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Biomedical subjects

E Weber

Publications and source records attributed to E Weber.

At least 235 records · Page 13Linked to original sources
PubMed1990

Risk factors for adverse drug reactions--epidemiological approaches.

Age by itself is not an important risk factor for ADRs. Age-related changes are the consequence of a number of individual factors, for example morbidity associated with polypharmacy, decline in renal or liver function in the elderly, hypoalbuminaemia, reduced body weight, etc. The relationship between gastrointestinal bleeding and non-steroidal anti-inflammatory drugs can be assessed globally in large cohort studies with access to computerized data, but complete accuracy requires access to the original patient records. The increase in the risk of GI bleeding in users of NSAIDs and aspirin was 50% above that in non-users. About a quarter of ADRs in hospitalized patients seem not to arise from purely pharmacological mechanisms. They are mainly due to allergic, anaphylactoid, or idiosyncratic reactions and to intolerance. In such non-pharmacological reactions, the time of exposure, reaction time, and even dosage may be important factors in identification of the causal drug. The use of benzodiazepines can be optimized by taking into account potency, time of action and the different syndromes encountered after withdrawal. Following long-term use problems of relapse and rebound are being increasingly recognized, in addition to organic withdrawal symptoms. In psychiatric patients extrapyramidal disorders due to neuroleptics are common. The rates of these ADRs differ markedly between various drugs, even after dosages and co-medications are taken into account. Epidemiological screening for potentially carcinogenic drugs can only be done in large cohorts of patients with pre-recorded full information sets as may be found in an HMO (Health Maintenance Organization). The findings of several such studies have been published in specialist cancer journals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles.

Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation. 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes. 10 subjects who eliminated the drug rapidly (S1-10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0-96) of the parent drug in S11 was 145 micrograms.ml-1 h. and in the other individuals it averaged 18.3 (11.4-24.5) micrograms.ml-1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77-5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1-10 amounted to 20.1 (11.9-41.2) h for M1, and 17.2 (12.9-30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.

Adult↗
PubMed1990

Synthesis and structure-activity relationships of N,N'-di-o-tolylguanidine analogues, high-affinity ligands for the haloperidol-sensitive sigma receptor.

With an eye toward the development of novel atypical antipsychotic agents, we have studied the structure-affinity relationships of N,N'-di-o-tolylguanidine (DTG, 3) and its congeners at the haloperidol-sensitive sigma receptor. A number of DTG analogues were synthesized and evaluated in in vitro radioligand displacement experiments with guinea pig brain membrane homogenates, using the highly sigma-specific radioligands [3H]-3 and [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and the phencyclidine (PCP) receptor specific compounds [3H]-N-[1-(2-thienyl)-cyclohexyl]piperidine and [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine. The affinity of N,N'-diarylguanidines for the sigma receptor decreases with increasing steric bulk of ortho substituents larger than C2H5. Hydrophobic substituents are generally preferred over similarly positioned hydrophilic ones. Furthermore, electroneutral substituents are preferred over strongly electron donating or withdrawing groups. Significant binding to the sigma receptor is usually retained as long as at least one side of the guanidine bears a preferred group (e.g. 2-CH3C6H5). Replacement of one or both aryl rings with certain saturated carbocycles (e.g. cyclohexyl, norbornyl, or adamantyl) leads to a significant increase in affinity. By combining the best aromatic and best saturated carbocyclic substituents in the same molecule, we arrived at some of the most potent sigma ligands described to date (e.g. N-exo-2-norbornyl-N'-(2-iodophenyl)guanidine, IC50 = 3 nM vs [3H]-3). All of the compounds tested were several orders of magnitude more potent at the sigma receptor than at the PCP receptor, with a few notable exceptions. This series of disubstituted guanidines may be of value in the development of potential antipsychotics and in the further pharmacological and biochemical characterization of the sigma receptor.

Animals↗
PubMed1990

Left ventricular filling in hypertensive blacks and whites following adrenergic blockade.

