RESUMEN
The absolute bioavailability and pharmacokinetics of three formulations of ondansetron hydrochloride 24 mg--an oral tablet, an intravenous solution, and an extemporaneous rectal suppository--were studied. Twelve healthy, nonsmoking volunteers (six men and six women) were given ondansetron in a study with a three-way cross-over design. All subjects received each dosage form on the same day in the following order: oral tablet, rectal suppository, and intravenous infusion. Administrations were separated by one week. Blood sampling times varied, depending on the administration route. Mean absolute bioavailability for the oral tablet and the rectal suppository differed significantly. Absorption of ondansetron was prolonged when it was administered as the rectal suppository. Absolute bioavailability for the 24-mg tablet was similar to that for other tablet strengths in previous studies. All subjects completed the study without significant adverse effects. Absorption of ondansetron from the rectal suppository was prolonged compared with the oral tablet and the i.v. infusion. Bioavailability for the 24-mg suppository formulation was considerably lower than for the 24-mg tablet.
Asunto(s)
Antieméticos/farmacocinética , Ondansetrón/farmacocinética , Disponibilidad Biológica , Estudios Cruzados , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Ondansetrón/administración & dosificación , Supositorios , ComprimidosRESUMEN
STUDY OBJECTIVE: To compare the relative bioavailability of two 16-mg extemporaneously prepared suppository formulations with that of an 8-mg commercially available oral tablet. DESIGN: Prospective, crossover bioavailability study. SETTING: Inpatient clinical research center. SUBJECTS: Sixteen young, nonsmoking, healthy volunteers. INTERVENTIONS: Blood samples were obtained 24 and 48 hours after administration of an 8-mg oral ondansetron tablet and 16-mg suppository, respectively. Two 16-mg suppository formulations were compounded using commercially available Fattibase and Polybase. MEASUREMENTS AND MAIN RESULTS: Ondansetron was well absorbed by both routes of administration. The following pharmacokinetic parameters (mean+/-SEM) were obtained for the 8-mg tablet, 16-mg Fattibase suppository, and 16-mg Polybase suppository, respectively: area under the curve (AUC) in men 154.2+/-21.77, 253.4+/-72.3, 304.8+/-62.2 ng x hr/ml; AUC in women 353.6+/-32.7, 561.6+/-103.6, and 768.7+/-117.9 ng x hr/ml; maximum concentration (Cmax) in men 45.5+/-7.0, 40.6+/-10.4, and 51.2+/-6.7 ng/ml; Cmax in women 51.4+/-.8, 47.1+/-3.9, and 82.9+/-6.6 ng/ml. Times to Cmax (Tmax; mean+/-SEM) for men were 1.5+/-0.3, 4.4+/-0.5, and 2.9+/-0.3 hours; Tmax for women were 1.8+/-0.3, 4.1+/-0.4, and 4.4+/-0.6 hours for the three formulations, respectively. Women had a consistently higher AUC for all three formulations than men (p<0.05). CONCLUSION: With the exception of the 16-mg Polybase formulation in women, the two suppositories closely approximated the pharmacokinetics of the 8-mg oral tablet. These results suggest that gender may be a significant factor in ondansetron's disposition.
