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Biomedical subjects

I Magnussen

Publications and source records attributed to I Magnussen.

At least 19 recordsLinked to original sources
PubMed1994

Passive, intrinsic and reflex-mediated stiffness in the ankle extensors of hemiparetic patients.

The total mechanical response to a stretch in a contracting muscle is the sum of the response from the properties of the fibres contracting prior to the stretch (intrinsic properties), the response from the passive tissues and the response from the stretch reflex-mediated contraction of the muscle fibres. The passive, the intrinsic and the reflex-mediated mechanical response to a 4 degrees stretch of the ankle extensors in both legs of nine spastic hemiparetic patients and, as control, the left ankle extensors in eight healthy subjects were measured. The stretch was imposed at the top of a maintained contraction, which was varied from zero to maximal contraction. The torque increments, measured 200 ms after stretch, were converted into stiffness by dividing by the amplitude of the stretch. We found that the reflex stiffness of the spastic and contralateral leg was within the normal range of the reflex stiffness in healthy subjects, and that the passive stiffness of the spastic and the contralateral leg is larger than the passive stiffness in healthy subjects, whereas the intrinsic stiffness is unchanged in the spastic extensor muscles.

Adult↗
PubMed1985

p,p'-DDT-induced myoclonus in mice: the effect of enhanced 5-HT neurotransmission.

The acute behavioural consequences of intragastric p,p'-DDT in high doses to mice are stimulus sensitive abrupt muscle jerks (myoclonus). The serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) ameliorated in contrast to the natural precursor tryptophan, the neurotoxin-induced myoclonus. The extracerebral decarboxylase inhibitor carbidopa and the selective 5-HT reuptake inhibitor paroxetine both enhanced the antimyoclonic action of 5-HTP. The effect was reversed by the 5-HT receptor blockers cinanserine and methysergide. The data add further evidence to a central serotonergic mechanism involved in p,p'-DDT induced myoclonus.

5-Hydroxytryptophan↗
PubMed1984

Effects of carbidopa on the cerebral accumulation of exogenous L-5-hydroxytryptophan in mice.

The concentration of L-5-hydroxytryptophan (5-HTP) was measured in plasma and whole brain tissue from mice by use of high pressure liquid chromatography with fluorimetric detection after reaction with phthaldialdehyde. 5-HTP was injected intraperitoneally and the rise in plasma and brain 5-HTP concentrations was found directly related to the size of amino acid dose. Carbidopa, an extracerebral inhibitor of L-aromatic amino acid decarboxylation, increased dose dependently the brain bioavailability of systemically administered 5-HTP not only by peripheral enzyme inhibition, but also by inhibition of the decarboxylase activity within the blood-brain barrier as indicated by a rise in the calculated brain/plasma 5-HTP concentration ratio.

5-Hydroxytryptophan↗
PubMed1983

Palatal myoclonus during sleep.

Standard polysomnographic recordings were carried out in three patients with verified diagnoses of palatal myoclonus (PM). Findings showed that PM continued during sleep; its frequency and amplitude varied consistently with different sleep stages. Gradual decrease in rate and amplitude, together with amplitude irregularities, occurred as sleep progressed from light to deep non rapid eye movement sleep. The most characteristic change was seen during rapid eye movement sleep. Here the PM occurred in the form of clusters of two to four high-amplitude movements at rather variable intervals.

Adult↗
PubMed1983

Fluoxetine in the treatment of intention myoclonus.

Some types of intention myoclonus respond to serotonin precursor therapy (e.g., L-5-hydroxytryptophan, L-5HTP). Fluoxetine, a specific serotonin (5HT) uptake blocker, was found to have no antimyoclonic effect when administered by itself to four patients with intention myoclonus. However, in two patients with intention myoclonus responsive to L-5HTP and carbidopa, fluoxetine reduced the required dose of L-5HTP to approximately one-third, with greater antimyoclonic activity, decreased side effects, and reduction in platelet 5HT and plasma 5-hydroxyindoleacetic acid and L-5HTP concentrations. These findings further support the hypothesis that some forms of intention myoclonus are caused by a deficiency of brain 5HT, and suggest that the addition of fluoxetine to L-5HTP and carbidopa may improve antimyoclonic therapy.

5-Hydroxytryptophan↗
PubMed1983

Pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam with an adjunct test of the inattention effect in humans.

