[A case of lethal theophylline poisoning. Slow-release preparation gave treacherous and late symptoms].
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Adult↗
Biomedical subjects
L L Gustafsson
Publications and source records attributed to L L Gustafsson.
Determination of metrifonate and dichlorvos in whole blood using gas chromatography and gas chromatography-mass spectrometry.
Analytical methods for determining metrifonate and dichlorvos in whole blood and a sampling procedure suitable for pharmacokinetic studies in man are described. Metrifonate concentrations were determined after chloroform extraction using gas chromatography-nitrogen-phosphorus detection. The within-assay coefficients of variation were 4 and 9% at 19.4 and 0.8 mumol/l (limits of determination), respectively. Dichlorvos was determined using gas chromatography-mass spectrometry of toluene extracts. The within-assay coefficients of variation were 2 and 5% at 225 and 50 nmol/l (limits of determination), respectively. Since both substances are chemically unstable, the blood was collected by dripping it directly from the vein into 0.74 M phosphoric acid.
Chromatography, Gas↗
Metrifonate in healthy volunteers: interrelationship between pharmacokinetic properties, cholinesterase inhibition and side-effects.
Metrifonate concentrations in plasma, its inhibition of blood cholinesterase, and side-effects were studied in 16 healthy volunteers who received a single oral dose of 2.5, 5, 7.5 or 15 mg/kg in a randomized double-blind study (4 subjects for each dose). Metrifonate was determined by a gas chromatographic method. Peak plasma levels were reached within 2 hours; the half-life in plasma, oral clearance, and normalized Cmax and AUCs did not differ significantly between the four groups. Plasma cholinesterase (BuchE) was inhibited to low levels in all subjects, while erythrocyte cholinesterase (AchE) was affected in a dose-dependent fashion. The occurrence of side-effects correlated strongly with peak plasma levels but not with maximum AchE inhibition or with increase in salivation. This study shows that the absorption of metrifonate was not significantly different for doses between 2.5 and 15 mg/kg. The plasma levels of this drug correlated with the occurrence of side-effects.
Adult↗
Field trial of the efficacy of a simplified and standard metrifonate treatments of Schistosoma haematobium.
In a randomized double-blind study, the percentage egg reduction and cure rate after the standard schedule of metrifonate treatment of Schistosoma haematobium (3 doses of 7.5 mg.kg-1 at two-weekly intervals; A) and an abbreviated regimen (3 doses of 5 mg.kg-1 in one day; B) were compared in five villages in Somalia. 300 patients who were excreting 20 or more eggs of S. haematobium in 10 ml urine were recruited. The patients were classified according to their home villages and were then, randomly allocated to treatment A or B. They had similar ages, weights and egg output. Each patient received 3 doses of metrifonate and 2 doses of identical appearing placebo. Group A received metrifonate on the 1st, 4th and 5th dosing occasions and placebo on the 2nd and 3rd times. Group B received metrifonate on the 1st, 2nd and 3rd dosing times and placebo on the 4th and 5th times. Two hundred and one patients were followed up from 1 to 6 months. The remaining 99 (33%) patients either did not complete treatment or were lost during follow up. Egg reduction in the groups 1, 2, 3 and 6 months after treatment were 97, 97, 95 and 93% in Group A and 96, 96, 94 and 92% in Group B (NS). Corresponding cure rates for Group A were 52, 50, 48 and 44%, and in Group B they were 47, 48, 43 and 40% (NS). Seven patients from Group A and 9 from Group B complained of minor side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Poor patient compliance reduces the efficacy of metrifonate treatment of Schistosoma haematobium in Somalia.
The degree of compliance during metrifonate therapy of Schistosoma haematobium infection has been evaluated together with its impact on drug efficacy in two rural villages in Somalia. Drug treatment was offered to all subjects with S. haematobium infection. 243 subjects were screened for the presence of eggs in the urine using a sensitive Nucleopore filtration method and 211 were positive. All infected patients were put on a treatment schedule of 3 doses of metrifonate 7.5 mg/kg at fortnightly intervals. Drug efficacy was evaluated 6, 12 and 32 weeks after treatment. Only 48% of the patients took all 3 doses, 15% took 2 doses and 37% only took 1 dose. The cure rate was maximal in Week 6 at 60, 44 and 30% in those who took 3, 2 and 1 dose, respectively. Corresponding egg reduction rates were 98, 90 and 84%, respectively. Drug efficacy throughout the follow up period was much greater in patients who complied with all 3 doses. It is unlikely that the goal of mass treatment programmes for endemic S. haematobium in villages in Africa will be realized due to poor compliance with the current dosage schedule for metrifonate of 3 doses of 7.5 mg/kg at fortnightly intervals.
