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1.
Saudi Pharm J ; 23(5): 573-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26594125

RESUMO

BACKGROUND: In Saudi Arabia there is an estimated need of more than 100,000 pharmacy graduates to cover all present sectors. The shortage of pharmacists has affected many of these sectors especially the pharmaceutical industry. The contribution of Saudi pharmacists to local pharmaceuticals industry would be extremely beneficial and important for shaping the future of the drug industry within the Kingdom. It is not clear whether future Saudi pharmacists are willing to contribute to local pharmaco-industrial fields. METHODS: A cross-sectional, questionnaire-based survey was conducted on all final-year pharmacy students in King Saud University (KSU), Riyadh, Kingdom of Saudi Arabia (KSA). RESULTS: Out of a total of 130 students registered in the final-year of the pharmacy program in KSU, 122 (93.8%) were able to complete the questionnaire. The results showed that the majority (83%) of Saudi pharmacy students indicated that they had not received practical training in the pharmaceutical companies, while only 17.2% of the students felt that they had the knowledge and the skills to work in the pharmaceutical industry after graduation. The majority of the students (66.7%) chose clinical pharmacy as their future career field while only 10.9% indicated willingness to work in a pharmaceutical industry career. Only 8.2% selected working in the pharmaceutical industry. The significant predictor of possibly choosing a career in the local drug industry is a student with a bachelor's degree (compared to Pharm D degree) in pharmacy (OR = 2.7 [95% CI 1.1-6.3]). CONCLUSION: Pharmacy students who are enrolled in the capital city of Riyadh are not properly trained to play an influential role in local drug companies. As a result, their level of willingness to have a career in such important business is not promising (more among Pharm D program). Future research in other pharmacy colleges within Saudi Arabia is needed to confirm such results.

2.
Saudi Pharm J ; 23(4): 397-404, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27134541

RESUMO

OBJECTIVES: The current study aimed to explore the knowledge, perception, and attitude of physicians toward generic medicines in Saudi Arabia. BACKGROUND: The local market of generic medicine share in Saudi Arabia is low compared to global and regional statistics. The reason for this low market share and the role of physicians has not previously been investigated. The purpose of this study was to assess health practitioner level of perceived knowledge, opinions and attitudes about local generic medication, and identify factors that influence infrequency of generic prescriptions. METHODS: A random sample of 231 physicians was recruited from two hospitals in Riyadh (one government one private) and 178 (77%) responded. Information on the physicians' perceived knowledge, opinions and attitude toward local generic medication was extracted, analyzed and interpreted. Factors that influence infrequent prescription of local generic drugs were identified. RESULTS: Among the 178 participants in the physicians' survey, 76% and 47% reported that they are knowledgeable about the terms "generic" and "bioequivalence" respectively, while 44% reported that they are able to explain bioequivalence to their patients. Approximately 52% of physicians reported that local generics should be substituted for brands if suitable for the case, and 21.9% reported that they believe SFDA approved local generics are therapeutically equivalent to their brands. Clinical effectiveness was reported by 71.9% of physicians as the most influential factor effecting prescription of brand over local generic medication. The three independent significant predictors for infrequent prescription of local generics among physicians: Government sector employment (OR = 3.74, [95%CI 1.50-9.43]), consultant level (OR = 3.94, [95%CI 1.50-10.31]) and low level of knowledge about local generics (OR = 4.11, [95%CI 1.56-10.84]). CONCLUSION: The low market share of local generics medicines attributed to low prescription rates is significantly more among senior-level physicians working in governmental hospitals. Low level of knowledge about generic drugs among physicians was the strongest predictive factor for low prescription. Future bigger studies are needed to confirm these results.

3.
J Virol ; 83(16): 8254-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19494021

RESUMO

A small animal model that reproduces human immunodeficiency virus type 1 (HIV-1) pathogenesis may allow modeling of new therapeutic strategies in ways not approachable in mononuclear cell culture. We find that, as in humans, combination antiretroviral therapy (ART) in humanized (hu-) Rag2(-/-)gamma(c)(-/-) mice allows suppression of viremia below the limits of detection and recovery of CD4(+) cells, while interruption of ART results in viral rebound and renewed loss of CD4(+) T cells. Failure of ART in infected mice is associated with the appearance of drug resistance mutations. The hu-Rag2(-/-)gamma(c)(-/-) mouse may therefore facilitate testing of novel approaches to HIV replication and persistence.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores de Integrase/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Viremia/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Camundongos , Camundongos Knockout , Viremia/imunologia , Viremia/patologia , Viremia/virologia
4.
Antimicrob Agents Chemother ; 53(6): 2367-74, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19307360

