RESUMEN
AIM: Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme-N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n = 7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. METHODS: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. RESULTS: The area under the plasma concentration-time curve (AUC(0-t)) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC(0-t) was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations. CONCLUSION: Pharmacokinetic parameters appear to be independent of the duration of treatment and are not linear between the 0.2 and 1.0 mg/kg/week doses. Antibodies to rhASB develop in most patients, but their concentration decreases over time. Antibody formation may influence pharmacokinetic parameters during the early phases of treatment, although it appears to have limited impact on biochemical efficacy.
Asunto(s)
Glicosaminoglicanos/orina , Mucopolisacaridosis VI/tratamiento farmacológico , N-Acetilgalactosamina-4-Sulfatasa/farmacocinética , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Adolescente , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Modelos Biológicos , Mucopolisacaridosis VI/metabolismo , N-Acetilgalactosamina-4-Sulfatasa/metabolismo , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: A rigorous model to describe concentration-effect relations-the median effect analysis-was applied to quantitate immunosuppressive versus adverse effects in human renal transplantation. METHODS: The median effect equation was used to analyze data collected from three clinical studies, including the two phase III blinded, placebo-controlled trials (n = 1295 patients) of sirolimus versus azathioprine or placebo treatment added to a cyclosporine (INN, ciclosporin)/prednisone regimen and a sirolimus/azathioprine/prednisone (in the absence of cyclosporine) phase II cohort (n = 41 patients). RESULTS: The clinical effects correlated with drug concentrations as expressed by the median effect equation. Sirolimus or cyclosporine alone permitted drug concentrations that were 5-fold and 2.2-fold lower, respectively, to render 90% of patients rejection-free, suggesting a synergistic interaction between the two drugs. Further, the sirolimus concentrations to render 50% of patients rejection-free were about 200-fold and 60-fold less, respectively, than the concentration that caused 50% of patients to experience thrombocytopenia or hypertriglyceridemia. The correlation coefficient of the median effect analysis for the occurrence of hypercholesterolemia was more robust for sirolimus than for cyclosporine. Although the concentrations for 50% of patients rendered rejection-free versus 50% affected by hypercholesterolemia were similar, a 7-fold difference was calculated between the concentrations at which 90% of patients were free of rejection versus patients who were affected by hypercholesterolemia. CONCLUSION: The median effect analysis proffers a useful tool to assess both drug interactions and the windows between therapeutic versus toxic effects of immunosuppressive agents. The current analysis suggests a synergistic interaction between sirolimus and cyclosporine.
Asunto(s)
Ciclosporina/efectos adversos , Ciclosporina/farmacología , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Trasplante de Riñón , Sirolimus/efectos adversos , Sirolimus/farmacología , Enfermedad Aguda , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Rechazo de Injerto/prevención & control , Humanos , Hipertrigliceridemia/inducido químicamente , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Incidencia , Sirolimus/administración & dosificación , Sirolimus/sangre , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Plasma pharmacokinetics of oral furosemide have been shown to be influenced by degree of decompensation in patients with congestive heart failure (CHF). This open-label, sequential comparison trial was conducted to determine whether CHF decompensation also alters the pharmacokinetics and pharmacodynamics of torsemide. Twelve patients with CHF, defined by either hemodynamic parameters or clinical signs and symptoms, were enrolled. On admission for treatment of their CHF, the patients were given 100 mg oral torsemide (phase A). A second dose of oral torsemide 100 mg was administered after hemodynamic parameters and clinical signs and symptoms of decompensated CHF resolved (phase B). Plasma and urine samples were collected over a 24-hour period for determination of torsemide concentrations and urine sodium. Hemodynamic measurements and physical signs and symptoms also were evaluated. During phase A, patients had significantly greater urine output and fractional sodium excretion compared with phase B. A significant increase in the area under the plasma concentration-time curve (AUC) was observed during phase B compared with phase A. However, no significant differences in maximal excretion rate of torsemide were noted between phase A and phase B. Heart failure status slightly affects the plasma pharmacokinetics of torsemide; however, this does not significantly alter the maximal urinary excretion rate of torsemide.
Asunto(s)
Diuréticos/farmacocinética , Insuficiencia Cardíaca/metabolismo , Sulfonamidas/farmacocinética , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Creatinina/sangre , Diuréticos/orina , Semivida , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Sodio/orina , Sulfonamidas/orina , TorasemidaRESUMEN
PURPOSE: To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS: We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS: Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION: Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.
