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At least 343 records · Page 19Linked to original sources
PubMed1999

Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion. METHODS: Eight healthy male volunteers received 1030 nmol x min(-1) of clevidipine together with a tracer dose of 3[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days. RESULTS: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l x min(-1) x kg(-1) and a mean volume of distribution at steady state of 0.6 (0.1) l x kg(-1). The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. CONCLUSION: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The tmax value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short.

Adult↗
PubMed2002

Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous intravenous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity.

PURPOSE: Ecteinascidin 743 (ET-743) is a potent cytotoxic alkaloid of marine origin that has shown promising evidence of antitumor activity during phase I clinical trials. In the study reported here, the influence of clinical characteristics and pretreatment pathophysiological variables on the pharmacokinetics of ET-743 and their associations with drug-related toxicity was examined in sarcoma patients treated in three phase II clinical trials. METHODS: Adult patients with various histological subtypes of soft tissue sarcoma received 1.5 mg/m(2) of ET-743 by 24-h continuous i.v. infusion once every 3 weeks. Eligibility criteria were similar for each study, except for the histological subtype of the tumor or the extent of prior treatment with other anticancer agents, and all patients had normal or near-normal liver and renal function. The maximum plasma concentration (C(max)) and area under the plasma profile from time zero to infinity (AUC) of the drug were determined during the first cycle of therapy. Patients were evaluated for toxicity every week. RESULTS: Geometric mean +/- SD values of the pharmacokinetic parameters in 69 patients were: C(max) 1.14 +/- 0.52 ng/ml, AUC 39.9 +/- 16.6 ng.h/ml, and total body clearance (CL) 36.7 +/- 16.4 l/h per m(2). The only significant correlation involving physical characteristics of the patients or pretreatment pathophysiological variables was a very weak relationship between alkaline phosphatase and AUC (r=0.39, P<0.01). The 15 patients with any baseline liver function test exceeding the upper limit of the normal ranges had a significantly greater (P=0.02) incidence of severe toxicity (80% vs 44%). Although the mean AUC of ET-743 in patients with elevated serum levels of hepatic enzymes was 17% greater than that in patients with normal pretreatment liver function tests, the difference was not significant ( P=0.22). In addition, there was no distinct relationship between the grade of the most severe drug-related toxicity that occurred during the first cycle of therapy and the AUC for the entire cohort. The CL of ET-743 was found to be 27% greater in patients concurrently receiving dexamethasone as a preventative antiemetic than in those who were not, but the difference did not achieve statistical significance (P=0.08). There were no significant associations between CL (liters per hour) and body surface area or any other variable related to body size. CONCLUSIONS: The risk of developing severe toxicity was substantially enhanced in patients with relatively moderate indications of hepatic dysfunction without a coincident effect on the CL of ET-743. Dexamethasone cotreatment appeared to decrease the incidence of severe toxicity as well as the AUC of the drug. Delivering a fixed amount of drug without adjustment for the height or weight of the patient may be more appropriate than dose normalization due to the absence of an association between CL and body surface area. Optimizing dosing strategies to further enhance the therapeutic index of ET-743 may depend upon obtaining a better understanding of the metabolic fate of the drug in humans.

Adult↗
PubMed1996

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients.

PURPOSE: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). METHODS: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary beta2-microglobulin (BMGp and BMGu), urinary N-acetyl-beta-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. RESULTS: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dt(max)), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. CONCLUSION: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 microg/ml in a standard continuous infusion schedule over 2 h and 4 h.

Adult↗
PubMed1990

Sustained beneficial effect of a seventy-two hour intravenous infusion of nitroglycerin in patients with severe chronic congestive heart failure.

To determine whether a 72-hour infusion of nitroglycerin produces hemodynamic improvement in patients with severe congestive heart failure and to assess the contributing role of various possible causes of hemodynamic tolerance to nitroglycerin, 19 patients received an infusion of nitroglycerin 1.5 micrograms/kg/min for 72 hours. In a subgroup of patients (n = 10), there was an increase in stroke work index and a decrease in ventricular filling pressures throughout the infusion and even after it was discontinued. Tolerance to the hemodynamic effects of nitroglycerin was partially reversed 8 hours after the infusion was stopped. Neurohumoral changes occurred but appeared to play only a minor role in the development of nitroglycerin tolerance. However, hematocrit fell 9 +/- 5%, which suggests that an increased intravascular volume contributed to tolerance. In summary: (1) a 72-hour infusion of nitroglycerin improves ventricular function in some patients with severe heart failure; (2) volume shifts from the extravascular to the intravascular compartments may, at least in part, be responsible for nitroglycerin tolerance; and (3) reflex neurohumoral activation may also play a small role in nitrate tolerance.

Administration, Sublingual↗
PubMed1992

Effects of intravenous infusion of substance P on arginine vasopressin and oxytocin secretion in normal men.

In order to establish possible stimulatory effects of increasing plasma concentrations of substance P (SP) on the arginine vasopressin (AVP) and/or oxytocin (OT) secretion, successively increasing doses of SP(0.5, 1 and 1.5 pmol/kg-1/min-1; each dose for 20 min) were infused in 7 normal men. Plasma AVP and OT levels were measured before infusion and every 20 min, just before increasing the infusion dose of SP. During tests, SP infusion did not produce untoward side effects or changes in blood osmolality and/or pressure. Plasma OT levels did not change during SP infusion. Plasma AVP concentrations were not modified by the infusion of the lowest dose of SP, whereas they were significantly increased in a dose response fashion when higher amounts of SP were given. These findings demonstrate for the first time in humans that the systemic administration of SP exerts stimulatory effects on AVP, but not on OT secretion.

Adult↗
PubMedDate not supplied

A study on the effects of the rapid intravenous infusion of hypertonic Na and K solutions into normal conscious sheep on some cardiac characteristics and blood analytes.

Five normal, conscious, aged Merino ewes were infused with 200 ml of an aqueous solution containing 5% NaCl and 0.25% KCl (HNaK) at a mean rate of 0.024 ml/kg/s and four similar sheep with 0.9% saline at a mean rate of 0.018 ml/kg/s. Five ECG tracings were obtained over a 6-h period--two (20 s each) before, one (continuous tracing) during the infusion, and two (20 s each) afterwards. The heart was auscultated during the infusion. Seven heparinized blood samples were obtained--three before the infusion (1.5 h, 1.0 h, and immediately before), and four afterwards (immediately, 2.5 h, 4.5 h, and 24 h after). Determinations were made of changes in mean PCV, red cell counts, mean corpuscular volumes, plasma Na, K, Ca and Mg, and of erythrocyte Na and K concentrations. Analysis of variance revealed increases in heart rate when the results from both groups were combined, but no significant effects on cardiac rhythm. Auscultation revealed marked fluctuations in cardiac intensity within individual sheep and marked differences between sheep, particularly in those infused with HNaK. In the HNaK group there were significant increases in erythrocyte and plasma Na, and erythrocyte K and decreases in plasma Ca during the infusion. Plasma K increased from the termination of the infusion to 2.5 h afterwards in the saline group but decreased unexpectedly during the same period in the group infused with HNaK [corrected].

Animals↗