RESUMO

The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Líquido Amniótico/metabolismo , Fármacos Anti-HIV/farmacocinética , Sangue Fetal/metabolismo , Genitália Feminina/metabolismo , HIV-1 , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/biossíntese , Feminino , Genitália Feminina/virologia , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Gravidez , RNA Viral/sangue
5.
J Clin Pharmacol ; 49(9): 1079-90, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19628728

RESUMO

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)-coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean +/- SD [% coefficient of variation [CV]) were 7.3 +/- 2.8 (39%), 31.9 +/- 33.6 (106%), and 16.4 +/- 5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2 +/- 1.9 (46%), 8.1 +/- 7.9 (98%), and 1.5 +/- 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein in UGT2B7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB-coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance.


Assuntos
Lamivudina/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Estavudina/farmacocinética , Zidovudina/farmacocinética , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Adulto , Combinação de Medicamentos , Quimioterapia Combinada , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/uso terapêutico , Feminino , Gana , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Meia-Vida , Humanos , Lamivudina/administração & dosagem , Lamivudina/uso terapêutico , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/administração & dosagem , Estavudina/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/etiologia , Zidovudina/administração & dosagem , Zidovudina/uso terapêutico
6.
Antimicrob Agents Chemother ; 52(9): 3035-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18573930

RESUMO

Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [+/- standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC(0-24)), the plasma concentration 24 h after the dose (C(min)), and the maximum concentration during the dosing interval (C(max)) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC(0-24), C(min), and C(max) with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.


Assuntos
Anticonvulsivantes , Transtornos Cognitivos/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Minociclina , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ácido Valproico , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Sulfato de Atazanavir , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Infecções por HIV/psicologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/farmacologia , Minociclina/uso terapêutico , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
7.
Ther Drug Monit ; 30(5): 611-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18758393

RESUMO

Studying the pharmacokinetics of antiretroviral drugs in breast milk has important implications for the health of both the mother and the infant, particularly in resource-poor countries. Breast milk is a highly complex biological matrix, yet it is necessary to develop and validate methods in this matrix, which simultaneously measure multiple analytes, as women may be taking any number of drug combinations to combat human immunodeficiency virus infection. Here, we report a novel extraction method coupled to high-performance liquid chromatography and tandem mass spectrometry for the accurate, precise, and specific measurement of 7 antiretroviral drugs currently prescribed to infected mothers. Using 200 microL of human breast milk, simultaneous quantification of lamivudine (3TC), stavudine (d4T), zidovudine (ZDV), nevirapine (NVP), nelfinavir (NFV), ritonavir, and lopinavir was validated over the range of 10-10,000 ng/mL. Intraday accuracy and precision for all analytes were 99.3% and 5.0 %, respectively. Interday accuracy and precision were 99.4 % and 7.8%, respectively. Cross-assay validation with UV detection was performed using clinical breast milk samples, and the results of the 2 assays were in good agreement (P = 0.0001, r = 0.97). Breast milk to plasma concentration ratios for the different antiretroviral drugs were determined as follows: 3TC = 2.96, d4T = 1.73, ZDV = 1.17, NVP = 0.82, and NFV = 0.21.


Assuntos
Fármacos Anti-HIV/metabolismo , Antirretrovirais/metabolismo , Leite Humano/química , Leite Humano/metabolismo , Espectrometria de Massas em Tandem/normas , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Cromatografia Líquida/normas , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lactente , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Leite Humano/efeitos dos fármacos
8.
Bioanalysis ; 10(14): 1087-1097, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29692180

RESUMO

AIM: The purpose of this study was development, validation and application of ultra-performance liquid chromatography (UPLC)-ESI-MS/MS method for quantitation of flibanserin in plasma samples. METHOD & RESULTS: After extraction of analyte from plasma by diethyl ether, separation was performed on UPLC C18 column using mobile phase composition of 10 mM ammonium formate-acetonitrile (30:70, v/v) by isocratic elution of 0.3 ml/min. The multiple reaction monitoring transitions of m/z 391.13 → 161.04 and 384.20 → 253.06 were used for detection of analyte and internal standard (quetiapine), respectively. The calibration curves were linear (r ≥ 0.995) between 0.22 and 555 ng/ml concentration and all validation results were within the acceptable range as per US FDA guidelines. CONCLUSION: The assay procedure was fully validated and successfully applied in pharmacokinetic interaction study of flibanserin with bosentan in rats.


