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Biomedical subjects

L J Hak

Publications and source records attributed to L J Hak.

At least 37 records · Page 2Linked to original sources
PubMed1993

Stability of ondansetron hydrochloride injection in extemporaneously prepared oral solutions.

The stability of ondansetron hydrochloride in extemporaneously prepared oral solutions containing orange juice, cola, or cherry syrup was determined. Solutions were prepared by adding ondansetron hydrochloride to orange juice, cola, or cherry syrup to produce ondansetron concentrations of 0.267 and 0.067 mg/mL in orange juice or cola and 0.533 mg/mL in cherry syrup. The ondansetron concentration in orange juice and cola solutions was assayed at the time of preparation and at 30 minutes and one hour. The cherry syrup solution was stored at both 3-5 and 25-27 degrees C, with the ondansetron concentration being determined at the time of preparation and daily for seven days. All the solutions were prepared in triplicate. Ondansetron concentrations were measured by stability-indicating high-performance liquid chromatography. At each time interval, the mean ondansetron concentration remained > or = 97% of the initial measurement for all solutions. The appearance and color of the solutions did not change. Ondansetron hydrochloride was stable for at least one hour in orange juice or cola and at least seven days in cherry syrup.

Administration, Oral↗
PubMed1993

Ondansetron: a novel antiemetic agent.

Ondansetron hydrochloride is a new serotonin receptor antagonist that is effective in preventing emesis associated with cancer chemotherapy. The antiemetic effect appears to be exerted through a peripheral vagal blocking within the gastrointestinal tract, as well as an inhibitory effect within the chemoreceptor trigger zone (CTZ). Plasma concentrations of ondansetron peak 1 hour after an oral dose, and the tablet has an absolute bioavailability of 59%. Ondansetron undergoes extensive hepatic oxidative metabolism in the liver. The half-life of ondansetron is 3.5 hours in healthy volunteers; elderly patients have a slightly reduced clearance, and pediatric patients have increased clearance. Although less than 10% of ondansetron is recovered unchanged in the urine, most metabolites are eliminated by this route. The recommended dose of ondansetron is 0.15 mg/kg for three doses on the day of chemotherapy (30 minutes before chemotherapy and 4 and 8 hours afterward). An alternative regimen includes a single-day dose of 32 mg IV in adult patients before chemotherapy. The efficacy of ondansetron therapy for delayed emesis has not been determined. Ondansetron has proven to be appropriate as a single agent or as an addition to standard antiemetic therapy (ie, corticosteroids, benzodiazepines, neurotransmitter blockers) in preventing and treating acute chemotherapy-induced emesis (CIE). Initial results of clinical trials in prevention of radiotherapy-induced emesis and anesthesia-induced emesis appear positive. Ondansetron is well tolerated, with few adverse events (eg, headache, sedation).

Antineoplastic Agents↗
PubMed1992

Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine.

Twelve healthy male subjects completed this randomized, placebo controlled, four-period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7-day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2-hydroxyimipramine (mean decrease: 22%) and from desipramine to 2-hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2-hydroxyimipramine and 2-hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.

Administration, Oral↗
PubMed1992

Influence of gastrointestinal site of drug delivery on the absorption characteristics of ranitidine.

