RESUMO
OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.
Assuntos
Analgésicos/administração & dosagem , Azepinas/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Imidazóis/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Sumatriptana/administração & dosagem , Adulto , Azepinas/efeitos adversos , Azepinas/farmacocinética , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Sumatriptana/efeitos adversos , Sumatriptana/farmacocinética , Adulto JovemRESUMO
Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89-1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Antivirais/farmacocinética , Benzofuranos/farmacocinética , Famotidina/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacocinética , Quinoxalinas/farmacocinética , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Adulto , Amidas , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzofuranos/efeitos adversos , Benzofuranos/sangue , Benzofuranos/farmacologia , Carbamatos , Ciclopropanos , Demografia , Interações Medicamentosas , Famotidina/efeitos adversos , Famotidina/farmacologia , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/sangue , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Pantoprazol , Quinoxalinas/efeitos adversos , Quinoxalinas/sangue , Quinoxalinas/farmacologia , Sulfonamidas , Fatores de Tempo , Adulto JovemRESUMO
Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC)0-∞ and maximum concentration (Cmax ) increased in a greater-than-dose-proportional manner. The geometric mean ratios (GMRs; fed/fasted) were 1.22 and 0.79 for AUC0-∞ and Cmax , respectively. Following multiple doses, GMR accumulations for AUC0-12h and Cmax (day 14/day 1) ranged from 1.53 to 1.90 and from 1.41 to 1.92, respectively. These data support the use of vaniprevir with peginterferon and ribavirin in patients with HCV infection.
Assuntos
Saúde , Indóis/administração & dosagem , Indóis/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Ciclopropanos , Relação Dose-Resposta a Droga , Jejum , Humanos , Indóis/sangue , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Prolina/análogos & derivados , Sulfonamidas , Adulto JovemRESUMO
MK-383 (L-tyrosine, N-(n-butylsulfonyl)-O-[4-butyl(4-piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo-controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-383 administered as 1- and 4-hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 microgram/kg/min over 1 hour or up to 0.2 microgram/min over 4 hours, it provided a well-tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 microgram/kg/min for 1 and 4 hours, respectively, MK-383 extended baseline bleeding time by 2.0- to 2.5-fold and inhibited adenosine diphosphate (ADP)-induced platelet aggregation by at least 80%. The pharmacokinetics of MK-383 include a mean plasma clearance of 329 ml/min, steady-state volume of distribution of 76 L, and half-life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK-383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum-effect model. The plasma concentration yielding 50% inhibition (C50) for MK-383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient > 5. Based on a naive pooled analysis, an exponential empirical model best describes the MK-383 C-extension of template bleeding time (BTE) relationship. The model indicates that the MK-383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5-fold greater than the C50 for ADP-induced inhibition of platelet aggregation). The pharmacokinetics of MK-383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50 and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic-pharmacodynamic profile, MK-383 should be evaluated in patients with unstable angina.
Assuntos
Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Tirosina/análogos & derivados , Análise de Variância , Plaquetas/efeitos dos fármacos , Método Duplo-Cego , Humanos , Masculino , Valores de Referência , Tirofibana , Tirosina/farmacocinética , Tirosina/farmacologiaRESUMO
We investigated the dose-response and reproducibility of the intraocular pressure-lowering effect of MK-927 in ocular hypertensive patients. Patients were enrolled until at least 8 "marked responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye greater than or equal to 6 mm Hg) and 7 "mild responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye less than or equal to 3 mm Hg) were identified. In part A, 27 patients received one drop of 2% MK-927 in one eye (baseline mean +/- SEM intraocular pressure, 28.0 +/- 1.0 mm Hg) and placebo in the contralateral eye. Intraocular pressure was measured at baseline and 1, 2, 3, 4, and 6 hours. Maximum reduction in intraocular pressure was 4.0 +/- 0.8 mm Hg at 3 hours, with a duration of 4 hours. Ten patients were identified as marked responders and 7 as mild responders. In part B, 8 of the marked responders entered a four-period crossover study and received 2%, 0.5%, and 0.125% MK-927 and placebo in the same treated eye as in part A, and placebo in the contralateral eye. The 7 mild responders in part C received 2% MK-927 in a similar fashion as in part A. MK-927 in concentrations of 0.125% and 0.5% had little or no effect on intraocular pressure in patients with a marked response to 2% MK-927. Within-patient variability in peak response to single doses of 2% MK-927 was substantial (coefficient of variation of 0.3 and 0.5 for marked responder and mild responder groups, respectively.