Single dose pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam were investigated in 6 younger healthy human volunteers of either sex. The plasma concentration profile after intravenously administered lorazepam could in all cases be fitted by NONLIN to a biexponential function of time with a mean terminal (biological) half-life of 14.10 hrs +/- 2.94 S.D. (range 9.68 - 18.42 hrs). The mean half-life of the initial alpha-phase of distribution was 0.31 hrs +/- 0.11 S.D. The mean apparent volume of distribution derived from AUC, Vd-area (=Vd beta), was 1.24 1 kg-1 +/- 0.17 S.D. Mean plasma clearance of the drug was 62.17 ml kg-1 hr-1 +/- 8.85 S.D. The apparent central volume of distribution characterizing the open two-compartment pharmacokinetic model was 0.59 1 kg-1 +/- 0.19 S.D. After intramuscular administration to the same subjects the plasma concentration time lapse could be described by either tri- or bi-exponential kinetics, which are representative of open two- and one-compartment models with absorption phases, respectively. Mean biological half-life was 14.01 hrs +/- 2.31 S.D. and Vd-area 1.24 l kg-1 +/- 0.14 S.D., both values in full agreement with the findings based on intravenous administration. Half-life of the absorption phase varied from 0.08 to 1.76 hrs. Mean systemic availability of the drug was 88.8% +/- 8.3 S.D. The inattention effect of lorazepam was assessed by exposing the subjects during the intravenous pharmacokinetic experiments to a binaural stimulation test, which revealed various degrees of acute reduced attention in only three of the subjects.

Adult↗
PubMed1982

Human pharmacokinetics of long term 5-hydroxytryptophan combined with decarboxylase inhibitors.

L-5-Hydroxytryptophan (5HTP) and its major metabolites 5-hydroxytryptamine (5HT) and 5-hydroxyindoleaceticacid (5HIAA) were measured in blood and cerebrospinal fluid from neurological patients receiving steady state treatment with 5HTP. There was accumulation of 5HT in blood platelets and 5HIAA in plasma in all patients, despite concomitant administration of the L-aromatic amino acid decarboxylase inhibitors, carbidopa and benserazide. There was no correlation between the 5HTP dose and the circulating concentrations of the aminoacid or its metabolites. Preliminary comparison of the biochemical and therapeutic effects of carbidopa versus benserazide suggest that 5HTP: carbidopa is superior to 5HTP: benserazide. A direct proportionality between plasma 5HTP concentrations and the levels of 5HTP in the lumbar cerebrospinal fluid was found. The binding to serum proteins of 5HTP in the clinically relevant concentration range of 10 to 100 microM was investigated; 19% of circulating 5HTP was bound to serum proteins. 5HTP did not displace protein-bound tryptophan in serum.

5-Hydroxytryptophan↗
PubMed1981

Relationship of inferior olive-climbing fibers to p,p'-DDT-induced myoclonus in rats.

The effects of 3-acetylpyridine (3-AP), which destroys the inferior olive, and harmaline, which stimulates inferior olive-climbing fiber activity, on DDT-induced myoclonus, wee studied in rats. 3-AP shortened and harmaline delayed the time of onset of myoclonus after intragastric administration of DDT. 3-AP also counteracted the antimyoclonic action of L-5-hydroxytryptophan plus chlorimipramine, clonazepam and phenoxybenzamine in this animal model. The results suggest that these antimyoclonic agents require an intact olivocerebellar pathway for their action.

Animals↗
PubMed1981

Plasma accumulation of metabolism of orally administered single dose L-5-hydroxytryptophan in man.

Single oral doses of L-5-hydroxytryptophan (5-HTP) were administered in combination with L-aromatic amino acid decarboxylase inhibitors. The time courses of plasma concentrations of 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) and the concentrations of 5-HT in blood platelets were measured. Carbidopa enhanced the rise in plasma concentrations of 5-HTP 5-15 fold and counteracted the increase in plasma 5-HIAA levels induced by 5-HTP alone. A single dose of the decarboxylase inhibitor was equipotent to 14 days' pretreatment. Plasma or platelet concentrations of 5-HT failed to reflect the metabolism of 5-HTP. The ratio of 5-HTP to carbidopa influenced the systemic bioavailability of single dose administered 5-HTP indicating dose dependent absorption kinetics. Co-administration of L-dopa with 5-HTP and decarboxylase inhibitors had no effect on gastrointestinal absorption of 5-HTP in six parkinsonian patients.

5-Hydroxytryptophan↗
PubMed1980

Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa.

