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Biomedical subjects

M H Bickel

Publications and source records attributed to M H Bickel.

At least 37 records · Page 2Linked to original sources
PubMed1988

[Side-effects of frequently administered hypnotics and sedatives as well as of anxiolytics. Results from a Comprehensive Hospital Drug Monitoring (CHDM) program].

The occurrence and age distribution of patients with adverse drug reactions (ADR) were studied on the basis of a total of 17,653 admissions to the medical divisions of the Zieglerspital Bern and the Anna-Seiler-Haus, Inselspital Bern, during the period 1976-1982. Among this population 12,424 patients (70.4%) happened to have been treated with hypnotics, sedatives or anxiolytics. Results are as follows: 1. The occurrence rate of psychic and neurologic symptoms (with the exception of somnolence and hangover) is 0.14% of all treatments if the casualty category "definitely or probably drug-induced" is considered. For "other ADR" (non-psychic, non-neurologic) the rate is 0.16%. For the benzodiazepine preparations, the psychic and neurologic ADR occurred at about the same rate as for the neuroleptic drugs studied, whereas "other ADR" related to benzodiazepines were observed in only 0.04% of treatments. 2. There is a marked difference in ADR symptoms between benzodiazepines and neuroleptics. With benzodiazepines the most severe reactions were two episodes of shortlived respiratory arrest immediately after intravenous administration. With neuroleptic drugs the most severe symptoms were choreoathetosis, dyskinesia, hyperkinesia and Parkinson's syndrome. There was no fatal reaction. 3. With benzodiazepines there is a slight but significant increase in the occurrence of psychic and neurologic symptoms in the older group of patients, as compared to the younger patients, whereas with neuroleptics there is no age dependence.

Anti-Anxiety Agents↗
PubMed1988

Differences in adipose tissue distribution of basic lipophilic drugs between intraperitoneal and other routes of administration.

1. Distribution of 14C-methadone in male rats was studied after administration of single i.p. doses. Highest concentrations were attained after 30 min in the decreasing order of abdominal adipose tissues, liver, lung, other organs. Concentrations in abdominal adipose tissues were 20 times higher than in subcutaneous adipose tissue. This is in contrast with what occurs with other routes of administrations, where only low concentrations are attained in both subcutaneous and abdominal adipose tissues. 2. The situation in the peritoneal cavity after i.p. injection was simulated in vitro by incubation of whole, excised abdominal adipose tissues of rats with methadone and other basic drugs (dibenzepine, alprenolol, opipramol, propranolol, chlorpheniramine, desipramine, imipramine and chlorpromazine) for 6 h at pH 7.4. These drugs were readily taken up (25 to 74% at equilibrium). 3. There was a positive correlation between uptake and lipophilicity of the drugs as measured by log P (octanol/water). Less lipophilic drugs such as amphetamine, morphine and chlorphentermine were not appreciably taken up from the incubation medium. The threshold log P-value for appreciable adipose tissue uptake is around 2. 4. It is concluded from these data and related studies that basic lipophilic drugs are not stored in adipose tissues in vivo, except when given via the i.p. route. In the latter case the storage appears to result from non-systemic, diffusional uptake from the peritoneal cavity.

Adipose Tissue↗
PubMed1987

Tissue distribution of phenoxybenzamine in the rat. Lack of adipose tissue storage.

Rats were given the basic lipophilic drug, phenoxybenzamine, in single i.v. doses of 0.4 and 30 mg/kg. The drug was determined in plasma and 7 tissues by a new HPLC method. Adipose tissue reached peak levels after 30 minutes. At that time levels in heart, kidney, and brain were higher than in subcutaneous, epididymal, and mesenteric adipose tissues. The percentage metabolites in adipose tissue, kidney, and liver was 0, 88, and 96, respectively. Pretreatment with SKF 525-A inhibited metabolism and increased the tissue levels of unchanged drug, however, even under these conditions storage in adipose tissues did not occur, the adipose storage index being still less than unity. These results contradict findings of the 1950s which have been repeatedly reported in textbooks and reviews, but they confirm observations that basic drugs, even when highly lipophilic, are not being stored in adipose tissues.

