Investigating the dissolution profiles of amoxicillin, metronidazole, and zidovudine formulations used in Trinidad and Tobago, West Indies.

Trinidad and Tobago is a twin-island Republic in the Caribbean and like many developing countries, it has included generic drugs on the national drug formulary to decrease the financial burden of pharmaceutical medications. However, to ensure that medications received by patients are beneficial, generic drugs need to be interchangeable with the innovator which has demonstrated safety, efficacy, and quality. The objective of the study was to compare the dissolution profiles and weight variations for different formulations of amoxicillin, metronidazole, and zidovudine that are on the national drug formulary and marketed in Trinidad and Tobago. All the products investigated are categorized as class 1 drugs according to the Biopharmaceutics Classification System (BCS) and the dissolution profiles were assessed according to the World Health Organization (WHO) criteria for interchangeability between products. The similarity factor, f 2, was used to determine sameness between the products. No generic formulation was found to be similar to Amoxil® 500-mg capsules. The two generic products for metronidazole 200-mg tablets demonstrated more than 85% drug release within 15 min in all three of the buffers; however, their 400-mg counterparts did not fulfill this requirement. The zidovudine 300-mg tablet complied with the requirements in buffer pH 4.5 and simulated gastric fluid (SGF) but not for simulated intestinal fluid (SIF). Some Class 1 pharmaceutical formulations may possess the same active ingredient and amount of drug but may show significant differences to in vitro equivalence requirements. Nevertheless, the dissolution process is suitable to detect these variations.

Development and evaluation of a floating multiparticulate gastroretentive system for modified release of AZT.

The aim of this study was to develop and evaluate a floating multiparticulate gastroretentive system for the modified release of zidovudine (AZT). AZT was used as a model drug water-soluble at therapeutic doses. The floating gastroretentive system was obtained by co-precipitation, after solvent diffusion and evaporation. The proposed system was evaluated in vitro for particle morphology, lag time and floating time, loading rate, release profile, and the release kinetic of AZT release. AZT's physico-chemical characteristics were evaluated by differential scanning calorimetry (DSC), X-ray diffraction (XDR) and infrared spectroscopy (IR). The particles obtained were sphere-shaped, hollow, and had porous walls. The floating was immediate, and floating time was higher than 12 h. The loading rate was 34.0 ± 9.0%. The system obtained had an extended release. DSC and XDR results showed a modification in AZT's solid state. IR spectroscopy revealed that the chemical structure of the AZT was unchanged. The hollow microballoons presented gastroretentive, floating, and extended-release properties.

Evaluación de desempeño del método de ensayo de disolución para tabletas de zidovudina 300 mg producidas en Cuba / Performance assessment of dissolution assay method of 300 mg of Zidovudine tablets produced in Cuba

Se validó un método por cromatografía líquida de alta resolución para evaluar la disolución de las tabletas de zidovudina 300 mg producidas en Cuba, con detección ultravioleta a 265 nm. Se evaluaron los parámetros de especificidad, linealidad, precisión e influencia de la filtración. En el estudio de la influencia de la filtración se demostró que a través del filtro de línea, no se absorbe el principio activo, ni se aportan interferencias al filtrado, por lo que se recomienda su empleo. Se demostró la especificidad del método al no observarse interferencias de los excipientes de la formulación, en la determinación del principio activo. La curva de linealidad se realizó en el intervalo de concentraciones estudiadas con un coeficiente de correlación igual a 0,999. El método resultó preciso ya que los valores se encontraron dentro de los límites establecidos. Se realizó además la comparación estadística de los perfiles de disolución de las tabletas producidas en Cuba contra el Retrovir® (medicamento líder), lo cual demostró que existe similitud entre el perfil de liberación de las formulaciones

A high-performance liquid chromatography method was validated to assess the dissolution of 300 mg Zidovudine tablets manufactured in Cuba with 265 nm ultraviolet (UV) detection. Filtration specificity, linearity, accuracy parameters were assessed. In influence filtration study it was shown that through the line-filter the active principle it isn't absorbed and without filtrate interferences thus it is recommended its use. It was possible to demonstrate the method specificity due to no interferences of the formula excipients in active principle assessment. Linearity curve was drawed in the interval of study concentrations with a correlation coefficient similar to 0.999. The method was precise since the values were within the established limits. Also, we made a statistical comparison of dissolution profiles of tablets manufactured in Cuba versus Retrovir® (leading drug) demonstrating that there is a similarity between the formulas release profile

Three-year outcome data of second-line antiretroviral therapy in Ugandan adults: good virological response but high rate of toxicity.

OBJECTIVE: To evaluate the safety and virological response to lopinavir/ritonavir containing second-line therapy after failing a first line nonnucleoside reverse transcriptase inhibitor (NNRTI) based regimen. DESIGN: Prospective 36 months cohort study of patients switched to zidovudine/stavudine plus didanosine plus lopinavir/ritonavir capsules as second-line regimen. METHODOLOGY: Structured interview, medical examination, and laboratory assessment performed every 6 months. RESULTS: We enrolled 40 patients; 1 died and 3 were lost to follow-up. Median CD4+ count at baseline was 108 cell/microL, median log viral load was 4.8 copies/mL. Sixteen (40%) patients had baseline genotypic resistant test, 14 (87%) had lamivudine resistance mutations, and all had NNRTIs resistance mutations. At month 36, 82% of the patients achieved viral suppression (<400 copies/ mL) and the median increase in CD4+ count was 214 cell/microL, (interquartile range: 128-295). Twenty-five patients (62%) experienced at least one adverse event. CONCLUSIONS: Our study confirms lopinavir/ ritonavir-based second-line regimen but with a high rate of toxicities.

