PubMed Health⌕ Search

Biomedical subjects

L L Gustafsson

Publications and source records attributed to L L Gustafsson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Determination of ketamine and norketamine enantiomers in plasma by solid-phase extraction and high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for determination of sub-anaesthetic concentrations of the enantiomers of ketamine and its metabolite norketamine in plasma. The samples are purified by reversed-phase solid-phase extraction. The enantiomers are separated on a Chiral AGP column with a mobile phase containing 16% methanol and a 10 mM phosphate buffer at pH 7.0, and measured by UV-detection at a wavelength of 220 nm. Linear calibration curves with correlation coefficients better than 0.995 have been obtained in the range 10-320 ng/ml. Minimum detectable concentrations were about 2 ng/ml.

Anesthetics, Dissociative↗
PubMed1996

Lack of effect of chloroquine on the debrisoquine (CYP2D6 and S-mephenytoin (CYP2C19) hydroxylation phenotypes.

The effects of chloroquine (CHQ) on debrisoquine hydroxylase (CYP2D6) and S-mephenytoin hydroxylase (CYP2C19) were assessed in 11 black Zimbabwean and 12 white Swedish healthy volunteers. The activity of CYP2D6 was measured as the urinary debrisoquine to 4-hydroxydebrisoquine metabolic ratio and that of CYP2C19 as the urinary S- to R-mephenytoin enantiomer ratio (S/R). There were no statistically significant differences in either metabolic ratio as a result of prophylactic or loading doses of CHQ. This indicates that CHQ does not inhibit CYP2D6 or CYP2C19 in vivo and is unlikely to compromise the metabolism of substrates for these two enzymes. It is, therefore, also unlikely that residual CHQ in populations under study will interfere with phenotyping of either CYP2D6 or CYP2C19.

Adult↗
PubMed1996

Cyclophosphamide-induced acute liver failure requiring transplantation in a patient with genetically deficient debrisoquine metabolism: a causal relationship?

Severe liver damage can occur after treatment with cyclophosphamide. The possible linkage to genetically deficient drug metabolic capacity is unknown. A 58-year-old woman with rheumatoid arthritis was treated with oral cyclophosphamide 50 mg twice daily for 2 months. Due to poor response the dose was doubled and liver failure requiring transplantation developed within weeks. After surgery PCR amplification using DNA from leukocytes showed that she was homozygous for the mutated allele CYP2D6B, which is predictive of the poor metaboliser phenotype for debrisoquine, occurring in 7% of Caucasians. Our patient may have accumulated high levels of the hepatotoxic 4-hydroxylated cyclophosphamide metabolite. Pharmacogenetic methods can help in exploring mechanisms of unexpected severe adverse effects.

Antirheumatic Agents↗
PubMed1996

Quantitation of depth of thiopental anesthesia in the rat.

BACKGROUND: In contrast to that of inhalational anesthetics, quantitation of anesthetic depth for intravenous agents has not been well defined. In this study, using rodents, the relationship between the constant plasma thiopental concentrations and the clinical response to multiple nociceptive stimuli were investigated characterizing the anesthetic state from light sedation to deep anesthesia and correlated to the degree of electroencephalogram (EEG) drug effect. METHODS: Thirty rats were instrumented with chronically implanted EEG electrodes, arterial and venous catheters. A computer-driven infusion pump was used to rapidly attain and then maintain constant, target plasma thiopental concentrations ranging from 7 to 100 micrograms/ml. Three different target plasma thiopental concentrations were achieved in each rat. Electroencephalographic effects were monitored with aperiodic waveform analysis. The following nociceptive stimuli were applied: (1) unprovoked righting reflex, (2) provoked righting reflex, (3) noise stimulus, (4) tail clamping with an alligator clip, (5) constant tail pressure with an analgesiameter, (6) corneal reflex, and (7) tracheal intubation. For tail clamping, tail pressure, and intubation, either purposeful extremity movement or abdominal muscle contraction response was noted to be present or absent. The clinical responses (present or absent) were modeled using logistic regression to estimate the Cp50, the plasma thiopental concentration with a 50% probability of no response. RESULTS: The following mean Cp50 values (95% confidence interval) were obtained: unprovoked righting reflex, 15.9 (15.1-16.6) micrograms/ml; provoked righting reflex, 21.4 (20.2-22.7) micrograms/ml; noise stimuli, 31.3 (29.7-33.0) micrograms/ml; tail clamp and limb movement, 38.3 (36.1-40.4) micrograms/ml; tail pressure and limb movement, 39.2 (37.1-41.3) micrograms/ml; tail pressure and abdominal muscle contraction, 52.5 (50.0- 55) micrograms/ml; tail clamping and abdominal muscle contraction, 56.1 (50.0-56.2) micrograms/ml; corneal reflex, 60.0 (56.6-63.4) micrograms/ml; and limb movement or muscle abdominal contraction response to intubation, 67.7 (59.2-76.1) micrograms/ml. At an EEG-effect of 9.1 and 2.2 waves/s, there was a 50% chance of limb movement response to tail clamping and tracheal intubation, respectively. There was a poor relationship between the plasma thiopental concentration and the percent increase of either heart rate or mean arterial blood pressure after applying either tail pressure or tail clamp stimuli. CONCLUSIONS: A range of nociceptive stimuli and their observed clinical responses can be used to quantitate thiopental anesthetic depth, ranging from light sedation to deep anesthesia (isoelectric EEG and unresponsive to intubation) in the rodent. Clinical response can be mapped to surrogate EEG measures.