Left ventricular diastolic filling was investigated in 12 black and 15 white subjects before and after double-blinded randomized treatment of mild to moderate hypertension with combined alpha- and beta-adrenergic receptor blockade (labetalol) and beta-blockade alone (atenolol). At baseline (off medication), both groups were similar for age (46 +/- 8 years v 48 +/- 12 years), mean blood pressure (121 +/- 8 mm Hg v 115 +/- 8 mm Hg), left ventricular dimensions, left ventricular mass index (118 +/- 24 g/m2 v 113 +/- 13 g/m2), and left ventricular filling as reflected by transmitral flow velocity ratio A/E (0.97 +/- 0.33 v 0.92 +/- 0.19, normal age-matched control A/E ratio is 0.64 +/- 14). There were 6 blacks and 6 whites in the labetalol group; 6 blacks and 9 whites in the atenolol group. At six weeks of treatment, whites in the labetalol group showed a significantly greater drop in mean blood pressure (114 +/- 7/102 +/- 11, P less than .007 v 123 +/- 9/114 +/- 11, P = NS) and correspondingly greater improvement in A/E ratio (1.04 +/- 0.14/0.74 +/- 0.23, P less than .024 v 1.02 +/- 0.23/0.89 +/- 0.16, P = NS). However, this difference was no longer significant when controlling for age and blood pressure level. In the atenolol group, whites showed a significant increase in the rapid filling phase velocity E, while late filling phase velocity A significantly dropped only in blacks, without significant improvement in A/E ratio in either subgroup. In conclusion, greater improvement in left ventricular filling is seen with combined alpha-beta-blockade than beta-blockade alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The purine-cytosine permease gene of Saccharomyces cerevisiae: primary structure and deduced protein sequence of the FCY2 gene product.

A 2.1 kb DNA segment carrying the purine-cytosine permease gene (FCY2) of Saccharomyces cerevisiae was sequenced, the primary structure of the protein (533 amino acids) deduced and a folding pattern in the membrane is proposed for the permease protein. Expression of the FCY2 gene product requires a functional secretory pathway and is reduced in mnn9, a mutant strain deficient in outer chain glycosylation. The FCY2 gene was mapped on the right arm of chromosome V close to the HIS1 gene.

Amino Acid Sequence↗
PubMed1990

(+)-[3H]MK-801 binding sites in postmortem human brain.

The pharmacological specificity and the regional distribution of the N-methyl-D-aspartate receptor-associated 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) binding sites in human postmortem brain tissue were determined by binding studies using (+)-[3H]MK-801. Scatchard analysis revealed a high-affinity (KD = 0.9 +/- 0.2 nM, Bmax = 499 +/- 33 fmol/mg of protein) and a low-affinity (KD = 3.6 +/- 0.9 nM, Bmax = 194 +/- 44 fmol/mg of protein) binding site. The high-affinity site showed a different regional distribution of receptor density (cortex greater than hippocampus greater than striatum) compared to the low-affinity binding site (cerebellum greater than brainstem). The rank order pharmacological specificity and stereoselectivity of the high-(cortex) and low-(cerebellar) affinity binding sites were identical. However, all compounds tested showed greater potency at the high-affinity site in cortex. The results indicate that (+)-[3H]MK-801 binding in human postmortem brain tissue shows pharmacological and regional specificity.

Aged↗
PubMed1990

Effects of corn oil addition to the diet on the energy metabolism of heart, liver and kidney of female rats.

Female rats (SIV-50, Sprague Dawley) given a diet enriched with corn oil (10% and 25% addition to rat chow, w/w) for four weeks showed changes in the energy metabolism of heart, liver and kidneys, that is, changes in oxygen consumption and uncoupling of oxidative phosphorylation of heart, liver and kidney mitochondria, concomitant to a decrease in heart mitochondrial creatine kinase activity and an increase in heart mitochondrial creatine content. The high fat diet also affected calcium binding and Na/K-, Mg- and Ca-ATPases of a cardiac myocyte membrane fraction. Lipid feeding also led to increase (biphasic and transient) of phospholipids, triglycerides and free fatty acids in the three organs studied, but in no case to hypertrophy.

