RESUMO
Four patients with chronic ventricular arrhythmias, shown to respond over the short term to N-acetylprocainamide (NAPA), were treated for between 3 and 4 yr with NAPA, and 24-hr ambulatory ECGs were obtained monthly to monitor their responses. When the patients were ambulatory and receiving NAPA, the mean frequency of premature ventricular complexes averaged 70% (range 60% to 82%) below that recorded at 6-mo intervals when the patients were hospitalized and receiving placebo. Analysis of variance showed that NAPA exerted an antiarrhythmic effect in these patients and that tolerance to this effect did not develop with long-term therapy. Plasma NAPA concentrations required to achieve this level of response averaged 21 micrograms/ml (12 to 35 micrograms/ml) and were roughly twice as high as those which appeared to be maximally effective when the patients were hospitalized for their initial evaluation. NAPA therapy was associated with positive antibody titers in only one patient and seems less prone to cause drug-induced lupus erythematosus than procainamide, but NAPA shares the gastrointestinal and other side effects of procainamide.
Assuntos
Acecainida/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Procainamida/análogos & derivados , Acecainida/efeitos adversos , Acecainida/sangue , Idoso , Assistência Ambulatorial , Análise de Variância , Arritmias Cardíacas/fisiopatologia , Cromatografia Líquida de Alta Pressão , Avaliação de Medicamentos , Eletrocardiografia , Meia-Vida , Ventrículos do Coração , Hospitalização , Humanos , Assistência de Longa Duração , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Volume SistólicoRESUMO
A specially designed tablet dosage form of the benzodiazepine clorazepate dipotassium (Tranxene) was developed for once-a-day administration. The drug was administered at a dose of 22.5 mg as (1) the tablet, (2) three 7.5 mg capsules, or (3) one 7.5-mg capsule given every 6 hours. Peak serum levels from the tablet were intermediate between those of the single- and divided-dose capsule regimens. The desired decrease in magnitude of peak levels was obtained without affecting the extent of absorption. Pharmacokinetic analysis of the data according to a two-compartment open model with first-order absorption indicated that the serum half-life (t0.5beta) of nordiazepam, the major biotransformation product present in serum, was about 48 hours and served as a basis for the design of a multiple-dose steady-state study. Multiple-dose administration of the tablet and divided-capsule regimen to two groups of subjects for ten days indicated each dosage form yielded similar minimum steady-state serum levels of about 0.6 micrograms/ml which plateaued following seven days of drug administration. The dosage forms were crossed over between the groups on day 11 and administered for an additional four days. The minimum serum levels obtained with the tablet and capsule were not statistically different. Additionally, the peak serum level and area under the curve (pi=24 hours) at steady state were equivalent between the dosage forms. Good agreement was obtained between model-predicted and observed serum levels during multiple-dose administration for both the tablet and capsule regimens. The serum half-life of nordiazepam following 14 days of clorazepate dipotassium administration was similar to that found after a single dose. These results indicate that a single daily dose of drug as the tablet produced serum levels equivalent to a divided-capsule regimen.
Assuntos
Ansiolíticos/metabolismo , Clorazepato Dipotássico/metabolismo , Adulto , Disponibilidade Biológica , Biotransformação , Cápsulas , Ensaios Clínicos como Assunto , Clorazepato Dipotássico/administração & dosagem , Preparações de Ação Retardada , Meia-Vida , Humanos , Cinética , Masculino , Nordazepam/sangue , Comprimidos , Fatores de TempoRESUMO
The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.
Assuntos
Digoxina/administração & dosagem , Absorção , Adulto , Disponibilidade Biológica , Cápsulas , Digoxina/metabolismo , Humanos , Masculino , ComprimidosRESUMO
Two methaqualone tablets that exhibited different in vitro dissolution rates were administered to 11 normal healthy male volunteers. Serial blood samples were withdrawn following administration of each tablet, and plasma methaqualone concentrations were determined by an established spectrophotofluormetric assay. Both tablets produced virtually identical plasma concentration versus time profiles in humans, and no statistically significant differences in either the rate or extent of drug absorbed were detected. The results indicate that there is no correlation between in vivo bioavailability and the modified NF in vitro dissolution test used.