Anesthesia, Inhalation↗
PubMed1995

Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers.

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.

Adult↗
PubMed1995

Cerebral uptake of morphine in the pig calculated from arterio-venous plasma concentration gradients: an alternative to tissue microdialysis.

The aim of this study was to characterize the reversible cerebral uptake of morphine in the pig by measuring the changing arterio-venous plasma concentration gradient over the brain. Seven pigs were anaesthetized by continuous infusions of ketamine and pancuronium and ventilated with oxygen in nitrous oxide. During and after 5-min intravenous infusions of morphine hydrochloride, blood samples were drawn from a central artery and from the internal jugular vein. Concomitantly, cerebral blood flow (CBF) was repeatedly measured as clearance of 133Xe from the brain after intracarotid injection. Plasma concentrations of morphine and, in samples from two animals, morphine glucuronides were assayed by high-performance liquid chromatography. Drug flux (Jnet) from arterial blood to brain was calculated from the arterio-venous plasma concentration gradients, the blood:plasma concentration ratio and CBF. Uptake of morphine from arterial blood to brain was very rapid, with a maximal Jnet typically at 3 min after the beginning of the infusion. The initial cerebral extraction of morphine was close to 50%. When the arterial and jugular venous concentration curves crossed, 1-5 min after the end of the infusion, the initially rapid uptake of morphine changed into a slow and steady release. The cerebral extraction of morphine glucuronides was comparable to that of morphine, however, Jnet was lower due to lower plasma concentrations at time of maximal extraction. The findings demonstrate how the cerebral uptake and release of morphine and its metabolites can be studied with a method that is entirely non-invasive to the brain and permits very flexible sampling. Uptake and release of drug is observed directly and need not be inferred from cerebral concentration curves.

Animals↗
PubMed1995

Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.

1. Plasma concentrations of pentamidine were measured up to 1-8 months after a single 2 h i.v. infusion of 3.0 to 4.8 mg kg-1 pentamidine isethionate in 11 patients with late stage Trypanosoma gambiense sleeping sickness. 2. Maximum plasma drug concentrations varied between 713 and 2461 nmol 1-1. After termination of infusion, a rapid distribution phase over 10 min was followed by a slower distribution phase and an elimination phase prolonged over weeks to months. 3. The 'terminal' elimination rate constant could be determined in six patients and subsequent kinetic calculations showed a three to fourfold variation in plasma clearance and 'terminal' half-life (median 1126 (range 553-2036) ml min-1 and 265 (107-446) h, respectively). The median apparent volume of distribution (Vss) was 11,850 1. Renal clearance accounted for a median of 11% of total plasma clearance, indicating that metabolism is a major route of pentamidine elimination in man. 4. Side effects were few and mild and a slight or moderate decrease in blood pressure was the most common registered adverse reaction observed in four subjects. 5. The prolonged elimination of pentamidine seems inconsistent with the present recommended dosage regimen of pentamidine for treatment of trypanosomiasis of 7 to 10 parenteral doses given once daily or every second day.

Adult↗
PubMed1995

Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry.