Adolescent↗
Distribution of 11C-labelled morphine and pethidine after spinal administration to Rhesus monkey.
The kinetics of 11C-labelled morphine and pethidine were studied by positron emission tomography (PET) at different levels of the spinal canal (C4, T4, T5, T6, L1 and L6). Studies were performed in the Rhesus monkey after intrathecal and extradural administration of the drugs at the lumbar level (L3-L4 or L4-L5, seven experiments). Radioactivity 100-300 times higher than with even distribution in the body was measured initially near the site of injection for both morphine and pethidine, irrespective of the route of administration. After injection of pethidine, high activity was observed at the L6 and L1 levels, whilst the radioactive uptake was lower at T6 (10-20% of those at lumbar level). Morphine-derived 11C-radioactivity showed more constant levels along the spinal canal, except at C4 where radioactivity was low. In CSF taken from the cervical level the peaks of radioactivity of the two drugs appeared 80-170 min after injection. The importance of different distribution routes was quantified in a pharmacokinetic compartment model, using the above results. The systemic distribution was extensive, irrespective of drug or route of administration. From the site of injection the systemic distribution was at least 60 times larger than the rostral distribution within the spinal canal.
Animals↗
Clinical experience of long-term treatment with epidural and intrathecal opioids--a nationwide survey.
Long-term use of spinal opioids to treat chronic severe pain is widely established. However, the indications, shortcomings and complications of the method have not been completely described. Experience with spinal opioids was analysed for the period 1979-1984 in a nationwide Swedish survey. Out of 93 anaesthesia departments, 69 used the method. Approximately 750 patients were treated with epidural morphine for an average duration of 124 days (3-450). Eighteen patients were treated with intrathecal morphine for an average period for 47 days (3-90). The intrathecal approach was used in all clinics because of failure of the epidural route. In only one department was the intrathecal approach used as the primary route of therapy, depending on the mechanism of pain. The highest daily morphine dose was 480 mg and 50 mg for epidural and intrathecal routes, respectively. The patients given the highest dosages were not necessarily those subjected to the longest treatment. The need for increased dosage seems to be related not only to changes in receptor sensitivity but also to changes in pain mechanisms. No case of threatening ventilatory depression was reported. Thirty-two departments had treated a few patients with chronic non-cancer pain conditions. Initial results were considered "excellent" in 11 departments, but at follow-up results were excellent in only one department. In addition to dislocation, occlusion of the catheters or leakage, injection pain was an obstacle to successful treatment. Pruritus urinary retention, and local infections were not reported as significant problems, but one case of meningitis was reported.
Anesthesia Department, Hospital↗
Spinal opioid analgesia. A critical update.
Small spinal (intrathecal or extrathecal) doses of opioids induce a long-lasting and regional analgesic effect in various experimental animal models. Nowadays extrathecal morphine administration is considered an established method of controlling postoperative and cancer-induced pain conditions. The potency of morphine applied by the spinal route is higher than when the drug is applied by the intravenous (IV) route. Opioids which are more lipophilic than morphine will provide a marginally better analgesic effect when administered by the spinal route as compared with the IV route. Several controlled clinical trials in postoperative patients have demonstrated that a single dose of morphine administered by the spinal route gives a more long-lasting action than a similar IV dose. It is not known whether frequent patient-controlled administration of morphine may provide equally good analgesia without additional side effects. The use of spinal morphine in the treatment of cancer-related pain is based on clinical experience only. There are risks in replacing opioid administration by the oral or IV route with spinal opioids. Morphine should only be used in selected cases until the advantage of spinal opioid analgesia to control postoperative and cancer pain has been clearly defined in well-designed clinical studies. Spinal morphine dosages must be individualised according to the intensity of the nociceptive stimuli and should take into account intra-individual variability in drug responses due to pharmacokinetic and pharmacodynamic factors.
Analgesia↗
Monitoring quinidine concentrations in serum: discrepancies in results by fluorometry and immunoassay.
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Fluorometry↗
A simplified dosage schedule of metrifonate in the treatment of Schistosoma haematobium infection in Somalia.
