RESUMEN
The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antifúngicos/efectos adversos , Arritmias Cardíacas/inducido químicamente , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Nitrilos/efectos adversos , Piridinas/efectos adversos , Triazoles/efectos adversos , Adulto , Antifúngicos/farmacocinética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Masculino , Modelos Biológicos , Nitrilos/farmacocinética , Piridinas/farmacocinética , Medición de Riesgo , Factores de Tiempo , Transfección , Triazoles/farmacocinética , Adulto JovenRESUMEN
The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.
Asunto(s)
Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/uso terapéutico , Electrocardiografía/efectos de los fármacos , Síndrome de QT Prolongado/tratamiento farmacológico , Adulto , Fármacos Cardiovasculares/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Modelos Lineales , Síndrome de QT Prolongado/fisiopatología , Masculino , Estudios ProspectivosRESUMEN
This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 µg/mL and 6.5 to 55409.6 h·µg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/farmacocinética , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/metabolismo , Inmunosupresores/farmacología , Inmunosupresores/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Coagulación Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
Potential effects of the selective ß(3)-adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four-arm, parallel, two-way crossover study was double-blind and placebo- and active (moxifloxacin)-controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once-daily (10 days) 50, 100, or 200 mg mirabegron or a single 400-mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one-sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95% CI >10 ms) in females, but not in males.
Asunto(s)
Acetanilidas/efectos adversos , Agonistas Adrenérgicos beta/efectos adversos , Electrocardiografía/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Tiazoles/efectos adversos , Acetanilidas/administración & dosificación , Acetanilidas/uso terapéutico , Adolescente , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/uso terapéutico , Adulto , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacocinética , Compuestos Aza/efectos adversos , Compuestos Aza/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Fluoroquinolonas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Síndrome de QT Prolongado/epidemiología , Masculino , Persona de Mediana Edad , Moxifloxacino , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Caracteres Sexuales , Tiazoles/administración & dosificación , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Adulto JovenRESUMEN
AIMS: To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects. METHODS: Three trials with an open-label, randomized, two-way crossover design were conducted in healthy subjects. Ipragliflozin 150 mg, sitagliptin 100 mg, pioglitazone 30 mg or glimepiride 1-2 mg were administered alone or in combination. Primary endpoints were the area under the curve from the time of dosing to infinity (AUC(inf)) and the maximum observed plasma concentration (C(max)) of each drug. RESULTS: Multiple doses of ipragliflozin did not change the AUC(inf) and C(max) of a single dose of sitagliptin, pioglitazone or glimepiride. All geometric mean ratios and 90% CIs for AUC(inf) and C(max) , with and without ipragliflozin, were within the predefined range of 80-125% (AUC(inf) : sitagliptin 100.1 [96.9-103.5], pioglitazone 101.7 [96.6-107.0], glimepiride 105.1 [101.3-109.0], and C(max) : sitagliptin 92.4 [82.8-103.1], pioglitazone 98.6 [87.7-110.8], glimepiride 110.0 [101.9-118.8]). Similarly, multiple doses of sitagliptin, pioglitazone or glimepiride did not change the pharmacokinetics of a single dose of ipragliflozin (AUC(inf) : 95.0 [93.4-103.1], 100.0 [98.1-102.0], 99.1 [96.6-101.6]; and C(max) : 96.5 [90.4-103.1], 93.5 [86.3-101.2], 97.3 [89.2-106.2]). Ipragliflozin either alone or in combination with any of the three glucose-lowering drugs was well tolerated in healthy subjects. CONCLUSION: Ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa, suggesting that no dose-adjustments are likely to be required when ipragliflozin is given in combination with other glucose-lowering drugs in patients with type 2 diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacocinética , Hipoglucemiantes/farmacocinética , Pirazinas/farmacocinética , Compuestos de Sulfonilurea/farmacocinética , Tiazolidinedionas/farmacocinética , Tiofenos/farmacocinética , Triazoles/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Índice de Masa Corporal , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Glucósidos/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Persona de Mediana Edad , Pioglitazona , Pirazinas/administración & dosificación , Fosfato de Sitagliptina , Compuestos de Sulfonilurea/administración & dosificación , Tiazolidinedionas/administración & dosificación , Tiofenos/administración & dosificación , Triazoles/administración & dosificaciónRESUMEN
Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [(14)C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [(14)C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC(0-∞); IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [(14)C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion.