Quantitative determination of zidovudine diaryl phosphate triester pro-drugs in rat plasma by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

A rapid, simple, and sensitive high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS) method was developed and validated for quantitative analysis of 3'-azido-3'-deoxythymidine (zidovudine, AZT) diaryl phosphate triester pro-drugs, in rat plasma using 2',3'-dideoxy-2'3'-didehydrothymidine (d4T) as internal standard (IS). The analytes were extracted from rat plasma with methanol after protein precipitation. The compounds were separated by HPLC with gradient elution (on a Shim-pack VP-ODS C(18) analytical column using a mobile phase of methanol/10mM ammonium acetate). All the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. LLOQs were 10 ng mL(-1) for M1, M2, M3, M4, and M5, respectively. Correlation coefficient (r) values for the linear range of 10-10,000 ng mL(-1) were greater than 0.999 for all the analytes. The intra-day and inter-day precision and accuracy were higher than 7.13%. The relative and absolute recovery was above 72% and no matrix effects were observed for all the analytes. This validated method provides a modern, rapid, and robust procedure for the pharmacokinetic studies of the pro-drugs after intravenous administration to rats. Some important results of AZT diaryl phosphate triester pro-drugs concerning chemical effect on pharmacokinetic performance are also studied.

HIV/AIDS treatment and physicochemical quality control of medicines: evaluation of non-generic lamivudine + zidovudine tablets manufactured in Brazil

In this work it was evaluated the physicochemical quality of lamivudine + zidovudine tablets, whose association belongs to the list of drugs distributed by the Brazil's National Program on Sexually Transmitted Diseases and AIDS. Four non-generic products (lamivudine + zidovudine tablets) were analyzed. They were obtained from different Brazilian manufacturers, besides a reference product. The quality was evaluated by physicochemical tests described in the official codes. A validated reversed-phase high performance liquid chromatography (HPLC) method was used for the assay of the active substances. All samples were in accordance to the requisites in relation to their physicochemical characteristics. Dissolution studies showed similar drug percentual dissolved among all samples. The results reflect the interest of the national pharmaceutical industry to ensure the delivery of safer and cheaper drugs to the Brazilian people, with particular importance in the National Program on Sexually Transmitted Diseases and AIDS.

HIV/AIDS treatment and physicochemical quality control of medicines: evaluation of non-generic lamivudine + zidovudine tablets manufactured in Brazil.

In this work it was evaluated the physicochemical quality of lamivudine + zidovudine tablets, whose association belongs to the list of drugs distributed by the Brazil's National Program on Sexually Transmitted Diseases and AIDS. Four non-generic products (lamivudine + zidovudine tablets) were analyzed. They were obtained from different Brazilian manufacturers, besides a reference product. The quality was evaluated by physicochemical tests described in the official codes. A validated reversed-phase high performance liquid chromatography (HPLC) method was used for the assay of the active substances. All samples were in accordance to the requisites in relation to their physicochemical characteristics. Dissolution studies showed similar drug percentual dissolved among all samples. The results reflect the interest of the national pharmaceutical industry to ensure the delivery of safer and cheaper drugs to the Brazilian people, with particular importance in the National Program on Sexually Transmitted Diseases and AIDS.

Effects of cytokines on antiviral pharmacokinetics: an alternative approach to assessment of drug interactions using bioequivalence guidelines.

The effects of cytokines on the pharmacokinetics of nucleoside analogs were evaluated in two separate studies using zidovudine in combination with interleukin-2 and didanosine in combination with alpha interferon. In each study, drug interactions were evaluated by using both a standard method (Student's t test) and bioequivalence testing. Serial blood samples were collected from human immunodeficiency virus-infected patients prior to and during cytokine therapy for determination of nucleoside analog concentrations. Concentrations were fit separately to a two-compartment model by using the iterative two-stage approach to population analysis. No alterations in area under the curve or oral clearance were observed for either drug during combination therapy. In general, there was good agreement between statistical methods for determining if antiviral pharmacokinetic parameters were altered by concomitant cytokine therapy. However, large individual changes in the maximum concentration of zidovudine in serum were detected by bioequivalence testing but no difference was found by Student's t test. For didanosine, significant but clinically irrelevant decreases determined by standard hypothesis testing were seen for both the volume of the central compartment (1.91 to 1.86 liters) and the absorption rate constant (0.79 to 0.73 h-1) in the presence of alpha interferon. No interaction was noted for these parameters by using bioequivalence guidelines. Bioequivalence testing may provide an alternative approach to assessment of drug interactions. Interleukin-2 and alpha interferon do not alter the pharmacokinetics of zidovudine and didanosine, respectively.

Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art conference. National Institute of Allergy and Infectious Diseases State-of-the-Art Panel on Anti-Retroviral Therapy for Adult HIV-Infected Patients.

This document summarizes recommendations from a state-of-the-art conference convened to evaluate the role of nucleoside analogue reverse transcriptase inhibitors in the treatment of human immunodeficiency virus (HIV) infection. Data from controlled clinical trials of zidovudine, didanosine, and zalcitabine were reviewed by an expert panel, which then formulated guidelines to assist clinicians and HIV-infected patients in the use of these agents. Recommendations were framed in the context of clinical scenarios for patients with asymptomatic HIV infection who have not had prior antiretroviral therapy; those with signs and symptoms of HIV-related disease who have not received prior therapy; clinically stable patients who are tolerating initial zidovudine therapy; patients experiencing clinical progression while on zidovudine therapy; and those who are intolerant of antiretroviral therapy. The panel concluded that physicians need to integrate up-to-date scientific knowledge with other relevant needs to improve the care of HIV-infected patients.