We have carried out an open clinical study in Somalia to evaluate the efficacy and safety of a simplified dosage schedule of metrifonate in the treatment of Schistosoma haematobium infection. The doses used were: I. 10 mg X kg-1 once daily for 3 days II. 5 mg X kg-1 thrice daily for one day III. 7.5 mg X kg-1 thrice daily for one day. We screened a total of 550 subjects in four villages for egg excretion in urine, and selected patients with more than 200 eggs per 10 ml of urine. In the initial phase of the study eight patients were assigned to each of the three dose schedules. In an extended study 38 additional patients were treated with regimen II which gave the best outcome in the initial study. Dosage Schedules I and III turned out to be toxic, and none of the patients was treated with all three doses. Adverse effects, such as abdominal colic, nausea, salivation, dizziness, and headache, were seen in almost all the patients in those two groups. Two patients from Group I reported that they fainted within 2 h after the second dose. None of the patients in Group II reported adverse effects. After 4-6 weeks follow-up, egg reduction was 96-100% for Groups I and II and the cure rate was around 60%. This study has shown that a shorter course of treatment with metrifonate might be equally effective and safer than the recommended dosage schedule with three doses of 7.5-10 mg X kg-1 fortnightly.
Colic↗
Present state of extradural and intrathecal opioid analgesia in Sweden. A nationwide follow-up survey.
A nationwide follow-up survey was undertaken to study the use of extradural and intrathecal opioids in the management of pain, to estimate the incidence of delayed ventilatory depression and to study post-injection surveillance routines. A questionnaire was sent to all 93 anaesthetic departments in Sweden; 96% responded. The major indication for using extradural opioids was the treatment of postoperative, traumatic and cancer pain. During 1984 over 14,000 patients received extradural, and over 1100 patients intrathecal, opioids. Morphine was the predominant opioid for extradural administration and was used in 96% of patients. Extradural opioid analgesia constitutes about 25% of all extradural blocks performed in Sweden. Pruritus and urinary retention were considered as minor problems; however, the risk was considerably higher after intrathecal morphine. The incidence of delayed ventilatory depression was about 1:1100 (0.09%) following extradural morphine and 1:275 (0.36%) following intrathecal morphine. Risk factors for delayed ventilatory depression are discussed. Administration of extradural morphine for postoperative pain relief in patients undergoing major surgery is considered a high benefit-low risk technique by most Swedish anaesthetists. The results of the present nationwide survey suggests that, following extradural morphine, surveillance of patients for more than 12 h appears unnecessary.
Adult↗
Chloroquine excretion following malaria prophylaxis.
Urinary excretion of chloroquine and its desethyl-metabolite was monitored for up to 395 days after the last dose of oral chloroquine (300 mg base) taken once weekly for 10 weeks as malaria prophylaxis. Concentrations in plasma could be followed for up to 70 days after the last dose. A three exponential decay was applied to the urinary excretion data. The half-life of the terminal phase varied from 45 to 55 days for chloroquine and from 59 to 67 days for the metabolite. Mean residence time was approximately 20 days for the parent compound and 35 days for the metabolite, indicating that the terminal phases are of less importance for the effective half-lives.
Adult↗
Positron emission tomography: an animal model of spinal distribution of drugs after intrathecal administration.
An animal model has been developed in the Rhesus monkey for noninvasive monitoring of CSF transport of drugs by external detectors i.e. positron emission tomography. The model compromises the cannulation of the subarachnoid space (with a spinal needle), and has been used without any damage to the monkey. With the method it was shown that injection rate had a major influence on the transport rate of 68GaCl3 in the CSF. Injection of 0.5 ml over 60 sec gave the highest radioactivity near the injection site, whereas an injection rate of this volume over 10 sec resulted in high radioactivity more rostrally shortly after injection. This method have been of value for the determination of drug kinetics after spinal administration.
Animals↗
Extradural and parenteral pethidine as analgesia after total hip replacement: effects and kinetics. A controlled clinical study.
Twenty-one patients who had undergone total hip replacement were randomly assigned to one of three groups in order to compare a single dose of 1 mg/kg of pethidine im (I) and 20 mg (II) or 60 mg of extradural pethidine (III) in a double-blind design. The degree of analgesia, the adverse effects, and the kinetics were studied for 18 h. Pain was monitored using a visual analogue scale (VAS). Supplementary doses of oxycodone if required were given no earlier than 0.75 h after pethidine. Plasma concentrations of pethidine were measured with gas chromatography mass spectrometry (GCMS). Hypoalgesia to pin prick test was evaluated. Low pain scores were observed in the extradural groups between 0.25 and 1.5 h after the dose. A significant difference in pain score compared with the im group was found after the higher extradural dose only between 0.5 and 1 h (p less than 0.05). The area under the curve (AUC) of pain score versus time (0-18 h) was not significantly different between groups. The recorded adverse effects were minor in all three groups. The terminal half-lives and plasma clearances of pethidine, and the time to peak concentration were not different between the groups. Single patients in the extradural groups showed hypoalgesia to pin prick in parallel to the effect. The present study shows that extradural pethidine produces shortlived analgesia, in contrast to the long-lasting effect of morphine found in other studies.