Adipose Tissue↗
PubMed1987

Characterization of drug distribution and binding competition by two-chamber and multi-chamber distribution dialysis.

Binding competition between blood and tissue, a determinant of drug distribution, can be simulated and quantitated in vitro by distribution dialysis. In a study with a standardized two-chamber system, six model drugs, selected according to their ratio of plasma to tissue binding, were allowed to distribute between blood and eight tissue homogenates of rats. The tissue:blood concentration ratios were 1 for antipyrine, less than 1 for salicylic acid and phenylbutazone, slightly greater than 1 for pentobarbital and thiopental, and much greater than 1 for imipramine. Comparable values of tissue:blood ratios were obtained in rats in vivo. A modified dialysis system was developed which allows the simultaneous distribution of a drug between blood and four tissue homogenates. This multi-chamber system was used for homogenates of liver, lung, muscle, and adipose tissue. The drugs tested reached a first apparent distribution equilibrium after 2.5 to 4 h, comparable with the distribution in the two-chamber system, as a result of tissue:blood binding competition. In the following hours there was a redistribution as a result of binding competition among individual tissues, except in the case of pentobarbital. A minor redistribution from muscle to adipose tissue was observed with phenylbutazone, and from muscle to liver with imipramine. There was a considerable redistribution from all tissues, including blood, to adipose tissue with thiopental. In a sequential mode of operation this multi-chamber system was used to simulate the influence of the different perfusion rates of individual tissues by adding the homogenates of muscle and/or adipose tissue several hours after the other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1986

[Acute and chronic toxicity of psychotropic drugs].

Within psychotropic drugs acute toxicity is highest in antidepressants (thymoleptics, MAO-inhibitors, lithium), lower in neuroleptics, and very low in anxiolytics. The order of decreasing chronic toxicity is: neuroleptics, antidepressants, anxiolytics. Each class of psychotropic drugs has a specific toxicological problem. With anxiolytics the major problems stem from their misuse and overuse. With neuroleptics tardive dyskinesia is a serious threat to longterm therapy. Finally, antidepressants are characterized by a low therapeutic index and a resulting high incidence of severe and fatal poisoning cases, both intentional and accidental.

Anti-Anxiety Agents↗
PubMed1986

Uptake of lipophilic model compounds into the isolated perfused rat epididymal adipose tissue.

Uptake of xenobiotics into isolated perfused rat adipose tissue was studied. Aorta and vena cava were cannulated and ligations were placed so that only an epididymal fat pad was perfused. Perfusion experiments were performed in situ and nonrecirculating, for up to 350 min, with Krebs-Ringer bicarbonate buffer containing 4% serum albumin. The functionality of the preparation was tested by an after-perfusion with methylene blue as well as with the volume and mass balances. Formation of edema was not a problem under the experimental conditions used. The following model compounds were used at influx concentrations of 2 to 8 microM: thiopental, imipramine, chlorpromazine, 1,1-bis-(p-chlorophenyl)-2,2-dichloroethane (DDE) and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB). Uptake was determined during the experiments using the arteriovenous difference and after the experiments by direct determination in the perfused fat pad. All five model compounds were taken up readily. Rate of uptake tended to decrease initially and to reach a constant value. Only with 6-CB was the difference between initial and terminal rate considerable. Mean uptake fraction was: thiopental, 38 +/- 8%; imipramine, 69 +/- 4%; chlorpromazine, 85%; DDE, 56%; and 6-CB, 13 +/- 1%. Thus, imipramine and chlorpromazine, which do not accumulate in adipose tissue in vivo, are even taken up more rapidly into the isolated perfused adipose tissue than is thiopental. The difference between these two experimental situations is therefore not due to a permeability barrier, but rather to factors outside the adipose tissue, such as competing nonadipose tissues present in vivo only. For the neutral, insoluble and almost totally albumin-bound compounds, DDE and 6-CB, albumin may act as an additional binding competitor that inhibits adipose tissue uptake.

