RESUMO
Insomnia is becoming increasingly prevalent in the world general population. Therapies used by patients include over-the-counter therapies, herbal and dietary supplements, and pharmacological or nonpharmacological treatments. Among these, zolpidem is a pharmacological treatment popularly used for insomnia. Zolpidem is well tolerated and especially efficacious for initiation of sleep, and therefore is effective for the treatment of sleep-onset insomnia. The purpose of the present study was to design and evaluate zolpidem nanoparticle-impregnated buccal films to prolong the duration of its action. Zolpidem nanospheres were prepared by double emulsion solvent evaporation and then loaded into buccoadhesive films (Z1-Z4) comprised of different concentrations of HPMC K100, Eudragit® RL 100, and carbopol 974P. The prepared films were characterized for physicomechanical properties, mucoadhesion, percent hydration, in vitro drug release, ex vivo permeation, and in vivo studies. In vitro drug release was found to depend upon film composition. Ex vivo studies showed that film Z4 had the highest flux. In vivo studies revealed that administration of zolpidem nanosphere-impregnated film enhanced absorption of the drug (p < 0.0001), with a higher peak plasma concentration (52.54 ± 8.22 ng/mL) and area under the curve from time 0 to α (236.00 ± 39.51 ng.h/mL) than oral administration. The increase in time taken to reach the maximum drug concentration (1.5 h) further signifies the potential of these films to provide prolonged drug release. Given these promising results, we concluded that these buccal films could be an alternative route for effective zolpidem delivery.
Assuntos
Resinas Acrílicas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Hipnóticos e Sedativos/administração & dosagem , Nanosferas/administração & dosagem , Piridinas/administração & dosagem , Resinas Acrílicas/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Hipnóticos e Sedativos/farmacocinética , Masculino , Microscopia Eletrônica de Varredura , Piridinas/farmacocinética , Coelhos , Valores de Referência , Reprodutibilidade dos Testes , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Água/química , ZolpidemRESUMO
Abstract Insomnia is becoming increasingly prevalent in the world general population. Therapies used by patients include over-the-counter therapies, herbal and dietary supplements, and pharmacological or nonpharmacological treatments. Among these, zolpidem is a pharmacological treatment popularly used for insomnia. Zolpidem is well tolerated and especially efficacious for initiation of sleep, and therefore is effective for the treatment of sleep-onset insomnia. The purpose of the present study was to design and evaluate zolpidem nanoparticle-impregnated buccal films to prolong the duration of its action. Zolpidem nanospheres were prepared by double emulsion solvent evaporation and then loaded into buccoadhesive films (Z1-Z4) comprised of different concentrations of HPMC K100, Eudragit® RL 100, and carbopol 974P. The prepared films were characterized for physicomechanical properties, mucoadhesion, percent hydration, in vitro drug release, ex vivo permeation, and in vivo studies. In vitro drug release was found to depend upon film composition. Ex vivo studies showed that film Z4 had the highest flux. In vivo studies revealed that administration of zolpidem nanosphere-impregnated film enhanced absorption of the drug (p < 0.0001), with a higher peak plasma concentration (52.54 ± 8.22 ng/mL) and area under the curve from time 0 to α (236.00 ± 39.51 ng.h/mL) than oral administration. The increase in time taken to reach the maximum drug concentration (1.5 h) further signifies the potential of these films to provide prolonged drug release. Given these promising results, we concluded that these buccal films could be an alternative route for effective zolpidem delivery.
Assuntos
Animais , Masculino , Piridinas/administração & dosagem , Resinas Acrílicas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanosferas/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Piridinas/farmacocinética , Coelhos , Valores de Referência , Fatores de Tempo , Resinas Acrílicas/farmacocinética , Água/química , Disponibilidade Biológica , Microscopia Eletrônica de Varredura , Administração Oral , Reprodutibilidade dos Testes , Resultado do Tratamento , Zolpidem , Hipnóticos e Sedativos/farmacocinética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológicoRESUMO
R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Oxazinas/administração & dosagem , Pró-Fármacos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Quinase Syk/antagonistas & inibidores , Administração Oral , Aminopiridinas , Antirreumáticos/sangue , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/enzimologia , Biotransformação , Ensaios Clínicos Fase II como Assunto , Europa (Continente) , Humanos , América Latina , Modelos Lineares , Cadeias de Markov , México , Morfolinas , Oxazinas/sangue , Oxazinas/farmacocinética , Pró-Fármacos/farmacocinética , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Quinase Syk/metabolismo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). Design: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm³, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). no statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: in summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068).
Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Fármacos Anti-HIV/sangue , Infecções por HIV/sangue , Oligopeptídeos/sangue , Piridinas/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida , Estudos de Coortes , Estudos Transversais , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Estudos Prospectivos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Carga ViralRESUMO
INTRODUCTION: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported. METHODS: A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism. RESULTS: A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem. CONCLUSION: It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state.