The absorption characteristics of ranitidine after delivery to three locations in the gastrointestinal tract were compared in an open-label study of eight healthy males. Subjects received ranitidine HCl (150 mg) for injection via a nasoenteric tube directly into their stomach, jejunum, or cecum sequentially in three separate periods (24 hr apart). Plasma samples were collected at periodic time intervals for 12 hr following each dosing and analyzed for ranitidine concentration by high-pressure liquid chromatography. Mean concentrations following cecal dosing were lower (P less than 0.05) than concentrations following gastric or jejunal dosing at each sampling time except baseline. Mean concentrations following gastric and jejunal dosing were similar except at 2 hr (gastric greater than jejunal). Mean pharmacokinetic parameters for cecal administration were different (P less than 0.05) from either the gastric or the jejunal periods with the exception of Tmax. There was no difference in any pharmacokinetic parameter after gastric or jejunal dosing. The relative bioavailability after cecal administration was less than 15% of that observed after administration into the stomach or jejunum. Additionally, Wagner-Nelson analysis indicated that the rate of ranitidine absorption was much slower following cecal administration than after gastric or jejunal dosing. Two plasma concentration peaks were observed in three of eight subjects after gastric dosing, in eight of eight subjects after jejunal dosing, and in zero of eight subjects after cecal dosing. These data demonstrate that the absorption profile of ranitidine is equivalent, in extent and duration, after delivery to the stomach or jejunum, while absorption from the cecum is significantly less.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of cefepime were studied in 10 male patients receiving continuous ambulatory peritoneal dialysis therapy. Five patients received a single 1,000-mg dose and the other five received a single 2,000-mg dose; all doses were given as 30-min intravenous infusions. Serial plasma, urine, and peritoneal dialysate samples were collected; and the concentrations of cefepime in these fluids were measured over 72 h by using a high-performance liquid chromatographic assay with UV detection. Pharmacokinetic parameters were calculated by noncompartmental methods. The peak concentrations in plasma and the areas under the plasma concentration-versus-time curve for the 2,000-mg dose group were twice as high as those observed for the 1,000-mg dose group. The elimination half-life of cefepime was about 18 h and was independent of the dose. The steady-state volume of distribution was about 22 liters, and values for the 1,000- and 2,000-mg doses were not significantly different. The values for total body clearance and peritoneal dialysis clearance were about 15 and 4 ml/min, respectively. No dose dependency was observed for the clearance estimates. Over the 72-h sampling period, about 26% of the dose was excreted intact into the peritoneal dialysis fluid. For 48 h postdose, mean concentrations of cefepime in dialysate at the end of each dialysis interval exceeded the reported MICs for 90% of the isolates (MIC90s) for bacteria which commonly cause peritonitis resulting from continuous peritoneal dialysis. A parenteral dose of 1,000 or 2,000 mg of cefepime every 48 h would maintain the antibiotic levels in plasma and peritoneal fluid above the MIC90s for the most susceptible bacteria for the treatment of systemic and intraperitoneal infections [corrected].

Cefepime↗
PubMed1992

Stability of ondansetron in large-volume parenteral solutions.

OBJECTIVE: To determine the stability of ondansetron hydrochloride in large-volume parenteral solutions under four storage and time-period conditions. DESIGN/METHOD: Ondansetron was added to each of the following commercially available solutions to make final concentrations of approximately 24 and 96 micrograms/mL: NaCl 0.9%, D5W, and lactated Ringer's solution. SETTING: University analytical laboratory. MAIN OUTCOME MEASURES: Each solution was studied at both concentrations under the following conditions: (1) 1 day refrigerated, 2 days room temperature; (2) 7 days refrigerated, 2 days room temperature; (3) 14 days refrigerated, 2 days room temperature; and (4) 14 days room temperature. All solutions were exposed to fluorescent light when under room temperature conditions and were studied in triplicate. Ondansetron concentrations of samples were obtained periodically throughout each storage/time condition via a specific, stability-indicating HPLC method. RESULTS: A clinically significant loss of concentration was defined as greater than 10 percent decrease from the initial concentration. In all solutions and at both concentrations studied, the mean ondansetron concentration was greater than or equal to 90 percent under all storage and time conditions. CONCLUSIONS: Ondansetron can be stored and administered in these solutions without loss of potency.

Drug Stability↗
PubMed1992

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.

Adult↗
PubMed1991

The effect of aldose reductase inhibition and dietary protein restriction on renal function in experimental diabetes mellitus.

The effects of aldose reductase inhibition on renal function in hyperphagic diabetic rats were examined at 3 months. To prevent a high dietary protein intake from influencing renal function, protein intake in the diabetic animals was reduced to that of nondiabetic animals. To determine the influence of renal prostaglandins, clearance studies were performed before and after indomethacin infusion. Experiments were performed in uninephrectomized sorbinil-treated and -untreated streptozocin-diabetic and sorbinil-treated and -untreated control rats. Despite normalization of protein intake, the mean value of the insulin clearance (CIn, mL/min/100 g BW) was 83% greater in the untreated diabetic rats when compared to the untreated control rats (1.06 +/- 0.15 vs. 0.58 +/- 0.07; p less than 0.05). In contrast, the mean value of the CIn in the sorbinil-treated diabetic rats was significantly less than that in the untreated diabetic rats and only 38% greater than the mean value in the sorbinil-treated control rats (0.84 +/- 0.17 vs. 0.61 +/- 0.05; p less than 0.05). In a similar fashion, without sorbinil treatment the mean value of renal blood flow (RBF, mL/min/100 g BW) was greater in the diabetic than the control rats (6.58 +/- 2.03 vs. 3.70 +/- 0.68; p less than 0.05); whereas the mean values of RBF in the sorbinil-treated diabetic and control rats were not significantly different (4.75 +/- 0.73 vs. 4.17 +/- 0.64; NS). Indomethacin infusion failed to cause changes in the CIn and RBF in any group of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1990

Evaluation of the pharmacokinetic interaction between diazepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers.