Aged↗
Tolerance and pilot pharmacokinetics of amiflamine after increasing single oral doses in healthy subjects.
Oral doses of 1 to 100 mg amiflamine, a new reversible monoamine oxidase type A-selective inhibitor, were given for the first time in humans to six healthy men. No apparent pharmacologic effects were recorded until the 80 mg dose. After 100 mg, one subject developed symptoms indicative of an overdose. Amiflamine is extensively metabolized by two consecutive N-demethylations. The biotransformation patterns in plasma and urine were found to correlate with the debrisoquin metabolic ratio.
Adult↗
Pressor response of oral tyramine in healthy men given amiflamine and placebo.
During two baseline challenge tests, oral tyramine (50 to 400 mg) was given to 12 healthy men to find each individual's cardiovascular pressor response. All 12 subjects "tolerated" 200 mg oral tyramine, but three of the 12 developed an increment in systolic blood pressure greater than 30 mm Hg when given a dose of 400 mg. Thereafter, amiflamine, 5 mg bid (n = 8), or placebo, 1 capsule twice a day (n = 4), were given in a double-blind fashion for 7 days, and oral tyramine challenge tests (12.5 to 400 mg) were given on days 5 to 7. During dosing with amiflamine or placebo, no subject tolerated 400 mg oral tyramine and no difference between the two regimens was found with regard to tyramine response. Plasma concentrations of amiflamine and two of its metabolites were measured on days 4 to 7. Steady-state concentrations were reached within 4 to 5 days. Plasma concentrations of tyramine after 400 mg tyramine showed a positive correlation with the increase in systolic blood pressure (P less than 0.001).
Administration, Oral↗
Evaluation of three qualitative tests for detection of chloroquine in urine--agreement with plasma concentrations determined with liquid chromatography.
Three qualitative tests for detection of chloroquine in urine were compared and evaluated against concomitant plasma concentrations determined with liquid chromatography. All urine tests from five volunteers taking a single dose of 5 mg chloroquine base kg-1 were positive for at least ten days with the Haskins test, and for at least three days with the Wilson Edeson test. Even on the first day, the Dill-Glazko test indicated chloroquine in the urine of one volunteer only. After a single dose of 10 mg kg-1 to five other volunteers the Haskins test was uniformly positive for 14 days while the Wilson Edeson test was positive for four days. The Dill-Glazko test was positive for one day only. No false negative results were obtained with the Haskins test when plasma concentrations were above 0.03 mumol 1(-1), as compared to 0.11 mumol 1(-1) with the Wilson Edeson test. The Dill-Glazko test was uniformly positive when plasma concentrations were above 0.38 mumol 1(-1). The Dill-Glazko test was affected by low urinary pH and by addition of erythrocytes to urine. We conclude that the Dill-Glazko test should not be used.
Chloroquine↗
Clinical pharmacological evaluation of an assay kit for intoxications with tricyclic antidepressants.
The performance of an enzyme immunoassay kit (EMIT) to diagnose intoxications with tricyclic antidepressants was compared with a high performance liquid chromatography (HPLC) technique in vitro and in vivo. The cut-off reference solution contained in the kit of nominally 1,140 nM nortriptyline varied from 1,250 to 1,600 nM. In vitro addition of antidepressants gave positive results (change in absorbance above the cut-off value) of approximately 1,100 nM for amitriptyline, imipramine, and desmethylimipramine and approximately 1,600 nM for clomipramine and desmethylclomipramine. In contrast, high concentrations of the tetracyclic antidepressant maprotiline (7,000 nM) and the bicyclic zimeldine (2,000 nM) gave negative results. False positive results were obtained with high concentrations of thioridazine (4,000 nM), chlorpromazine (300 nM), and alimemazine (trimeprazine) (5,000 nM). Of 51 patient samples, five gave readings above the cut-off value, consistent with a tricyclic antidepressant intoxication, but two of these were false positives as compared with the specific HPLC analysis. However, no false negative results were obtained with the EMIT. In conclusion, the EMIT kit is likely to detect intoxications with tricyclic antidepressants but miss intoxications with nontricyclic antidepressants. For a screening method, this is a serious drawback, since maprotiline and zimeldine together make up approximately 25% of the total of antidepressants used in Sweden. Users of the kit must also be aware that certain phenothiazines in high therapeutic doses or in intoxication cases could interfere with this test and might lead to the false diagnosis of intoxication with tricyclic antidepressants.
Antidepressive Agents, Tricyclic↗