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Biomedical subjects

T Thomsen

Publications and source records attributed to T Thomsen.

32 records · Page 2Linked to original sources
PubMed1991

Pharmacokinetics of galanthamine in humans and corresponding cholinesterase inhibition.

Measurements were done to determine the plasma concentrations of galanthamine and two of its metabolites, as well as the corresponding inhibition of acetylcholinesterase activity in erythrocytes after applying 5 and 10 mg galanthamine hydrobromide as a constant-rate intravenous infusion for 30 minutes and single oral doses of 10 mg in eight healthy male volunteers. The data obtained revealed first-order pharmacokinetics, complete oral bioavailability, and a mean terminal half-life of 5.68 hours (95% confidence interval, 5.17 to 6.25 hours). Renal clearance accounted for only 25% of the total plasma clearance (CL = 0.34 L.kg-1.hr-1). Only negligible quantities of the putative metabolites, epigalanthamine and galanthaminone, were detected in blood and urine. The inhibition of acetylcholinesterase activity was closely correlated with the pharmacokinetics of galanthamine, a median maximal value of 53% being achieved by applying 10 mg galanthamine intravenously. Analysis of in vitro and ex vivo concentration responses revealed no differences, indicating that no metabolites of galanthamine exert additional inhibition of acetylcholinesterase activity.

Acetylcholinesterase↗
PubMed1991

Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galanthamine, physostigmine and tacrine.

Galanthamine, physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (tacrine) were evaluated as inhibitors of human acetylcholinesterase activity from samples of postmortem human brain, fresh brain cortex biopsies and human erythrocytes. Acetylcholinesterase activity was most effectively inhibited in all tissues by physostigmine, followed by tacrine and galanthamine. The respective inhibitor concentrations exerting a half maximal effect (IC50) on acetylcholinesterase in postmortem human brain frontal cortex were 14 nmol/l, 1.0 mumol/l and 3.2 mumol/l versus 15 nmol/l, 1.1 mumol/l and 2.8 mumol/l in the hippocampus region. In addition, the inhibition of acetylcholinesterase by galanthamine was similar in postmortem brain and brain cortical biopsies from patients submitted to brain-tumour removal, indicating that postmortem changes up to 28 h after death probably did not influence the measurement of acetylcholinesterase inhibition. While physostigmine and tacrine acted equally on acetylcholinesterase from different sources, galanthamine was 10-fold less potent in inhibiting the enzyme activity from human brain that from human erythrocytes. Comparison with issues from mice revealed that galanthamine was selectively more potent in suppressing acetylcholinesterase in human erythrocytes. The results are discussed in the light of pharmacokinetic data, and conclusions are drawn for further clinical studies.

Acetylcholinesterase↗
PubMed1991

Acute poisoning with bromofosmethyl (bromophos).

One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl, CAS: 2104-96-3 (bromophos), a 52 year-old female was admitted to the hospital with extreme miosis, hypersalivation, hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos, hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4, the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates, red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis, hyperperistalsis, hypersalivation, agitation, nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative, parathion.

Adolescent↗
PubMed1991

Pericardial patch angioplasty.

The authors describe the case of a man with severe left coronary ostial stenosis who was treated with direct left main angioplasty with a pericardial patch. This approach may be superior to artery bypass grafting in certain patients.

Coronary Angiography↗
PubMed1990

Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans.

The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36-55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5-7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.

Administration, Oral↗
PubMed1990

Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo.

We investigated the inhibition of human cholinesterases by galanthamine, an alkaloid of the common snowdrop (galanthus nivalis). In vitro, the compound showed potent enzyme inhibition and 50-fold selectivity for acetylcholinesterase (EC 3.1.1.7) as opposed to butyrylcholinesterase (EC 3.1.1.8). There was no difference between enzyme inhibition by galanthamine in whole blood and separated fractions of plasma and erythrocytes. We conclude that galanthamine does not accumulate in large amounts in red blood cells. In vivo, administration of galanthamine in a healthy volunteer and in a patient who underwent long-term treatment confirmed the selectivity of galanthamine for acetylcholinesterase.