Assuntos
Metaqualona/metabolismo , Adulto , Disponibilidade Biológica , Humanos , Masculino , Metaqualona/administração & dosagem , Metaqualona/sangue , Solubilidade , ComprimidosRESUMO
This investigation compared the bioavailability of chlorpheniramine and pseudoephedrine from a sustained-action capsule and a combination of two reference standard tablets in 24 normal human subjects. The capsule contained 8 mg of chlorpheniramine maleate and 120 mg of pseudoephedrine hydrochloride, and the tablets each contained half of the amount of the chlorpheniramine or pseudoephedrine in the capsule. Because the capsule was a combination product, a new study design had to be developed to accommodate steady-state conditions for both drugs. Each subject received the capsule (every 12 hr) and the combination of the reference tablets (every 6 hr) for 8 days according to a two-way crossover design. Serial blood and urine samples were taken during the entire study. Plasma and urine samples were assayed for chlorpheniramine and pseudoephedrine by sensitive and specific high-pressure liquid chromatographic or GLC methods. There were no significant differences in the plasma concentration profiles of chlorpheniramine and pseudoephedrine at all times, except when the capsule developed peaks or the tablets developed nadirs. The highest mean peak plasma concentrations for the capsule and the tablets were 38.7 and 32.9 ng of chlorpheniramine/,ml and 525 and 515 ng of pseudoephedrine/ml, respectively. The mean biological half-lives of chlorpheniramine and pseudoephedrine were 21.6 and 8.0 hr, respectively. The AUC and unchanged drug excreted in urine, after a single dose and at steady state, showed that the sustained-action capsule (given every 12 hr) and the reference standard tablets (given every 6 hr) were bioequivalent.
Assuntos
Clorfeniramina/administração & dosagem , Efedrina/administração & dosagem , Adulto , Pressão Sanguínea/efeitos dos fármacos , Cápsulas , Clorfeniramina/farmacologia , Preparações de Ação Retardada , Combinação de Medicamentos , Efedrina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Fatores de TempoRESUMO
OBJECTIVE: To compare the survival between intraperitoneal cisplatin-based chemotherapy (IPCT) and intravenous cisplatin-based chemotherapy (IVCT) in stage III epithelial ovarian cancer with minimal residual disease (<1 cm) after primary debulking surgery. METHOD: One hundred and thirty-two patients with stage III epithelial ovarian cancer after optimal primary debulking surgery with minimal residual disease between April 1990 and March 1995 were entered into a randomized clinical trial in which IPCT or IVCT was administered at 3-week intervals. Patients in the IPCT arm received cisplatin-based (100 mg/m(2)) intraperitoneal chemotherapy. Patients in the IVCT arm received cisplatin-based (50 mg/m(2)) intravenous chemotherapy. The tumor response was assessed every 3 months. The hematological toxicity using the South West Oncology Group (SWOG) toxicity criteria was assessed. Catheter complications associated with intraperitoneal chemotherapy were also analyzed. RESULT: The estimated median survival in the IPCT group was 43 months (95% confidence interval, 34-54) and IVCT group was 48 months (95% confidence interval, 37-59). The hazard ratio of death was not statistically significant between IPCT and IVCT (hazard ratio, 1.13; 95% CI, 0.69-1.86; P=0.317). The frequencies of hematological toxic effects were significantly lower in the IPCT group than in the IVCT group. CONCLUSION: Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/cirurgia , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Injeções Intraperitoneais , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Ovariectomia/métodos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do TratamentoRESUMO
The increase in heart rate caused by intravenous injections of atropine sulfate (AS) and methscopolamine bromide (MSB) were compared in 12 healthy volunteers. AS, 200 micrograms, or MSB, 100 micrograms, were injected every 3 min for five doses on successive days. Mean heart rate from the second and fifth injections of MSB was significantly greater than after corresponding injections of atropine. The ratio of equivalent doses of MSB and AS was found to be 1:3. Three subjects with AS and four subjects with MSB exhibited reduced heart rates after the first injection. Excellent correlation of plasma atropine concentrations and heart rate increase were obtained in two volunteers (correlation coefficient, r = 0.84). In the second study, AS, 180 micrograms, and MSB, 60 micrograms, were compared in 20 patients undergoing cardiac catheterization and coronary arteriography. Both drugs produced equivalent increments in heart rate. MSB produced a more predictable dose response than AS. Side effects were similar with both drugs when equivalent doses were used. This study confirms previous investigations that MSB can be titrated by intravenous injections to increase heart rate to desired levels. Absence of central nervous system stimulation by MSB suggests that it may be more appropriate for use in patients with myocardial infarction.