Adenosine Triphosphatases↗
PubMed1990

[Extracardiac risk factors in heart surgery--drugs].

Preoperative long-term medication continued during and after cardiac surgery may cause dangerous situations, including risks due to drug interactions, and risks as a result of contraindications to previously beneficial substances that develop during the surgical procedure. In the case of a lege-artis-performed anesthesia there is no urgent reason to postpone cardiac surgery because of previous drug treatment. Nevertheless, some compounds or groups of therapeutic agents can cause undue risk. These drugs are: acetylsalicylic acid (known to increase the bleeding tendency), and cardiac glycosides (which produces intraoperative dysrhythmias). Tricyclic antidepressants considerably intensify the effects of sympathomimetic agents. Monoamine-oxidase inhibitors, especially when combined with indirectly acting sympathomimetic agents or pethidine, may cause fluctuations of blood pressure that are difficult to control or can even precipitate a hypertensive crisis. In these cases preoperative discontinuation of drugs needs to be considered. The time of discontinuation must be chosen selectively for each active substance. The most important point for prevention of drug-related risk is to take a precise medical history, including previous drug treatment, in order to take future intraoperative precautions.

Contraindications↗
PubMed1990

Pharmacokinetics of technetium-99m-MAG3 in humans.

Technetium-99m-mercaptoacetylglycylglycylglycine (99mTc-MAG3) is introduced to replace o-iodohippurate (OIH) for renal function studies. For interpretation of clinical findings, extensive pharmacokinetic studies were performed on patients. These showed that 99mTc-MAG3, compared with OIH, has a higher plasma-protein binding, an essentially higher intravascular concentration, a smaller volume of distribution and, with practically identical biologic half-lives, a correspondingly lower clearance. Simultaneous steady-state measurements resulted in a 1.5-fold higher clearance of OIH than of 99mTc-MAG3 (n = 124). Competitive inhibition of the tubular transport system by p-aminohippurate (PAH) (20 patients) revealed a distinctly higher suppression of the 99mTc-MAG3 clearance than of OIH which indicates a lower affinity of the 99mTc complex to the tubular cell. The plasma extraction efficiencies of both agents, measured during surgery (n = 5), did not indicate an extrarenal elimination of 99mTc-MAG3. This new radiopharmaceutical is a pragmatic alternative to OIH and offers advantages not only for scintigraphic imaging but is also suited for quantitative renal function studies.

Humans↗
PubMed1990

Trisomy 4: a specific karyotype anomaly in primary and secondary acute myeloid leukemia.

Trisomy 4 as single karyotype anomaly has recently been proposed as an acute myeloid leukemia (AML) specific aberration. Up to now, 20 cases have been reported in which the single abnormality occurred without additional chromosomal aberrations. Trisomy 4 has been found in both primary and secondary AML, the majority of cases being diagnosed as FAB M4 or M2 subtypes. In the cytogenetic analysis of 305 patients with AML, we found 209 cases with aberrant karyotypes, among them two patients (22a, male, M2; and 69a, male, M4) with trisomy 4 as single aberration. The younger patient achieved complete remission lasting 13 months and survived 22 months whereas the older patient died in aplastic phase due to septicaemia 5 weeks after admission. Trisomy 4 is proposed to be the primary aberration in both these cases of de novo AML. Although in one case, as in two cases reported earlier, cytogenetic results were only available in first relapse, we have no indication that trisomy 4 appeared in a secondary induced leukemia, because the leukemic blasts of the relapse were morphologically identical to first acute phase. In contrast to other specific chromosomal aberrations, results indicate that trisomy 4 has as yet no prognostic relevance concerning the clinical outcome.

