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1.
J Clin Pharmacol ; 50(11): 1273-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20107202

RESUMO

Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This study evaluated the effects of LRPT (50 mg and 600 mg, respectively) on the QT interval with Fridericia's correction (QTcF). QTcF measurements were made over a 24-hour period following administration of single-dose moxifloxacin 400 mg, LRPT 50 mg, LRPT 600 mg, or placebo. The primary hypothesis was supported if the 90% confidence intervals (CIs) for the least squares (LS) mean differences between placebo and LRPT in change from baseline in QTcF interval were <10 milliseconds at every time point. The upper limits of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for LRPT 50 mg and 600 mg were <5 milliseconds at every time point. The lower limits of the 90% CIs for placebo-adjusted LS mean changes from baseline in QTcF intervals for moxifloxacin exceeded 0 milliseconds at every time point, demonstrating the sensitivity of this assay to detect increases in the QTcF interval. In conclusion, single doses of LRPT 50 mg and 600 mg do not prolong the QTcF interval relative to placebo and are generally well tolerated.


Assuntos
Compostos Aza/efeitos adversos , Indóis/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Quinolinas/efeitos adversos , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Adolescente , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Feminino , Fluoroquinolonas , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Adulto Jovem
2.
J Clin Pharmacol ; 49(4): 416-22, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19246721

RESUMO

Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to prostaglandin D2 (PGD2)-mediated cutaneous vasodilation. Adjunctive treatment with the PGD2 receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P=.180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.


Assuntos
Aspirina/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Rubor/induzido quimicamente , Rubor/prevenção & controle , Hipolipemiantes/efeitos adversos , Indóis/administração & dosagem , Niacina/efeitos adversos , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Aspirina/efeitos adversos , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Método Duplo-Cego , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Hipolipemiantes/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Niacina/administração & dosagem , Placebos
3.
Curr Ther Res Clin Exp ; 70(6): 421-38, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24692835

RESUMO

BACKGROUND: Recombinant human hyaluronidase (rHuPH20) (150 U) is approved by the US Food and Drug Administration to facilitate subcutaneous fluid administration in adults and children. OBJECTIVE: This Phase IV, double-blind, randomized pilot study was designed to compare the tolerability, flow rate, and safety profile of subcutaneous infusions of normal saline (NS) and lactated Ringer's (LR) solutions following subcutaneous administration of rHuPH20. METHODS: Healthy volunteers received 1 mL rHuPH20 (150 U) in each thigh, followed by simultaneous gravity-driven subcutaneous infusions of 500 mL of LR solution into 1 thigh and NS solution into the contralateral thigh. Subjects rated infusion-site discomfort in each thigh using a 100-mm (0 = no pain to 100 = most severe pain) visual analog scale (VAS) at baseline (ie, after catheter placement/ rHuPH20 injection and just prior to the start of the infusions) and at the following times: after infusion of 250 mL, after infusion of 500 mL (end of infusion), and when thigh circumference returned to within 5% of baseline. Adverse events (AEs) were recorded throughout the study. The primary tolerability end point was the maximal increase from baseline in infusion-site discomfort on the VAS. Secondary end points included infusion flow rate, change in thigh circumference, subject preference for leftversus right-thigh infusion, and safety profile measures. RESULTS: Fifteen subjects (14 women, 1 man; mean age, 41 years [range, 20-60 years]) were included in the study. Mean (SD) maximal increase from baseline VAS pain score was significantly greater with NS solution than with LR solution (20.0 [19.4] vs 9.4 [18.3] mm, respectively; P = 0.005). Mean infusion flow rate was not significantly different between the NS and LR solutions (384.1 [118.1] vs 395.8 [132.8] mL/h). No significant differences between solutions were observed in mean maximal change in thigh circumference (5.2% [1.6%] vs 5.3% [1.5%]). All subjects expressed global preference for LR infusion over NS infusion. All subjects experienced ≥1 AE; the majority of AEs were mild, localized infusion-site reactions. Of all AEs (regardless of their relationship to study drug or procedure), 81% were mild injectionsite reactions that were similar in nature for the NS and LR solutions. Although the types of mild local AEs were similar for the 2 infusions, they were numerically more common with NS infusions (15 subjects [100%]) than with LR infusions (9 subjects [60%]). For the NS and LR solutions, the most frequent infusion-site AEs were pain (67% vs 40%, respectively), erythema (47% vs 13%), and irritation (27% vs 20%). CONCLUSIONS: This small pilot study found that the mean maximal increase from baseline in self-assessed pain VAS scores was statistically significantly higher with NS solution than LR solution. In addition, all subjects preferred LR solution to NS solution, and the incidence of some infusion-site AEs was numerically greater with NS solution. Although the VAS score indicated a statistically significant difference in tolerability favoring LR, the modest changes from baseline suggest both solutions were generally well tolerated and support the use of both NS and LR, as appropriate, for rHuPH20-facilitated subcutaneous isotonic fluid infusion in healthy adults. These results need to be confirmed in larger, controlled clinical studies.