Asunto(s)
Ondansetrón/administración & dosificación , Ondansetrón/farmacocinética , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Administración Rectal , Adulto , Análisis de Varianza , Disponibilidad Biológica , Estudios Cruzados , Femenino , Cefalea/inducido químicamente , Humanos , Masculino , Ondansetrón/sangre , Preparaciones Farmacéuticas/clasificación , Estudios Prospectivos , Antagonistas de la Serotonina/efectos adversos , Factores Sexuales , Supositorios , Comprimidos , Factores de TiempoRESUMEN
OBJECTIVE: To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide. RESULTS: One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects. CONCLUSIONS: Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/administración & dosificación , Compuestos de Sulfonilurea/administración & dosificación , Adulto , Anciano , Glucemia/metabolismo , Péptido C/sangre , Estudios Cruzados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Masculino , Persona de Mediana Edad , Periodo Posprandial , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
The efficacy and safety of amlodipine, 10 mg, a new long-acting calcium antagonist, was compared with placebo in 103 patients with stable angina pectoris in a multicenter double-blind crossover study. The trial consisted of an initial 2-week single-blind placebo period followed by a first period of 4 weeks of double-blind therapy, which was followed by a 1 week washout period and then a second 4-week double-blind period after treatments were crossed over. Twenty-four-hour Holter electrocardiographic monitoring was carried out in 12 patients at three centers. In the first double-blind period amlodipine produced a significantly greater increase in symptom-limited exercise duration (amlodipine 478.5 to 520.6 vs placebo 484.6 to 485.2 seconds; change +8.8% vs +0.1%, respectively; p = 0.0004) and total work (amldipine 2426 to 2984 vs placebo 2505 to 2548 kilopondmeters; change +24% vs +1.7%, respectively; p = 0.0006) and a decrease in angina attack frequency (from 3 to 1 per week; p = 0.016) and nitroglycerin consumption (from 2 to 0.5 tablets/wk; p = 0.01) compared with placebo. Holter monitoring revealed significant reductions in numbers (amlodipine 4.65 to 2.22 vs placebo 1.84 to 1.54; change -52% vs +84%, respectively; p = 0.06), absolute total area (amlodipine 87.66 to 11.43 vs placebo 5.76 to 35.24; change -87% vs +513%, respectively; p = 0.02), and duration (amlodipine 12.29 to 2.95 vs 1.66 to 7.74 seconds; change -76% vs +367%, respectively; p = 0.008) of ST-segment depressions after treatment with amlodipine compared with placebo. After the treatments were crossed over changes continued to favor amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Amlodipino/uso terapéutico , Angina de Pecho/tratamiento farmacológico , Adulto , Anciano , Amlodipino/efectos adversos , Angina de Pecho/fisiopatología , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Electrocardiografía Ambulatoria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Método Simple CiegoRESUMEN
Losartan potassium (DuP 753), an orally active angiotensin II receptor antagonist, is metabolized to a more potent active metabolite, E-3174, which contributes to losartan's long duration of action. The acute pharmacodynamic actions of intravenous (i.v.) E-3174 (20 mg infused over 4 h) were compared to placebo (vehicle) in two groups of patients with essential hypertension. Patients with supine diastolic blood pressure (SuDBP) of 100 to 120 mm Hg entered a 2-day inpatient phase and received vehicle on day 1. Patients with SuDBP > or = 95 mm Hg were randomized to double-blind treatment the next day. E-3174 significantly (P < .05) reduced SuDBP compared to placebo, beginning at approximately 100 min after the start of the infusion, with a maximum hypotensive effect at 8 h. Supine systolic blood pressure was also reduced by E-3174. Supine and standing heart rates did not differ between treatments. Mean E-3174 plasma levels were 324.6 ng/mL at 20 min and approximately 1000 ng/mL at the end of the 4-h infusion; during this time there was a modest decrease in blood pressure. Following the infusion, the relationship between plasma E-3174 levels and SuDBP was confounded by much larger decreases in blood pressure, which occurred as plasma drug concentrations declined. Urinary excretions of sodium, potassium, or chloride were not significantly altered by E-3174 nor was the fractional excretion of uric acid significantly different between groups. There were no drug-related or serious adverse experiences and no patient discontinued treatment due to an adverse experience.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Imidazoles/uso terapéutico , Tetrazoles/uso terapéutico , Adulto , Anciano , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Inyecciones Intravenosas , Pruebas de Función Renal , Losartán , Masculino , Persona de Mediana Edad , Renina/sangre , Tetrazoles/administración & dosificación , Tetrazoles/efectos adversos , Ácido Úrico/sangreRESUMEN
