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Biomedical subjects

R L Stiller

Publications and source records attributed to R L Stiller.

At least 55 records · Page 3Linked to original sources
PubMed1989

Pharmacokinetics of alfentanil in newborn premature infants and older children.

Because developmental pharmacokinetics appear to be closely associated with anatomic and physiologic changes that occur with growth, we were interested in determining the disposition and elimination of alfentanil in premature infants and older children. The pharmacokinetic profile of alfentanil was determined in 6 premature infants requiring sedation for medical management or analgesia for stressful intensive-care procedures. These pharmacokinetic profiles were compared with pharmacokinetic profiles determined in 9 older infants and children undergoing operative procedures that required invasive monitoring. In both groups the plasma decay curves best fit a 2-compartment model. Compared with older children, premature infants demonstrated a significantly larger apparent volume of distribution (1.0 +/- 0.39 vs. 0.48 +/- 0.19 l/kg), a smaller clearance (2.2 +/- 2.4 vs. 5.6 +/- 2.4 ml/kg/min) and a markedly prolonged elimination half-life (525 +/- 305 vs. 60 +/- 11 min).

Age Factors↗
PubMed1989

A method to increase recovery of fentanyl from urine.

Fentanyl, a highly lipophilic drug (pk(a) 7.7), is a common drug of abuse. The current standard techniques to detect fentanyl in urine have low recovery rates and poor sensitivity. We report a modified solvent extraction technique that can recover between 63 and 86% of the drug with a detection limit of 0.2 ng/10 ml of urine. In addition, we report the duration of urinary fentanyl excretion in 11 adolescent patients administered either low (less than 10 mg/kg) or high (20-40 mg/kg) doses of fentanyl as part of anesthesia. The mean duration of urinary fentanyl excretion was similar in the two groups, with duration ranging from 1 to 5 days, and urine fentanyl concentration ranging from 0.1 ng to 10.3 ng/10 ml of urine.

Adolescent↗
PubMed1989

Effects of cholestatic hepatic disease and chronic renal failure on alfentanil pharmacokinetics in children.

The role of the liver and the kidney in alfentanil metabolism has not been defined. The effects of cholestatic hepatic disease and chronic renal failure on the pharmacokinetics of alfentanil were evaluated in 9 children undergoing liver transplantation and 10 children undergoing kidney transplantation. These findings were compared with data from 10 children with normal hepatic and renal function undergoing other surgical procedures. There was no statistical difference among the 3 groups with respect to apparent volume of distribution, half-life, or clearance. In a subgroup of 3 patients undergoing liver transplantation alfentanil kinetics were determined both before and after the allograft was incorporated into the recipient's circulation. Though both volume of distribution and elimination half-life increased in the posttransplantation period, only the decrease in clearance was statistically significant. Thus, it appears that alfentanil may be a useful anesthetic agent in pediatric patients with cholestatic hepatic disease or chronic renal failure. The dose of alfentanil in these patients need not be altered except in the period immediately after liver transplantation.

Adolescent↗
PubMed1989

In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine.

The in vitro rates of metabolism of mivacurium chloride and succinylcholine in pooled human plasma were compared. In addition, the rate of metabolism of mivacurium in buffered solutions of butyrylcholinesterase (E.C. 3.1.1.8) and acetylcholinesterase (E.C. 3.1.1.7) was determined. Succinylcholine concentrations were measured spectrophotometrically, and mivacurium concentrations were determined with a high-pressure liquid chromatographic assay. The hydrolysis of mivacurium in plasma followed first-order kinetics, and the rate of hydrolysis decreased as plasma was serially diluted. The Michaelis-Menten constant (Km) for mivacurium metabolism in plasma was 245 mumol/L, and the maximum velocity (Vmax) was 50 U/L; the Km for succinylcholine was 37 mumol/L, and Vmax was 74 U/L. At comparable multiples of the Km the hydrolysis rate of mivacurium was 70% of that of succinylcholine. Mivacurium was metabolized significantly in solutions containing butyrylcholinesterase, but only minimally in solutions containing acetylcholinesterase.

Butyrylcholinesterase↗
PubMed1988

Pharmacokinetics of sufentanil in adolescent patients with chronic renal failure.

The role of the kidney in sufentanil elimination or metabolism has not been defined. The effects of chronic renal failure (CRF) on the pharmacokinetic profile of sufentanil were evaluated in six adolescent patients undergoing renal transplantation, and these findings were compared with data from age-matched control patients with normal renal function who were undergoing other surgical procedures. Patients with CRF weighed significantly less than did the control patients (28.7 +/- 5.7 vs 44.7 +/- 12.9 kg [mean +/- SD]). Although there was no statistical difference in the rate of clearance or apparent volume of distribution and half-life between the two groups, clearance and half-life were more variable among patients with CRF. In these patients, therefore, sufentanil dose must be carefully administered based on responses elicited in individual patients.

Adolescent↗
PubMed1988

Cimetidine does not inhibit plasma cholinesterase activity.