Asunto(s)
Anisoles/farmacocinética , Antiarrítmicos/farmacocinética , Pirrolidinas/farmacocinética , Administración Oral , Adulto , Anisoles/administración & dosificación , Anisoles/efectos adversos , Radioisótopos de Carbono , Citocromo P-450 CYP2D6/genética , Genotipo , Humanos , Inyecciones Intravenosas , Masculino , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversosRESUMEN
The pharmacokinetics, safety and tolerability of a once-daily formulation of tacrolimus (tacrolimus extended-release formulation; XL formerly referred to as MR or MR4) were assessed in 18 stable pediatric liver transplant recipients who were converted from the twice-a-day formulation of tacrolimus (TAC) to XL. Patients received their twice-a-day dose of TAC on study days 1 through 7. Beginning on the morning of study day 8, patients were converted to XL on a 1:1 (mg:mg) basis for their total daily dose, and were maintained on a once-daily AM dosing regimen using the same therapeutic monitoring and patient care techniques employed with TAC. Based on pharmacokinetic profiles obtained on study days 7 (TAC) and 14 (XL), steady state exposure (AUC(0-24)) was equivalent between XL and TAC; the mean XL/TAC ratio for lnAUC(0-24) was 100.9% (90% CI: 90.8%, 112.1%). AUC(0-24) and C(min) were strongly correlated at steady state (correlation coefficient: XL 0.90, TAC 0.94). During the first year post-conversion, there were no cases of acute rejection, discontinuation of XL, graft loss or death. The safety profile of XL was consistent with that known for TAC. These results support the safe and convenient conversion of pediatric liver transplant recipients from twice-a-day TAC to once-daily XL.
Asunto(s)
Trasplante de Hígado/inmunología , Tacrolimus/uso terapéutico , Adolescente , Área Bajo la Curva , Niño , Preescolar , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Masculino , Tacrolimus/administración & dosificación , Tacrolimus/farmacocinética , Factores de TiempoRESUMEN
We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.
Asunto(s)
Antifúngicos/farmacocinética , Lipoproteínas/farmacocinética , Péptidos Cíclicos/farmacocinética , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Adolescente , Adulto , Antifúngicos/administración & dosificación , Esquema de Medicación , Interacciones Farmacológicas , Quimioterapia Combinada , Equinocandinas , Femenino , Humanos , Lipopéptidos , Lipoproteínas/administración & dosificación , Masculino , Micafungina , Persona de Mediana Edad , Péptidos Cíclicos/administración & dosificación , Pirimidinas/administración & dosificación , Triazoles/administración & dosificación , VoriconazolRESUMEN
In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.
Asunto(s)
Antifúngicos/farmacocinética , Antifúngicos/toxicidad , Fluconazol/farmacocinética , Fluconazol/toxicidad , Lipoproteínas/farmacocinética , Lipoproteínas/toxicidad , Micosis/prevención & control , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/toxicidad , Adolescente , Adulto , Antifúngicos/uso terapéutico , Área Bajo la Curva , Trasplante de Médula Ósea/efectos adversos , Quimioprevención , Método Doble Ciego , Quimioterapia Combinada , Equinocandinas , Femenino , Fluconazol/uso terapéutico , Humanos , Lipopéptidos , Lipoproteínas/uso terapéutico , Masculino , Micafungina , Persona de Mediana Edad , Micosis/tratamiento farmacológico , Neoplasias/terapia , Péptidos Cíclicos/uso terapéutico , Trasplante de Células Madre/efectos adversosRESUMEN
The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by beta-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nevirapina/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Animales , Bilis/metabolismo , Biotransformación , Perros , Heces/química , Femenino , Glucuronidasa/metabolismo , Haplorrinos , Hidrólisis , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Tasa de Depuración Metabólica , Ratones , Nevirapina/sangre , Nevirapina/farmacología , Nevirapina/orina , Pan troglodytes , Conejos , Ratas , Factores Sexuales , Especificidad de la EspecieRESUMEN