Adipose Tissue↗
PubMed1985

Uptake in vitro of lipophilic model compounds into adipose tissue preparations and lipids.

In vitro uptake of 11 lipophilic model compounds into rat epididymal adipose tissue slices, adipocytes, triglycerides, and lecithin was studied. Relative uptake at equilibrium into adipose tissue slices increased from 6 to 87% in the following sequence: phenazone, morphine less than pentobarbital less than glutethimide, phenylbutazone less than thiopental, methadone less than chlorpromazine, imipramine. In the presence of albumin a similar sequence was obtained at lower uptake levels, with DDE and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) on top with 95% uptake. However, the time to reach equilibrium was unproportionately greater for DDE and 6-CB (16-40 hr) than for other compounds (1-4 hr). A linear positive correlation was found between relative uptake and partition coefficient (octanol/water). Relative uptake was independent of drug concentration. There were no significant differences between uptake values measured with adipose tissue slices, adipocytes, triolein, and a saturated short-chain triglyceride. In contrast, uptake into lecithin was not correlated with the octanol partition coefficient. Thiopental, imipramine, and 6-CB were taken up into lean tissue slices (liver, lung, skin) in excess of their lipid content, suggesting additional binding sites. Release from preloaded adipose tissue slices followed first order kinetics, was accelerated by albumin, and was much slower for 6-CB and DDE than for thiopental and imipramine. The results indicate that uptake of lipophilic xenobiotics in vitro is a partition process between the aqueous medium and the triglyceride of the adipose tissue preparation. In contrast, the extent of adipose tissue storage of drugs in vivo has recently been shown not to correlate with octanol partition coefficients.

Adipose Tissue↗
PubMed1985

Comparative adipose tissue kinetics of thiopental, DDE and 2,4,5,2',4',5'-hexachlorobiphenyl in the rat.

A comparative study on the fate of thiopental, DDE, and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) with emphasis on adipose tissue kinetics was carried out after single i.v. doses to adult male rats. The time course of the concn. in blood, adipose and other tissues were determined for the three compounds for periods up to 40 h, 14 and 28 d, respectively, allowing for mass balances and for calculation of pharmacokinetic parameters. Appreciable amounts of thiopental, DDE and 6-CB appeared in adipose tissues, but the kinetics were profoundly different, the adipose tissue concn. peaking after one hour, 17 h, and five to six weeks, respectively. Thus, although DDE and 6-CB are much more lipophilic than thiopental, they were very much slower in entering adipose tissue. The results indicate that adipose tissue storage of drugs and other xenobiotics cannot be explained as a simple partition phenomenon. Rather, disposition in adipose tissue may be determined by initial binding in other tissues.

Adipose Tissue↗
PubMed1984

[Not Available].

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Education, Medical↗
PubMed1983

Distribution of chlorpromazine and imipramine in adipose and other tissues of rats.

Adipose tissue kinetics of chlorpromazine and imipramine, two drugs which are more lipophilic than thiopental, were studied in the rat. After single i.v. doses, the time-course of drug distribution was followed in adipose and various other tissues, until their concentrations in adipose tissues declined. Under these conditions the two drugs behaved almost identically. Among the tissues analyzed, the lowest concentrations were found in adipose tissue, with the exception of plasma. At its maximum concentration after about 30 minutes, total adipose tissue contained only 3% of the dose of administered drugs. Adipose/plasma and adipose/lung concentration ratios were 2-5 and 0.05, respectively. After maximum tolerated oral doses of imipramine for 3 weeks, similar steady state concentration ratios (plasma:adipose:brain:lung 1:3:12:96) were observed. In adipose tissue the imipramine/desmethylimipramine ratio was about 1, and the desmethylimipramine steady state levels did not increase with time. Literature data indicate that many basic lipophilic drugs are not stored in adipose tissue. This is now clearly shown for chlorpromazine and imipramine, even under extreme, subchronic conditions in the case of imipramine.