Assuntos
Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Sulfonamidas/química , Animais , Bosentana , Cromatografia Líquida de Alta Pressão , Feminino , Ratos , Ratos Wistar , Sulfonamidas/sangue , Espectrometria de Massas em Tandem
9.
AIDS ; 21(14): 1899-907, 2007 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-17721097

RESUMO

OBJECTIVES: To describe first dose and steady state antiretroviral drug exposure in the female genital tract. DESIGN: Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women. METHOD: Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA). RESULTS: For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%). CONCLUSIONS: This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.


Assuntos
Antirretrovirais/administração & dosagem , Genitália Feminina/metabolismo , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/sangue , Adenina/farmacocinética , Administração Oral , Adulto , Alcinos , Antirretrovirais/sangue , Antirretrovirais/farmacocinética , Sulfato de Atazanavir , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Benzoxazinas/farmacocinética , Ciclopropanos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/sangue , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Humanos , Lamivudina/administração & dosagem , Lamivudina/sangue , Lamivudina/farmacocinética , Lopinavir , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/sangue , Organofosfonatos/farmacocinética , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir , Zidovudina/administração & dosagem , Zidovudina/sangue , Zidovudina/farmacocinética
10.
J Pharm Biomed Anal ; 43(4): 1562-7, 2007 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-17236737

RESUMO

An accurate, sensitive and simple reverse-phase (RP) high-performance liquid chromatography (HPLC) assay has been developed and validated for the simultaneous quantitative determination of tipranavir with nine other antiretroviral drugs in plasma. A liquid-liquid extraction of the drugs in tert-butylmethylether (TBME) from 200 microL of plasma is followed by a reversed phase gradient HPLC assay with UV detection at 210 nm. The standard curve for the drug was linear in the range of 80-80,000 ng/mL for tipranavir; 10-10,000 ng/mL for nevirapine, indinavir, efavirenz, and saquinavir; and 25-10,000 ng/mL for amprenavir, atazanavir, ritonavir, lopinavir, and nelfinavir. The regression coefficient (r(2)) was greater than 0.998 for all analytes. This method has been fully validated and shown to be specific, accurate and precise. Due to an excellent extraction procedure giving good recovery and a clean baseline, this method is simple, rapid, accurate and provides excellent resolution and peak shape for all analytes. Thus this method is very suitable for therapeutic drug monitoring.


Assuntos
Fármacos Anti-HIV/sangue , Cromatografia Líquida de Alta Pressão/métodos , Inibidores da Protease de HIV/sangue , Piridinas/sangue , Pironas/sangue , Alcinos , Fármacos Anti-HIV/química , Sulfato de Atazanavir , Benzoxazinas , Carbamatos/sangue , Carbamatos/química , Ciclopropanos , Estabilidade de Medicamentos , Furanos , Inibidores da Protease de HIV/química , Humanos , Indinavir/sangue , Indinavir/química , Lopinavir , Estrutura Molecular , Nelfinavir/sangue , Nelfinavir/química , Nevirapina/sangue , Nevirapina/química , Oligopeptídeos/sangue , Oligopeptídeos/química , Oxazinas/sangue , Oxazinas/química , Piridinas/química , Pirimidinonas/sangue , Pirimidinonas/química , Pironas/química , Reprodutibilidade dos Testes , Ritonavir/sangue , Ritonavir/química , Saquinavir/sangue , Saquinavir/química , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta , Sulfonamidas/sangue , Sulfonamidas/química , Fatores de Tempo
11.
Artigo em Inglês | MEDLINE | ID: mdl-16920412

RESUMO

A simple, sensitive and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of omeprazole and its three metabolites in human plasma was developed and validated. This method provides excellent chromatographic resolution and peak shape for the four components and the internal standard within a 17 min run time. The simple extraction method results in a clean base line and relatively high extraction efficiency. The method was validated over the range of 2-2000 ng/mL, with 2.0 ng/mL as the lower limit of quantification. Within- and between-day accuracies for five different concentrations ranged from 95 to 102%, and 95 to 114%, respectively. Within- and between-day precision ranged from 1.1 to 6.3% and 0.5 to 6.2%, respectively. Simplicity and high throughput make this method suitable for clinical pharmacokinetic studies.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Omeprazol/sangue , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Omeprazol/análogos & derivados , Omeprazol/química , Reprodutibilidade dos Testes
12.
J Chromatogr B Analyt Technol Biomed Life Sci ; 822(1-2): 201-8, 2005 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-16005269