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of 14C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22 +/- 2% (mean +/- S.D.) and 25 +/- 4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21 +/- 5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76 +/- 15% (mean +/- S.D.) of the total excreted radioactivity on day 1 and 97 +/- 1% on day 6. HPLC--tandem mass spectometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.

Animals↗
PubMed1994

Stereoselective inhibition by chloroquine of histamine N-methyltransferase in the human liver and brain.

This study was designed to determine whether both enantiomers of chloroquine inhibit histamine N-methyltransferase. The mean estimates of IC50 for the d- and l-enantiomers of chloroquine were 4.9 and 17.8 microM (liver), respectively and 6.9 and 21.6 microM (brain), respectively. Ki estimates were significantly lower with d- than with l-chloroquine; hence, d-chloroquine interacts with the enzyme more effectively than l-chloroquine. If the adverse effects of chloroquine are due to the inhibition of histamine N-methyltransferase, therapy with the l-enantiomer might have lower toxicity. The residual activity of histamine N-methyltransferase should reflect both the degree of inhibition by chloroquine and the level of enzyme expression. The rate of histamine methylation was measured in 100 human liver samples and its range and fold of variation were 29% and threefold, respectively. Susceptibility to chloroquine should be greater in subjects with limited expression of histamine N-methyltransferase

Adult↗
PubMed1994

The concentration-effect relationship of quinine-induced hearing impairment.

Quinine-induced reversible hearing impairment at the frequencies of 1000 and 2000 Hz was investigated in healthy volunteers to analyze the plasma concentration-effect relationship of the drug. Six subjects were given two identical oral doses of quinine and a constant rate infusion of quinine over 6 hours (15 mg.kg-1) on three separate occasions. A simple pharmacodynamic model, E = k.C gamma (in which E is effect, k is a proportionality constant, C is drug concentration, and the exponent gamma is a fitting parameter), was found to describe well the relationship between hearing impairment and quinine concentrations in a hypothetical effect compartment. No statistical differences were found in the estimated parameters when the three dosings were compared, indicating that quinine-induced hearing impairment is independent of route of administration. The first-order rate constant (keo), linking plasma concentrations to the concentrations in the effect compartment, was (mean +/- SD) 0.71 +/- 0.19 and 0.99 +/- 0.37 hr-1 for 1000 and 2000 Hz, respectively. The corresponding values of k were 0.15 +/- 0.10 and 0.12 +/- 0.19 and the values of gamma were 2.13 +/- 0.57 and 3.44 +/- 1.04 for 1000 and 2000 Hz, respectively. Effect was also analyzed by semiparametric pharmacodynamic modeling, which gave results comparable to those obtained with the link model. We conclude that a simple power function is a reliable pharmacodynamic model for describing quinine-induced hearing impairment in healthy subjects.

Administration, Oral↗
PubMed1994

Plasma pentamidine concentrations vary between individuals with Pneumocystis carinii pneumonia and the drug is actively secreted by the kidney.

The multiple-dose pharmacokinetics of pentamidine were studied in six AIDS patients with acute Pneumocystis carinii pneumonia given infusions of pentamidine isethionate 3.7-4 mg/kg/day i.v. Plasma and urine concentrations of pentamidine of repeated samples taken on days 1, 4 and 7 of treatment were assayed by HPLC. Creatinine clearance Clcr was also determined. On day 7, the area under the plasma concentration versus time curve (AUC) varied fourfold (3263 to 12776 nmol.h/L) between individuals. It was lowest in a patient receiving concomitant treatment with carbamazepine, suggesting that this drug may induce the metabolism of pentamidine. On day 7, a mean of 12% of the dose was excreted unchanged in the urine. Clcr was decreased significantly on day 7 compared with day 1 (mean decrease 31%, range 11-63%). Renal clearance of pentamidine (Clr) decreased over time but always exceeded the Clcr, indicating tubular secretion. The decrease of Clr may be explained by capacity-limited secretion and/or a tubulotoxic effect of the drug. The variation of the AUC values is consistent with interindividual differences in rates of metabolism, which supports individual dosing strategies for pentamidine.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Pentamidine accumulates in rat liver lysosomes and inhibits phospholipid degradation.