Cimetidine increases the duration of action of succinylcholine several-fold by an unknown mechanism. The hydrolysis rate of succinylcholine by human plasma was measured with a modified spectrophotometric assay. At a concentration of 1-50 micrograms/ml cimetidine did not inhibit the hydrolysis of succinylcholine. It is concluded that cimetidine may have an effect at the neuromuscular junction but does not inhibit plasma cholinesterase.

Cholinesterase Inhibitors↗
PubMed1987

Imipramine in prepubertal major depressive disorders.

The potential effectiveness of imipramine hydrochloride (up to 5 mg/kg/d) was investigated in 53 prepubertal children suffering from major depressive disorder. Two complementary strategies were used simultaneously: a five-week, double-blind, placebo-controlled design (N = 38), and a plasma level/clinical response study (N = 30). Fifteen of the 16 children randomly assigned to active drug in the first study also participated in the second. Subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children and diagnosed according to unmodified Research Diagnostic Criteria. Response rates in the double-blind study were similar in both groups (imipramine, 56%; placebo, 68%). In the plasma level study, total maintenance plasma level (imipramine plus desipramine) was found to positively and linearly predict clinical response of the depressive syndrome (P less than .003). No evidence of a curvilinear relationship was found. Depressive hallucinations during the episode negatively predicted clinical response (P less than .05). Weight-corrected imipramine dosage did not predict either clinical response or plasma level in the individual subject. No predictors of response were found in the placebo group. These results suggest that the mean imipramine dosage was too low, and that future double-blind, placebo-controlled studies of imipramine in prepubertal major depression should include plasma level titration to above 150 ng/mL and an initial placebo washout period.

Age Factors↗
PubMed1987

Pharmacokinetics of pimozide in adults and children with Tourette's syndrome.

Pimozide is a neuroleptic drug with dopamine receptor and calcium channel blocking activity that is used in the treatment of Tourette's syndrome. A comparison of the pharmacokinetics of pimozide was made in children and adults with Tourette's syndrome. Seven adults (ages 23-39) and four children (ages 6-13) received a single 2-mg oral dose of pimozide and a minimum of nine blood samples were collected over a four-day period. Mean elimination half-life of pimozide in children was 66 hours compared with 111 hours in adults with Tourette's syndrome. Significant interindividual variability of pimozide pharmacokinetics was found in both adults and children with Tourette's syndrome. The pharmacokinetics of pimozide in patients with Tourette's syndrome differs from that reported in adult populations with chronic schizophrenia.

Administration, Oral↗
PubMed1987

Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery.

The pharmacodynamic and pharmacokinetic profiles of high-dose sufentanil (15 micrograms/kg) and oxygen were determined in 20 infants and children undergoing repair of congenital heart defects. Sufentanil provided marked hemodynamic stability after an infusion and during the stress periods of incision and sternotomy. Two patients required supplemental nitrous oxide because of an increase in blood pressure greater than 20% of baseline. Mean plasma catecholamine concentrations varied widely among patients and increased, although not significantly, during intraoperative stress. Pharmacokinetic data best fit a two-compartment model. In infants younger than 10 months (group 1) and children older than 10 months (group 2) who were not surface-cooled, elimination half-lives were similar (mean +/- SD, 53 +/- 15 min vs 55 +/- 10 min) as were clearance values (27.5 +/- 9.3 vs 18.1 +/- 10.7 ml X kg-1 X min-1). However, the volumes of distribution were significantly smaller in group 1 compared with group 2 (1.6 +/- 0.46 vs 3.0 +/- 1.3 L/kg). In infants younger than 10 months who were surface-cooled (group 3) elimination half-life was longer (120 +/- 36 min) and volume of distribution larger (3.7 +/- 1.1 L/kg), but clearance rate was similar (21.5 +/- 5.0 ml X kg-1 X min-1) compared with age- and weight-matched infants (group 1).

Anesthesia, Intravenous↗
PubMed1987

Plasma haloperidol and clinical response: a role for reduced haloperidol in antipsychotic activity?

Seventeen hospitalized psychotic patients were treated with a fixed oral dose of haloperidol, 5 mg twice daily for 28 days. Most were chronic schizophrenics with an acute exacerbation of their illness. All patients also received benztropine 3 mg twice daily during the last 11 days of the study, regardless of the presence or absence of extrapyramidal side effects. No significant linear or curvilinear relationship was found between steady state plasma levels of haloperidol and clinical response measured by total Brief Psychiatric Rating Scale score. At 28 days, the correlations between plasma levels and percent improvement were rs = 0.187 (not significant) for haloperidol and rs = 0.582 (p = 0.04) for the hydroxymetabolite, reduced haloperidol. The correlation for the sum was rs = 0.511 (p = 0.078). Metabolite levels were substantially higher than plasma haloperidol, on the average 2.7 times greater. Eleven days of benztropine treatment had no significant effect on haloperidol or metabolite plasma levels or on clinical status. At the end of the study, nine of 17 patients (53%) had recovered as judged by discharge readiness. Within the limitations implied by the small number of patients, these data suggest that reduced haloperidol is an important component of plasma antipsychotic activity and cannot be neglected in correlative studies, and that a substantial proportion of patients--about half--can be successfully treated with only 10 mg of haloperidol. The routine use of large doses is thus not necessary for many patients.

