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Biomedical subjects

O Beck

Publications and source records attributed to O Beck.

At least 55 records · Page 3Linked to original sources
PubMed1995

Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.

The effect of the aldehyde dehydrogenase inhibitors disulfiram (Antabuse) and cyanamide (calcium carbimide, Dipsan) on the metabolism of serotonin measured as relative amounts of the metabolites 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol in urine were studied in alcoholic patients. Sixteen out of 23 patients receiving drug therapy showed elevated excretion of 5-hydroxytryptophol. However, there was a marked, 15-fold, variability in 5-hydroxytryptophol excretion rate between patients. A high degree of variability was also seen in another group of patients studied before and after introduction of drug therapy. When patients were followed during the dose interval, a time-dependent response after each single dose could be observed. The disulfiram response lasted over the course of several days whereas the response to cyanamide lasted for less than 12 hr. It is concluded that treatment with disulfiram and cyanamide affects serotonin metabolism leading to increased production of 5-hydroxytryptophol, but there is a marked inter-individual variability in degree of response.

Adult↗
PubMed1995

Distinguishing ingested ethanol from microbial formation by analysis of urinary 5-hydroxytryptophol and 5-hydroxyindoleacetic acid.

During the metabolism of ethanol, the metabolic conversion of serotonin (5-hydroxytryptamine) is altered, and, as a consequence, the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) excreted in urine increases appreciably. The ratio of metabolites remains elevated for several hours after ethanol is no longer detectable. In the present study, urine specimens were supplemented with glucose and Candida albicans, a common human pathogenic yeast, and the formation of ethanol and the changes in the 5HTOL/5HIAA ratio were examined during one week of storage. Despite the production of high concentrations of ethanol (peak level 171 mmol/L, or 788 mg/dL), the 5HTOL/5HIAA ratio remained constant. The urinary 5HTOL/5HIAA ratio was also compared with urinary and blood ethanol levels in specimens selected at random during forensic autopsies. Elevated 5HTOL/5HIAA ratios were found in all specimens with detectable urinary ethanol. Some specimens showed elevated ratios of serotonin metabolites even though no ethanol was detected, indicating that these subjects had consumed ethanol prior to death but that the concentration had already returned to zero or was below the detection limit. In one case, postmortem ethanol formation was suspected, because blood ethanol concentration was 16.8 mmol/L (77 mg/dL) whereas urinary ethanol was zero. The urinary 5HTOL/5HIAA ratio fell within normal limits, which confirmed the suspicion of postmortem ethanol synthesis in the blood specimen. The present results indicate that the 5HTOL/5HIAA ratio in urine provides a useful method to distinguish between ethanol that might have been synthesized postmortem, or generated in vitro, from ethanol excreted in urine as a result of drinking.

Adult↗
PubMed1994

Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release.

Using in vivo microdialysis, changes in extracellular dorsolateral striatum and nucleus accumbens dopamine, GABA and acetylcholine following acute and chronic haloperidol (0.25 mg/kg, s.c.) were evaluated in rats concurrent with the measurement of catalepsy. When administered to drug-naive and chronically treated rats, haloperidol was associated with a consistent and prolonged (> 150 min) increase in dorsolateral striatum and nucleus accumbens DA release and a transient (60 min) increase in dorsolateral striatum GABA release. Haloperidol was also associated with a transient (30 min) increase in dorsolateral striatum acetylcholine release in the chronically treated rats. Basal dopamine and acetylcholine levels were similar in both brain regions; however, basal dorsolateral striatum GABA levels were two-fold higher in the chronically treated rats. Administration of haloperidol was associated with a prolonged (> 150 min) catalepsy in the drug-naive rats which was greatly diminished or absent in chronically treated rats. Additionally, serum haloperidol levels were shown to be similar 120 min following administration of haloperidol in both groups. These results indicate a marked behavioral difference in the effects of haloperidol in drug-naive and chronically treated rats which is not related to an altered bioavailability of the drug and which is dissociated from both basal and haloperidol induced effects on dopamine and acetylcholine release in both brain regions. However, the selective elevation of basal dorsolateral striatum GABA release following chronic administration of haloperidol may contribute to the development of tolerance to catalepsy as well as providing an in vivo neurochemical marker of the long-term effects of haloperidol.

Acetylcholine↗
PubMed1994

Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis. A possible mechanism of reduced hepatotoxicity.

OBJECTIVE: To evaluate the effects of a single dose of chloroquine (CQ) on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: Eleven patients (ages 41-75 years) who were taking oral doses of MTX (15 mg/week) were studied after a dose of MTX alone and after a dose of MTX plus CQ (250 mg). Plasma and urine samples were collected for 24 hours after dose intake, and the concentrations of MTX and its major metabolite 7-hydroxymethotrexate were determined by high-performance liquid chromatography. RESULTS: Administration of CQ together with MTX caused a reduction in the area under the plasma MTX concentration versus time curve (AUC). The median value of individual AUC ratios (MTX/MTX + CQ) was 1.6 (95% confidence interval 1.2-3.6). CONCLUSION: The most likely mechanism for the interaction is that CQ reduces the bioavailability of MTX. This gives a possible explanation for a suggested reduction in MTX-associated liver toxicity by coadministration of CQ. The significance of the interaction for the therapeutic effect remains to be elucidated.