Asunto(s)
Diuresis , Diuréticos/farmacocinética , Furosemida/farmacocinética , Insuficiencia Cardíaca/sangre , Sulfonamidas/farmacocinética , Anciano , Diuréticos/sangre , Femenino , Furosemida/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sulfonamidas/sangre , TorasemidaRESUMEN
The natriuretic and diuretic effects of a 100-mg dose of torsemide administered as a continuous infusion of torsemide and as a single bolus were compared in a group of patients with stable mild-to-moderate congestive heart failure (CHF). Patients received in random order 100 mg of torsemide as an intravenous bolus and as a 75-mg infusion over 24 hours started simultaneously with a 25-mg loading bolus. Administration of torsemide to patients with CHF as a continuous infusion was an effective dosing regimen, resulting in 24-hour diuresis and natriuresis that was numerically but not statistically greater than that observed with bolus administration. The response with continuous infusion occurred with less torsemide in the urine, resulting in a significantly greater efficiency of torsemide with this regimen. The effectiveness of torsemide as a continuous infusion does not mean that this mode of administration should be used in all patients. The response to 100 mg of torsemide in patients with mild-to-moderate CHF is the same whether administered as an intravenous bolus, a continuous intravenous infusion, or by mouth. This is consistent with the high bioavailability demonstrated in previous studies. The mode of therapy used should be dictated by each individual patient's needs. This study shows that continuous infusion is a viable option for administration of torsemide, and dosing guidelines for use of such a strategy are presented.
Asunto(s)
Diuréticos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Sulfonamidas/farmacología , Adulto , Diuréticos/administración & dosificación , Femenino , Insuficiencia Cardíaca/orina , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Natriuresis , Sulfonamidas/administración & dosificación , Sulfonamidas/orina , TorasemidaRESUMEN
The bioavailability, pharmacokinetics, and pharmacodynamics of torsemide (10 mg orally and intravenously) and furosemide (40 mg orally and 20 mg intravenously) were determined in a randomized crossover clinical trial in 16 patients with compensated congestive heart failure. Torsemide (time to reach maximum concentration [tmax], 1.1 +/- 0.9 hour) was more rapidly absorbed than furosemide (tmax, 2.4 +/- 2.5 hours), the absorption of which was delayed compared with that in healthy volunteers. Bioavailability of torsemide was also greater and less variable than that of furosemide. All four treatments yielded comparable changes from baseline in 24-hour electrolyte excretion. Based on the relationships between sodium excretion rate and fractional sodium and urinary drug excretion rate, response to both diuretic agents at the level of the nephron was decreased compared with previous studies with healthy subjects. Assessment of the clinical relevance, if any, of the difference in the variability of absorption warrants further study.
Asunto(s)
Diuréticos/farmacocinética , Furosemida/farmacocinética , Insuficiencia Cardíaca/metabolismo , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Disponibilidad Biológica , Diuresis/efectos de los fármacos , Diuréticos/administración & dosificación , Diuréticos/farmacología , Femenino , Furosemida/administración & dosificación , Furosemida/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , TorasemidaRESUMEN
As part of a development program for controlled- and extended-release formulations of isosorbide-5-mononitrate (ISMN), the rate and extent of drug absorption was evaluated after site-specific delivery in the gastrointestinal (GI) tract. Seven healthy male subjects received, on separate occasions, 20 mg of ISMN solution orally and via nasogastric tube to the jejunum, terminal ileum, and ascending colon. Compared with oral administration (AUC 2,963 hr x ng/mL, Cmax 442 ng/mL, Tmax 0.81 hr), placement of drug directly into the jejunum did not change the extent (AUC 2,844 hr x ng/mL) but increased the rate of absorption (Cmax 630 ng/mL, Tmax 0.28 hr) due to direct placement of drug into the intestine. Administration to the terminal ileum resulted in a rate of absorption comparable to that from the jejunum (Tmax 0.28 hr) but a reduction in extent (mean AUC 2,377 hr x ng/mL). Delivery to the ascending colon resulted in a further decrease in the extent (AUC 2,017 hr x ng/mL) and a "slowing" of the rate of absorption compared with the two intestinal sites (Cmax 392 ng/mL, Tmax 0.68 hr). Overall, bioavailability throughout the GI tract was sufficient to support development of controlled- and extended-release formulations.
