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Biomedical subjects

R Brandt

Publications and source records attributed to R Brandt.

At least 127 records · Page 7Linked to original sources
PubMed1988

Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.

Administration, Oral↗
PubMed1988

Restriction-fragment-length-polymorphisms close to the human insulin gene on chromosome 11 and their possible relation to diabetes mellitus in a GDR population.

A polymorphic DNA sequence flanking the 5'-region of the human insulin gene was studied by means of Southern blot hybridization techniques in 92 diabetic and non-diabetic individuals in order to investigate the possible relation of their allelic variants to certain types of diabetes. DNA was isolated from nucleated blood cells and digested with the restriction endonucleases EcoRI or Bg1 I. Only two classes of alleles were found (U and L). The small L-allele was predominantly found with the following frequency: 0.64 in controls, 0.795 in insulin-dependent diabetics, and 0.625 in non-dependent patients. It could be demonstrated that the L-allele and IDDM are associated. These data suggest that this allele seems to be a genetic marker for insulin-dependent diabetes mellitus. The putative function of the polymorphic region in the aetiology of diabetes mellitus and the possible genes being in linkage disequilibrium with it are not known so far.

Adult↗
PubMed1988

Dose-effect relationship of adenosine provoked angina pectoris-like pain--a study of the psychophysical power function.

In an analysis of the psychophysical power function of chest pain induced by adenosine, this agent was repeatedly given in increasing doses into a peripheral vein to six healthy volunteers (five men) aged 23-44 years. On the first day the maximum tolerable dose was determined. On the second day seven doses of adenosine (20, 30, 40, 50, 60, 80 and 100% of the maximum dose) were given single blind in randomized order followed by another seven doses in reversed order. The heart rate was calculated from electrocardiographic recordings. Chest pain was continuously rated according to the CR-10 scale. Before the adenosine test, the perception of sourness was tested similarly with six concentrations of citric acid (1-100 mM). The psychophysical power functions were similar for the perception of sourness provoked by citric acid and chest pain provoked by adenosine, with exponents of 0.69 +/- 0.21 and 0.60 +/- 0.32, respectively. The two modalities showed the same high goodness of fit to the power function (rxy being 0.965 +/- 0.030 and 0.967 +/- 0.033, respectively). For adenosine the group mean relation was R = 1.66(S-2.36)0.6, rxy = 0.999. No signs of tolerance were observed for the chest pain provoked by adenosine. In conclusion, chest pain provoked by adenosine follows a psychophysical power function as with other sensory modalities.

Adenosine↗
PubMed1987

The major histocompatibility complex and diabetes mellitus.

Recent studies have greatly increased the knowledge of the genetics of diabetes mellitus. At present several markers of the disease are under discussion. For insulin-dependent diabetes mellitus there is an association between markers of the histocompatibility complex and the incidence of the disease. The genes of the human histocompatibility complex code for at least three different classes of polymorphic proteins involved in the immune response. Two of them, the class I and the class II antigens are described in the article. The class II antigens are primarily expressed on special cells of the immune system. A typical feature of these antigens is their extensive polymorphism, which is the result of their genetic organization. The occurrence of insulin-dependent diabetes mellitus is more or less strongly associated with the class II antigen types DR3 and/or DR4. Using recombinant DNA technology it is possible to further characterize these and other class II specificities at genetic level. There are data on the occurrence of some class II antigen related DNA restriction fragments. They are much more strongly associated with the susceptibility to the disease than other markers found so far.

Chromosome Mapping↗
PubMed1987

Polymorphism of HLA and insulin gene is correlated to type I diabetes.

A polymorphic locus flanking the 5'-end of the insulin gene was studied by means of the recombinant DNA technique in 62 diabetic and nondiabetic subjects. The small allele predominantly was found with the following frequencies: 28 insulin-dependent diabetics 0.89; 6 probands of a family with one type I diabetic member 0.92; 10 patients with a non-insulin-dependent diabetes mellitus 0.55; 18 control probands (normal glucose tolerance) 0.64. --Because of the relatively high number of all probands with the small allele we assume that the presence of this allele on both chromosomes increases the susceptibility but is not sufficient for the onset of an insulin-dependent diabetes mellitus. By a correlation of the polymorphic region of the insulin gene with other DNA regions (in particular with the major histocompatibility complex) the susceptibility may be further increased. Therefore, the HLA-DR gene polymorphism of type I diabetes is of interest.