Nevirapine (NVP), a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is concomitantly administered to patients with a variety of medications. To assess the potential for its involvement in drug interactions, cytochrome P-450 (CYP) reaction phenotyping of NVP to its four oxidative metabolites, 2-, 3-, 8-, and 12-hydroxyNVP, was performed. The NVP metabolite formation rates by characterized human hepatic microsomes were best correlated with probe activities for either CYP3A4 (2- and 12-hydroxyNVP) or CYP2B6 (3-and 8-hydroxyNVP). In studies with cDNA-expressed human hepatic CYPs, 2- and 3-hydroxyNVP were exclusively formed by CYP3A and CYP2B6, respectively. Multiple cDNA-expressed CYPs produced 8- and 12-hydroxyNVP, although they were produced predominantly by CYP2D6 and CYP3A4, respectively. Antibody to CYP3A4 inhibited the rates of 2-, 8-, and 12-hydroxyNVP formation by human hepatic microsomes, whereas antibody to CYP2B6 inhibited the formation of 3- and 8-hydroxyNVP. Studies using the CYP3A4 inhibitors ketoconazole, troleandomycin, and erythromycin suggested a role for CYP3A4 in the formation of 2-, 8-, and 12-hydroxyNVP. These inhibitors were less effective or ineffective against the biotransformation of NVP to 3-hydroxyNVP. Quinidine very weakly inhibited only 8-hydroxyNVP formation. NVP itself was an inhibitor of only CYP3A4 at concentrations that were well above those of therapeutic relevance (K(i) = 270 microM). Collectively, these data indicate that NVP is principally metabolized by CYP3A4 and CYP2B6 and that it has little potential to be involved in inhibitory drug interactions.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Microsomas Hepáticos/metabolismo , Nevirapina/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Anticuerpos/farmacología , Biotransformación/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/inmunología , ADN Complementario/genética , Interacciones Farmacológicas , Transcriptasa Inversa del VIH/efectos de los fármacos , Transcriptasa Inversa del VIH/metabolismo , Humanos , Técnicas In Vitro , Cetoconazol/farmacología , Microsomas Hepáticos/enzimología , Nevirapina/metabolismo , Nevirapina/farmacología , Fenotipo , Proteínas Recombinantes/metabolismo , Inhibidores de la Transcriptasa Inversa/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Troleandomicina/farmacologíaRESUMEN
The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for approximately 75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Nevirapina/farmacocinética , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/orina , Biotransformación , Cromatografía Líquida de Alta Presión , Heces/química , Semivida , Humanos , Hidrólisis , Masculino , Espectrometría de Masas , Nevirapina/sangre , Nevirapina/orina , Espectrofotometría Ultravioleta , Distribución TisularRESUMEN
Ontazolast is a potent inhibitor (IC50 = 1 nm) of calcium ionophore A23187-stimulated leukotriene B4 (LTB4) biosynthesis in human peripheral blood leukocytes. The compound is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The emulsion formulation and three additional lipid-based formulations were administered by gavage to conscious, minimally restrained rats in a novel, double-cannulated model to determine the effects of formulation on systemic blood absorption and mesenteric lymph transport of ontazolast. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. While these formulations also significantly increased the amount of ontazolast transported by the lymph, the total amounts transported were insufficient to account for the improvement in bioavailability, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazolast from the gastrointestinal tract, or the effects of lipid on the gastrointestinal membrane permeability, transit time, or metabolism of ontazolast. Semisolid SEDDS formulations, composed of Peceol and Gelucire 44/14, produced bioavailability similar to the emulsion formulation. The total amount of ontazolast transported by the lymph varied directly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or promote rapid absorption of ontazolast from the gastrointestinal tract.
