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D Jacobsen

Publications and source records attributed to D Jacobsen.

At least 73 records · Page 4Linked to original sources
PubMed1989

Non-linear kinetics of 4-methylpyrazole in healthy human subjects.

In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase-I study" was performed in healthy male volunteers at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4) and 100 mg.kg-1 (n = 3). In the 10 and 20 mg.kg-1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 mumol.l-1.h-1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this. The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 mumol.l-1.h-1 at 100 mg.kg-1. The average renal clearance of 4-MP was low, 0.016 ml.min-1.kg-1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.

Adult↗
PubMed1989

Ethylene glycol and glycolate kinetics in rats and dogs.

Ethylene glycol (EG) toxicity results from its metabolism to glycolic acid and other toxic metabolites. The accumulation of glycolate and the elimination kinetics of EG and its metabolites are not well understood, so studies with male Sprague-Dawley rats and mixed breed dogs have been carried out. EG was administered by gavage to rats and dogs, which were placed in metabolic cages for urine and blood sample collection at timed intervals. The peak plasma level of EG occurred at 2 hr after dosing and that of glycolate between 4-6 hr. The rate of EG elimination was somewhat faster in rats with a half-life of 1.7 hr compared to 3.4 hr in dogs. The maximum plasma level of glycolate was greater in rats, although the pattern of accumulation was similar to that in dogs. Glycolate disappeared from the plasma at the same time as EG, suggesting a slower rate of elimination of the metabolite than that of EG. Renal excretion of EG was an important route for its elimination, accounting for 20-30% of the dose. Renal excretion of glycolate represented about 5% of the dose. EG induced an immediate, but short-lived diuresis compared to that in control rats. Minimal clinical effects (mild acidosis with no sedation) were noted at these doses of EG (1-2 g/kg) in both rats and dogs. The results indicate that the toxicokinetics of EG and glycolate were similar in both species.

Animals↗
PubMed1988

Ethylene glycol intoxication: evaluation of kinetics and crystalluria.

Ethylene glycol and glycolate kinetics were studied in two cases of ethylene glycol intoxication with maximal ethylene glycol/glycolate concentrations of 40.9/26.8 and 56.4/22.4 mmol/liter, respectively. Both patients survived, but with prolonged renal failure, upon treatment with bicarbonate, ethanol, and hemodialysis. Glycolic acid was the major cause of the metabolic acidosis in both cases; lactate levels were only slightly elevated. Kinetic calculations showed that both ethylene glycol and glycolate were distributed in total body water with plasma half-lives of 8.4 and 7.0 hours, respectively. The half-life of ethylene glycol was increased more than 10-fold by ethanol treatment alone. Calcium oxalate monohydrate crystalluria was dominant in both cases, but in one was preceded by a short period with mainly dihydrate excretion; crystalluria was not present upon admission. Repetitive urine microscopy in search of needle- or envelope-shaped crystals should be performed when ethylene glycol intoxication is suspected.

Acidosis↗
PubMed1988

4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses.

4-Methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, is a possible future drug for the treatment of methanol and ethylene glycol intoxications and the severe ethanol-disulfiram reaction. Therefore a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase I study" was performed in healthy volunteers in order to determine the tolerance of 4-MP at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4), and 100 mg/kg (n = 3). Along with each dose group, there were two placebos except with the 100 mg/kg group where there was only one placebo. In the 10 and 20 mg/kg group there were no side-effects in any subject. At the 50 mg/kg level, three out of four subjects experienced slight to moderate nausea and dizziness from 0 to 2.5 h after dosing. In the 100 mg/kg group all three subjects reported side-effects like nausea, dizziness, and vertigo, that were short-lived in two subjects, but lasted up to 30 h in one subject. The study was stopped after evaluation of the latter subject, so fewer subjects were completed in this last group. Despite these subjective side-effects, there were no significant changes in objective clinical parameters like pulse, blood pressure, body temperature, or blood and urine chemistries. We conclude that at a single dose of 4-MP (10-20 mg/kg) producing plasma levels within a probable therapeutic range, no side-effects were attributed to 4-MP.

Adult↗
PubMed1988

Haemodialysis or haemoperfusion in severe salicylate poisoning?