Adult↗
PubMed1987

Adenosine-provoked angina pectoris-like pain--time characteristics, influence of autonomic blockade and naloxone.

In a study to characterize the time characteristics and the influence of blockade of beta, cholinergic and opioid receptors on the chest pain induced by adenosine, this agent was given as a bolus into a peripheral vein of six healthy volunteers (4 men) 24-45 years of age. On the first day the maximum tolerable dose was determined in each case. On the second day three doses of adenosine (1/3, 2/3, and a full maximum tolerable dose) and three doses of placebo were given as single blind doses in randomized order. Thereafter metoprolol (10 mg to males, 8 mg to females), followed by 1 mg atropine and then 0.4 mg naloxone were given intravenously. After each agent the test procedure was repeated. Heart rate and atrio-ventricular blocks were recorded by electrocardiography and respiration by dynamic spirometry. One minute after each dose of adenosine, the chest pain was scored. The maximum tolerable dose of adenosine was 8.0-15.9 mg. All subjects experienced angina pectoris-like pain. Following injection, onset of respiratory stimulation, AV-block and chest pain occurred after 14 +/- 4.0, 19 +/- 5.4 and 21 +/- 6.4 s, the differences being highly significant. Maximal respiratory stimulation occurred after 18 +/- 4.6, not statistically different from the onset of AV-block which in its turn occurred earlier (P less than 0.005) than the time for maximal central chest pain, 29 +/- 7.8 seconds. Metoprolol induced a 20% slowing of heart rate. After atropine there was a 30% faster heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗
PubMed1987

A convenient radiometric assay for hyaluronan.

Hyaluronan-binding proteins (HABP) isolated from bovine cartilage have been utilized in a radiometric assay for determination of hyaluronan (hyaluronic acid; HA) in serum. The samples to be analysed are preincubated with iodinated HABP. After 60 minutes the protein that is not bound to hyaluronan, in the solution, is recovered on HA-Sepharose in a 45-min incubation. Hyaluronan can be determined in the range from 10 to 1,000 micrograms/l. The sample size is 100 microliter and the intra-assay and inter-assay coefficients of variations are less than 10% and less than 10%, respectively for samples containing hyaluronan concentrations in the range 10-200 micrograms/l. Detection limit is 4 micrograms/l.

Carrier Proteins↗
PubMed1986

A competitive enzyme immunoassay of human beta 2-microglobulin based on separation by filtration.

A competitive enzyme immunoassay has been developed for the determination of beta 2-microglobulin in undiluted human serum. In the assay a beta 2-microglobulin-beta-galactosidase conjugate competes with beta 2-microglobulin from the sample for the binding to anti-beta 2-microglobulin antibodies bound to small size agarose particles (micro-Sepharose) via a double antibody. The conjugate is made by providing beta 2-microglobulin with 'reactive disulphide structures.' This is achieved by the heterobifunctional reagent SPDP and the subsequent linkage of the formed derivative to beta-galactosidase by a thioldisulphide exchange reaction. This procedure gives conjugates with high immunoreactivity and enzyme activity. The assay is fast and simple. The reagents are incubated together for 60 min in the wells of a Millititer plate and separation is performed by filtration. Bound enzyme-labelled beta 2-microglobulin is measured by incubation with substrate for 15 min. Both incubations are performed at room temperature without agitation. Due to the high capacity of the micro-Sepharose no sample predilution is needed. The use of the Millititer filtration system gives a rapid and efficient separation and the advantages of access to equipment for dispensing and reading adapted to the microtitre format.

Filtration↗
PubMed1986

Angina pectoris-like pain provoked by intravenous adenosine in healthy volunteers.