Adult↗
PubMed1990

Internalization of endothelin by cultured human vascular smooth muscle cells: characterization and physiological significance.

The binding and internalization of 125I-endothelin (125I-ET-1) was studied in cultured human vascular smooth muscle cells (hVSMC). Discrimination between surface-bound and internalized radiolabeled ligand was achieved using either acetic acid or trypsin treatment of cell layers, with the two procedures yielding comparable results. Total cellular 125I-ET-1 binding hVSMC at 37 degrees was rapid and reached near equilibrium within 30 min. Such binding could be resolved into surface-bound (acid/trypsin-sensitive) and internalized (acid/trypsin-resistant) components. The accumulation of internalized 125I-ET-1 was temperature dependent and occurred at 37 degrees (t1/2 approximately 15 min) but not at 4 degrees. Internalization of 125I-ET-1 by hVSMC was reversibly inhibited by the transglutaminase inhibitor dansylcadaverine (half-maximal inhibitory concentration, approximately 400 microM). Cytosolic acidification of hVSMC (from pH approximately 6.8 to approximately 6.3) by incubation with potassium acetate in a choline buffer also inhibited 125I-ET-1 internalization. Our observation indicate that smooth muscle cells internalize ET-1 via the clathrin-mediated endocytotic pathway. Dansylcadaverine and other inhibitors of transglutaminase inhibited ET-1-stimulated inositol phospholipid hydrolysis in hVSMC and decreased ET-1-induced vasoconstriction in isolated endothelium-denuded blood vessels. Internalization of ET-1 may, therefore, be relevant to the characteristically protracted physiological effects of this peptide on the vasculature.

Cadaverine↗
PubMed1990

[Does your patient take his medicine? Compliance problems in clinical practice].

There is convincing evidence from compliance research that deviations from the prescribed drug regimen is the rule rather than the exception. Demographic and psychosocial patient factors poorly correlate with non-compliance, whereas features of the disease, mechanisms of treatments, regimens and the patient physician interaction are particularly important determinants of patients' compliance behaviour. Non-compliance can not be predicted. There are problems in the assessment of non-compliance, more particularly of its clinical consequences. New microprocessor-based technology evaluated essential insight into patients' compliance behaviour and revealed different patterns of non-compliance. On one hand, the therapeutic outcome can be impaired by non-compliance, on the other hand, however, certain patterns of non-compliance appear to be appropriated from the patients' point of view. In medical practice it is important to consider non-compliance as essential impact on drug therapy and to promote the discussion of this issue with patients.

Drug Therapy↗
PubMed1990

[Craniogenesis in the laughing gull (Larus ridibundus L.). The reconstruction of the basic plan of the bird].

To contribute to the knowledge of the cranium of older bird embryos, the chondrocranium and osteocranium of the Black-headed Gull (Larus ridibundus) are described. The chondrocranium of the Black-headed Gull is compared with the chondrocranium of other bird species with special consideration of functional and phylogenetic aspects. As a result a "grundplan" of the bird chondrocranium is reconstructed. Most of the chondrocranial autapomorphies of birds are connected with the enlargement of the eyes, the development of a beak and a prokinetic skull, and the reduction of the olfactory system.

Animals↗
PubMed1990

Histological framework of lymphatic vasa vasorum of major arteries: an experimental study.

We investigated the histological framework of lymphatic vasa vasorum of major arteries in the rabbit and guinea pig combining the "natural filling method" with light and transmission electron microscopy. An absorbing adventitial lymphatic network consisting of large and sparsely distributed vessels with capillary structure occupied a more external arterial wall position than blood capillaries. The latter were smaller, more numerous, densely distributed, and located closer to the arterial lumen at the media-adventitial border. Periarterial lymphatics (with the structure of absorbing lymph vessels) encircled the wall of the major arteries and formed a rich and irregular plexus. The topography and anatomic structure of these absorbing lymph vessels suggest that lymphatic drainage plays a significant role in large arterial wall homeostasis.

Animals↗