Asunto(s)
Benzoxazoles/farmacocinética , Leucotrieno B4/antagonistas & inhibidores , Sistema Linfático/metabolismo , Triglicéridos/metabolismo , Administración Oral , Análisis de Varianza , Animales , Área Bajo la Curva , Benzoxazoles/sangre , Benzoxazoles/química , Disponibilidad Biológica , Quilomicrones/química , Portadores de Fármacos , Emulsiones/farmacocinética , Excipientes/química , Glicéridos/química , Semivida , Inyecciones Intravenosas , Absorción Intestinal/fisiología , Masculino , Ratas , Ratas Endogámicas , Solubilidad , Aceite de Soja/química , Suspensiones/farmacocinéticaRESUMEN
The objective of this study was to assess the effect of various aspects of pronuclear DNA microinjection on the early development of porcine ova in utero. Estrus was synchronized and superovulation was achieved in sexually mature gilts by the administration of allyl trenbolone, PMSG and hCG. Donor gilts were bred at 12 and 24 h after the onset of estrus. Ova were recovered between 60 and 62 h after the administration of hCG. One-cell ova that exhibited pronuclei after centrifugation were randomly allocated in equal numbers from each donor across one of two pairs of treatments: micro-DNA (ova were injected with two gene constructs that code for the human complement regulatory proteins decay accelerating factor and membrane cofactor protein) and control (ova were centrifuged only) or micro-buffer (ova were injected with buffer only) and pierced (a pipette was inserted into one pronucleus). Ova were transferred by treatment pairs to recipients. Treatments were segregated by oviduct. Ova were recovered after 120 h in utero, fixed and stained with 1% orcein. The proportion of ova that possessed > or = 80 nuclei, the mean number of nuclei present and proportion of ova that formed blastocysts were all significantly (P<0.05) greater for control and pierced ova than for micro-DNA and micro-buffer ova. No difference in these parameters was observed between micro-DNA and micro-buffer ova. These results demonstrate that pronuclear microinjection of a buffer alone can adversely affect the early development of porcine ova in utero.
RESUMEN
The objective of this study was to compare recovery of pronuclear and 2-cell ova from F2 50% Meishan (MX) gilts versus F1 White line (L42) gilts. Sexually mature MX and L42 gilts were allocated across 2 treatments: Super (MX:n=9; L42:n=10) and Control (MX:n=6; L42:n=5) in a 2 x 2 factorial experiment. Allyl trenbolone (AT) was used to synchronize estrus in all gilts. Super gilts were given pregnant mare serum gonadotropin (PMSG: 1250 IU) at 24 h after AT withdrawal. Eighty-five hours after PMSG administration, all Super gilts received 750 IU of human chorionic gonadotropin (hCG). Super gilts which exhibited estrus within 24 h of hCG administration (MX-Super: n=6; L42-Super: n=5) and all Control gilts were bred naturally to Line 3 boars at 12 and 24 hours after the onset of estrus. Ova were recovered from Super gilts between 60 and 64 h after hCG and Control gilts at 48 h after the onset of estrus. All 1- and 2-cell ova were centrifuged at 15000 x g and observed using differential interference contrast microscopy. The mean ovulation rate was greater (P<0.05) for both MX-Super and L42-Super gilts in comparison to their respective Control groups. No differences were detected in the mean ovulation rate (P>0.38) or the mean number of 1- and 2-cell ova recovered (P>0.50) between MX-Super and L42-Super gilts. The proportion of 1- and 2-cell ova which exhibited visible pronuclei or nuclei was also similar among MX-SUPER and L42-SUPER gilts. This study demonstrates that MX gilts respond/perform comparably to L42 gilts with respect to estrus synchronization, superovulation, ova yield, and the ease of visibility of pronuclei or nuclei in the ova.
RESUMEN
Nevirapine, a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, was administered for the first time to humans in a pilot study designed to investigate the pharmacokinetics and tolerance of the drug following single-dose administration to 21 HIV-1-infected individuals. The study followed a parallel design. Different groups of three subjects each were given one of seven dose levels (2.5 to 400 mg) in sequential order, starting with the lowest dose. Each subject received only one dose. Nevirapine was rapidly absorbed at all doses from a tablet formulation. Peak concentrations in plasma were generally achieved within 90 min of dose administration. Secondary peaks were also noted between 3 and 12 h or between 24 and 28 h, the latter being noted mainly in subjects receiving the higher doses. After 24 h, concentrations in plasma declined in a log-linear fashion. The terminal half-life and mean residence time exceeded 24 h in all but one subject, indicating a prolonged disposition time in this population. Both peak concentrations in plasma and areas under the plasma concentration-time curves increased proportionally with increasing dose from 2.5 to 200 mg; however, the increase in the peak concentration in plasma and the area under the plasma concentration-time curve appeared to be less than proportional at the 400-mg dose level in this small number of subjects. This observation may be due to increased clearance or decreased absorption at the highest dose or population differences in absorption or clearance between doses. Studies with a cross-over design are planned to resolve these issues. The pharmacokinetic characteristics of nevirapine are appropriate for once-daily administration. A daily 12.5-mg dose is predicted to achieve trough concentrations in plasma in the range required to totally inhibit replication of wild-type HIV-1 in human T-cell culture.