The pharmacokinetics of flosequinan and its active metabolite, flosequinoxan, were investigated following a single 100-mg oral dose in 10 patients with compromised hepatic function. Plasma and urine samples were collected for up to 144 h postdose and analyzed by HPLC. All 10 patients provided analyzable data even though one patient withdrew before the 144-h sample because of an adverse event unrelated to the study medication. Interpatient variability was appreciable for the plasma and urine concentrations was well as for the calculated pharmacokinetic parameters. Relative to a comparative cohort of normal subjects, flosequinan concentrations in the study patients were elevated, showing increases in mean AUC0-t (62.8 +/- 49.4 vs 3.4 +/- 1.5 micrograms.h/mL), AUC0-infinity (70.2 +/- 58.3 vs 3.8 +/- 1.6 micrograms.h/m:), Cmax (2.43 +/- 0.56 vs 1.30 +/- 0.39 micrograms/mL), and t1/2 (20.7 +/- 16.8 vs 1.7 +/- 0.5 h). The mean systemic clearance decreased (47.3 +/- 46.5 vs 544 +/- 279 mL/min), along with the elimination rate constant (0.066 +/- 0.069 vs 0.44 +/- 0.13 h-1). Mean flosequinoxan AUC0-t and AUC0-infinity values were unaffected by hepatic dysfunction. The mean time to peak was longer (36.4 +/- 27.4 vs 7.0 +/- 3.1 h) and Cmax was less (0.98 +/- 0.52 vs 1.84 +/- 0.26 micrograms/mL) than in normal subjects. These findings are consistent with a decrease in the rate of flosequinan metabolism to flosequinoxan. Five patients reported adverse events, which included headache (three patients) and syncope (one patient).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hepatopatías/metabolismo , Quinolinas/farmacocinética , Adulto , Biotransformación , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinolinas/efectos adversos , Quinolonas/farmacocinética , Espectrofotometría UltravioletaRESUMEN
Indomethacin, a nonsteroidal anti-inflammatory drug, may cause gastric mucosal damage as shown by fecal blood loss. A randomized, double-blind, placebo-controlled, parallel group study was conducted to determine the effects of 400 mcg b.i.d. misoprostol, a synthetic prostaglandin E1 analog, on intestinal blood loss caused by 50 mg t.i.d. indomethacin. Forty-two arthritic patients, mean age 59 years, received indomethacin for 14 days. Those with baseline blood loss of at least 1.5 ml/day during the first 7 days were randomized to 400 mcg of misoprostol or placebo (days 8 to 14). Fecal blood loss was measured using 51Cr labelled red blood cell technique. Success was defined as a reduction in mean daily blood loss of at least 50% during the treatment period compared to mean daily blood loss during the baseline (pre-treatment) phase. The mean daily blood loss on treatment days 9-15 was not significantly reduced from baseline in either group. These data neither confirm nor deny the effectiveness of misoprostol in reducing fecal blood loss caused by indomethacin. The results may have been confounded by the administration of misoprostol twice daily while indomethacin was administered three times daily. In addition, fecal blood loss as an indicator of gastrointestinal mucosal damage is not a sensitive measure; it is characterized by poor reproducibility and wide fluctuations within individual responses. Inappropriate laboratory techniques may have further reduced the sensitivity and reliability of this procedure.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Hemorragia Gastrointestinal/prevención & control , Indometacina/efectos adversos , Misoprostol/uso terapéutico , Osteoartritis/tratamiento farmacológico , Método Doble Ciego , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Indometacina/uso terapéutico , Masculino , Persona de Mediana Edad , Misoprostol/efectos adversos , Sangre Oculta , Resultado del TratamientoRESUMEN
The pharmacokinetics of flosequinan and its major active metabolite (BTS 53,554, 7-fluoro-1-methyl-3 methylsulfinyl-4-quinolone, 1) were investigated following a single oral dose of 100 mg of flosequinan in 20 patients with severe renal dysfunction (creatinine clearance, < or = 25 mL/min). Plasma and urine samples were collected for 144 h post-dose and analyzed by high-performance liquid chromatography. Flosequinan was well absorbed and rapidly eliminated, reaching mean peak concentrations in plasma of 1.37 +/- 0.67 micrograms/mL at 1.6 +/- 1.4 h post-dose. As in healthy volunteers, approximately 1% of the administered dose of flosequinan was excreted unchanged in urine. Renal clearance of flosequinan was decreased by an average of 20% relative to healthy volunteers. The active metabolite 1 reached mean peak concentrations in plasma of 2.22 +/- 0.58 micrograms/mL at 10.9 +/- 5.9 h post-dose and yielded mean areas under the curve of concentration in plasma versus time twice that of healthy volunteers. Elimination rates for 1 decreased by half, and the mean elimination half-life increased to 68.5 +/- 24.2 h compared with 34.5 +/- 6.7 h for healthy volunteers. The decrease in elimination rate resulted in higher exposure to total active drug substance (flosequinan plus metabolite) for renal patients than for healthy volunteers. These results suggest dosage adjustments may be necessary in patients with severe renal dysfunction to prevent excessive accumulation of 1 with repeated dosage of flosequinan.