The subcellular distribution and the effects of pentamidine on the ultrastructure of the rat liver were studied. Rats were given single or repeated daily intraperitoneal injections of 10, 25 or 50 mg pentamidine isethionate/kg b. wt. for 1, 4, 6, 9 or 16 days. The livers were removed for ultrastructural and biochemical analyses on the day after termination of each series of injections and in addition 7 and 35 days after the 16th injection. Electron microscopy of liver tissues showed that the general cellular architecture of the hepatocytes was preserved. The subcellular organelles were normal, except for the secondary lysosomes, which were severely altered and laden with multilamellar, myelin structures (myelin bodies) that gradually increased with dose and time course following repeated injections. These altered lysosomes were enriched in phospholipids. The alteration of the lysosomes persisted for up to 5 weeks after cessation of administration. Pentamidine was highly enriched in the lysosomal fraction (30-50 times more than in the liver homogenate). It was calculated that the lysosomal pentamidine accounted for practically all pentamidine distributed to the liver. The demonstrated accumulation of pentamidine in the lysosomes may explain the known large volume of distribution of this drug and may be one mechanism for organ toxicity.

Animals↗
PubMed1993

Reversed-phase high-performance liquid chromatography determination of quinine in plasma, whole blood, urine, and samples dried on filter paper.

The analysis of quinine in whole blood, plasma, urine, and samples dried on filter paper is described. Extraction was made with toluene followed by back-extraction into phosphate buffer. A reversed-phase liquid chromatography system with fluorescence detection was used. The within-day coefficient of variation of the method was 4-10% at the lower limit of determination (2 nM in plasma and 50 nM in whole blood, dried samples, and urine) and 2-4% at 10 microM. The quinine concentration was found to be lower in whole blood than in plasma (mean ratio, plasma-whole blood, 1.17). The concentration in capillary blood was lower than that in venous blood (mean ratio, capillary blood-venous blood, 0.93).

Capillaries↗
PubMed1992

Plasma concentration clamping in the rat using a computer-controlled infusion pump.

We have developed a computer-controlled infusion pump to achieve rapidly and then maintain stable plasma thiopental concentrations in rats. Initially we derived the parameters of a triexponential pharmacokinetic model for thiopental, administered as a brief infusion to 10 rats, using nonlinear regression and standard pharmacokinetic equations. These parameters were incorporated into the pharmacokinetic model of a computer-controlled infusion pump. In a second group of animals this device was used to maintain three consecutive target thiopental concentrations ranging from 5 to 100 micrograms/ml in a stepwise fashion. Arterial blood gases were kept normal through controlled ventilation when necessary. The plasma thiopental concentrations in this second group of animals were generally higher than the target concentrations. The bias in pump performance (median prediction error) was +25%, and the inaccuracy (median absolute prediction error) was 26%. We fit the parameters of a three-compartment model to the plasma thiopental concentrations observed in the second group of animals. This produced a second set of thiopental pharmacokinetic parameters with the unique characteristic of having been derived from a computer controlled infusion study. These parameters were tested prospectively with a computer-controlled infusion pump in a third group of animals. This second set of thiopental pharmacokinetic parameters performed better, with a median prediction error of 0% and a median absolute prediction error of 15%. This study shows that it is possible to achieve rapidly and maintain steady plasma thiopental concentrations in the rat. Our results suggest that it is feasible to derive robust pharmacokinetic parameters from unusual drug dosing approaches, such as employed by a computer-controlled infusion pump.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A placebo-controlled trial of flumazenil given by continuous infusion in severe benzodiazepine overdosage.

A controlled trial was performed to study the effect and any adverse reactions of continuously infused flumazenil in severe benzodiazepine overdosage. The study comprised 51 adults admitted to an intensive care unit with poisoning. Enrollment criteria were unconsciousness on admission and a clear response within 5 min after an i.v. bolus injection of 1 mg flumazenil. The level of consciousness was assessed according to a modified Glasgow coma scale immediately before and at defined intervals up to 12 h after injection. A double-blind infusion was started 15 min after the bolus injection and administered for 5 h. The patients were randomly allocated to one of three groups: a group given flumazenil 0.5 mg/h, a group given flumazenil 0.1 mg/h and a placebo group. The groups were comparable in age, sex and toxicological laboratory results. There were no significant differences between the groups in the average coma score on admission or 15 min after the bolus injection. In the flumazenil 0.5 mg/h group the level of consciousness remained unchanged between the 15-min recording and the subsequent assessments. In the two other groups the level of consciousness decreased significantly during the course of the infusion. The infusions were well tolerated. It is concluded that a continuous infusion of 0.5 mg of flumazenil per hour can prevent relapse into coma in patients with severe benzodiazepine poisoning aroused with a single injection of the antagonist.