Adipose Tissue↗
PubMed1983

A technique for the comparison of biological distribution and solvent partition of drugs.

A dialysis technique is described which allows the measurement of drug distribution between buffer and solvents as well as between buffer and biological preparations under identical experimental conditions. Partition and distribution coefficients of thiopental, pentobarbital, imipramine, and chlorpromazine were determined using octanol, other solvents, and tissue homogenates.

Animals↗
PubMed1982

[Drug side effects as the probable cause of death. Results of the Berne Comprehensive Hospital Drug Monitoring Program].

During the years 1974-1980, 19 of 17,285 inpatients of the divisions of internal medicine of two teaching hospitals showed a probable or definite adverse drug reaction (ADR) which was considered to be a major cause of death. In 7 patients the decisive ADR occurred during the hospital stay. The overall mortality from ADR is 0.040%. For each therapeutic group of drugs the following rate of drug-related death was calculated: for anticoagulants 0.047% (3/6378 inpatients), for cardiac glycosides 0.016% (1/6368), for analgesic/antirheumatic drugs 0.014% (1/7112) and for cytostatic drugs 0.38% (2/531). In 12 patients the ADR was already present on hospital admission.

Aged↗
PubMed1981

Pharmacokinetics in rats of 2,4,5,2',4',5'-hexachlorobiphenyl, an unmetabolizable lipophilic model compound.

1. Pharmacokinetics of the unmetabolizable lipophilic model compound, 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) was studied in rats, using g.l.c. and 14C methods. 2. After single i.v. doses of 0.6 and 3.6 mg/kg, 16% dose was excreted in 40 weeks in the faeces; the value for infinite time was 17% dose. This limited excretion was first-order with a half-life of 100 days for the terminal component. Urinary excretion was nearly complete after 1 week and amounted to 0.8% dose. 3. 6-CB was redistributed from blood to liver, muscle, skin, and adipose tissue. The latter contained a constant level of about 75% dose from 6 to 40 weeks, while the total lean tissue level fell to 6% dose; only 6-CB in the lean tissue compartment was available for excretion. 4. In rats given six oral doses of 0.6 mg/kg at weekly intervals, excretion and distribution patterns were similar to the single-dose situation, and were thus independent of dose, route of administration, and dose regimen. 5. It is concluded that in rats under physiological conditions, about 75% of every dose of 6-CB is irreversibly stored in adipose tissue and that excretion is limited to 18% dose. 6-CB in rats exhibit novel pharmacokinetics of unmetabolizable lipophilic compounds.

Animals↗
PubMed1980

Drug distribution as a function of binding competition. Experiments with the distribution dialysis technique.

In the distribution dialysis technique each of the two dialysis chambers contains a binding system, and a drug is allowed to distribute between them. This technique was tested by using various intracellular and extracellular binder preparations over wide concentration ranges, and model drugs selected for their known binding properties. The drugs were then tested at therapeutic concentrations in standardized systems of liver homogenate (0.5 g ml-1) and whole blood (0.02 ml ml-1). The resulting intracellular/extracellular concentrations ratios were characteristic for the binding properties of the various drugs. Thus, for imipramine, a drug with strong tissue and weaker plasma binding properties, the concentration ratios were 25 for the system homogenate/buffer, 0.8 for buffer/blood, and 15 for the competitive system homogenate/blood. In experiments with homogenates from various tissues (liver, lung, kidney, intestine, brain) and blood in the standard system, the following approximate ratios were obtained: 1 for antipyrine, 2 for phenylbutazone, 14 for imipramine (but only 8 with muscle, skin and adipose tissue). These results reflect both the individual binding to intracellular and extracellular components and the tissue/blood concentration ratios in vivo. It is suggested that distribution dialysis is an in vitro method for characterizing the distribution of the drugs. It is also concluded that drug distribution is largely determined by a binding competition between tissue and blood sites.

Animals↗