Assuntos
Atropina/farmacologia , Cateterismo Cardíaco , Frequência Cardíaca/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Derivados da Escopolamina/farmacologia , Adolescente , Adulto , Atropina/efeitos adversos , Atropina/sangue , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , N-Metilescopolamina , Fatores de TempoRESUMO
Hyperamylasemia and alternations of serum isoamylases have been recorded in lung tumors, tubal disorders such as acute salpingitis and ruptured ectopic pregnancies and a variety of ovarian tumors, and they have been suggested as potential tumor markers. Hyperamylasemia was noted in a patient with a stage IIIC endometroid adenocarcinoma of the ovary. Serum levels of amylase decreased rapidly after removal of the ovarian tumor. In patients presenting with acute abdominal pain and elevated amylase levels, ovarian cancer should be considered in addition to acute pancreatitis.
Assuntos
Amilases/sangue , Carcinoma Endometrioide/enzimologia , Neoplasias Ovarianas/enzimologia , Dor Abdominal/etiologia , Adulto , Feminino , HumanosRESUMO
The hypotensive effects of N-acetylprocainamide (NAPA) were studied in anesthetized dogs and in a normal subject. In dogs, intravenous NAPA infusions reduced mean arterial pressure and the pressor response of the isolated, perfused gracilis muscle vascular bed to preganglionic, but not postganglionic, sympathetic stimulation. The kinetics of these effects were correlated with NAPA pharmacokinetics. The time course of NAPA concentrations in a hypothetical biophase was characterized, and the relationship between NAPA biophase concentrations and the intensity of the effects was determined. From these results, it was estimated that peak effects would occur in dogs 6.6 min after intravenous bolus injection of NAPA, and that biophase NAPA concentration would lower mean arterial pressure 0.39 mm Hg/microgram/ml and would attenuate by 0.224 mm Hg/microgram/ml the gracilis muscle vascular bed pressor response to preganglionic stimulation. In the normal subject, a similar analysis indicated that maximal hypotension would occur 8.0 min after intravenous NAPA injection, and that blood pressure would fall 0.40 mm Hg/microgram/ml relative to biophase NAPA concentrations. These results suggest that blood pressure should be monitored for at least 10 min after patients receive and intravenous NAPA injection, and that repeated NAPA doses probably should not be administered more frequently.
Assuntos
Acecainida/farmacologia , Bloqueadores Ganglionares , Procainamida/análogos & derivados , Vasodilatadores , Adulto , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Hemodinâmica/efeitos dos fármacos , Humanos , Cinética , Masculino , Fatores de TempoRESUMO
D-Xylose kinetics were studied in 12 normal subjects and in nine patients with chronic renal failure requiring dialysis (five hemodialysis and four peritoneal dialysis). None of the study subjects had demonstrable gastrointestinal disease. Doses of D-xylose were given intravenously (10 gm) and orally (25 gm) on different nondialysis days in order to determine the distribution and elimination kinetics and the absolute bioavailability of this compound. Our findings were as follows. (1) The nonrenal clearance of D-xylose is markedly reduced in chronic renal failure patients (43.3 vs. 90.9 ml/min, p less than 0.002). (2) D-Xylose is less completely absorbed in patients with chronic renal failure than in normal subjects (48.6% vs. 69.4%, p less than 0.01). (3) The absorption rate of D-xylose is slower in these patients than in normal subjects (0.555 hr-1 vs. 1.03 hr-1, p less than 0.05). (4) The absorption rate is positively correlated with the extent of D-xylose absorption (r = 0.49, p = 0.03). (5) Although peak D-xylose concentrations measured 1 hr after oral administration are well correlated with the extent of D-xylose absorption in normal subjects and in functionally anephric patients (r = 0.59, p less than 0.01), formal kinetic study is required to determine D-xylose bioavailability precisely because of the large variability in peak serum D-xylose concentrations and in the time required to reach these peak concentrations.