Asunto(s)
Absorción Intestinal , Dinitrato de Isosorbide/análogos & derivados , Vasodilatadores/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Colon/metabolismo , Preparaciones de Acción Retardada , Humanos , Íleon/metabolismo , Intubación Gastrointestinal , Dinitrato de Isosorbide/administración & dosificación , Dinitrato de Isosorbide/farmacocinética , Yeyuno/metabolismo , Masculino , Vasodilatadores/administración & dosificaciónRESUMEN
Torsemide is a diuretic that acts in the thick ascending limb of the loop of Henle. Unlike furosemide, it undergoes substantial hepatic elimination and should not accumulate in patients with renal insufficiency. Therefore the pharmacokinetics of intravenous and oral torsemide and its metabolites were investigated in patients with chronic renal insufficiency. Two groups of 24 patients stratified by creatinine clearance (30 to 60 ml/min and < 30 ml/min) were studied in two separate randomized dose escalating crossover studies, one using intravenous torsemide and the other using oral torsemide. The pharmacokinetics of both intravenous and oral torsemide were linear over the dosage range studied. Absolute bioavailability was essentially 100%. Renal clearance was greatly diminished and correlated with renal function. Total plasma clearance and half-life were not related to renal function and were found to be similar to those of healthy subjects. The substantial nonrenal clearance of torsemide prevents accumulation in patients with chronic renal insufficiency.
Asunto(s)
Diuréticos/farmacocinética , Fallo Renal Crónico/metabolismo , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Anciano , Análisis de Varianza , Diuréticos/administración & dosificación , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , TorasemidaRESUMEN
The pharmacodynamics of intravenous and oral torsemide were determined in two randomized cross-over clinical trials in patients with chronic renal insufficiency. There was no significant difference in the rate or magnitude of the diuretic response between oral and intravenous administration. As has been shown with other loop diuretics, patients with chronic renal insufficiency have a reduced diuretic response compared with healthy subjects. This diuretic resistance is primarily related to a diminished delivery of drug to the urinary site of action. The response of torsemide at the tubular level is not different from that seen in subjects with normal renal function. Metabolites of torsemide do not appear to contribute to the diuretic response. A dose of 50 to 100 mg dependent on renal function is required to obtain a maximal response. A ceiling dose of approximately 100 mg in patients with chronic renal insufficiency is therefore recommended.
Asunto(s)
Diuréticos/farmacología , Fallo Renal Crónico/metabolismo , Sulfonamidas/farmacología , Administración Oral , Bumetanida/farmacología , Diuréticos/administración & dosificación , Método Doble Ciego , Furosemida/farmacología , Humanos , Inyecciones Intravenosas , Fallo Renal Crónico/sangre , Fallo Renal Crónico/orina , Sulfonamidas/administración & dosificación , TorasemidaRESUMEN
The pharmacodynamics of torsemide (a new loop diuretic of the pyridine sulfonylurea class) was studied in 16 subjects who had compensated congestive heart failure and had been receiving stable diuretic therapy. Oral doses of 50, 100, and 200 mg were studied by use of a randomized crossover design. The results of this study show that the pharmacokinetics of torsemide is linear up to at least a dose of 200 mg in patients with congestive heart failure. Approximately 20% of each of the three doses was excreted unchanged, consistent with previous findings in healthy volunteers. A hyperbolic relationship between diuretic effect and drug excretion rate was defined. The maximum urinary sodium excretion rate attained was about 0.6 mEq/min, which is about 20% of that in healthy subjects, indicating diuretic resistance in these patients. Although there was no saturation of the urinary excretory pathway with doses as high as 200 mg, the upper plateau of the dose-response curve was reached with doses of 50 mg, indicating that this dose represents a ceiling dose in patients with New York Heart Association class II and III congestive heart failure.
Asunto(s)
Diuréticos/farmacología , Insuficiencia Cardíaca/metabolismo , Sulfonamidas/farmacología , Administración Oral , Adulto , Anciano , Diuréticos/administración & dosificación , Diuréticos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , TorasemidaRESUMEN
The pharmacokinetic profile and pharmacodynamic activities of torasemide, a new pyridine sulfonylurea acting on the loop of Henle, are described. Absorption of the drug was unchanged in patients with congestive heart failure, though maximum concentrations occurred at 1.7 h compared with 0.9 h in healthy subjects. The volume of distribution after oral administration was also unchanged in patients with heart failure, but oral clearance was reduced by 50%, consistent with the increase in elimination half-life; renal clearance and maximum urinary torasemide excretion rate were also reduced by 50%. Thus, the primary pharmacokinetic alteration in patients with heart failure compared with healthy subjects was a reduction in the rate of delivery of torasemide to its site of action in the loop of Henle. Fractional sodium excretion and urinary torasemide excretion rate were similar in patients with heart failure and healthy subjects, though the relationship between the excretion rates of sodium and torasemide was depressed in the patients with heart failure. Thus, the primary pharmacodynamic alteration in patients with heart failure compared with healthy subjects was less total sodium excretion per molecule of torasemide reaching the renal tubule. Torasemide was effective in inducing loss of body weight and increased sodium excretion in patients with congestive heart failure. Single intravenous and oral doses of 20 mg both produced similar significant increases in total sodium excretion. Torasemide, 5-20 mg once daily for up to 6 weeks, produced significant loss of body weight and increased total sodium excretion confirming the diuretic effectiveness of torasemide in patients with congestive heart failure.