Administration, Oral↗
PubMed1989

A suitable method to monitor inhibition of cholinesterase activities in tissues as induced by reversible enzyme inhibitors.

A radiometric method has been used to estimate in vivo activities of cholinesterases in various tissues in the presence of reversible inhibitors. Determination of the samples was performed with the lowest possible degree of dilution to avoid reactivation of the enzyme which would prevent reliable calculation. Dose-response curves and concentration-response curves were performed using physostigmine and tetrahydroacridine, two reversible anticholinesterases in clinical use. Specific inhibition of acetyl- and butyrylcholinesterase was performed using BW284C51 and iso-OMPA, respectively.

Acetylcholinesterase↗
PubMed1989

[The hall--reflections on the site of open interaction between patients and the therapeutic team].

Starting from an apparent every-day situation in daily clinic life--the encounter between patients and therapeutic team in a sojourn chosen by the first ones--reflections are made about patterns of relations shown there. These contain partly complicated transference - and counter-transference-mechanisms and represent an always new challenge for the team to deal with the own professional role and the engagement toward the mentally sick.

Countertransference↗
PubMed1988

Estimation of cholinesterase activity (EC 3.1.1.7; 3.1.1.8) in undiluted plasma and erythrocytes as a tool for measuring in vivo effects of reversible inhibitors.

In vivo effects of reversible inhibitors of cholinesterase activity were determined radiometrically in undiluted samples of erythrocytes and plasma. [14C]acetylcholine at substrate saturation, 25 degrees C and pH 7.4 permitted rapid and precise determination of butyrylcholinesterase (EC 3.1.1.8) and acetylcholinesterase (EC 3.1.1.7) activities. Reference values for acetylcholinesterase and butyrylcholinesterase were estimated in the plasma and erythrocyte haemolysate of 102 healthy volunteers. The time course of in vitro inhibition was monitored, starting immediately after addition of 9-amino-1,2,3,4-tetrahydroacridine (tacrine), eserine or pyridostigmine to undiluted human plasma. Maximal inhibition (in vitro) was seen within 60 min with tacrine and eserine, in contrast to 180 min with pyridostigmine. The inhibition remained constant for more than 10 h except with eserine, from which enzyme activity showed an early recovery. Concentration response experiments were performed in undiluted human plasma and undiluted human erythrocyte haemolysate. Ki-values of tacrine, eserine and pyridostigmine were estimated. In contrast to pyridostigmine and eserine, tacrine was found to have a higher affinity for butyrylcholinesterase than for acetylcholinesterase. Tacrine at 2.5 mumol/l resulted in complete inhibition of butyrylcholinesterase and 70% inhibition of acetylcholinesterase activity. Dilution of these samples up to 100-fold was accompanied by almost complete recovery of acetylcholinesterase and by 50% recovery of butyrylcholinesterase.

Acetylcholinesterase↗
PubMed1987

Cardiovascular actions in vitro and cardioprotective effects in vivo of nileprost, a mixed type PGI2/PGE2 agonist.

Cardiovascular, platelet- and neutrophil-inhibitory effects of the chemically stable prostacyclin analog nileprost (5-cyano-16-methyl-PGI2) (NIL, ZK 34798) were studied in vitro and in a feline model of acute myocardial ischemia in vivo. Isolated bovine coronary arteries were relaxed by NIL at low concentrations (less than 3 microM), whereas higher concentrations produced a marked vasoconstriction. NIL inhibited human platelet aggregation and reduced the coronary vascular resistance of Langendorff-perfused rabbit hearts. Myocardial contractile force and oxygen consumption were not affected. The superoxide anion generation of stimulated granulocytes was modestly antagonized by NIL. NIL (0.5 microgram/kg/min intravenously, i.v.) protected the left ventricular myocardium of cats subjected to 5 h of coronary artery ligation from ischemic injury, as evidenced by the reduction in ischemia-induced ST-segment elevation, prevention of the large increase in plasma creatinine kinase (CK), and loss of myocardial CK and free amino nitrogen. These effects and the extent of cardiac protection by NIL were comparable to those of PGI2 (0.2 microgram/kg/min), whereas PGE2 (1.5 microgram/kg/min) was less effective. The data demonstrate a combination of PGI2-like and PGE2-like activities for NIL in vitro and a significant cardioprotective action of NIL in vivo.