The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.

Adult↗
PubMed1990

Omeprazole: a novel antisecretory agent for the treatment of acid-peptic disorders.

Omeprazole represents the first agent of a unique class of acid inhibitory drugs, the proton pump inhibitors. Omeprazole inhibits basal gastric acid secretion, as well as gastrin-, histamine-, or pentagastrin-stimulated secretion, which results in decreased gastric acidity, decreased gastric acid output, and decreased gastric volume. Omeprazole is acid labile, necessitating its oral administration in an enteric-coated formulation. Bioavailability appears to be dose-dependent, with more drug being absorbed with increasing dosage as well as after repeated dosing. This is probably secondary to decreased gastric acidity and, therefore, less degradation of the administered drug. Despite its relatively short half-life (1-2 h), omeprazole's pharmacologic action is prolonged. Clinical trials have shown omeprazole to be at least as effective as histamine2-receptor antagonists in the treatment of gastric ulcers, duodenal ulcers, gastroesophageal reflux, and Zollinger-Ellison syndrome. Adverse reactions have been minimal. Omeprazole has been approved by the Food and Drug Administration for short-term therapy of severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, and long-term management of Zollinger-Ellison syndrome.

Animals↗
PubMed1990

In vitro evaluation of the stability of ranitidine hydrochloride in total parenteral nutrient mixtures.

The stability of ranitidine hydrochloride in various total parenteral nutrient (TPN) solutions was studied, as well as the effect of ranitidine on the stability of lipid emulsion and amino acids in these solutions. Ranitidine hydrochloride 25 mg/mL was added to each of the following mixtures to make final concentrations of approximately 50 and 100 mg/L: (1) TPN solution containing 4.5% amino acids, 22.7% dextrose, and electrolytes; (2) 10% lipid emulsion; (3) TPN solution containing 3.7% amino acids, 18.5% dextrose, 3.7% lipid emulsion, and electrolytes (all-in-one mixture); and (4) 0.9% sodium chloride injection. Mixtures were tested at room temperature and at 4 degrees C and were either protected from or exposed to fluorescent light. Sampling was done at 0, 12, 24, 36, and 48 hours, and the ranitidine concentration was determined by high-performance liquid chromatography. Samples were also analyzed for lipid particle size distribution and for amino acid content. At 48 hours, the all-in-one mixtures retained 86.0% to 91.4% of the initial ranitidine concentration. With one exception (ranitidine 50 mg/L in 0.9% sodium chloride injection, stored at room temperature and not protected from light), all other solutions retained at least 90% of the initial concentration at 48 hours. No visible changes in color and minimal changes in pH values were noted. There were no important changes in lipid particle-size distribution; 96% of all particles counted from any mixture were smaller than 1.44 microns in diameter at 48 hours. Ranitidine did not have an effect on amino acid concentrations in these mixtures.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1989

Influence of the rate of infusion on cyclosporine nephrotoxicity in the rat.