Asunto(s)
Enfermedades Renales/metabolismo , Quinolinas/farmacocinética , Administración Oral , Presión Sanguínea/efectos de los fármacos , Creatinina/orina , Fatiga/metabolismo , Femenino , Humanos , Riñón/metabolismo , Riñón/fisiología , Masculino , Persona de Mediana Edad , Oliguria/metabolismo , Quinolinas/administración & dosificación , Quinolinas/efectos adversosRESUMEN
In a double-blind, crossover study, five white men with mild-to-moderate hypertension received placebo and fixed doses of atenolol, metoprolol, chlorthalidone, verapamil, and the combination of atenolol and chlorthalidone in a quasi-random order. Daily dosages were: atenolol, 100 mg; metoprolol, 200 mg; chlorthalidone, 50 mg; verapamil, 240 mg; and the same doses of atenolol and chlorthalidone in combination. Standard office and daytime ambulatory blood pressures were assessed at the end of each month-long trial. Atenolol, metoprolol, chlorthalidone, and verapamil controlled office blood pressure with similar reductions. Verapamil did not lower ambulatory blood pressure at this dose (which is lower than is now commonly used), but reductions in ambulatory blood pressure were similar for atenolol, metoprolol, and chlorthalidone. The combination of atenolol and chlorthalidone maintained blood pressure control more effectively than the single drug treatments in both office and ambulatory settings, and the combined hypotensive effects were additive. However, reductions in the office due to the combination appeared to overestimate hypotensive effectiveness in the ambulatory setting. This study suggests that the effectiveness of commonly prescribed antihypertensive regimens varies according to setting as well as drug, and that assessment of treatment effectiveness can be improved by automated ambulatory blood pressure monitoring.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Atención Ambulatoria , Antihipertensivos/farmacología , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Determinación de la Presión Sanguínea , Clortalidona/uso terapéutico , Método Doble Ciego , Combinación de Medicamentos , Humanos , Metoprolol/uso terapéutico , Persona de Mediana Edad , Monitoreo Fisiológico , Visita a Consultorio Médico , Verapamilo/uso terapéuticoRESUMEN
The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cmax) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUCo-infinity) showed a dose-proportional response. The steady-state volume of distribution (Vss) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80% of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime linear pharmacokinetics in healthy subjects.
Asunto(s)
Cefalosporinas/farmacocinética , Adulto , Cefepima , Cefalosporinas/administración & dosificación , Cefalosporinas/sangre , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Evaluación de Medicamentos , Semivida , Humanos , Inyecciones Intravenosas , MasculinoRESUMEN
This double-blind, double-dummy, randomized clinical trial, conducted in elderly patients with mild hypertension, compared adherence to treatment, efficacy, side effects, and quality of life during treatment with transdermal clonidine versus oral sustained-release verapamil (verapamil-SR). Blood pressure declined significantly--from 148/95 mm Hg at baseline to 139/84 after titration and 135/86 after maintenance--with transdermal clonidine (n = 29), and from 156/96 to 144/85 and 148/88, respectively, with verapamil-SR (n = 29). Adverse event rates and quality-of-life questionnaire responses were similar in the two treatment groups. Transdermal clonidine was worn as directed during more than 96% of patient-weeks of treatment. Compliance with the oral verapamil regimen was less consistent: Verapamil-SR was taken as directed during approximately 50% of patient-weeks of therapy, and individual compliance, assessed by tablet counts, varied from 50-120%. In all, 86% of subjects were satisfied or highly satisfied with the convenience of transdermal therapy; 87% reported that side effects were slightly or not bothersome; 65% indicated that transdermal patches were more convenient than oral therapy; and almost 60% preferred transdermal to oral therapy. In this study transdermal clonidine and oral verapamil were equally safe and effective. A substantial majority of patients preferred transdermal to oral therapy, and adherence to treatment was greater with transdermal therapy.
