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1.
AIDS ; 34(13): 1883-1889, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32694416

RESUMEN

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.


Asunto(s)
Fármacos Anti-VIH/líquido cefalorraquídeo , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/líquido cefalorraquídeo , Lamivudine/farmacocinética , Zidovudina/líquido cefalorraquídeo , Zidovudina/farmacocinética , Complejo SIDA Demencia/prevención & control , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Infecciones por VIH/metabolismo , VIH-1/genética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Punción Espinal , Estavudina/administración & dosificación , Estavudina/sangre , Estavudina/líquido cefalorraquídeo , Estavudina/uso terapéutico , Carga Viral , Zidovudina/sangre , Zidovudina/uso terapéutico
2.
Indian Pediatr ; 51(3): 191-7, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24736906

RESUMEN

OBJECTIVE: To determine the trough and two hour plasma levels of nevirapine, stavudine, and lamivudine when administered in fixed dose combinations (FDC). DESIGN: Cross sectional. SETTING: Tertiary care hospital in Northern India. PARTICIPANTS: 79 HIV-infected children receiving antiretroviral therapy with FDCs for more than month. INTERVENTION: Two-point sampling (0 and 2 hours after the morning dose). OUTCOME MEASURES: Plasma concentrations of all three drugs were simultaneously assayed by liquid chromatography/mass spectroscopy. RESULTS: Majority (77%) of children were receiving fixed dose combination of stavudine, lamivudine, nevirapine in the ratio of 6:30:50 mg. The median (IQR) trough and 2-hour plasma levels (µg/mL) of nevirapine, stavudine and lamivudine were 5.2 (4.0, 6.3) and 7.9 (6.0, 9.7); 0.1 (0.06, 0.16) and 1.1 (0.59, 1.6); 0.1 (0.02, 0.2) and 2.5 (1.4, 3.1), respectively. Very few children had sub-therapeutic plasma drug levels of stavudine (2.5%), lamivudine (7.6%) and nevirapine (10%). Inadequate viral suppression at 6 months follow up was significantly associated with initial high viral load, low CD4 percentage at the time of enrolment in study, and lower doses of lamivudine and stavudine. CONCLUSIONS: The currently available generic pediatric fixed dose antiretroviral combinations in India provide adequate drug exposure in majority of children.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Medicamentos Genéricos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/farmacocinética , Nevirapina/farmacocinética , Estavudina/farmacocinética , Adolescente , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Niño , Preescolar , Estudios Transversales , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/uso terapéutico , Femenino , Infecciones por VIH/epidemiología , Humanos , Lactante , Lamivudine/administración & dosificación , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , Nevirapina/administración & dosificación , Nevirapina/sangre , Nevirapina/uso terapéutico , Estavudina/administración & dosificación , Estavudina/sangre , Estavudina/uso terapéutico
3.
Antimicrob Agents Chemother ; 58(2): 1084-91, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24295968

RESUMEN

The antiviral efficacy of stavudine depends on the trough concentration of its intracellular metabolite, stavudine-triphosphate (d4T-TP), while the degree of stavudine's mitochondrial toxicity depends on its peak concentration. Rates of mitochondrial toxicity are high when stavudine is used at the current standard pediatric dose (1 mg/kg twice daily [BID]). Evidence from adult work suggests that half of the original standard adult dose (i.e., 20 mg BID) may be equally effective, with markedly less mitochondrial toxicity. We present a population pharmacokinetic model to predict intracellular d4T-TP concentrations in pediatric HIV-infected patients administered a dose of 0.5 mg/kg BID. Our model predicted that the reduced pediatric dose would result in a trough intracellular d4T-TP concentration above that of the reduced 20-mg adult dose and a peak concentration below that of the 20-mg adult dose. The simulated pediatric intracellular d4T-TP at 0.5 mg/kg BID resulted in median peak and trough values of approximately 23.9 fmol/10(6) cells (95% prediction interval [PI], 14.2 to 41 fmol/10(6) cells) and 14.8 fmol/10(6) cells (95% PI, 7.2 to 31 fmol/10(6) cells), respectively. The peak and trough concentrations resulting from a 20-mg BID adult dose were 28.4 fmol/10(6) cells (95% PI, 17.3 to 45.5 fmol/10(6) cells) and 13 fmol/10(6) cells (95% PI, 6.8 to 28.6 fmol/10(6) cells), respectively. Halving the current standard pediatric dose should therefore not compromise antiviral efficacy, while markedly reducing mitochondrial toxicity.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Modelos Estadísticos , Estavudina/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/toxicidad , Niño , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , VIH/efectos de los fármacos , VIH/fisiología , Infecciones por VIH/sangre , Infecciones por VIH/virología , Humanos , Masculino , Estavudina/sangre , Estavudina/toxicidad
4.
Analyst ; 137(18): 4327-34, 2012 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-22858583