The effect of the rate of infusion of single and multiple doses of cyclosporine (CsA) on renal function was evaluated in Sprague-Dawley rats. CsA was dissolved in cremophore (Crem) or Tween 80 (Tween) and infused over consecutive 10-min periods at doses of 10, 20, 30 and 40 mg/kg. CsA-Crem and CsA-Tween produced similar and progressive changes in MAP, RBF, and RVR. By the end of the infusion, the mean values (% of control) of MAP (122 +/- 16% and 131 +/- 22%), RBF (56 +/- 11% and 66 +/- 20%), and RVR (222 +/- 38% and 232 +/- 134%) were significantly different from their respective preinfusion values. Infusion of Crem alone resulted in renal vasodilation at low doses and renal vasoconstriction at high doses. Vasoconstriction was not produced by infusion of Tween alone. In addition, animals were treated with vehicle alone (Gp 1), CsA 10 mg/kg/day by injection (Gp 2), or CsA 20 mg/kg/day by i.v. infusion over 4 hr (Gp 3), and were studied at 1 week. Systemic toxicity was greater with the 4-hr infusion as judged by an increase in MAP. The mean values of MAP were 107 +/- 8 (Gp 1), 101 +/- 13 (Gp 2), and 135 +/- 5 mm Hg (Gp 3; p less than 0.05). However, renal function was less severely affected with the 4-hr infusion. The mean values of CIn were 434 +/- 99 (Gp 1), 298 +/- 101 (Gp 2; p less than 0.05), and 425 +/- 114 microL/min/100 g BW (Gp 3); and the mean values for RBF were 2.72 +/- 0.74 (Gp 1), 2.08 +/- 0.17 (Gp 2; p less than 0.05), and 3.35 +/- 0.61 mL/min/100 g BW (Gp 3), respectively. Microangiograms showed marked abnormalities in the intrarenal perfusion pattern in the rats injected with CsA, 10 mg/kg BW. In rats infused over 4 hr with CsA, 20 mg/kg BW, the microangiographic pattern was normal. These studies demonstrate that the acute hemodynamic effects of CsA are directly related to the rate of infusion. Furthermore, the renal toxicity which follows repetitive injection of CsA can be minimized or avoided by administering CsA as a slow infusion. In addition to the total dose administered, the rate of infusion is an important determinant of nephrotoxicity.

Animals↗
PubMed1987

Protective effect of prostacyclin on postischemic acute renal failure in the rat.

Infusion of prostacyclin (PGI2) reportedly attenuates renal ischemic injury in the dog and the rat. In the dog, PGI2 is a potent renal vasodilator; in the rat a direct action on the renal vasculature is not always apparent. To determine whether or not the protective effect of PGI2 on postischemic ARF was hemodynamically mediated, studies were performed in uninephrectomized Sprague-Dawley rats before and after a 40 minute period of complete renal artery occlusion. In response to the preischemic infusion of PGI2 for 30 minutes at 160 ng/kg body wt/min i.v. (N = 7), MAP and RBF fell to 86 +/- 7% (P less than 0.0001) and 84 +/- 9% (P less than 0.05) of baseline values, respectively. RVR initially declined to 81 +/- 9% of baseline values (P less than 0.025) but returned to 102 +/- 13% of baseline values prior to the period of ischemia. Following the period of ischemia, reflow of blood in the rats receiving PGI2 was delayed when compared to rats not receiving PGI2 (N = 7). RBF returned to only 76 +/- 19% of the initial values in PGI2-treated rats (P less than 0.01) but to 90 +/- 12% of the initial values in rats receiving buffer alone (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1985

Use of plasma somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients.

Changes in plasma somatomedia-C/insulin-like growth factor I (Sm-C/IGF-I) concentrations are a sensitive indicator of the anabolic response of normal human volunteers to alterations in nutritional intake. To determine if measurement of this peptide could be used to monitor the response to nutritional repletion in malnourished patients, six patients were studied while receiving nutritional support for periods of 10-16 days. Plasma Sm-C/IGF-I increased from a mean basal level of 0.67 +/- 0.15 U/ml (+/-1 SD) to a peak of 1.80 +/- 0.44 U/ml on day 10, then declined to a concentration of 1.28 +/- 0.49 U/ml by day 16. All patients entered positive nitrogen balance by day 2 and nitrogen accretion continued throughout the study. Changes in serum concentrations of prealbumin, transferrin, and retinol-binding protein were compared to changes in Sm-C/IGF-I during nutritional support. Prealbumin increased to a posttreatment mean of 121 +/- 23% of control by the end of the study (p greater than 0.05, NS). Likewise, there was minimal change in retinol-binding protein, a peak value of 118 +/- 21% of control being reached by day 12 of treatment (p greater than 0.05, NS). Transferrin also showed minimal change, increasing to a mean value of 110% +/- 13% of control by day 12 (p greater than 0.05, NS). Measurement of plasma Sm-C/IGF-I concentrations appears to be a much more sensitive index of acute directional changes in nutritional status than other plasma proteins commonly used to monitor nutritional responses. The increase of Sm-C/IGF-I correlated temporally with entry into positive nitrogen balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