Asunto(s)
Clonidina/uso terapéutico , Hipertensión/tratamiento farmacológico , Cooperación del Paciente , Verapamilo/uso terapéutico , Administración Cutánea , Administración Oral , Anciano , Presión Sanguínea , Clonidina/administración & dosificación , Clonidina/efectos adversos , Método Doble Ciego , Femenino , Humanos , Hipertensión/fisiopatología , Hipertensión/psicología , Masculino , Calidad de Vida , Encuestas y Cuestionarios , Verapamilo/administración & dosificación , Verapamilo/efectos adversosRESUMEN
This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses--the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead-in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P less than .05) in a dose-related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Captopril/administración & dosificación , Guanabenzo/administración & dosificación , Hipertensión/tratamiento farmacológico , Administración Oral , Adulto , Captopril/uso terapéutico , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Guanabenzo/uso terapéutico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0-1.6 hours. Pharmacokinetics were linear over the 250-mg to 2000-mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose-proportional manner. The apparent elimination half-life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple-dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.
Asunto(s)
Cefalosporinas/farmacocinética , Adulto , Disponibilidad Biológica , Cefepima , Cefalosporinas/administración & dosificación , Cefalosporinas/efectos adversos , Cefalosporinas/farmacología , Esquema de Medicación , Estudios de Seguimiento , Humanos , Inyecciones Intramusculares , Masculino , Distribución Aleatoria , Método Simple CiegoRESUMEN
Ambulatory blood pressure was studied as a function of posture, place, and mood in 131 subjects classified according to race, gender, and hypertensive status. The effect of posture was significant and explained a substantial proportion of within-subject variability. After controlling for posture, significant place and mood effects were observed when subjects were sitting but not when they were standing. Home vs. work differences in both systolic and diastolic blood pressure were significantly greater in Whites than in Blacks. Similar differences in systolic blood pressure were greater in mild hypertensive than in normotensive subjects. The results of this study underscore the need to control for effects of posture when interpreting ambulatory blood pressure readings.
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Afecto , Nivel de Alerta , Monitores de Presión Sanguínea , Hipertensión/psicología , Postura , Medio Social , Adulto , Presión Sanguínea , Femenino , Humanos , Hipertensión/diagnóstico , MasculinoRESUMEN
The safety and efficacy of labetalol and hydrochlorothiazide (HCTZ) were compared in a group of 34 patients aged 65 years or older with mild to moderate essential hypertension. After a 4-week placebo run-in period, during which all previous antihypertensive medication was discontinued, patients were randomized to receive either labetalol (100 mg bid) or HCTZ (25 mg bid). The patients' blood pressure and heart rate were evaluated biweekly and drug dosage was titrated (up to 400 mg and 50 mg bid of labetalol and HCTZ, respectively) to achieve a standing diastolic blood pressure less than 90 mm Hg. Patients underwent 24-hour ambulatory blood pressure monitoring at the end of the placebo run-in period and again after the 6-week titration period. Both labetalol and HCTZ significantly (P less than .01) reduced standing systolic (-19.4 vs -27.7 mm Hg) and diastolic (-14.0 vs -15.2 mm Hg) blood pressures following 12 weeks of treatment. Both antihypertensives effectively controlled the 24-hour ambulatory blood pressure, however, the labetalol group experienced a significantly lower rate of rise in diastolic blood pressure (P = .02) and mean arterial pressure (P = .02) during the acceleration period (400-1200) compared to the HCTZ group. HCTZ caused significant decreases in serum potassium (P less than .01) and alkaline phosphatase (P less than .05) and increases in uric acid (P less than .01) and urea nitrogen (P = .07). These results indicate that labetalol may offer some unique advantages over thiazide diuretics that may be particularly important in the treatment of elderly patients with hypertension.
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Determinación de la Presión Sanguínea/métodos , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Labetalol/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Monitoreo Fisiológico , Distribución Aleatoria , Factores de Riesgo , Factores de TiempoRESUMEN
In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.