5.
Biopharm Drug Dispos ; 28(6): 315-22, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17575559

RESUMO

The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Pirazinas/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Dipeptidil Peptidase 4 , Método Duplo-Cego , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pirazinas/sangue , Pirazinas/urina , Fosfato de Sitagliptina , Comprimidos , Triazóis/sangue , Triazóis/urina
6.
Drug Metab Dispos ; 35(4): 533-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17220239

RESUMO

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.


Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Inibidores Enzimáticos/farmacocinética , Glicoproteínas/antagonistas & inibidores , Hipoglicemiantes/farmacocinética , Pirazinas/farmacocinética , Triazóis/farmacocinética , Adenosina Desaminase/metabolismo , Administração Oral , Adulto , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Biotransformação , Radioisótopos de Carbono , Ciclização , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Dipeptidil Peptidase 4/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/urina , Fezes/química , Glucuronídeos/metabolismo , Glicoproteínas/metabolismo , Humanos , Hidroxilação , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/urina , Técnicas In Vitro , Rim/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredução , Pirazinas/administração & dosagem , Pirazinas/sangue , Pirazinas/urina , Proteínas Recombinantes/metabolismo , Valores de Referência , Fosfato de Sitagliptina , Ésteres do Ácido Sulfúrico/metabolismo , Triazóis/administração & dosagem , Triazóis/sangue , Triazóis/urina
7.
J Clin Pharmacol ; 43(2): 187-92, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12616672

RESUMO

Patients receiving nonsteroidal anti-inflammatory drug therapy may also require administration of corticosteroids, particularly patients with rheumatoid arthritis. To investigate the effect of rofecoxib on the single-dose pharmacokinetics of oral prednisone and intravenous prednisolone, the authors conducted a randomized, double-blind, placebo-controlled crossover study in 12 healthy subjects. Oral rofecoxib (250.0 mg/day for 14 days) failed to influence prednisone or prednisolone pharmacokinetics after intravenous prednisolone or oral prednisone administration. The geometric mean ratio (GMR) (90% confidence interval) of prednisolone AUC infinity (rofecoxib/placebo) following intravenous and oral corticosteroid was 0.97 (0.94, 1.01) and 0.99 (0.91, 1.08), respectively. Similarly, the prednisone AUC infinity GMRs (rofecoxib/placebo) after intravenous and oral corticosteroid were 1.03 (0.95, 1.11) and 1.08 (0.92, 1.28), respectively. The absence of an effect of rofecoxib on the pharmacokinetics of oral prednisone or intravenous prednisolone indicates that no adjustment in dose of this corticosteroid is necessary when administered concurrently with rofecoxib.


Assuntos
Lactonas/farmacologia , Prednisolona/farmacocinética , Prednisona/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Prednisolona/sangue , Prednisona/sangue , Sulfonas
8.
J Clin Pharmacol ; 42(2): 215-21, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11831545

RESUMO

The effect of rofecoxib, a highly selective cyclooxygenase (COX)-2 inhibitor, on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET), two common components of a combination oral contraceptive product, was examined. A double-blind, two-period crossover study was conducted in 18 healthy women who received ORTHO-NOVUM 1/35, a combination of EE (35 microg) and NET (1 mg), concurrently for 14 days with either 175 mg rofecoxib or matching placebo during two consecutive menstrual cycles. Plasma was sampled for EE, NET, sex hormone binding globulin (SHBG), and albumin. The AUC(0-24 h) geometric mean ratio (GMR: rofecoxib/placebo) with corresponding 90% confidence interval (CI) of EE and NET was 1.13 (1.06, 1.19) and 1.18 (1.13, 1.24), respectively. The Cmax GMR of EE and NET was 1.06 (0.98, 1.16) and 1.04 (0.99, 1.09), respectively. In each case, the 90% CIs satisfied the predefined bioequivalence limits of (0.80, 1.25). Measures of SHBG and albumin and routine clinical and laboratory safety parameters showed no clinically meaningful changes. The addition of rofecoxib to the oral contraceptive was not associated with any clinically important changes in EE or NET pharmacokinetics and thus would not be anticipated to influence the efficacy of this contraceptive regimen.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anticoncepcionais Orais Hormonais/farmacocinética , Lactonas/farmacologia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Área Sob a Curva , Anticoncepcionais Orais Hormonais/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Congêneres do Estradiol/farmacocinética , Etinilestradiol/farmacocinética , Feminino , Humanos , Lactonas/efeitos adversos , Pessoa de Meia-Idade , Noretindrona/farmacocinética , Albumina Sérica/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , Sulfonas
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