Two cases of severe salicylate poisoning with maximal plasma levels of 6.9 and 8.9 mmol/l are described. In addition to supportive treatment and forced alkaline diuresis, one case was treated with haemoperfusion and the other with haemodialysis. The use of the same blood pump and blood flow allowed us to compare directly the effect of these methods in removing salicylate. There was a non-significant higher dialysance (mean 86 ml/min, s.d. +/- 8) than haemoperfusion clearance (mean 81 ml/min s.d. +/- 17) at a blood flow of 200 ml/min. As haemodialysis offers the theoretical advantage of correcting acid-base and electrolyte disturbances, does not trap platelets and has a lower heparin requirement, the present comparison indicates that haemodialysis is preferable when extracorporal elimination is indicated in salicylate poisoning.

Acid-Base Equilibrium↗
PubMed1987

Determination of ionic metabolites from ethylene glycol in human blood by isotachophoresis.

Conditions for isotachophoretic determination of anionic metabolites in blood from ethylene glycol in poisoned humans were established. Leading electrolytes with 5 mM chloride and and 2.5 gave good separation. Optimal separation was found with leading electrolytes at pH 2.5, and 10 mM acetic acid as terminating electrolyte. Separation and quantification of four out of six metabolites were possible. The four were glycolic acid, glyoxylic acid, oxalic acid and formic acid. Besides these compounds, citric acid, lactic acid, and alpha- and beta-hydroxybutyric acid were separated and quantified. The formation of mixed zones did not give any serious problems, although in samples with high amounts of glycolic acid we had to reduce the maximum injected amount from 3 to 1 microliter. This method might be valuable in further studies of the mechanism of ethylene glycol toxicity and as an important supplement in the diagnosis of late stages of ethylene glycol poisoning in which the glycol has been metabolized to glycolic acid.

Electrolytes↗
PubMed1987

Effect of regulatory withdrawal of drugs and prescription recommendations on the pattern of self-poisonings in Oslo.

A two-year prospective study of 1350 admissions for self-poisoning, covering the Oslo area was undertaken to identify the sources of the toxic agents. After the first year of the study, four barbiturates were withdrawn from the Norwegian market and recommendations were made by the Health Authorities to promote more restrictive attitudes when prescribing psychoactive drugs. The patterns of self-poisonings in the two periods were compared. The withdrawal of four barbiturates resulted in a 55% decrease in the rate of barbiturate poisonings in general (p less than 0.001). No increase could be detected in the rate of self-poisoning with benzodiazepines and other hypnotics, but the incidence of self-poisonings with antidepressants (p less than 0.01) and neuroleptics (p less than 0.01) was found to have increased significantly. The regulations and recommendations resulted in a significant decrease in drugs obtained from doctors randomly consulted (p less than 0.01), and a significant increase in drugs prescribed by psychiatrists (p less than 0.01). Drugs obtained from non-medical sources increased from 28% in the first period to 33.2% in the second. The total number of admissions and toxic agents taken remained unaltered. Thus, regulatory measures can influence the pattern of self-poisoning but do not seem to influence the tendency to abuse drugs or to take an overdose.

Adolescent↗
PubMed1987

Lithium intoxication: pharmacokinetics during and after terminated hemodialysis in acute intoxications.

Pharmacokinetics of lithium were studied in 4 females acutely intoxicated with lithium with maximal plasma concentrations of 8.7, 4.0, 3.4 and 1.3 mmol/l. Mean plasma dialysance values were 103, 105, 102 and 89 ml/min compared to mean renal clearance values of 13, 16, 20 and 30 ml/min, respectively. A rebound effect in plasma concentration suggested that the sum of the dialysance and renal clearance overestimated the total body clearance of lithium during hemodialysis. During hemodialysis the measured half-lives of the plasma lithium levels in three cases were 4.8, 3.4 and 2.3 hours compared to the corrected values of 12.0, 7.3 and 6.2 hours respectively, when this rebound effect was taken into consideration. These corrected half-lives were 30-66% of the control half-lives recorded later when each patient served as her own control, thus illustrating the effectiveness of hemodialysis in removing lithium. Forced diuresis with sodium chloride did not significantly increase renal lithium elimination.