RESUMEN

A methodology based on micellar liquid chromatography to monitor five antiretroviral drugs (lamivudine, stavudine, tenofovir, zidovudine and efavirenz) was proposed. Antiretrovirals were studied in sets of three, corresponding to each highly active antiretroviral therapy (HAART) regime, prescribed to acquired immunodeficiency syndrome (AIDS)-infected patients. Four aqueous micellar mobile phases buffered at pH 7 were optimized to separate these compounds, using sodium dodecyl sulfate as the tensioactive, and 1-propanol or 1-pentanol as the organic modifier. The composition of each mobile phase was optimized for each antiretroviral. The common separation conditions were: C18 apolar column (125 × 4.6 mm, 5 µm particle size), UV detection set at 214 nm, and mobile phase running at 1 mL min(-1) without controlling the temperature. The finally suggested method was validated for five analysed antiretroviral drugs following the US Food and Drug Administration guidelines in terms of: linearity between 0.5 and 50 ppm (r(2) > 0.9995), sensitivity (LOD lower than 0.25 ppm), intra- and inter-day precision (<7.1 and <5.2%, respectively) and accuracy (recovery 88.5-105.3% and 93.5-101.3%, respectively), as well as robustness (<6.5%). The proposed method was used to monitor the level of antiretrovirals in the serum of AIDS patients. The suggested methodology was found to be useful in the routine analysis of antiretrovirals in serum samples.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Monitoreo de Drogas , Síndrome de Inmunodeficiencia Adquirida/sangre , Adenina/análogos & derivados , Adenina/sangre , Adenina/uso terapéutico , Alquinos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Cromatografía Liquida , Ciclopropanos , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Organofosfonatos/sangre , Organofosfonatos/uso terapéutico , Estavudina/sangre , Estavudina/uso terapéutico , Tenofovir , Zidovudina/sangre , Zidovudina/uso terapéutico
5.
Biomed Chromatogr ; 26(12): 1472-81, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22344535

RESUMEN

A high-performance liquid chromatography/positive ion electrospray tandem mass spectrometry method for the simultaneous quantification of lamivudine, stavudine and nevirapine was developed and validated in dried blood spot (DBS) cards. The analytes were separated using an isocratic mobile phase on a reverse phase column and analyzed by MS/MS in the MRM mode using the respective [M + H]⁺ ions, m/z 230-112 for lamivudine, m/z 225-127 for stavudine, m/z 267-226 for nevirapine, m/z 383-337 for zidovudine (IS). The lower limit of quantification was 1 ng/mL for both lamivudine and stavudine and 10 ng/mL for nevirapine. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The method was successfully applied to quantify them in a rat pharmacokinetic study in whole blood, plasma and DBS cards after a single oral co-administration at the dose of 10, 2 and 13 mg/kg for lamivudine, stavudine and nevirapine, respectively, to male Wistar rats. Following oral administration the pharmacokinetic results in all the matrices are in close agreement. Thus accomplishment of this method would facilitate the ease of collection of clinical samples on DBS cards for lamivudine, stavudine and nevirapine during human clinical trials and therapeutic drug monitoring.