RESUMO

An accurate, sensitive and simple reverse-phase (RP) high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of emtricitabine and tenofovir in human blood plasma is described. Using 200 microL of plasma and BOND ELUT-C18 Varian columns, the solid phase extraction (SPE) method results in a clean baseline and high extraction efficiencies (100% for emtricitabine and 98.6% for tenofovir). An Atlantistrade mark dC-18 analytical column is used along with an 18 min linear gradient elution of phosphate buffer (pH 5.7) and methanol to provide sharp peaks for emtricitabine at 280 nm, tenofovir at 259 nm, and the internal standard 2',3'didoxyuridine (DDU) at 262 nm. The method was validated over the range of 10-10,000 ng/mL for both analytes, and is accurate (average accuracies of three different concentrations ranged from 98 to 105% for emtricitabine and 97 to 103% for tenofovir) and precise (within- and between-day precision ranged from 1.7 to 3.7% and 3.7 to 5.2%, respectively). This method is suitable for use in clinical pharmacokinetic studies and is nimble enough for therapeutic drug monitoring.


Assuntos
Adenina/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Desoxicitidina/análogos & derivados , Organofosfonatos/sangue , Adenina/sangue , Desoxicitidina/sangue , Estabilidade de Medicamentos , Emtricitabina , Humanos , Inibidores da Transcriptase Reversa/sangue , Sensibilidade e Especificidade , Tenofovir
13.
Talanta ; 132: 29-36, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25476275

RESUMO

Canagliflozin is the first sodium-glucose co-transporter-2 inhibitor, approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus. In this study, a sensitive UHPLC-MS/MS assay for rapid determination of canagliflozin in rat plasma was developed and validated for the first time. Chromatographic separation of canagliflozin and zafirlukast (IS) was carried out on Acquity BEH C18 column (100×2.1 mm, i.d. 1.7 µm) using acetonitrile-water (80:20, v/v) as mobile phase at a flow rate of 0.3 mL min(-1). Canagliflozin and IS were extracted from plasma by protein precipitation method using acetonitrile. The mass spectrometric detection was performed using electrospray ionization source in negative mode to avoid canagliflozin adduct ions formation. Multiple reaction monitoring were used for quantitation of precursor to product ion at m/z 443.16 >364.96 for canagliflozin and m/z 574.11>462.07 for IS, respectively. The assay was fully validated in terms of selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. The validated method was successfully applied to the characterization of oral pharmacokinetic profiles of canagliflozin in rats. The mean maximum plasma concentration of canagliflozin of 1616.79 ng mL(-1) was achieved in 1.5 h after oral administration of 20 mg kg(-1) in rats.


Assuntos
Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Tiofenos/farmacocinética , Acetonitrilas , Administração Oral , Animais , Canagliflozina , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Glucosídeos/sangue , Hipoglicemiantes/sangue , Indóis , Limite de Detecção , Masculino , Fenilcarbamatos , Ratos , Ratos Wistar , Padrões de Referência , Reprodutibilidade dos Testes , Sulfonamidas , Espectrometria de Massas em Tandem/métodos , Tiofenos/sangue , Fatores de Tempo , Compostos de Tosil/sangue , Água
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 791(1-2): 137-47, 2003 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-12798174

RESUMO

An accurate, sensitive and specific reversed-phase high-performance liquid chromatography assay for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors zalcitabine, lamivudine, didanosine, stavudine, zidovudine, and abacavir with the non-nucleoside reverse transcriptase inhibitor nevirapine in human blood plasma is described. The new Polarity dC C(18) silica column used in this method provides better resolution and peak shape than all other columns tested. Also, four different ultraviolet wavelengths were used for accurate and specific quantitation of the analytes. The method was validated over the range of 10-10000 ng/ml for all analytes except zalcitabine (10-5000 ng/ml). This method is accurate (average accuracies of three different concentrations ranged from 97.2 to 105%), and precise (within- and between-day precision measures ranged from 0.5 to 5.1% and 0.5 to 5.6%, respectively), and is currently being used for determination of plasma drug concentrations in our laboratory.