Adult↗
PubMed1987

Meprobamate kinetics during and after terminated hemoperfusion in acute intoxications.

We report four cases of severe meprobamate intoxication. Maximal plasma levels reached 800 (176), 816 (180), 863 (190) and 923 mumol/l (203 mg/l). All patients survived without sequelae including one patient resuscitated from cardiac arrest. The clinical course was complicated by coma, hypotension, and hypothermia in all patients. Three cases were treated with charcoal hemoperfusion with mean hemoperfusion clearance ranging from 134-164 ml/min compared to 174 ml/min in one case treated with resin filter and the same blood flow of 200 ml/min. In two cases, a mean renal meprobamate clearance of 15 and 23 ml/min was calculated comprising only 9-15% of the hemoperfusion clearance. The amount of meprobamate removed by hemoperfusion ranged from 1.6-6.2 g. In one case, the half-life of plasma meprobamate during hemoperfusion was 2.6 hours compared to 8.3 hours after hemoperfusion. Thus the half-life was reduced more than 3-fold. These data show that hemoperfusion may be indicated in severe meprobamate intoxication.

Adult↗
PubMed1986

Self-poisoning and the menstrual cycle.

A study of the menstrual cycle phase on day of admission was conducted on 156 women with regular menstruation admitted for self-poisoning to a medical department. No relation of statistical significance was found between the day of self-poisoning and the menstrual cycle phase. This was also the case when a distinction was made between suicidal and non-suicidal attempts and between the main toxic agents taken. The findings are partly in contrast to earlier investigations.

Adolescent↗
PubMed1986

Self-poisoning and moon phases in Oslo.

During 1980 the relation between the moon phases and 1187 cases of self-poisonings in Oslo was studied. In contrast to a previous report from India no significant correlation was found between the full moon and self-poisoning. The aetiology of self-poisonings in western countries is rather more complex than to be explained by speculative 'human tidal waves'.

Astronomical Phenomena↗
PubMed1984

Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning.

Charcoal haemoperfusion was performed for 5-12 h in three patients with maximal plasma phenobarbital concentrations of 600, 946 and 1044 mumol/l (138, 217 and 240 micrograms/ml). During haemoperfusion with constant blood flow phenobarbital elimination followed first order kinetics with half-lives of 11.1, 10.0 and 7.2 h, respectively. After termination of the haemoperfusion there was no rebound effect in plasma phenobarbital concentration and the elimination was first order with half-lives of 51, 82 and 48 h, respectively. Thus, the plasma phenobarbital half-life was reduced by 78-88% during haemoperfusion. In the same period 76-86% of the total body clearance of phenobarbital was due to the haemoperfusion column at a calculated volume of distribution of phenobarbital of 1.1-1.21/kg. This is clear evidence for recommending haemoperfusion in cases of serious poisoning with phenobarbital.

Adult↗
PubMed1984

A prospective study of 1212 cases of acute poisoning: general epidemiology.

A prospective multicentre study of all acute poisonings among adults admitted to hospital (n = 1145) or dying outside hospital (n = 67) in Oslo was performed during 1980. Of the 1212 episodes, 98.3% were self-poisonings, giving an annual incidence of 2.8 per 1000 inhabitants (0/00), 3.1 0/00 in males and 2.6 0/00 in females. The main toxic agents among the self-poisoned patients were ethanol (19.7%), benzodiazepines (17.8%), opiates (14.9%), neuroleptics (10.4%) and antidepressants (9.3%). In 58.9% of the episodes more than one toxic agent was taken. Abuse among the self-poisoned patients was significantly (p less than 0.005) more common among males than females (64.2 v. 34.5%). The rate of suicide attempts was significantly (p less than 0.005) higher among females than males (20.2 v. 12.9%), females showing increasing rate with age. However, when excluding abusers the rate of suicide attempts was similar in both sexes (27.6 v. 25.0%). Compared to a reference population self-poisonings were most common in the lower middle and the lowest social classes. Patients in these social classes, however, showed a lower rate of suicide attempts than those in the two highest social classes. Overall mortality was 6.0% (n = 73), but 91.8% of all deaths occurred outside hospital indicating the importance of including these figures when self-poisonings are studied.

Acute Disease↗