Assuntos
Anti-Hipertensivos/administração & dosagem , Inibidores da Anidrase Carbônica/administração & dosagem , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Administração Tópica , Anti-Hipertensivos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Fatores de TempoRESUMO
OBJECTIVE: To investigate the activity and local and systemic safety of the topical carbonic anhydrase inhibitor, dorzolamide hydrochloride. DESIGN: Four-week, double-masked, randomized, placebo-controlled, parallel, three-center study. SETTING: Referral centers. PATIENTS: Forty-eight patients with bilateral open angle glaucoma or ocular hypertension and intraocular pressure (IOP) greater than 22 mm Hg entered the study. Two of 28 patients receiving dorzolamide and two of 20 patients receiving placebo were withdrawn due to adverse experiences. INTERVENTION: Dorzolamide (2%) or placebo to each eye three times daily for 4 weeks. MAIN OUTCOME MEASURES: Diurnal IOP curves; ophthalmologic evaluations including corneal ultrasound pachymetry and endothelial cell count; and systemic evaluations including vital signs, blood chemistries, complete blood cell counts, urinalysis, electrocardiogram, and drug and carbonic anhydrase activity levels in red blood cells. RESULTS: Mean IOP at morning trough (8 AM) decreased from 27.1 mm Hg at baseline to 23.5 mm Hg on day 29 with dorzolamide (-13.3%) compared with a decrease from 27.1 mm Hg to 26.4 mm Hg with placebo (-2.3%). Peak activity occurred 2 hours after administration, with IOP decreasing from 26.8 mm Hg at baseline to 21.8 mm Hg on day 29 with dorzolamide (-18.4%) vs 26.1 mm Hg to 25.5 (-2.4%) with placebo. Mean corneal thickness was slightly increased for the dorzolamide-treated group compared with the placebo-treated group (0.009 mm vs 0.001 mm, respectively, P < .05) and changes in endothelial cell counts were similar (-24 cells/mm2 vs -27 cells/mm2, respectively, P > .25). Mean carbonic anhydrase isoenzyme II activity in red blood cells decreased to 21% of baseline in dorzolamide-treated patients. There were no clinically significant differences in ocular or laboratory parameters between the dorzolamide and placebo groups. CONCLUSIONS: Dorzolamide demonstrated significant IOP lowering activity over 4 weeks. It was well tolerated and there were no clinically significant changes in ocular or systemic safety parameters.
Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Administração Tópica , Adulto , Idoso , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/farmacocinética , Anidrases Carbônicas/sangue , Contagem de Células , Córnea/patologia , Método Duplo-Cego , Tolerância a Medicamentos , Endotélio Corneano/patologia , Eritrócitos/metabolismo , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas , Segurança , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinéticaRESUMO
The dose response to a single topical administration of the carbonic anhydrase inhibitor MK-927 was investigated in 24 patients with primary open angle glaucoma or ocular hypertension. Three concentrations of MK-927 (2%, 1%, and 0.5%) and placebo were administered in a two-center, double-masked, randomized, placebo-controlled, four-period crossover study. MK-927 at the 0.5% concentration appeared to be minimally effective in reducing intraocular pressure. A single topical dose of 1% MK-927 resulted in a significantly greater percent reduction in intraocular pressure for up to 6 hours when compared with treatment with placebo. Similarly, a single dose of 2% MK-927 significantly lowered intraocular pressure for 8 hours compared with treatment with placebo. The pressure reduction from baseline measured 23.7% and 11.3% at 8 hours after instillation of a single drop of 2% MK-927. The medication was well tolerated and appeared to lower intraocular pressure in a dose-dependent fashion.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Acuidade VisualRESUMO
The multiple-dose twice-daily efficacy of the topical carbonic anhydrase inhibitor MK-927, a racemic compound, was compared with that of its pharmacologically more active S-enantiomer in a four-center, double-masked, randomized, placebo-controlled, parallel study of 1.8% sezolamide hydrochloride (MK-417), 2% MK-927, and placebo, given twice daily to 48 patients with bilateral primary open angle glaucoma or ocular hypertension and morning intraocular pressure greater than 24 mm Hg in both eyes following washout of ocular hypotensive medications. Parallel 10-hour modified diurnal curves were performed before the study and on day 14, with 4-hour curves on days 1 and 4. Both compounds demonstrated significant lowering of intraocular pressure at 8 AM, 12 hours following the evening dose, and through 10 and 6 hours following the 8 AM dose for sezolamide and MK-927, respectively. Morning trough (evening) activity as measured by mean percent change in intraocular pressure from prestudy was -9.2% for sezolamide and -11.1% for MK-927 (-13.5% and -9.6%); peak effect occurred 2 hours after dose administration and was -19.4% and -19.2% for sezolamide and MK-927, respectively. From 2 hours after dose administration, sezolamide consistently demonstrated a slightly greater decrease in intraocular pressure than MK-927; however, these differences were not statistically significant.
Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Administração Tópica , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Anidrase Carbônica/administração & dosagem , Ritmo Circadiano , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , EstereoisomerismoRESUMO
The effects on intraocular pressure of the novel topical carbonic anhydrase inhibitor MK-927 were investigated for the first time in patients. Three drops of 2% MK-927 was administered in a two-center, double-masked, randomized, placebo-controlled, two-period crossover study in 25 patients with bilateral primary open angle glaucoma or ocular hypertension. At 4.5 hours after the dose, MK-927-treated eyes demonstrated a peak mean change of -7.7 mm Hg from a mean intraocular pressure of 27.8 mm Hg immediately before the dose; this compares with a change of -3.9 mm Hg from a mean intraocular pressure of 28.2 mm Hg when the same eyes were treated with placebo. The peak mean percent change in intraocular pressure in eyes treated with MK-927 was -26.7% at 6 hours after the dose compared with a change of -13.7% after treatment with placebo. No contralateral effect on intraocular pressure due to MK-927 was observed.
Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Anidrase Carbônica/administração & dosagem , Ensaios Clínicos como Assunto , Método Duplo-Cego , Cor de Olho , Feminino , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Placebos , Distribuição Aleatória , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagemRESUMO
MK-852, a cyclic heptapeptide, is a potent platelet fibrinogen receptor antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.44 microgram/kg/min for 4 hours, respectively, MK-852 extended baseline bleeding time by greater than 2.2-fold and 2.6-fold, inhibited ADP-induced platelet aggregation by 76% and 69%, and inhibited collagen-induced platelet aggregation by 65% and 67%, respectively. The pharmacokinetics of MK-852 include an elimination half-life of approximately 2 hours, total clearance of about 150 ml/min, and volume of distribution of about 18 liters. Examination of the relationship between MK-852 whole-blood concentration in vitro and inhibition of platelet aggregation showed an EC50 of about 55 ng/ml and a Hill coefficient of 1.55. The infusions were generally well tolerated, with no study drug-related changes in blood counts or biochemical profiles.
Assuntos
Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Difosfato de Adenosina/farmacologia , Adulto , Área Sob a Curva , Colágeno/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacocinética , Testes de Função Plaquetária , Tiazolidinas , Fatores de TempoRESUMO
Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.
Assuntos
Anti-Hipertensivos/farmacocinética , Enalapril/farmacocinética , Hipertensão/sangue , Adolescente , Análise de Variância , Anti-Hipertensivos/sangue , Anti-Hipertensivos/urina , Área Sob a Curva , Criança , Pré-Escolar , Intervalos de Confiança , Enalapril/sangue , Enalapril/urina , Enalaprilato/sangue , Enalaprilato/urina , Feminino , Humanos , Hipertensão/urina , Lactente , MasculinoRESUMO
Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma.