Adult↗
PubMed1994

Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.

A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.

Administration, Oral↗
PubMed1994

Influence of genetic variation in alcohol and aldehyde dehydrogenase on serotonin metabolism.

The influence of genetic variation in alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3) on the metabolic pattern of serotonin (5-hydroxytryptamine, 5-HT) in humans was examined from the relative urinary concentrations of the end products 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL). Healthy Caucasian (Swedish) and Oriental (Chinese) subjects were genotyped for ADH2, ADH3 and ALDH2 by a PCR/SSCP technique. The 5-HTOL/5-HIAA ratios ranged between 0.9-9.4 pmol/nmol (4.4 +/- 1.8, mean +/- SD, n = 143). No significant difference in the 5-HT metabolic pattern was observed between Caucasians and Orientals (4.3 +/- 1.8 and 4.4 +/- 1.8 pmol/nmol, respectively), nor between any of the ADH2, ADH3 and ALDH2 genotypes. Despite the modulatory effects of genetic variation of these enzymes on ethanol metabolism, the present results indicate that the individual isozyme composition of ADH2, ADH3 and ALDH2 is not important for the metabolic pattern of 5-HT.

Alcohol Dehydrogenase↗
PubMed1994

Methotrexate in rheumatoid arthritis--a limited sampling strategy for estimation of the area under the plasma concentration versus time curve.

A limited sampling strategy for determination of the area under the plasma concentration versus time curve (AUC) of methotrexate (MTX) in patients with rheumatoid arthritis (RA), treated with weekly oral doses, has been validated. Stepwise linear regression analysis was used for optimal inclusion of data points in mathematical models to estimate AUC. A new plot for evaluation of the accuracy and precision of the estimated AUC values was introduced in the present study. By plotting the ratio of determined/estimated AUC values versus estimated AUC values, the influence of number of sampling points on the precision and accuracy of estimated AUC values was easily validated. Our results show that AUC values of MTX in RA patients can be estimated from a single plasma sample at 3 h or preferably, due to increased precision, by additional samplings at 5 and 1 h. A further increase of the number of sampling points increased the precision of the AUC estimates only to a minor extent. The accuracy of the estimated AUC values was independent of the number of sampling points. A limited sampling procedure can now be used for further studies on the relationship between MTX levels and its effects.

Administration, Oral↗
PubMed1994

Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia.

Platelet function was studied in 10 patients with familial hypercholesterolaemia, following lipid-lowering treatment with selective LDL-apheresis and with the HMG-CoA reductase inhibitor pravastatin. Platelet function was assessed before, and 2, 5 and 14 days after LDL-apheresis, and before and after 4 weeks of pravastatin therapy. Both treatments significantly reduced total- and LDL-cholesterol, whereas LDL-apheresis also reduced VLDL-cholesterol. Lp(a)-levels were reduced by LDL-apheresis and elevated by pravastatin treatment. Pravastatin therapy significantly enhanced platelet aggregability in vivo, as measured by ex vivo filtragometry. Plasma serotonin levels also increased. Other markers of in vivo activation of platelets, i.e. beta-thromboglobulin in plasma and urine, and 11-dehydro-thromboxane B2 in urine were unaltered. Adenosine diphosphate-induced platelet aggregation in vitro remained unchanged during pravastatin therapy, and the platelet volume distribution was not affected. LDL-apheresis reduced the mean platelet volume, as well as the percentage of large platelets, whereas the percentage of small platelets increased. Other measures of platelet function in vivo or in vitro were, however, unaltered following LDL-apheresis. Thus, pravastatin therapy enhances certain aspects of platelet aggregability in vivo, whereas a single treatment with selective LDL-apheresis does not consistently affect platelet aggregability during resting conditions. These results do not support the concept that reduction of LDL-cholesterol improves platelet function in hypercholesterolaemic patients, at least not in the short-term. However, the reduction of platelet volume after LDL-apheresis may be beneficial for patients receiving this therapy regularly.

Adult↗
PubMed1994

Deficient performance of drugs of abuse testing in Sweden: an external control study.

