion to depict a sustained release profile.Conventional hard gelatine capsules were loaded with these pellets and tested in vitro for their release profile of didadosine.Dissolution testing confirmed that chitosan microsphere pellets provides appropriate sustained release up to 2 h behavior for didanosine.

Didanosine Exposure and Noncirrhotic Portal Hypertension in a HIV Clinic in North America: a Follow-up Study.

Aims: To describe: 1) our cohort of patients diagnosed with NCPH in a HIV academic clinic in North America, and 2) longitudinal follow-up and outcomes of patients following NCPH diagnosis. Study design: Retrospective case series Place and Duration of Study: Owen clinic, University of California, San Diego, United States, between October 1990 and December 2010. Methodology: We describe a cohort of patients diagnosed with NCPH in a HIV academic clinic with emphasis on their follow-up and outcomes after NCPH diagnosis. Results: During the study period, eight HIV-infected men were diagnosed with NCPH. All patients were exposed to Didanosine (ddI) for a median of 37 months. One patient died soon after NCPH diagnosis due to a condition unrelated to NCPH. The other seven patients have received B-blocker therapy and annual esophago-gastro-duodenectomy screenings with banding of esophageal varices when indicated and remain still alive. Three patients were on ddI at the time of NCPH diagnosis. In one patient ddI was discontinued shortly after NCPH diagnosis. The other two patients continued to use ddI after NCPH diagnosis and developed recurrent upper gastrointestinal bleeding in the subsequent 2 years, requiring revascularization interventions. The four patients that were already off ddI at the time of NCPH diagnosis have been followed for a median of 6 years. These four patients remained minimally symptomatic for up to 16 years of follow-up from NCPH diagnosis. Conclusion: When ddI was discontinued before portal hypertension was clinically apparent the progression of NCPH appeared to subside without major clinical complications.

Desenvolvimento de formulações de comprimidos tamponados mastigáveis de didanosina com perfil de dissolução e capacidade neutralizante ácida otimizados / Development of didanosine chewable buffered tablets with optimized dissolution profile and acid neutralizing capacity.

Neste estudo buscou-se desenvolver formulações de comprimidos tamponados mastigáveis (CTM) de didanosina com eficiência de dissolução (ED%) e capacidade neutralizante ácida (CNA) otimizados, tendo como base o medicamento referência e especialidades farmacêuticas disponíveis no mercado nacional. Cinco formulações de CTM foram produzidas e avaliadas quanto a ED% e CNA, por meio de ensaio de dissolução e titulação ácido-base, respectivamente. Os resultados iniciais de CNA foram próximos aos encontrados para as especialidades farmacêuticas, aproximadamente 12 mEq HCl, porém distantes do medicamento referência (especialidade A, CNA = 17,93 mEq HCl). Já as formulações derivadas de CTM-4 conduziram à obtenção de comprimidos tamponados com CNA otimizada de aproximadamente 17,5 mEq HCl, o mesmo ocorrendo para ED%, (61,33% e 62,00%, CTM-4-2-1 e3, respectivamente). Esse resultado mostra-se próximo ao valor de 59,33% da especialidade A, quando utilizado o mesmo método de dissolução, indicando haver equivalência entre estas formulações e o medicamento referência para estes parâmetros.

The aim in this study was to develop chewable buffered tablets (CBT) of didanosine with optimized dissolution efficiency (DE) and acid-neutralizing capacity (ANC), using the reference medicine and other pharmaceutical didanosine products available in Brazil as models. Five CBT formulations were prepared and assessed for DE and ANC, through the dissolution test and acid-base titration, respectively. The initial ANC results fell short of those for the reference medicine (product A, ANC= 17.93 mEq HCl), but were close to those obtained for other pharmaceutical products (approximately 12 mEq HCl). The formulations derived from CBT-4 resulted in buffered tablets with an optimized ANC of 17.5 mEq HCl, approximately. The same was found for DE (61.33% and 62.00%, CBT-4-2-1 and CBT 3, respectively). This result proved to be close to that of product A (59.33%), when the same method was used for the dissolution test, indicating that both formulations and the reference medicine were equivalent with respect to these properties.

A new model for the population pharmacokinetics of didanosine in healthy subjects

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0 percent, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2 percent, respectively. The relatively high (>30 percent) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

Desenvolvimento e avaliação de formas farmacêuticas sólidas contendo didanosina / Development and evaluationof solid dosage forms with didanosine

A Síndrome da Imunodeficiência adquirida (AIDS) é uma doença de amplo espectro de manifestações, sendo razão de preocupação para qualquer autoridade sanitária. A terapêutica da AIDS é complexa sendo utilizados vários medicamentos, diversas vezes ao dia. Deste modo, objetivou-se o desenvolvimento de formas farmacêuticas sólidas como comprimidos tamponados mastigáveis (CTM), comprimidos com revestimento gastro-resistentes (CRGR) e pellets (PEL) para a veiculação de didanosina (ddl). Seis especialidades farmacêuticas na forma de CTM forma estudadas quanto ao perfil de dissolução, pH do meio e capacidade neutralizante ácida (CNA). Formulações teste de CTM foram propostas visando obter CNAs e perfis de dissolução adequados. Também foram testadas formulações de comprimidos e de pellets para posterior revestimento com filme gastro-resistente derivado do ácido metacrílico. Os ensaios de dissolução das amostras de CTM revelaram diferenças nas características de liberação do fármaco. Também foram observadas diferenças relacionadas a CNA. As formulações de CTM propostas apresentaram, na maioria dos casos, adequados perfis de dissolução e CNA. As formulações CRGR que receberam revestimento gastro-resistente apresentaram perfis de dissolução de ddl adequados, entretanto os comprimidos testados intumesceram em meio ácido, indicando descontinuidade do filme polimérico sobre os comprimidos. Testes para a produção de pellets veiculando ddl mostraram-se adequados quanto à morfologia e dissolução do fármaco, o mesmo sendo observado após o revestimento com filme gastro-resistente

The Acquired Immune Deficiency Syndrome (AIDS) is a disease that manifests itself in a myriad of ways. Because of this, the condition has been subject of concern to all sanitary authorities. The treatment of AIDS is complex and many types of medicine are used, many times a day. The objective of the present study was to develop solid pharmaceutical dosage forms such as buffered chewable tablets (CTM), gastro-resistant coating tablets (CRGR) and pellets (PEL) for the loading of didanosine (ddl). Six pharmaceutical specialties in the form of CTM were studied so as to identify the profile of the dissolution, the pH of the environment, and the neutralizing acid capacity (CNA). The use of CTM tests formulations was proposed with the objective of obtaining adequate CNA and dissolution profiles. Different compositions of tablets and pellets were tested for a later addition of gastro-resistant film derived from the methacrylic acid. The experiments on the dissolution of the sample of CTM showed differences in the characteristic of the release of the substance. Differences related to the CNA were also observed. The formulations of the CTM proposed showed to have, in the most number of the cases, both adequate dissolution behavior and CNA. The formulations of the CRGR that had received the gastro-resistant coating showed adequate profile of ddl dissolution; the tested tablets, however, swelled in the acid environment, therefore indicating a lack of continuity of the polymeric film over the tablets. The tests for the production of pellets showed adequate results as to its morphology and dissolution of ddl. The same was observed after coating the pellets with gastro-resistant film.