Assuntos
Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Agonistas do Receptor de Serotonina/administração & dosagem , Fatores de Tempo , Triazóis/administração & dosagem , TriptaminasRESUMO
OBJECTIVE: Rizatriptan is a serotonin 5-HT1B/1D receptor agonist for acute treatment of migraine. Its pharmacokinetics were assessed in healthy elderly males and females receiving a single 10 mg tablet oral dose. The pharmacokinetic data (AUC(0-infinity) and Cmax) for the elderly in this study were compared with historical data from previous studies for healthy young adults (n = 65). METHODS: In a double-blind, parallel, placebo-controlled study, healthy elderly female and male subjects aged 65 or older (n = 8 each) received a single oral dose of 10 mg rizatriptan. Plasma and urine concentrations of drug were determined by HPLC with tandem mass spectrometry detection at several collection time points or intervals starting at predose and postdose over 24 h. RESULTS: In elderly subjects, the geometric mean values for AUC(0-infinity) and Cmax were 77.7 ng/h/ml and 21.9 ng/ml; the average values for tmax, half-life (t 1/2), renal clearance (Clr), and percent urinary excretion of dose (Ue) were 1.2 h, 1.8 h, 197 ml/min and 9.3%, respectively. The AUC(0-infinity) and Cmax of rizatriptan were similar in elderly and young subjects. The geometric mean AUC ratio of elderly to young was 0.96 with 90% confidence interval (0.83, 1.11), p > 0.25. The geometric mean Cmax ratio was 0.89 with 90% confidence interval (0.72, 109), p > 0.25. No significant pharmacokinetic differences were observed between elderly males and females. CONCLUSIONS: The plasma pharmacokinetics of rizatriptan appear to be similar in the elderly and young. In the elderly, the pharmacokinetics of rizatriptan do not appear to differ between male and female to a clinically significant extent.
Assuntos
Envelhecimento/metabolismo , Agonistas do Receptor de Serotonina/farmacocinética , Triazóis/farmacocinética , Adulto , Idoso , Análise de Variância , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Agonistas do Receptor de Serotonina/sangue , Agonistas do Receptor de Serotonina/urina , Triazóis/sangue , Triazóis/urina , TriptaminasRESUMO
Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.
Assuntos
Angina Estável/tratamento farmacológico , Azepinas/uso terapêutico , Teste de Esforço/métodos , Imidazóis/uso terapêutico , Angina Estável/fisiopatologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Estudos Cross-Over , Método Duplo-Cego , Eletrocardiografia/métodos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Vasodilatadores/uso terapêuticoAssuntos
Medicina na Literatura , Poesia como Assunto , Religião e Medicina , História Medieval , ItáliaRESUMO
Inhibition of cathepsin K (CatK) is a potential new treatment for osteoporosis. In two double-blind, randomized, placebo-controlled phase I studies, postmenopausal female subjects received odanacatib (ODN), an orally active, potent, and selective CatK inhibitor, once weekly for 3 weeks or once daily for 21 days. Bone turnover biomarkers, safety monitoring, and plasma ODN concentrations were assessed. These studies showed ODN to be well tolerated. Pharmacokinetic (PK) analysis revealed a long half-life (t(1/2); 66-93 h) consistent with once-weekly dosing. Pronounced reductions in C-terminal telopeptide of type I collagen (approximately 62%) and N-terminal telopeptide of type I collagen normalized to creatinine (NTx/Cr) (approximately 62%) at trough (C(168 h)) were seen following weekly administration. Robust reductions in CTx (up to 81%) and NTx/Cr (up to 81%) were seen following daily administration. ODN exhibits robust and sustained suppression of bone resorption biomarkers (CTx and NTx/Cr) at weekly doses > or = 25 mg and daily doses > or = 2.5 mg.
Assuntos
Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Catepsinas/antagonistas & inibidores , Osteoporose Pós-Menopausa/tratamento farmacológico , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Administração Oral , Idoso , Biomarcadores/sangue , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacocinética , Reabsorção Óssea/sangue , Catepsina K , Colágeno Tipo I , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Peptídeos , Resultado do TratamentoRESUMO
OBJECTIVE: To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK1)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting. METHODS: This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10-12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1-3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day -1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily. RESULTS: The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC(0-24 h) and C(max). However, compared with placebo, trough S(-) warfarin concentrations decreased on days 5-8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011). CONCLUSION: These data are consistent with a significant induction of CYP2C9 metabolism of S(-) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7-10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.