Asunto(s)
Antirretrovirales/sangre , Pruebas con Sangre Seca/métodos , Animales , Antirretrovirales/química , Antirretrovirales/farmacocinética , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Lamivudine/sangre , Lamivudine/química , Lamivudine/farmacocinética , Masculino , Nevirapina/sangre , Nevirapina/química , Nevirapina/farmacocinética , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estavudina/sangre , Estavudina/química , Estavudina/farmacocinética , Espectrometría de Masas en Tándem
6.
Antivir Ther ; 16(7): 1131-4, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22024529

RESUMEN

BACKGROUND: Stavudine, a nucleoside reverse transcriptase inhibitor, is used commonly to treat HIV-infected children in the developing world. The paediatric liquid formulation presents major logistical difficulties in rural and resource-limited areas, and prescribers are frequently forced to employ off-label 'opened capsule' dosing methods using the adult capsule. The South African Department of Health (DoH) has advised that caregivers should be instructed to disperse the contents of an adult capsule in 5 ml water and then withdraw the required dose using a syringe. The bioavailability of stavudine using the opened capsule dosing method has not previously been validated. METHODS: This was a randomized crossover pharmacokinetic study with each subject serving as his/her own control. A total of 28 healthy HIV-negative adult volunteers were randomized on a 1:1 basis to receive one of the two generic preparations typically available in state hospitals. They were then further randomized to receive either intact or opened 30 mg capsules. After 1 week, those who initially received intact capsules, were given opened capsules and vice versa. The capsule dispersion technique used was identical to that prescribed by the DoH. Serial blood samples were collected and plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Stavudine pharmacokinetics were analysed using non-compartmental methods and formulations were compared using ANOVA. RESULTS: Plasma drug exposure after stavudine administration as a solution using an opened capsule dosing method was found to be bioequivalent to intact capsule administration. This was true for both generics tested. CONCLUSIONS: The opened capsule dosing technique is bioequivalent to intact capsule dosing for stavudine in HIV-seronegative adults.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Estavudina/administración & dosificación , Estavudina/farmacocinética , Administración Oral , Adulto , Fármacos Anti-VIH/sangre , Cápsulas , Cromatografía Liquida , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacocinética , Estavudina/sangre , Espectrometría de Masas en Tándem , Equivalencia Terapéutica
7.
J Pharm Sci ; 100(8): 3260-3267, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21484806

RESUMEN

In the present work, a single model-independent approach was developed to optimize the release kinetics of drugs from sustained-release formulations, using stavudine (d4T) as a model drug. This approach is based on the pharmacokinetic simulation of drug plasma levels through a semiparametric approach of the input function and on convolution with an empirical polyexponential unit impulse response function. Input functions were evaluated using different zero-order and first-order release constants. Optimum drug release to obtain a specific pharmacokinetic profile was approached using target model-independent pharmacokinetic parameters such as C(max)(SS), C(min)(SS), t(max)(SS), and peak-trough fluctuations. A Monte Carlo simulation was performed to estimate the fractional attainment of d4T plasma concentrations over therapeutic d4T levels. Zero-order (K(0) = 4 mg/h) and first-order (K(1) = 0.05 h(-1)) release constants were optimal for the formulation of sustained-release d4T tablets, plasma concentrations within the therapeutic range being achieved.


Asunto(s)
Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Modelos Biológicos , Modelos Químicos , Química Farmacéutica , Simulación por Computador , Humanos , Cinética , Método de Montecarlo , Solubilidad , Estavudina/sangre , Estavudina/química , Estavudina/farmacocinética , Comprimidos
9.
Antivir Ther ; 15(3): 343-50, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20516554

