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At least 307 records · Page 17Linked to original sources
PubMed1995

Pharmacokinetics of amphotericin B in rats as a function of dose following constant-rate intravenous infusion.

Amphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague-Dawley rats were given different two-step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 +/- 0.33, 0.86 +/- 0.24, and 0.37 +/- 0.04 mL min-1 kg-1 for the low-medium and high-dose groups, respectively; p < 0.05). Signs of renal impairment were observed in the high-dose group, as documented by decreased creatinine clearance. Dose-dependent renal clearance may have been due either to nephrotoxicity associated with the high dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time-averaged values (based on the estimation of area under the plasma concentration-time profile). This suggests that clearance calculations from time-averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation of systemic clearance.

Amphotericin B↗
PubMed2001

Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein binding.

Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6-7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature.

Algorithms↗
PubMed1996

Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group.

The purpose of this study was to compare the hemodynamic and clinical effects of milrinone, a vasodilating and positive inotropic agent, with those of dobutamine in patients with congestive heart failure (CHF) following acute myocardial infarction (AMI). Thirty-three patients in Killip classification II or III within 12 h to 5 days after AMI were randomized in a multicenter, open-label clinical trial to receive a 24-h infusion of milrinone or dobutamine. Drugs were titrated to achieve at least a 30% increase in cardiac index (CI) from mean baseline or at least a 25% decrease in mean pulmonary capillary wedge pressure (MPCWP) from baseline. Both drugs improved CI, MPCWP, and other hemodynamic parameters. Criteria for decrease in MPCWP were met by 94% (15/16) of the milrinone-treated patients and 57% (8/14) of dobutamine-treated patients (p = 0.03). Both groups met the minimum efficacy criterion for CI. Maximal reduction in MPCWP over 0-3 h was greater in the milrinone group (-53.2%) than in the dobutamine group (-31.0%; p < or = 0.01); reductions were sustained over 24 h. Both drugs improved echocardiographic global ejection fraction and were generally well tolerated. The short-term infusion of milrinone may have a role in the management of CHF following AMI, especially when the aim is the rapid reduction of pulmonary congestion.

Acute Disease↗
PubMed1991

Pharmacokinetic modeling of plasma and cerebrospinal fluid methotrexate after high-dose intravenous infusion in children.

A pharmacokinetic study was performed in plasma and cerebrospinal fluid (CSF) of patients suffering from brain tumors to describe the disposition of methotrexate. An open three-compartment model was developed to fit together the data obtained in plasma and CSF. The pharmacokinetic parameters obtained by the model agreed with those obtained with classical analysis and the fitting correctly depicted the plasma and CSF concentration decays. According to the results, such a model could be applied to other anticancer drugs.

Adolescent↗
PubMed1993

Urinary excretion of aminohydroxypropylidene bisphosphonate in cancer patients after single intravenous infusions.

The effect of the rate of infusion of disodium aminohydroxypropylidene bisphosphonate (APD; CGP 23339A), an inhibitor of bone resorption, on urinary excretion of this agent was studied in a randomized open-label study in 20 cancer patients. Ten patients received 60 mg of APD over 4 h, and the remaining 10 patients received the same dose over 24 h. Urine collected during specified intervals for 72 h after the start of the infusion was analyzed by high-performance liquid chromatography for unchanged APD. Mild and transient adverse experiences were observed in 12 (60%) patients; the most common were headache, fever, and phlebitis at the infusion site. No clinically significant laboratory abnormalities were observed, and none of the experiences were serious enough to require discontinuation of treatment. Cumulative urinary excretion of APD was a linear function of time, increasing rapidly after both the 4- and 24-h infusions were started. The mean (+/- standard deviation) cumulative urinary excretion of APD was 51.1 +/- 13.0% of the dose in the 20 patients, 55.0 +/- 15.0% in the 10 patients given the 4-h infusion, and 47.2 +/- 9.9% in the 10 patients receiving the 24-h infusion. Thus, the rate of infusion of the 60-mg dose did not influence retention of APD at 72 h after the start of therapy. Similarly, the presence or absence of bone metastases did not influence cumulative urinary excretion or the retention of APD.

Adult↗
PubMed1994

Continuous rat intravenous infusion.

Hypovolemic shock and ischemic injury to the graft commonly cause death in small animals after organ transplantation. A venous line must be readily available to replace fluids before fatal complications occur. To establish a venous line, researchers expose a vein by preliminary surgery. This time-consuming procedure adds unnecessary trauma to the recipient and worsens the results. The possibility of long-term fluid transfusion in small animals by serial injections at close intervals is quite limited. We describe a simple technique of continuous i.v. infusion by catheterization of the rat dorsal penile vein with a 24-gauge, 3/4-inch catheter. This easy-to-learn technique has permitted us to establish a venous line quickly without trauma in 148 rats while doing donor and recipient procedures for small bowel and ileocecal segment transplantation. The technique we describe has eliminated one of the most frequent causes of postoperative mortality after organ transplantation-hypovolemic shock. We would like to emphasize that other measures, including avoiding massive bleeding and reducing operative and warm ischemic time, are also very important in preventing this complication. The massive i.v. infusion alone may not totally eliminate hypovolemic shock if other factors are neglected. The use of this technique has allowed us to perform small bowel transplantation with 90% success.

Animals↗
PubMed1986

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion.

A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m2 per day for 5 days and repeated every 21-28 days. The patient population had a median age of 55 years (range 38-76) and a median Karnofsky performance status of 80 (range 60-100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/microliter (range 100-4800) in 8 heavily pretreated patients treated at 350 mg/m2 per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m2 and had WBC nadirs of 800/microliter and 600/microliter. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m2 per day, nadir 85,000/microliter). Neither hyponatremia nor symptomatic hypo-osmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m2 per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09-6.79 micrograms/ml. Steady state was achieved in 14.5 +/- 5.9 h (mean +/- SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t 1/2 of 5.3 +/- 3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543 +/- 150 micrograms/ml h and reflected a cyclophosphamide total-body clearance (CLTB) of 103 +/- 31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6-4.3 micrograms/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3% +/- 7.6% and 15.1% +/- 2.0% of the administered daily dose, respectively. The t1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m2 as an i.v. bolus.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