Assuntos
Anticoagulantes/farmacocinética , Antieméticos/farmacologia , Morfolinas/farmacologia , Varfarina/farmacocinética , Anticoagulantes/sangue , Anticoagulantes/farmacologia , Antieméticos/administração & dosagem , Aprepitanto , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/biossíntese , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C9 , Método Duplo-Cego , Interações Medicamentosas , Indução Enzimática , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Taxa de Depuração Metabólica , Morfolinas/administração & dosagem , Tempo de Protrombina , Fatores de Tempo , Varfarina/sangue , Varfarina/farmacologiaRESUMO
A single-dose, randomised, double-masked, placebo-controlled, five-period cross-over comparative ocular tolerance study was undertaken with the topical carbonic anhydrase inhibitor (CAI) MK-927 (1% and 2% concentrations) and its S-enantiomer MK-417 (1% and 1.8% concentrations) in 20 healthy, normal volunteers. Subjects received one drop of placebo (common vehicle) or CAI in each eye on five different days that were separated by washout intervals of 1 week. The incidence of burning increased significantly after treatment with 2% MK-927 (P less than 0.01) and 1.8% MK-417 (P less than 0.05) as compared with placebo. The mean duration of burning following placebo was 16.8 s, somewhat less than that following CAI application (23-37.1 s). The duration of tearing following CAI treatment was also significantly prolonged (P less than 0.05). Pupil size was not changed by CAIs. No other side effects were observed. At 3 h after instillation, intraocular pressure (IOP) was found to be decreased following all four CAI treatments, significantly so with 1% and 1.8% MK-417. The reasonable single-dose tolerability of MK-927 and MK-417 in this sensitive normal-volunteer model supports their potential as topical glaucoma medications. This study suggests that MK-417 may possess greater IOP-lowering activity than MK-927 in man.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Córnea/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Administração Tópica , Adulto , Método Duplo-Cego , Tolerância a Medicamentos , Humanos , Pressão Intraocular/efeitos dos fármacos , Masculino , Pupila/efeitos dos fármacos , EstereoisomerismoRESUMO
MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post-menopausal female migraine patients aged 22-51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.
Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Triazóis/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Medição da Dor , Projetos Piloto , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , TriptaminasRESUMO
BACKGROUND: Fibrinogen-dependent cross-linking of glycoprotein (GP) IIb/IIIa on activated platelets is the final mechanism leading to platelet aggregation. Inhibition of this mechanism may result in a novel antithrombotic agent. We studied the activity of MK-383 (L-700,462), a new, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man. METHODS AND RESULTS: MK-383, a nonpeptide tyrosine derivative, dose-dependently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of 125I-labeled fibrinogen to activated platelets was prevented in a competitive manner with an IC50 of 10 +/- 4.2 nmol/L. The activity and tolerability of MK-383 were evaluated in a two-part double-blind, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated. Twenty-four subjects participated in the 1-hour part. Six received placebo and 18 MK-383 in doses ranging from 0.05 to 0.40 microgram.kg-1 x min-1. MK-383 inhibited platelet aggregation and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 microgram.kg-1 x min-1 and returned to 55% and 89% of baseline, respectively, at 3 hours after infusion. TBT was prolonged at this dose from 5.0 +/- 1.3 minutes predose to 22.7 +/- 6 minutes at the end of the infusion (P < .01) and was normalized by 3 hours after infusion. In the 4-hour infusion part, 15 subjects received MK-383 (0.1 to 0.2 microgram.kg-1 x min-1), and five received placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 microgram.kg-1 x min-1. At 0.2 microgram.kg-1 x min-1, TBT was prolonged from 4.4 +/- 1.2 to 23.9 +/- 4.3 minutes at the end of infusion (P < .01) and remained slightly prolonged 3 hours after infusion (7.2 +/- 1.8 minutes). No adverse effects were observed in any of the 33 subjects receiving MK-383. CONCLUSIONS: The results from this study indicate that MK-383 appears to be well tolerated and active in man. It is the first nonpeptide GPIIb/IIIa antagonist that can be used to investigate the antithrombotic potential of this new class of antiplatelet agents.