RESUMEN

BACKGROUND: Children remain under-represented in national antiretroviral treatment (ART) programmes in settings with limited resources and high HIV prevalence. In Malawi, an increasing number of HIV-infected children have been started on ART with split tablets of an adult fixed-dose combination drug in the past few years. In 2006, the national paediatric ART regime was changed from Triomune 40 (T40) to Triomune 30 (T30). METHODS: This was a cross-sectional study conducted at the paediatric ART clinic in Blantyre (Malawi) from September 2006 to July 2007. Children taking T30 for > 6 weeks from each dosing weight band (<5, 5-<8, 8-<12, 12-<14, 14-<19, 19-<26, 26-<30 and > or = 30 kg) were recruited. Plasma drug concentration, CD4+ T-cell count and HIV viral load were measured. RESULTS: A total of 74 children were analysed. The median nevirapine (NVP) concentration was 7.35 mg/l. A therapeutic NVP plasma level > 3 mg/l was found in 62 (87.8%) children. A subtherapeutic NVP level (< 3 mg/l) occurred significantly more often in children treated with T30 doses between one-quarter tablet once daily and one-half tablet twice daily (P=0.035). Median prescribed NVP dose was 342 mg/m(2)/day, but 13 (17.6%) children received a dose below the recommended dose of 300 mg/m(2)/day. Compared with a historical control, the median prescribed NVP dose was increased (from 243 to 342 mg/m(2)/day). CONCLUSIONS: Our findings indicate that with the Malawian T30-based ART regime, the majority (87.8%) of children in the study group achieved a therapeutic NVP level. However, treatment remains suboptimal especially for young children receiving T30 dosages less than or equal to one-half tablets twice daily and child appropriate formulations are warranted.


Asunto(s)
Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Lamivudine/sangre , Nevirapina/sangre , Estavudina/sangre , Comprimidos , Adolescente , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Niño , Preescolar , Estudios Transversales , Formas de Dosificación , Esquema de Medicación , Combinación de Medicamentos , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Lactante , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Malaui , Masculino , Nevirapina/administración & dosificación , Nevirapina/uso terapéutico , Estavudina/administración & dosificación , Estavudina/uso terapéutico , Comprimidos/administración & dosificación , Comprimidos/uso terapéutico , Resultado del Tratamiento , Carga Viral
10.
Artículo en Inglés | MEDLINE | ID: mdl-20578520

RESUMEN

A high performance liquid chromatographic method with UV detection was developed and validated for simultaneous determination of stavudine and lamivudine in human plasma using solid-phase extraction for sample clean-up. Zidovudine was used as an internal standard. Separation was performed on a C18 column by gradient elution with a mobile phase of 10 mM acetate buffer pH 6.5 and acetonitrile. The UV detection was set at 265 nm. The method proved to be specific, accurate, precise and linear over the concentration ranges of 50-3000 ng/ml for stavudine and 50-5000 ng/ml for lamivudine with correlation coefficients always > 0.996 for both drugs. The intra-day and inter-day precision and accuracy were less than 9.2% for both analytes. The absolute recoveries of both compounds ranged from 93.3 to 97.5%. The method was successfully applied to a bioavailability study of a combined tablet formulation containing 30 mg of stavudine and 150 mg of lamivudine compared with each reference formulation concurrently administered in 26 healthy Thai male volunteers.


Asunto(s)
Fármacos Anti-VIH/sangre , Cromatografía Líquida de Alta Presión/métodos , Lamivudine/sangre , Estavudina/sangre , Disponibilidad Biológica , Estabilidad de Medicamentos , Humanos , Estándares de Referencia , Zidovudina/sangre
11.
Biomed Chromatogr ; 24(9): 926-34, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20058328

RESUMEN

A new high-throughput LC-MS/MS method for the simultaneous determination of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in human plasma is presented, with zidovudine as an internal standard. The analytes were extracted from plasma by protein precipitation and only 150 microL plasma was needed. Chromatographic separation was achieved on a Shiseido C(8) column (150 x 2.0 mm, 5 microm) with a total run time of 6 min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring under positive ionization mode with an electrospray ionization interface. The method was developed and validated over the concentration range of 25-5000 ng/mL for 3TC and NVP and 20-4000 ng/mL for d4T. The method was validated in terms of intra- and inter-day precision (< or = 8.6%), accuracy (within +/- 8.4%), linearity and specificity. The method has been successfully applied to the pharmacokinetic study of a combination treatment of 300 mg lamivudine, 30 mg stavudine and 200 mg nevirapine in 22 healthy male volunteers under fasting conditions.


Asunto(s)
Cromatografía Liquida/métodos , Lamivudine/sangre , Lamivudine/farmacocinética , Nevirapina/sangre , Nevirapina/farmacocinética , Estavudina/sangre , Estavudina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Humanos , Masculino
12.
Indian J Med Res ; 130(4): 451-7, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19942751

RESUMEN

BACKGROUND & OBJECTIVES: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients' immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. METHODS: Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. RESULTS: The patients' immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/microl than those with > or = 200 cells/ microl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/microl at initiation of ART to 366 cells/microl at 12 months of treatment. INTERPRETATION & CONCLUSIONS: Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.