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Cefalosporinas/toxicidad , Adulto , Cefepima , Ceftazidima/farmacocinética , Cefalosporinas/administración & dosificación , Cefalosporinas/farmacocinética , Método Doble Ciego , Evaluación de Medicamentos , Humanos , Infusiones Intravenosas , Masculino , Estructura Molecular , Valores de ReferenciaRESUMEN
We determined the ability of a new opioid antagonist, naimefene, to prevent fentanyl-induced respiratory depression in 8 healthy male volunteers. Ventilation and pulmonary function were measured with the respiratory inductive plethysmograph (RIP), which is non-invasive and requires no connection to the airway. Each volunteer was tested two times on different days. During the first session, each volunteer was monitored for one hour of baseline measurement followed by 4 hourly injections of fentanyl (1 microgram/kg) administered in an open-label manner. In the second session, the subjects were monitored for one hour after 1 mg of intravenous nalmefene was administered. Intravenous fentanyl or identical placebo were then given in a double-blind manner as in the first session. Progressive and profound respiratory depression occurred with fentanyl administration alone. In the absence of nalmefene, fentanyl converted normal breathing pattern to an irregular breathing pattern. When the subjects were treated with nalmefene prior to fentanyl administration, all of these changes were almost completely prevented. Pulmonary variables which reflected this difference between the fentanyl-alone group and the nalmefene-pretreated groups included frequency (p less than 0.001), tidal volume (p less than 0.001), percent rib cage contribution to tidal volume (p less than 0.001) and expiratory time (p less than 0.001). This study showed that nalmefene is an effective long-acting opioid antagonist, and that RIP accurately measures changes in respiration caused by opioid administration.
Asunto(s)
Fentanilo/antagonistas & inhibidores , Naltrexona/análogos & derivados , Respiración/efectos de los fármacos , Adulto , Presión Sanguínea/efectos de los fármacos , Depresión Química , Método Doble Ciego , Fentanilo/efectos adversos , Fentanilo/sangre , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Naltrexona/efectos adversos , Naltrexona/farmacología , Pletismografía , Pruebas de Función RespiratoriaRESUMEN
The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti-inflammatory, antipyretic investigational drug with anti-prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open-label, parallel single-dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post-dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post-dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half-life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P less than .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half-life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Tolmetina/análogos & derivados , Trometamina/farmacocinética , Administración Oral , Adulto , Anciano , Envejecimiento/metabolismo , Proteínas Sanguíneas/metabolismo , Combinación de Medicamentos/administración & dosificación , Combinación de Medicamentos/farmacocinética , Femenino , Semivida , Humanos , Inyecciones Intramusculares , Ketorolaco Trometamina , Masculino , Unión Proteica , Tolmetina/administración & dosificación , Tolmetina/farmacocinética , Trometamina/administración & dosificaciónRESUMEN
The intrasubject and intersubject variabilities for CGS 16617, an angiotensin converting enzyme inhibitor, were evaluated in an open-label, repeat single-dose bioavailability trial. Eight healthy male volunteers each received a 20-mg oral dose of CGS 16617 as an aqueous solution on four separate occasions. Components of variance were evaluated for a mixed-effects statistical model in which subjects were regarded as a random factor. While intersubject variability was statistically significant (P less than 0.05) for all pharmacokinetic variables measured, AUC, Cmax, t1/2, and tmax, its contribution to the total observed variability was relatively small for AUC, t1/2, and tmax. The proportion of variation due to intrasubject variability was 70, 19, 61, and 72% for AUC, Cmax, t1/2, and tmax, respectively. Ramifications of the large intrasubject source component of variability as related to bioavailability trials and biological variation are discussed.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Benzazepinas/farmacocinética , Adulto , Semivida , Humanos , Masculino , Modelos Biológicos , Estadística como AsuntoRESUMEN
The relationship between blood pressure in the laboratory (both at rest and in response to laboratory tasks) and ambulatory blood pressure at home and at work was evaluated. One hundred nineteen normotensive and unmedicated mild-moderate hypertensive black and white females and males participated in laboratory blood pressure monitoring at rest and during four challenging tasks (structured interview, video game, bicycle exercise, and cold pressor test) as well as ambulatory blood pressure monitoring while at home and at work. Baseline blood pressure taken while subjects were at rest was the strongest predictor of ambulatory systolic blood pressure (r = .64) and diastolic blood pressure (r = .77) at work. Among reactivity tasks the strongest predictors of ambulatory blood pressure in the total population were the structured interview and the video game (both psychological tasks) followed by the cold pressor test. Racial comparisons, however, determined that the cold pressor test predicted diastolic blood pressure significantly better for blacks (r = .73) than for whites (r = .40), suggesting a possible difference in blood pressure regulation.