Asunto(s)
Diuréticos/farmacología , Diuréticos/farmacocinética , Insuficiencia Cardíaca/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/farmacocinética , Insuficiencia Cardíaca/metabolismo , Humanos , TorasemidaRESUMEN
The bioavailability, pharmacokinetics, and pharmacodynamics of torsemide (10 mg orally and intravenously) were determined in a randomized crossover clinical trial with 12 patients with ascites caused by cirrhosis. Torsemide was rapidly absorbed with a bioavailability of 96.3% (confidence interval, 84% to 109%). Compared with healthy subjects, patients with cirrhosis exhibit a decrease in nonrenal clearance and increases in bioavailability, volume of distribution, renal clearance, elimination half-life, and percentage of the dose excreted into the urine. A greater proportion of the dose is delivered to the site of action over a more prolonged period of time. In spite of a shift of the pharmacodynamic curve to the right in patients with cirrhosis, there was no significant difference in natriuresis. Pharmacokinetic changes of torsemide in cirrhosis therefore compensate for the pharmacodynamic abnormality.
Asunto(s)
Diuréticos/farmacocinética , Cirrosis Hepática/metabolismo , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Anciano , Ascitis/tratamiento farmacológico , Ascitis/etiología , Disponibilidad Biológica , Diuréticos/administración & dosificación , Diuréticos/farmacología , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , TorasemidaRESUMEN
Ten patients with spastic wrist flexion deformities secondary to traumatic brain injury were evaluated for carpal tunnel syndrome. The angle of wrist flexion deformity averaged 75 degrees (range, 58 to 115 degrees). Nerve conduction studies demonstrated prolonged median motor and/or sensory latencies in all patients. Preoperative wick catheter measurements of carpal tunnel pressures in eight patients averaged 11 mm Hg in the resting position, 21 mm Hg in maximal wrist flexion, and 15 mm Hg in maximal extension. Each patient had carpal tunnel release with simultaneous wrist and finger flexor tendon releases or lengthenings. At surgery nine of the median nerves were constricted at the proximal edge of the transverse carpal ligament. The presence of normal carpal tunnel pressures and impingement of the median nerve at the proximal edge of the transverse carpal ligament indicates that the chronically flexed posture of the wrist resulted in median nerve compression, and this condition may be aggravated by underlying pressure from the spastic finger flexors.
Asunto(s)
Lesiones Encefálicas/complicaciones , Síndrome del Túnel Carpiano/etiología , Dedos/fisiopatología , Espasticidad Muscular/fisiopatología , Articulación de la Muñeca/fisiopatología , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Movimiento , Espasticidad Muscular/complicaciones , Paraplejía/complicacionesRESUMEN
To complement a study on aminoglycoside dosing regimen and ototoxicity in the guinea pig, we designed an experiment to examine: (1) the effect of dosing regimen on guinea pig pharmacokinetic parameters, and (2) possible differential accumulation after repeated intramuscular administrations of netilmicin and amikacin (150 mg/kg/day) for 7 days by 1 or 3 daily injections. The area under the curve (AUC infinity) and the maximum plasma concentration (Cmax) were dose-dependent. Within each regimen, no significant difference was observed between days 1 and 7. Little or no accumulation was observed after 21 days of treatment. The results show a good dose-dependence of AUC infinity and Cmax and are in accordance with data from human studies. Moreover, the fact that no accumulation occurred in the guinea pig suggests that it is a suitable animal model to evaluate the relation between aminoglycoside ototoxicity and dosing regimen.