Asunto(s)
Fármacos Anti-VIH , Combinación de Medicamentos , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Lamivudine , Estavudina , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Femenino , Infecciones por VIH/sangre , Humanos , India , Lamivudine/sangre , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Embarazo , Estavudina/sangre , Estavudina/farmacocinética , Estavudina/uso terapéutico
13.
J Acquir Immune Defic Syndr ; 52(1): 64-9, 2009 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-19731452
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 877(11-12): 1101-8, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19299211

RESUMEN

A molecularly imprinted polymer (MIP) using zidovudine (AZT) as template and methacrylic acid as monomer was prepared. The synthesis of the MIP was performed in acetonitrile. The synthesized material was then tested for the solid-phase extraction of AZT from different media (pure organic solvents and hydro-organic mixtures). An optimised procedure was developed for the selective extraction of AZT with a recovery of 96% using the MIP and only 3% on a non-imprinted polymer used as control polymer. A specific capacity of 0.2 micromol g(-1) was determined. The specificity of the MIP was evaluated by studying the retention behaviour of two others nucleoside analogues. The feasibility of the MIP to selectively extract AZT and stavudine (d4T) from human serum was also demonstrated with recoveries of 80 and 85% respectively. The lower limit of quantification (LLOQ) and the lower limits of detection (LLOD) for AZT were 5.10(-7) and 10(-7) M respectively.


Asunto(s)
Fármacos Anti-VIH/sangre , Estavudina/sangre , Zidovudina/sangre , Cromatografía Líquida de Alta Presión , Reacciones Cruzadas , Humanos , Indicadores y Reactivos , Espectrometría de Masas , Polímeros/química , Solventes
15.
J Antimicrob Chemother ; 61(4): 933-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18281306

RESUMEN

OBJECTIVES: The objective of this study was to determine the correlation between plasma stavudine concentrations and lipoatrophy (LA), one of the major adverse events in patients on stavudine and one of the major reasons to discontinue stavudine. METHODS: Plasma drug concentrations were retrospectively analysed in patients who were on a stavudine-containing regimen for at least 12 months. We defined two groups of patients: 21 patients with LA and 15 patients without LA or other stavudine-related side effects (i.e. neuropathy). RESULTS: We analysed stavudine concentrations in 212 plasma samples: 87 in the control group and 125 in the LA group, with a mean of four plasma samples per person (at least two a year). Demographics were comparable in LA patients and controls, except the duration of stavudine use, which was longer in the LA group: 55 versus 42 months in the control group. Overall, LA patients had higher drug exposure to stavudine when compared with the controls, and this was seen in the geometric concentration ratios (CRs), which were 0.978 and 0.741, respectively (P = 0.04), and also a higher percentage of CR values >1.0, representing a drug concentration above the normal population curve (46% versus 23%, P = 0.02). In addition, the duration of stavudine therapy was independently associated with LA (P = 0.05). In the multivariate analysis, both duration of stavudine (P = 0.05) and CR > 1.0 (P = 0.02) were independently correlated with LA. CONCLUSIONS: Monitoring of plasma stavudine concentrations can be useful to prevent stavudine-related LA.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Lipodistrofia/inducido químicamente , Plasma/química , Estavudina/efectos adversos , Estavudina/sangre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Estavudina/uso terapéutico , Factores de Tiempo
16.
Artículo en Inglés | MEDLINE | ID: mdl-18258495

RESUMEN

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 x 10(-2)-1.00 pmol/microL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 x 10(-2)-1.00 pmol/microL. The limit of quantification value was 1.00 x 10(-2)pmol/microL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.