Adolescent↗
PubMed1991

Assay of theophylline: in vivo and in vitro evaluation of dry chemistry and immunoassay versus high-performance liquid chromatography.

In the last decade, kits using dry chemistry have been introduced for analysis of theophylline in biological fluids. We investigated the performance of Ames Seralyzer and Kodak Ektachem 700XR. They were compared to an enzyme immunotechnique (Syva EMIT) and high-performance liquid chromatography (HPLC). Mixed sera from theophylline-treated patients at concentrations of 20, 50, and 80 mumol/L were used. We also investigated the performance of the various methods when assaying theophylline concentrations obtained from individual patients treated or intoxicated with theophylline (n = 35 patients). In within-day analysis, the EMIT method deviated +1- + 9%. the Ektachem 700XR method deviated +2- + 8%, and the Seralyzer method deviated at least + 18% compared to HPLC. Within-day variability was low for all 4 methods. A similar pattern was seen during between-day assay. In five intoxicated patients, EMIT, Seralyzer and Ektachem 700XR deviated at least + 10% compared to HPLC. The Ektachem 700XR method deviated +16- + 36% compared to HPLC, when samples of 240 mumol/L and above were analyzed. Our study shows that theophylline assay kits cannot be recommended in drug analytical laboratories unless specific backup methods are available. EMIT showed the best performance compared to HPLC. Ektachem 700XR gave good results at therapeutic drug concentrations, but was not reliable in intoxicated patients or in those with decreased kidney function.

Adult↗
PubMed1990

Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised controlled study.

OBJECTIVE: To assess the diagnostic value and safety of the benzodiazepine antagonist flumazenil in patients with coma of unclear origin with suspected poisoning. DESIGN: Double blind, placebo controlled, randomised study. SETTING: Intensive care unit at a major teaching hospital. PATIENTS: 105 Unconscious adults admitted consecutively with suspected drug overdosage during 18 months from a total of 362 cases of poisoning. Exclusion criteria were pregnancy, epilepsy, obvious poisoning with drugs identified unequivocally from information from relatives or others as other than benzodiazepines, and coma score greater than 10 on a scale graded from 4 to 20. Patients were allocated randomly to receive flumazenil (21 men and 32 women) or placebo (25 men and 27 women). INTERVENTIONS: Intravenous injection of flumazenil (10 ml, 0.1 mg/ml) or placebo (10 ml vehicle alone) given double blind over three minutes. MAIN OUTCOME MEASURES: Serum and urine concentrations of benzodiazepines, antidepressants, and several other agents; blood gas tensions; standardised evaluation on admission and five minutes after the injection by means of coma scale score and urgent diagnostic or therapeutic interventions indicated according to the history and clinical examination; standardised interview after the injection to try to ascertain further information; and adverse reactions. RESULTS: Benzodiazepines were found in the serum in 36 of the 53 patients in the flumazenil group and in 37 of the 52 who received placebo. The average coma scale score increased significantly after injection in the flumazenil group (6.4 v 12.1, p less than 0.001) but not in the placebo group. In the flumazenil group several interventions were rendered unnecessary by the injection: gastric lavage and urinary catheterisation (19 patients each), intubation (21), artificial ventilation and computed tomography of the brain (three patients each), blood culture and lumbar puncture (one patient each), and electroencephalography (two). In the placebo group the indications for these procedures did not change in any patient after injection. The 95% confidence interval for the difference in reduction of the frequency of indications for gastric lavage after injection between the two groups was 21% to 51%, that for intubation 25% to 55%, and that for urinary catheterisation 21% to 51%. In the flumazenil group 21 patients gave valuable information on their drug ingestion within 10 minutes after injection compared with only one in the placebo group (p less than 0.001). Nine adverse reactions were recorded in the flumazenil group, eight of which were graded as mild and one severe. The safety of the antagonist was acceptable, even though 60% of the patients in the flumazenil group had multiple drug poisoning including benzodiazepine. No epileptic seizures or arrhythmias were recorded. CONCLUSION: Flumazenil is a valuable and safe differential diagnostic tool in unclear cases of multiple drug poisoning.

Adolescent↗