Asunto(s)
Amicacina/farmacocinética , Netilmicina/farmacocinética , Amicacina/administración & dosificación , Amicacina/sangre , Animales , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Cobayas , Semivida , Inyecciones Intramusculares , Masculino , Netilmicina/administración & dosificación , Netilmicina/sangre , Distribución Aleatoria , Factores de TiempoRESUMEN
The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Cimetidina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Labetalol/farmacocinética , Vasodilatadores/farmacocinética , Administración Oral , Adulto , Análisis de Varianza , Disponibilidad Biológica , Interacciones Farmacológicas , Electrocardiografía , Semivida , Humanos , Inyecciones Intravenosas , Labetalol/administración & dosificación , Labetalol/farmacología , Análisis de los Mínimos Cuadrados , Masculino , Distribución Tisular , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacologíaRESUMEN
Dilevalol is a novel antihypertensive agent combining vasodilation due to selective beta 2-adrenergic receptor agonism with nonspecific beta antagonism. To determine the relation of dilevalol dose and plasma concentration to antihypertensive effect, dilevalol (n = 15) or placebo (n = 3) was administered to 18 hypertensive subjects. The study was performed under blinded conditions during a 21-day hospitalization after a 3-week drug-free outpatient phase. In the 15 hypertensive patients receiving dilevalol orally in single morning doses of 200, 400 and 800 mg each for 5 days, the drug was shown to reduce blood pressure effectively for 24 hours at all doses. The antihypertensive effect was significantly related to dose administered and to the concentration of unchanged dilevalol measured in plasma. Dilevalol did not cause excessive changes in heart rate at rest and did not produce postural hypotension. The antihypertensive effectiveness of dilevalol was essentially the same after the first and fifth (steady state) doses at each dose level. Finally, no tendency toward rebound hypertension or tachycardia was observed after the abrupt discontinuation of dilevalol in these patients.
Asunto(s)
Hipertensión/tratamiento farmacológico , Labetalol/farmacología , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Labetalol/administración & dosificación , Labetalol/sangre , Masculino , Persona de Mediana Edad , PosturaRESUMEN
Dilevalol is a novel antihypertensive agent combining vasodilation due to selective beta 2-adrenergic receptor agonism with nonspecific antagonism of beta 1- and beta 2-adrenergic receptors. Studies of dilevalol's pharmacokinetics in normotensive and hypertensive volunteers have demonstrated that (1) it is rapidly and well absorbed; (2) because of extensive first-pass metabolism its absolute oral bioavailability is about 12%; (3) its mean elimination half-life is 8 to 12 hours after administration of single oral or intravenous doses to normal volunteers, a value consistent with once-daily dosing; and (4) food does not appear to alter its bioavailability or pharmacokinetics.
Asunto(s)
Hipertensión/tratamiento farmacológico , Labetalol/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Esquema de Medicación , Ayuno , Alimentos , Semivida , Humanos , Hipertensión/metabolismo , Infusiones Intravenosas , Labetalol/uso terapéutico , Distribución AleatoriaRESUMEN
The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 +/- 0.3 liters/kg, 65.3 +/- 5.2 liters/hr, and 4.2 +/- 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 +/- 240.9 pg/ml following iv administration and 528.6 +/- 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 +/- 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.
Asunto(s)
Escopolamina/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Cromatografía Liquida , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Escopolamina/administración & dosificaciónRESUMEN
The purposes of this investigation were to demonstrate how computer simulations may be employed to extrapolate data obtained from a single intravenous digoxin dose to multiple oral dosing patterns and how these simulations may apply to clinical situations. The intravenous data were obtained from a previous study of the pharmacokinetics of serum digoxin and its inotropic response (derived from systolic intervals) in 12 normal male volunteers. The simulations were applied to various clinical situations including variations in oral dosing, alternate loading doses, no loading versus loading dose, and intravenous versus oral dosing. A nonlinear relationship was found between response and the post-distribution serum digoxin concentration in the therapeutic range. Thus, the increase in inotropic response is less than proportional to the increase in digoxin concentration in serum. This nonlinear relationship has several important clinical implications for loading and maintenance dosing protocols. Such concepts may be important relative to more rational clinical use of digoxin and to decreasing digoxin toxicity.
Asunto(s)
Digoxina/sangre , Simulación por Computador , Digoxina/administración & dosificación , Digoxina/farmacocinética , Humanos , Inyecciones IntravenosasRESUMEN
Potential day-night differences of theophylline absorption and disposition were examined in day-active asthmatic children. Theophylline was given orally as TheoDur tablets and Somophyllin-CRT capsules (random crossover) every 12 hr (0700 and 1900), and patients were studied during two consecutive dosing intervals. In addition, patients were studied during the last 24 hr of a 48-hr continuous, intravenous aminophylline infusion. Serum theophylline concentrations were essentially constant during the intravenous infusion for the day and night periods. Thus, day and night clearances were nearly identical. Following oral administration of Somophyllin-CRT or TheoDur, areas under the serum concentration-time curves were greater during the day than the night, with Somophyllin-CRT yielding greater areas than TheoDur for both dosing intervals. Theophylline was absorbed more rapidly during the day than the night, as evidenced by a time to maximum concentration that occurred earlier in the daytime dosing interval. We conclude that theophylline clearance is not characterized by a circadian rhythm and that absorption of theophylline from Somophyllin-CRT and TheoDur is more rapid and complete during the day than the night.