In a study to characterise the chest pain induced by adenosine this agent was given as a bolus into a peripheral vein to six healthy volunteers (five men) aged 30-44. On the first day the maximum tolerable dose was determined in each case. On the second day three doses of adenosine (one third, two thirds, and the full maximum tolerable dose) and three doses of saline were given single blind in randomised order. Thereafter aminophylline 5 mg/kg was given and the procedure repeated in a different randomised order. On the third day between two thirds and the full maximum tolerable dose was given followed by 10 mg dipyridamole intravenously and a second injection of the same dose of adenosine. Heart rate and atrioventricular blocks were recorded by electrocardiography. One minute after each dose of adenosine the chest pain was scored. The maximum tolerable dose of adenosine ranged from 10.6 to 37.1 mg. All subjects experienced uneasy central chest pain provoking anxiety. The pain radiated to the shoulders, ulnar aspect of the arms, epigastric area, back, and into the throat. The pain began about 20 seconds after the injection and lasted 10-15 seconds. Increasing the dose of adenosine increased the intensity of the pain. Administration of aminophylline reduced the pain significantly. Second degree heart block was recorded in five of the six subjects during the time that the pain was experienced. After aminophylline no block was observed. Dipyridamole increased the intensity of pain. The duration of second degree heart block increased in four of the subjects, and in two of these third degree heart block occurred. These findings suggest that adenosine released from the myocardium during ischaemia induces angina pectoris by stimulating theophylline sensitive receptors.

Adenosine↗
PubMed1986

Effect of nicotine on prostacyclin formation in human endocardium in vitro.

The effect of nicotine on the formation of prostacyclin by human endocardium was studied in vitro. Slices of cardiac valve cusps were incubated in a saline medium and the prostacyclin-like activity generated spontaneously by the tissue specimens was assessed in terms of its capacity to inhibit ex vivo platelet aggregation. In separate experiments supernatants of valvular tissue homogenates were incubated with [14C]arachidonate. This resulted in the appearance of labelled 6-keto-prostaglandin F1 alpha in the radiochromatograms, indicating the formation of prostacyclin in the homogenates. Nicotine inhibited dose-dependently the spontaneous generation of prostacyclin-like activity (I50 approximately equal to 2 X 10(-4) M), as well as the formation of 6-keto-prostaglandin F1 alpha (I50 approximately equal to 2 X 10(-5) M), indicating an inhibitory effect of the drug on endocardial prostacyclin production.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

The human insulin gene and diabetes mellitus.

The recombinant DNA technology is a useful tool to characterize the insulin gene and adjacent areas. A highly polymorphic region near the human insulin gene was detected and its possible relation to certain types of diabetes mellitus is discussed. In three cases the synthesis of a structurally abnormal insulin of lower biological activity leads to hyperglycemia. These mutant insulin gene sequences can be identified with the help of restriction endonuclease cleavage analysis. Insulin gene expression is regulated mainly at translational level. Elements near or within the insulin gene seem to be required for a sufficient and cell-specific expression. But the role of the polymorphic locus is not yet clear. First results on gene transplantation by administration of liposome entrapped insulin gene sequences are surprising, but at this time only of speculative value for medical research.

Amino Acids↗
PubMed1985

The effect of stress hormones on the interorgan flux of amino acids and on the concentration of free amino acids in skeletal muscle.

Plasma concentrations of free amino acids have previously been found to decrease posttraumatically and this decrease can be reproduced by infusion of stress hormones. The mechanisms underlying this effect has not been investigated and therefore 14 healthy subjects were studied by infusing adrenaline alone or a combination of adrenaline, glucagon, and cortisol, in dosages giving pathophysiological plasma concentrations of the hormones. The influence on the interorgan fluxes of free amino acids and on the concentrations of free amino acids in skeletal muscle were determined. During hormone infusion splanchnic oxygen consumption doubled, indicating an increase in metabolic activity. There was a significant decrease in the arterial plasma level of all amino acids except alanine. Significant increases in alanine flux was noted, the release from one leg doubled and the splanchnic uptake increased by 60%. After only 1 h all essential amino acids showed a significantly decreased concentration in muscle while the level of alanine was increased. There were no differences between the two hormone groups. The results indicate that stress hormones can initiate an increased formation of alanine in skeletal muscle and an increase in alanine transport from the periphery to the splanchnic area.

Journal Article↗