Assuntos
Nevirapina/sangue , Inibidores da Transcriptase Reversa/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta
15.
Artigo em Inglês | MEDLINE | ID: mdl-15135096

RESUMO

An accurate, sensitive, and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of HIV-protease inhibitors (PIs) (indinavir, IDV; amprenavir, APV; saquinavir, SQV; nelfinavir, NFV; ritonavir, RTV; and lopinavir, LPV) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, NVP; delavirdine, DLV; and efavirenz, EFV) in human blood plasma is described. The method provides excellent resolution and peak shape for nine analytes through a linear gradient (36-86%) of 25% phosphate buffer (pH 4.5), 60% acetonitrile, 15% methanol, and 0.75 ml TFA, with a gradient mobile phase flow rate (0.9-1.1 ml) over 30 min run time. The optimized solid phase extraction (SPE) extraction method using (1.0 ml, 100mg BOND ELUT-C18 Varian) column provides a clean base line and high extraction efficiency using a 550 microl plasma sample. The method was validated over the range of 10-10,000 ng/ml for NVP, IDV, and SQV; 10-5000 ng/ml for EFV; 25-10000 ng/ml for APV; and 25-5000 ng/ml for DLV, NFV, RTV, and LPV. This method is accurate (average accuracies of three different concentrations ranged from 91 to 112%), and precise (within- and between-day precision measures ranged from 0.2 to 5.7% and 0.1 to 5.4%, respectively). This method is suitable for use in clinical pharmacokinetic studies as well as in therapeutic drug monitoring (TDM).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores da Protease de HIV/sangue , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta
16.
Artigo em Inglês | MEDLINE | ID: mdl-12052725

RESUMO

A simple reversed-phase high-performance liquid chromatography assay for the simultaneous quantitative determination of three HIV non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, and efavirenz) in human blood plasma is described. The method was validated over the range of 10 ng/ml to 50 microg/ml for nevirapine, 25 ng/ml to 25 microg/ml for delavirdine, and 10 ng/ml to 10 microg/ml for efavirenz. The method is accurate (average accuracies over eight concentrations ranging from 87.3 to 113%), and precise (within-day and between-day precision measures ranging from 0.12 to 7.9% and 0.26 to 5.9%, respectively). All three non-nucleoside reverse transcriptase inhibitors proved to be stable under various conditions. Due to its simplicity, this assay can readily be used for investigational or clinical monitoring of plasma concentrations.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Delavirdina/sangue , Nevirapina/sangue , Oxazinas/sangue , Inibidores da Transcriptase Reversa/sangue , Espectrofotometria Ultravioleta/métodos , Alcinos , Benzoxazinas , Ciclopropanos , Infecções por HIV/sangue , HIV-1 , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Talanta ; 85(4): 2074-9, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21872060

RESUMO

The highly potent non-nucleoside reverse transcriptase inhibitor UC-781 is under development as a potential microbicide to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). A sensitive and reproducible liquid chromatography-mass spectrometric method has been developed and validated for the quantification of the drug in New Zealand white rabbit plasma after liquid-liquid extraction procedure. The method was validated over the range of 1-500 ng mL(-1). Average recoveries of the extraction method were high and consistent: 72%. The method is accurate with average accuracies over three QC (n=30) concentrations ranging from 99.9% to 106.1%, and precise (within-day and between-day precision measures ranging from 2.2% to 9.9% and 6.50% to 9.0%, respectively). Plasma from other three species proved that extraction method did no affect analyte and internal standard stability. Due to its critical and consequential use, this assay could be readily used for investigational or clinical monitoring of plasma concentrations for low concentration as 1 ng mL(-1) without interference.


Assuntos
Anilidas/sangue , Anti-Infecciosos/sangue , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Furanos/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Limite de Detecção , Modelos Lineares , Coelhos , Tioamidas , Fatores de Tempo
18.
Artigo em Inglês | MEDLINE | ID: mdl-19942487

RESUMO

Understanding the pharmacokinetics of drugs in peripheral body compartments, such as the genital tract, is particularly important in the infectious diseases arena. However, extracting drugs from small volumes of viscous, proteinacious substances like cervicovaginal fluid is particularly challenging. The goal of this study was to develop a method to quantify raltegravir, an HIV-1 integrase inhibitor, in the female genital tract. The method included sample preparation with perchloric acid followed by solid-phase extraction, separation with reverse-phase high-performance liquid chromatography, and detection with an ultraviolet wavelength of 218nm. The method was linear from 0.05 to 10.0mg/L, with minimal endogenous interference. The method was accurate (1.2-11.0% deviation) and precise (1.1-12.6% CV) for both within and between-day analyses. The ability to detect raltegravir in the female genital tract is essential for future investigations of raltegravir as an agent for prevention of HIV acquisition, and this method will be used for clinical studies further evaluating pharmacokinetic-pharmacodynamic relationships in this body compartment.