Assuntos
Agonistas de Receptores de GABA-A/uso terapêutico , Oxigênio/sangue , Estado Vegetativo Persistente/sangue , Estado Vegetativo Persistente/fisiopatologia , Piridinas/uso terapêutico , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/fisiopatologia , Vigília/efeitos dos fármacos , Adulto , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Hemodinâmica , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Estado Vegetativo Persistente/tratamento farmacológico , Piridinas/farmacocinética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento , ZolpidemRESUMO
OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). DESIGN: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm(3), and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p=0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r=0.32 and r=0.33 respectively; p<0.05 in both cases). No statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: In summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. Prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p=0.068).
Assuntos
Fármacos Anti-HIV/sangue , Infecções por HIV/sangue , Oligopeptídeos/sangue , Piridinas/sangue , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir , Contagem de Linfócito CD4 , Cromatografia Líquida , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Estudos Prospectivos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Group 1026s is a prospective, nonblinded, pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including 2 cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the second trimester, 400/100 mg during the third trimester, and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by high-performance liquid chromatography. Pharmacokinetic targets were the 10th percentile atazanavir area under the concentration versus time curve (AUC) (29.4 µg·hr·mL·) in nonpregnant adults on standard dose and 0.15 µg/mL, minimum trough concentration. RESULTS: Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; median (range) pharmacokinetic parameters are presented for second trimester, third trimester, and PP and number who met target/total. ATAZANAVIR WITHOUT TENOFOVIR: AUC 30.5 (9.19-93.8), 45.7 (11-88.3), and 48.8 (9.9-112.2) µg·hr·mL, and 8/14, 29/37, and 27/34 met target. C24 h was 0.49 (0.09-4.09), 0.71 (0.14-2.09), and 0.90 (0.05-2.73) µg/mL; 13/14, 36/37, and 29/34 met target. ATAZANAVIR WITH TENOFOVIR: AUC 26.2 (6.8-60.9) (P < 0.05 compared with PP), 37.7 (0.72-88.2) (P < 0.05 compared with PP), and 58.6 (6-149) µg·hr·mL, and 7/17, 23/32, and 27/29 met target. C24 h was 0.44 (0.12-1.06) (P < 0.05 compared with PP), 0.57 (0.02-2.06) (P < 0.05 compared with PP), and 1.26 (0.09-5.43) µg/mL; 7/17, 23/32, and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events. CONCLUSIONS: Atazanavir/ritonavir increased to 400/100 mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Oligopeptídeos/farmacocinética , Organofosfonatos/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Terceiro Trimestre da Gravidez , Piridinas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Humanos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Organofosfonatos/administração & dosagem , Organofosfonatos/uso terapêutico , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/virologia , Segundo Trimestre da Gravidez , Estudos Prospectivos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir , Resultado do Tratamento , Adulto JovemRESUMO
Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.
Assuntos
Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Formulários de Hospitais como Assunto , Administração Oral , Anticoagulantes/farmacocinética , Antitrombinas/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Dabigatrana , Humanos , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Pennsylvania , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Rivaroxabana , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Varfarina/administração & dosagem , Varfarina/farmacocinética , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinéticaRESUMO
OBJECTIVE: There are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. METHODS: In this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/100 mg (n=20) or 400/100 mg (n=21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C(max) ), trough observed plasma concentration 24 hour post dose (C(min) ) and area under concentration-time curve in one dosing interval (AUC(τ) )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n=23). RESULTS: At or before delivery, all mothers achieved HIV RNA <50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC(τ) for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C(min) values were comparable. The C(min) value for atazanavir/RTV 400/100 mg was 39% higher than the C(min) for atazanavir/RTV 300/100 mg in historical controls, but the AUC(τ) values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (>2.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. CONCLUSIONS: In this study, use of atazanavir/RTV 300/100 mg qd produced C(min) comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.
Assuntos
Infecções por HIV/prevenção & controle , Inibidores da Protease de HIV/farmacocinética , HIV-1 , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Oligopeptídeos/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Piridinas/farmacocinética , Ritonavir/farmacocinética , Adulto , Sulfato de Atazanavir , Contagem de Linfócito CD4 , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Inibidores da Protease de HIV/administração & dosagem , HIV-1/imunologia , Humanos , Oligopeptídeos/administração & dosagem , Gravidez , Complicações Infecciosas na Gravidez/virologia , Porto Rico/epidemiologia , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , África do Sul/epidemiologia , Estados Unidos/epidemiologia , Carga ViralRESUMO
PURPOSE: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. METHODS: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. RESULTS: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. CONCLUSION: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.