A scleroderma-like illness developed in a patient treated with L-5 hydroxytryptophan (L-5HTP) and carbidopa for intention myoclonus. The patient had high plasma kynurenine levels that remained high when the L-5HTP-carbidopa combination was discontinued, However, levels rose futher on drug rechallenge, suggesting that the drug unmasked an abnormality in one of the enzymes that catabolize kynurenine. Plasma kynurenine was also determined to be high in seven of 15 patients wth idiopathic scleroderma, but not in eight patients with intention myoclonus treated with L-5HTP and a decarboxylase inhibitor and in whom scleroderma did not develop or in 10 patients with Parkinson's disease treated wth L-dopa and carbidopa. Our data and studies in the literature suggest that two factors may be important in the pathogenesis of some scleroderma-like illness: high plasma serotonin and the abnormality associated with elevated kynurenine.

5-Hydroxytryptophan↗
PubMed1980

Plasma induced biotransformation of thymoxamine and its kinetics.

Thymoxamine, 6-acetoxythymol-2-dimethylaminoethyl ether, is a competitive alpha-adrenoceptor blocking agent used as a vasodilator in the treatment of peripheral vascular disorders. The plasma half-life of the drug in vivo is very short. In vitro experiments showed that thymoxamine had a half-life in human plasma of about only 1 min. By using the compound as a substrate in increasing concentrations from 5-320 microgram/ml in the presence of a fixed, low concentration of plasma (0.1% v/v) at pH 7.4 and 37 degrees a hyperbolic correlation was found between the concentration of thymoxamine and the initial rate of formation of the involved reaction product, which was determined by HPLC. A linearized Michaelis-Menten plot indicated an enzymatic biotransformation. A Km-value of about 0.115 mumol ml-1 and a Vm-value of about 0.0037 mumol ml-1 min.-1 were found. Physostigmine, neostigmine and cinchocaine inhibited the biotransformation competitively. This indicated that plasma cholinesterase was the enzyme responsible. The metabolite was identified as desacetylthymoxamine by HPLC, spectrophotometry and direct inlet mass spectrometry.

Biotransformation↗
PubMed1980

Bioavailability and pharmacokinetics in man of orally administered theophylline.

The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3-16 hours and plasma clearance values of about 1.5-115 ml kg-1 hr-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory beta-phase (Vdbeta) were within the range 0.394-0.6161 kg-1 with a mean value of 0.484 1 kg-1 +/- 0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr-1 were found for the administered microparticulate theophylline tablet preparation, Nuelin from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.

Administration, Oral↗
PubMed1980

Bioavailability and related pharmacokinetics in man of orally administered L-5-hydroxytryptophan in steady state.

The bioavailability of orally administered L-5-hydroxytryptophan in steady state was investigated at four increasing multiple dose levels in five patients suffering from various myoclonic disorders. An L-aromatic amino acid decarboxylase inhibitor was co-administered in all the experiments. The disposition pharmacokinetics of the amino acid had been established in the same patients in preceding intravenous single dose experiments. The finding of a direct proportionality between the size of the oral dose level of L-5-hydroxytryptophan and the corresponding areas under the plasma concentration curves within a dosage interval at steady state strongly indicates dose independent, linear pharmacokinetics of the compound. The systemic availability of L-5-hydroxytryptophan exhibited an interindividual range of 47-84%, with a mean value of 69.2% +/- 4.7 S.E.M. The absorption took place at a rather slow rate as judged from times of 1.8 to 3.3 hours elapsing from administration of the compound until occurance of the maximum measured plasma concentrations. Transitory nausea and vomiting were only recognized in few instances during the gradual building up of increasing steady state levels of L-5-hydroxytryptophan in the patients, and the importance of a slow initiation of therapeutical treatment with the amino acid is emphasized.

5-Hydroxytryptophan↗
PubMed1979

Pharmacokinetics of intravenously administered L-5-hydroxytryptophan in man.

The pharmacokinetics of 5-hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acids (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L-aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5-hydroxytryptophan exhibited bi-exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants alpha and beta were 1.433 hr-1 +/- 0.177 S.D. and 0.113 hr-1 +/- 0.012 hr-1 S.D., respectively. The biological half-life of 5-hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, Vc, was found to be 0.336 1 kg-1 +/- 0.059 S.D. and the plasma clearance 0.105 1 hr-1 kg-1 +/- 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5-hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36--128 mg.

5-Hydroxytryptophan↗
PubMed1979

Absorption of diazepam in man following rectal and parenteral administration.

Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121--200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62--186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50 +/- 17 per cent (mean +/- S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.

Absorption↗