Assuntos
Secreções Corporais/química , Cromatografia Líquida de Alta Pressão/métodos , Genitália Feminina/metabolismo , Inibidores de Integrase de HIV/análise , Pirrolidinonas/análise , Administração Oral , Feminino , Humanos , Modelos Lineares , Percloratos , Raltegravir Potássico , Extração em Fase Sólida/métodos , Manejo de Espécimes/métodos , Espectrofotometria Ultravioleta
19.
Pharmacotherapy ; 30(1): 17-24, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20030469

RESUMO

STUDY OBJECTIVES: To evaluate whether patients with human immunodeficiency virus (HIV) infection who were receiving protease inhibitor therapy had altered bile acid concentrations compared with noninfected control subjects, and whether bile acid concentrations could predict the onset of hepatotoxicity caused by protease inhibitors. DESIGN: Retrospective sample analysis from a prospectively conducted clinical trial. SETTING: Academic research center. PATIENTS: Eleven adults with advanced HIV disease who were taking protease inhibitor-based antiretroviral therapy, one of whom had developed protease inhibitor-induced hepatotoxicity. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and taurocholic acid (TC) were analyzed by using a novel high-performance liquid chromatography with tandem mass spectrometry detection method. Comparisons of the relative contribution of each bile acid to the total bile acid pool were made with previously published values and with bile acid concentrations contained in two pooled plasma samples from healthy, non-HIV-infected volunteers analyzed in our laboratory. Each pooled plasma sample used for this analysis contained contributions from three non-HIV-infected volunteers. The LCA and TC concentrations in HIV-infected patients were 3-4-fold higher than those previously reported for non-HIV-infected subjects; concentrations of other bile acids were similar to those of previous reports. The relative contribution of CDCA to the total bile acid pool was 9% in HIV-infected patients compared with 30-50% in noninfected subjects. Total and individual bile acid concentrations in the HIV-infected patient who developed hepatotoxicity were similar to the bile acid concentrations from the other study patients who did not develop hepatotoxicity. CONCLUSION: These data suggest that bile acid concentrations may be altered by HIV infection and/or protease inhibitor therapy. However, further investigations should be performed to assess whether antiretroviral-associated hepatotoxicity can be predicted by alterations in individual bile acid concentrations.


Assuntos
Ácidos e Sais Biliares/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Infecções por HIV/sangue , Inibidores da Protease de HIV/efeitos adversos , Fígado/efeitos dos fármacos , Adulto , Doença Hepática Induzida por Substâncias e Drogas/sangue , Ácido Quenodesoxicólico/sangue , Cromatografia Líquida de Alta Pressão , Diagnóstico Precoce , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Ácido Litocólico/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem , Ácido Taurocólico/sangue , Fatores de Tempo
20.
Antivir Ther ; 15(1): 83-90, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20167994

RESUMO

BACKGROUND: The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL). METHODS: This was a prospective randomized three-way crossover study. Patients (8-<12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment. RESULTS: A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0-6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three-quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP. CONCLUSIONS: Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28-<32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg.


Assuntos
Fármacos Anti-HIV/farmacocinética , Medicamentos Genéricos/farmacocinética , Infecções por HIV/tratamento farmacológico , Lamivudina/farmacocinética , Nevirapina/farmacocinética , Estavudina/farmacocinética , Adolescente , Fármacos Anti-HIV/administração & dosagem , Peso Corporal , Criança , Pré-Escolar , Estudos Cross-Over , Formas de Dosagem , Esquema de Medicação , Medicamentos Genéricos/administração & dosagem , Feminino , HIV , Infecções por HIV/virologia , Humanos , Lactente , Lamivudina/administração & dosagem , Malaui , Masculino , Nevirapina/administração & dosagem , Estudos Prospectivos , Estavudina/administração & dosagem
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