Adult↗
PubMed1986

Studies with a plant fungicide, imazalil, with vapor-phase activity, in the therapy of human alternariosis.

The use of a plant fungicide, the imidazole imazalil, in the therapy of human alternariosis is described. The patient's disease involved the palate, nose and sinuses, and had been unresponsive to conventional therapy. Imazalil has been used to treat Alternaria infections of plant materials. The patient's isolate was susceptible in vitro. We also showed that the drug was inhibitory to fungi in vitro as a vapor, not requiring contact by diffusion through agar or broth. The drug was used topically, by installation and irrigation, in this case and administered orally in doses of up to 1 200 mg daily, for 6 months. Peak serum concentrations exceeded 4 mcg/ml. The infection was arrested but not cured. The drug was tolerated without evident toxicity, though an unpleasant taste and nausea at high doses were limiting.

Administration, Oral↗
PubMed1986

Pharmacokinetics of atracurium in anaesthetized infants and children.

The pharmacokinetics of atracurium were studied in infants and children anaesthetized with isoflurane and nitrous oxide in oxygen. There were no significant differences in volume of distribution (area) (139 v. 152 ml kg-1), clearance (5.1 v. 5.3 ml kg-1 min-1), T1/2 alpha (2.1 v. 2.0 min), or T1/2 beta (19.1 v. 20.3 min) between children with normal hepatic and renal function and those with moderately impaired hepatic function presenting for hepatic transplantation. There were significant differences in volume of distribution (area) (176 v. 139 ml kg-1) and in clearance of atracurium (9.1 v. 5.1 ml kg-1 min-1) between infants and children with normal excretory function. In infants the clearance of atracurium in ml m-2 min-1 (153 v. 133) tended to be greater and the T1/2 alpha and T1/2 beta tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1) than in children with normal excretory function; however, these trends did not reach statistical significance. Plasma laudanosine concentration was around 100 ng ml-1 greater in patients with liver disease than in normal children from 15-45 min following a bolus of atracurium 0.5 mg kg-1.

Anesthesia, Inhalation↗
PubMed1986

Cardiovascular and electroencephalographic effects of laudanosine in "nephrectomized" cats.

We studied a cat model simulating laudanosine accumulation in the "anephric" patient. Cardiovascular effects were seen only with the bolus doses of laudanosine 2 mg kg-1, and at plasma laudanosine concentrations unlikely to be achieved clinically. Similarly, EEG and power spectra analysis showed no evidence of epileptiform activity at all plasma laudanosine concentrations achieved. The non-specific EEG/power spectra changes observed may reflect a direct CNS activity with neurodepression, since laudanosine was shown by its presence in CSF to cross the blood-brain barrier. These EEG changes were observed at plasma concentrations eight to 10 times those observed in humans during infusion of atracurium. Thus, laudanosine accumulation and related CNS or cardiovascular toxicity seem unlikely following atracurium administration in the anephric patient.

Animals↗
PubMed1986

Plasma haloperidol levels drawn at neuroleptic threshold doses: a pilot study.

The daily haloperidol doses of 33 newly admitted, acutely psychotic schizophrenic patients were rapidly adjusted to a point at which slight hypokinesia-rigidity first appeared on clinical examination (the neuroleptic threshold). The mean daily haloperidol dose at which the neuroleptic threshold was crossed was 4.2 +/- 2.4 mg/day. The plasma haloperidol levels obtained at these neuroleptic threshold doses clustered around a mean of 4.9 +/- 2.9 ng/ml. This plasma haloperidol level distribution extensively overlaps the proposed lower boundaries for the therapeutically effective range of plasma haloperidol levels, but it is below the range in which coarse extrapyramidal side effects appear in high frequency (greater than 10 ng/ml). Sixty-seven percent of our patients demonstrated moderate or greater therapeutic improvement within 3 weeks of treatment at neuroleptic threshold doses, a therapeutic efficacy rate identical to that expected with standard neuroleptic doses. The authors propose that the neuroleptic threshold is a readily available clinical marker which identifies a range of plasma haloperidol levels capable of producing therapeutic response with minimal associated coarse extrapyramidal side effects.

Adolescent↗
PubMed1985

In vitro degradation of atracurium in human plasma.

The degradation of atracurium and the formation of laudanosine was examined in vitro in both Sorensen buffer and human plasma using sensitive, specific high pressure liquid chromatographic assays to determine drug concentrations. At normal physiological pH and temperature, the degradation of atracurium was threefold more rapid in plasma than in buffer. Laudanosine is the major end-product of atracurium degradation in buffer or in plasma; its production is more rapid in plasma than in buffer. Dilution of plasma constituents or the use of diisopropylfluorophosphate (a potent esterase inhibitor), slows the degradation of atracurium and the production of laudanosine. We conclude that, although ester hydrolysis is the major metabolic pathway of atracurium degradation, Hofmann elimination provides a "safety net" in its clinical use.

Atracurium↗