Asunto(s)
Fármacos Anti-VIH/sangre , Monitoreo de Drogas/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Alquinos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Benzoxazinas/sangre , Carbamatos/sangre , Ciclopropanos , Didanosina/sangre , Didesoxinucleósidos/sangre , Estudios de Factibilidad , Furanos , Humanos , Estructura Molecular , Nevirapina/sangre , Inhibidores de la Transcriptasa Inversa/sangre , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta , Estavudina/sangre , Sulfonamidas/sangre
17.
AIDS ; 21(17): 2341-3, 2007 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-18090283

RESUMEN

Early failures to stavudine/lamivudine/nevirapine used as a generic fixed-dose combination in Mali showed resistance mutations in 50% of cases (mostly M184V and Y181C). No thymidine analogue mutations were seen, suggesting that most nucleoside reverse transcriptase inhibitors could be used in a second-line regimen. This highlights the importance of the accessibility of HIV-RNA assays for monitoring treated patients in resource-poor countries to detect early virological failure in order to preserve future therapeutic options.


Asunto(s)
Países en Desarrollo , Farmacorresistencia Viral Múltiple , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Combinación de Medicamentos , Medicamentos Genéricos , Femenino , Genes MDR , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , Malí , Mutación , Nevirapina/sangre , Nevirapina/uso terapéutico , ARN Viral/sangre , Estavudina/sangre , Estavudina/uso terapéutico , Insuficiencia del Tratamiento , Carga Viral
18.
Farm Hosp ; 31(4): 243-7, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-18052620

RESUMEN

OBJECTIVE: Simple methods for the determination of zidovudine (AZT), stavudine (d4T), lamivudine (3TC) and indinavir (INV) in human plasma by reversed-phase liquid chromatography (HPLC) with UV detection were described and validated. METHOD: Solid-liquid extraction procedures were applied to the samples prior to analysis. Chromatography was performed on a C-18 analytical columns and the retention time ranged from 6.8 to 8.0 min for stavudine, 7.5 to 9.0 min for lamivudine, 11.2 to 11.9 min for zidovudine and indinavir. Four methods were validated for specificity, inter-and intra-assay precision and accuracy, absolute recovery and stability. RESULTS: Analytical curve ranged from 10-1600 ng/ml for stavudine, 50-3200 ng/ml for lamivudine, 0.05-5.0 microg/ml for zidovudine and 0.1-10.0 microg/ml for indinavir. Analytes stability during sampling processing and storage were established. Extraction recoveries are higher than 89% for all formulations. CONCLUSIONS: These methods proved to be simple, accurate and precise, and are currently in use in our laboratory for the quantitative analysis of antiretrovirals products in plasma, and for further pharmacokinetics and bioequivalence studies.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Indinavir/sangre , Lamivudine/sangre , Estavudina/sangre , Zidovudina/sangre , Humanos
19.
Antivir Ther ; 12(6): 981-6, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17926654

RESUMEN

BACKGROUND: Intracellular nucleoside reverse transcriptase inhibitor triphosphate (NRTI-TP) concentrations are crucial in suppressing HIV replication. Little is known about how commonly used dual-NRTI regimens affect the intracellular levels of NRTI-TPs, the active form of these drugs. This study investigates the effect of dual-NRTI therapy in intracellular NRTI-TP levels. METHODS: NRTI and NRTI-TP concentrations were evaluated in HIV-infected patients receiving either lamivudine (3TC) and stavudine (d4T) or lamivudine with zidovudine (ZDV); NRTI and NRTI-TP concentrations were determined using a validated HPLC/MS/MS method. Plasma HIV-1 RNA levels were determined at baseline and monthly to examine the relationship between NRTI-TP concentrations and plasma HIV-1 RNA. RESULTS: Forty-one subjects completed the study. 3TC-TP significantly increased between day 1 and week 28 from 1.48 to 5.00 pmol/10(6) peripheral blood mononuclear cells (PBMC; P < 0.0001). NRTI-TP concentrations for d4T and ZDV did not significantly increase, with values at week 28 of 0.011 and 0.02 pmol/10(6) PBMC, respectively. Mean NRTI-TP/plasma ratios were 3%, 0.007% and 0.05% for 3TC, d4T and ZDV, respectively. Linear relationships were observed between ZDV- and 3TC-TP and changes in plasma HIV-1 RNA. CONCLUSION: Of the three drugs studied, only 3TC-TP levels increased significantly between day 1 and week 28. ZDV-TP and 3TC-TP levels were unaffected by dual-NRTI therapy relative to monotherapy, regardless of the combination (3TC-ZDV or 3TC-d4T). Intracellular levels of d4T-TP were similar to previous reports for dual-NRTI therapy; however, in the case of d4T, these values appear lower than those achieved with d4T monotherapy.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Citidina Trifosfato/análogos & derivados , Didesoxinucleótidos/sangre , Infecciones por VIH/tratamiento farmacológico , Lamivudine/análogos & derivados , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Nucleótidos de Timina/sangre , Zidovudina/análogos & derivados , Fármacos Anti-VIH/sangre , Citidina Trifosfato/sangre , Quimioterapia Combinada , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Leucocitos Mononucleares/metabolismo , Masculino , Inhibidores de la Transcriptasa Inversa/sangre , Estavudina/sangre , Estavudina/uso terapéutico , Zidovudina/sangre , Zidovudina/uso terapéutico
20.
Farm Hosp ; 31(4): 243-247, July-Aug. 2007. tab, graf
Artículo en Inglés | CUMED | ID: cum-39971