Asunto(s)
Antivirales/farmacocinética , Piridinas/farmacocinética , Síndrome de Inmunodeficiencia Adquirida/metabolismo , Adulto , Antivirales/efectos adversos , Antivirales/sangre , Femenino , Infecciones por VIH/metabolismo , VIH-1/enzimología , Semivida , Humanos , Absorción Intestinal , Masculino , Persona de Mediana Edad , Nevirapina , Piridinas/efectos adversos , Piridinas/sangreRESUMEN
A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This redidue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]- 4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17B) (IC50 = 0.635 microM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N epsilon of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-valyl-N- (2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5- methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 microM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 micrograms, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality.
Asunto(s)
Hidrocarburos Fluorados/síntesis química , Oligopéptidos/síntesis química , Elastasa Pancreática/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Sitios de Unión/efectos de los fármacos , Cricetinae , Humanos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Elastasa de Leucocito , Masculino , Mesocricetus , Modelos Moleculares , Datos de Secuencia Molecular , Oligopéptidos/química , Oligopéptidos/farmacología , Relación Estructura-Actividad , PavosRESUMEN
The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CLCR 0 to 10 ml.min-1); group II, moderate renal insufficiency (CLCR 10 to 30 ml.min-1); and group III, mild renal dysfunction (CLCR 30 to 70 ml.min-1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis. There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02-1.56). Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CLCR 0 to 10 ml.min-1).
Asunto(s)
Fallo Renal Crónico/orina , Pirenzepina/administración & dosificación , Diálisis Renal , Administración Oral , Adulto , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Pirenzepina/farmacocinética , Pirenzepina/orinaRESUMEN
Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.
Asunto(s)
Obstrucción de las Vías Aéreas/etiología , Bisinosis/etiología , Gossypium/efectos adversos , Adolescente , Adulto , Obstrucción de las Vías Aéreas/patología , Obstrucción de las Vías Aéreas/fisiopatología , Animales , Quimiotaxis de Leucocito , Femenino , Volumen Espiratorio Forzado , Cobayas , Humanos , Técnicas In Vitro , Leucotrieno B4/fisiología , Masculino , Curvas de Flujo-Volumen Espiratorio Máximo , Contracción Muscular , Neutrófilos/patología , Neutrófilos/fisiología , Irrigación TerapéuticaRESUMEN
We detail a series of pharmacokinetic investigations to determine the dose linearity, the effect of site of application, the duration of steady-state plasma concentrations, and the effect of chronic application when clonidine is administered transdermally. Dose linearity was assessed in six subjects with normotension after application of increasing sizes of transdermal clonidine systems (3.5, 7.0, and 10.5 cm2 size) to the upper outer arm. Of the six subjects studied, five had linear relationships between clonidine plasma concentrations at steady state and system size of greater than 0.975; in the sixth subject the correlation was greater than 0.90. The mean steady-state plasma concentrations with 3.5, 7.0, and 10.5 cm2 systems were 0.39, 0.84, and 1.12 ng/ml, respectively. The influence of site and duration of application on the absorption of transdermal clonidine was studied in eight subjects with normotension by use of the 3.5 cm2 system. The mean steady-state plasma concentration over the time interval from 3 to 7 days after application to the arm or to the chest did not significantly differ. When a system was left on the chest or arm for a total of 11 days (4 days beyond the recommended time to change systems), the plasma concentrations of seven of eight subjects with application to the arm and of six of eight subjects with application to the chest remained constant through day 11. The influence of consecutive applications of 3.5 cm2 transdermal clonidine systems on steady-state plasma clonidine concentrations was also studied in eight subjects with normotension over an 11-day period.(ABSTRACT TRUNCATED AT 250 WORDS)