Animals↗
PubMed1984

Early and late administration of a PGI2-analogue, ZK 36 374 (iloprost): effects on myocardial preservation, collateral blood flow and infarct size.

A number of investigations have reported that prostacyclin or prostacyclin analogues protect the ischaemic myocardium when administered early after myocardial ischaemia. Thus far, there are no reports describing whether these substances exert a cardioprotective effect when administered later than 0.5 h after coronary artery occlusion. Adult cats were subjected to acute coronary artery ligation for 5 h and administered the vehicle or ZK 36 374 (iloprost) (1.19 micrograms X kg-1 X min-1), a prostacyclin analogue, beginning at 0.5, 2 or 4 h. Compared with the MI-vehicle cats, ZK 36 374 prevented a decrease in myocardial creatine kinase specific activity, the loss of free amino nitrogen and the fall in percentage bound cathepsin D in the ischaemic area when infusion was started at 0.5 or 2 h (P less than 0.05). In addition ZK 36 374 started at 4 h still showed a significant protective effect against myocardial creatine kinase specific activity and amino nitrogen concentrations but not against cathepsin D. In a separate group of animals, regional myocardial blood flow and late coronary resistance were determined with radioactive labelled 15 +/- 1 micron microspheres. ZK 36 374 consistently reduced late diastolic coronary vascular resistance and increased coronary blood flow in nonischaemic regions of the myocardium (P less than 0.05) but only attenuated the further increase in late coronary resistance in the ischaemic myocardial regions. The infarcted area (NTB-staining) amounted to 9% of the total left ventricle after 5 h and was not reduced by ZK 36 374 (P greater than 0.05). In conclusion, ZK 36 374 exerted a significant biochemical cardioprotective effect when administered to 0.5, 2 or 4 h. The mechanism of cardioprotection does not appear to be due to increased myocardial perfusion but rather to some direct cellular action whose exact nature has yet to be elucidated.

Animals↗
PubMedDate not supplied

Functional magnetic resonance imaging (fMRI) study of sex differences in a mental rotation task.

The main purpose of the present study was to: 1) to investigate differences between males and females in brain activation when performing a mental rotation task, 2) investigate hemisphere differences in brain activation during mental rotation. Brain activation was measured with functional magnetic resonance imaging (fMRI). Image acquisition was performed with a 1.5 Tesla Siemens Vision MR scanner equipped with 25 m T/m gradients. Scanning of anatomy was done with a T1-weighted 3D FLASH pulse sequence. Serial imaging with 70 BOLD sensitive echo planar (EPI) whole brain measurements was done during stimulus presentations, divided into 7 blocks of 10 EPI multi-slice volume measurements each. Eleven subjects were presented with black-and-white drawings of 3-D shapes taken from the set of 3-D perspective drawings developed by Shepard and Metzler [1], alternated with 2-D white bars as control stimuli. In the experimental condition, the subjects were shown 36 pairs of 3-D drawings, presented in three blocks of 12 pairs of drawings. The drawings were always presented pairwise. On half of the trials, the two 3-D shapes were congruent but portrayed with different orientation, in the other half the two shapes were incongruent. MR data were analyzed with the SPM-96 analysis software. After subtraction of activity related to the 2-D control stimuli, clusters of significant activation were found in the superior parietal lobule (BA 7), more intensely over the right hemisphere, and bilaterally in the inferior frontal gyrus (BA 44/45). Males showed predominantly parietal activation, while the females showed inferior frontal activation. It is suggested that males and females may differ in the processing strategy used when approaching a 3-D mental rotation task, males using a 'gestalt' strategy and females using a 'serial' reasoning strategy.

Adult↗