RESUMEN

Objetivo: Fueron descritos y validados m¨¦todos anal¨ªticos simplespara la determinaci¨®n de zidovudina (AZT), estavudina (d4T),lamivudina (3TC), e indinavir (INV) en plasma humano por cromatograf¨ªal¨ªquida de alta resoluci¨®n (HPLC) con detecci¨®n UV.M¨¦todo: Se aplic¨® la extracci¨®n en fase s¨®lida para la preparaci¨®nde las muestras previo al an¨¢lisis. La corrida cromatogr¨¢ficase realiz¨® en una columna anal¨ªtica C-18 y el tiempo de retenci¨®nse movi¨® en un rango de 6,8-11,9 min para d4T, 7,5-9,0para 3TC y 11,2-11,9 para AZT e INV. Se validaron 4 m¨¦todosen cuanto a especificidad, precisi¨®n y exactitud entre d¨ªas y en eld¨ªa, as¨ª como recobrado y estabilidad.Resultados: Los rangos de concentraciones de las curvasanal¨ªticas eran de 10-1600 ng/ml para d4T, 50-3200 ng/ml para3TC, 0,05-5,0 ¦Ìg/ml para AZT y 0,1-10,0 ¦Ìg/ml para INV. Sedemostr¨® la estabilidad del analito durante el procesamiento de lasmuestras y el almacenamiento. Para las 4 formulaciones los resultadosdel por ciento de recobrado fue superior al 89%.Conclusiones: Estos m¨¦todos demostraron ser simples, exactos,precisos y son los utilizados actualmente en nuestro laboratoriopara el an¨¢lisis cuantitativo de productos antirretrovirales enplasma, as¨ª como para posteriores estudios de farmacocin¨¦tica ybioequivalencia(AU)


Objective: Simple methods for the determination of zidovudine(AZT), stavudine (d4T), lamivudine (3TC) and indinavir (INV)in human plasma by reversed-phase liquid chromatography(HPLC) with UV detection were described and validated.Method: Solid-liquid extraction procedures were applied tothe samples prior to analysis. Chromatography was performed ona C-18 analytical columns and the retention time ranged from 6.8to 8.0 min for stavudine, 7.5 to 9.0 min for lamivudine, 11.2 to11.9 min for zidovudine and indinavir. Four methods were validatedfor specificity, inter-and intra-assay precision and accuracy,absolute recovery and stability.Results: Analytical curve ranged from 10-1600 ng/ml forstavudine, 50-3200 ng/ml for lamivudine, 0.05-5.0 ¦Ìg/ml forzidovudine and 0.1-10.0 ¦Ìg/ml for indinavir. Analytes stabilityduring sampling processing and storage were established. Extractionrecoveries are higher than 89% for all formulations.Conclusions: These methods proved to be simples, accurateand precise, and are currently in use in our laboratory for thequantitative analysis of antiretrovirals products in plasma, and forfurther pharmacokinetics and bioequivalence studies(AU)


Asunto(s)
Humanos , Indinavir/sangre , Lamivudine/sangre , Estavudina/sangre , Zidovudina/sangre
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