Testing for drugs of abuse in urine is usually performed in two steps; after initial screening positive findings are confirmed with specific chromatographic techniques. The use of different methods with different cut-off levels, may lead to variable results in a test sample containing a drug. Sixty-eight Swedish laboratories were enrolled in an external quality study and received three control samples. The laboratories were instructed to perform only in-house tests for amphetamines, benzodiazepines, cannabinoids, cocaine and opiates. Nineteen out of the 68 laboratories reported fully correct results. Thirty reported one o more false positive drug findings. One laboratory performing confirmation with gas chromatography--mass spectrometry reported a false positive finding of amphetamines in the sample containing ephedrine. Since testing for drugs of abuse in urine is a delicate matter, with both medical and legal implications, such testing should be performed with a zero rate of false positive results. Routine use of specific methods for confirmation should be used since performance of these laboratories was better in this study. It is concluded that there is a need to continuously measure the level of quality of laboratories by a program for external quality control.

Amphetamines↗
PubMed1994

Detection of relapses in alcohol dependent patients using serum carbohydrate deficient transferrin: improvement with individualized reference levels.

Alcohol dependent male outpatients were monitored for a period of six months. Indicators of alcohol consumption were compared using clinical information three times per week, serum levels of carbohydrate deficient transferrin (CDT) weekly and urine samples of 5-hydroxytryptophol daily. Individualized reference values of CDT were calculated by using an increase of three times the lowest coefficient of variation in the group, which meant that an increase of < or = 30% from the lowest value of each individual was considered a significant increase, and therefore an indication of alcohol consumption. By this approach, it was possible to improve the ability to detect relapses in alcohol dependent patients using serum CDT once a week compared to CDT using reference values recommended by the manufacturer.

Alcohol Drinking↗
PubMed1994

The use of 5-hydroxytryptophol as an alcohol intake marker.

5-Hydroxytryptophol (5HTOL) occurs naturally in animals as a metabolite of serotonin. Ethanol interacts with serotonin metabolism to increase the production of 5HTOL at the expense of 5-hydroxyindoleacetic acid (5HIAA). This can be used clinically in the treatment of alcohol dependence to improve the detection of relapse in alcohol drinking, by monitoring daily the urinary 5HTOL/5HIAA ratio. In one experiment the sensitivity of this marker in detecting alcohol drinking the previous day was more than 10-fold greater than measuring urinary ethanol. Genetic polymorphism in alcohol and aldehyde dehydrogenases, which is known to influence the ethanol metabolism, does not confound the clinical use of 5HTOL as a marker. Disulfiram and cyanamide, however, will elevate urinary 5HTOL/5HIAA ratio.

Alcohol Drinking↗
PubMed1993

On the accurate determination of serotonin in human plasma.

Serotonin (5-hydroxytryptamine, 5-HT) in blood is stored in platelets and has vascular and platelet stimulating effects when released into plasma. Accurate measurements of 5-HT in plasma are complicated by inadvertent platelet activation causing sampling artifacts and by analytical problems when determining trace levels. We developed an assay for plasma 5-HT based on solid-phase extraction (Sep-Pak C18), aqueous acetylation, pentafluoropropionylation, and negative ion chemical ionization gas chromatography-mass spectrometry. The method was able to recover 5-HT from plasma by > 90% and to quantitate with a precision of 7.5% at a level of 0.5 nmol/l. It was used to define blood sampling and sample handling procedures giving low and consistent values for 5-HT. A good blood sampling technique, adequate platelet stabilization in the test tube, and rapid high speed centrifugation of the blood resulted in low plasma levels of both 5-HT and beta-thromboglobulin (a platelet release product). Using these procedures plasma 5-HT levels in healthy volunteers were found to be 0.77 +/- 0.38 (mean +/- S.D.; range 0.27-1.49) nmol/l (n = 18), which is 4-100-fold lower than previously reported values.

Adult↗
PubMed1993

Time course of ethanol-induced changes in serotonin metabolism.

The effect of acute ethanol consumption on serotonin metabolism was examined in healthy volunteers in the fasted and fed state by determination of plasma and urinary levels of the serotonin metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL). The plasma and urinary levels of 5-HIAA were reduced by about 40% and 25%, while the 5-HTOL levels were increased on an average 7-fold and 50-fold, respectively, after oral intake of ethanol (0.8 g/kg) over 30 min in a fasted state. The maximal effect on both 5-HIAA and 5-HTOL levels was found 4-6 h after starting drinking. Urinary 5-HTOL and the 5-HTOL/5-HIAA ratio did not return to baseline until 19 h after the start of the administration (i.e., about 10 h after ethanol reached zero level). The mean 24-h excretion of 5-HTOL was increased 15-fold by the ethanol intake, while the 5-HIAA excretion was not significantly different. A clear dose dependent effect was observed in one individual who also ingested a lower amount of ethanol (0.5 g/kg). When ethanol (0.8 g/kg) was ingested over 3 h together with food, the urinary level of 5-HTOL and the 5-HTOL/5-HIAA ratio did not return to baseline until after 20-22 h. In other subjects who had unlimited access to ethanol and ingested between 1.3-2.3 g/kg together with food, the time to reach baseline 5-HTOL/5-HIAA ratio in urine ranged from 20 h to over 26 h.

Adult↗