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Biomedical subjects

A Widmer

Publications and source records attributed to A Widmer.

At least 55 records · Page 3Linked to original sources
PubMed1994

The 3D structure of a cyclosporin analogue in water is nearly identical to the cyclophilin-bound cyclosporin conformation.

The conformation of [D-MeSer3-D-Ser-(O-Gly)8]CS, a water soluble cyclosporin derivative, has been determined in (D6)DMSO and in water using NMR. In these polar solvents the conformation is identical and very similar to the structure found in the cyclophilin-cyclosporin complex. However, it differs significantly from its conformation in deuterated chloroform. This demonstrates unambiguously that the large structure change is induced primarily by the polar solvent rather than by complex formation with cyclophilin.

Amino Acid Isomerases↗
PubMed1994

Increase in calciuria and oxaluria after a single chocolate bar load.

Chocolate, a foodstuff rich in sucrose, fat and oxalate, is considered unsuitable in cases of obesity, diabetes mellitus, urolithiasis and postprandial hypoglycemia. However the pathophysiological effects of chocolate are poorly documented. Therefore we investigated the effects of ingestion of 100 g dark chocolate bar (45 g cocoa and 55 g sucrose) on carbohydrate, calcium and oxalate metabolisms in 10 healthy subjects. Results were compared to those of 55 g sucrose intake (control group) performed on another day. Chocolate caused i) a lesser but longer increase in plasma glucose, insulin, and C-peptide than sucrose (respectively +23% of baseline vs +60%, p < 0.001; +436% of baseline vs +755%, p < 0.01 and +200% of baseline vs +331%, p < 0.01), ii) a striking increase in triglyceridemia, calciuria and oxaluria (respectively +96%, p < 0.01; +147%, p < 0.01 and +213%, p < 0.001). Thus, chocolate (cocoa+sucrose) causes a lesser pancreatic stimulation than sucrose. However, the increases in both calciuria and oxaluria (induced respectively by sucrose and cocoa) following chocolate ingestion might contribute to urinary conditions favoring the development of calcium oxalate calculi.

Adult↗
PubMed1993

Structure-activity relationships in the trans-hexahydroindolo[4,3-ab]phenanthridine ("benzergoline") series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective D1 agonist CY 208-243 and its implication for an "extended rotamer-based dopamine receptor model".

4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described "rotamer-based dopamine receptor model", which allowed the localization of a "subtype selectivity-inducing site" (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed "additional" phenyl group of the benzergoline molecule.

Adenylyl Cyclases↗
PubMed1993

Extensive distance geometry calculations with different NOE calibrations: new criteria for structure selection applied to Sandostatin and BPTI.

To generate structures efficiently, a version of the distance geometry program DIANA for a parallel computer was developed, new objective criteria for the selection of NMR solution structures are presented, and the influence of using different calibrations of NOE intensities on the final structures are described. The methods are applied to the structure determination of Sandostatin, a disulfide-bridged octapeptide, and to model calculations of BPTI. On an Alliant FX2800 computer using 10 processors in parallel, the calculations were done 9.2 times faster than with a single processor. Up to 7000 Sandostatin structures were calculated with distance and angular constraints. The procedure for selecting acceptable structures is based on the maximum values of pairwise RMSDs between structures. Suitable target function cut-offs are defined independent of the number of starting structures. The method allowed for an objective comparison of three groups of Sandostatin structures that were calculated from different sets of upper distance constraints which were derived from the same NOE intensity data using three empirical calibration curves. The number of converged structures and the target function values differed significantly among the three groups, but the structures were qualitatively and quantitatively very similar. The conformation is well determined in the cyclic region Cys2-Cys7 and adopts a beta-turn centered at D-Trp4-Lys5. The criteria for structure selection were further tested with BPTI. Results obtained from sets of structures calculated with and without using the REDAC strategy are consistent and suggest that the structure selection method is objective and generally applicable.

Amino Acid Sequence↗
PubMed1991

A need to intensify drug surveillance in Germany.

Despite all its limitations, the spontaneous reporting system still forms the basis for drug safety assessments in the Federal Republic of Germany. Although there have been some promising attempts to standardise the methodology of detecting, analysing and evaluating adverse drug events (ADEs) in certain clinico-pharmacological institutes and psychiatric departments, the approaches have not been integrated and are used only locally. The only exception is the Freiburg Documentation Centre for Severe Skin Diseases, which is attempting comprehensive, country-wide documentation of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome. We show that surveillance of 40% of all hospital beds would allow the acquisition of reliable data even on rare and serious AEs which could then be extrapolated in a statistically meaningful way. The medical societies in Germany have traditionally taken a leading role in establishing standards for the preclinical and clinical investigation of new drug compounds. We suggest that they also make it their task to define the framework for an intensified adverse events monitoring system, since it is the patient who ultimately benefits from a quantification of drug therapy risks.

Bed Occupancy↗
PubMed1991

[Prosthesis infections: is ambulatory conservative therapy possible?].

Infections associated with prosthetic devices involve an increased risk of persistence or relapse if the foreign body is not removed. Clinical and experimental observations indicate a lack of correlation between the minimal bactericidal concentration of a drug and its efficacy in device-related infections. Alternative in-vitro tests indicate that the efficacy of a drug experimental implant-associated infections depends on its activity on non-growing and adhering microorganisms. These data have been evaluated in a clinical pilot study. 12 patients with orthopedic device-related infections were treated with rifampin-containing regimens because this drug has excellent activity on adherent microorganisms. The success rate was 83% during a follow-up period of 2 years or until the removal of the device. Nevertheless, before considering conservative treatment of device-related infections, controlled clinical studies are needed which confirm the experimental results.

Animals↗
PubMed1989

GEOM: a new tool for molecular modelling based on distance geometry calculations with NMR data.

GEOM is a new graphics tool which allows the use of distance geometry to compute linear and cyclic structures typically arising in drug design situations. Modified amino acids or monomeric organic entities can be easily constructed in an interactive way and deposited in the library of the distance geometry program together with geometric information required for structure calculation in dihedral angle space. In addition, GEOM is able to produce all files needed to calculate a structure based on NMR data (NOE and J-coupling constraints) and it permits the graphic analysis and comparison of computed structures. The application of GEOM is demonstrated in three examples: modelling of cyclosporin A structures with and without a limited set of H-bond constraints and modelling of a cyclic hexapeptide with a full NMR data set.

Computer Graphics↗
PubMed1988

[Fatal peripheral catheter phlebitis].

A 75-year-old man suffered from suppurative thrombophlebitis as a complication of a peripheral venous catheter (1.2 x 45 mm Teflon). In spite of rapid removal of the catheter at the time of clinical diagnosis of phlebitis and adequate antibiotic treatment, the Staphylococcus aureus sepsis developed into lethal endocarditis. The risk of thrombophlebitis can be minimized by limiting (less than 72 hours) the duration of cannulation. If pus is detected within the lumen of the vein, surgical excision of the involved vein remains the treatment of choice.

Aged↗
PubMed1988

[Reactivation of Staphylococcus aureus osteomyelitis after 49 years].

The treatment of chronic osteomyelitis is laborious and ill defined. We report the case of a 57-year-old woman admitted to hospital with Staphylococcus aureus septicemia due to relapse of osteomyelitis after an interval of 49 years. By surgical debridement, suction drainage and 8 months of high-dose antibiotic treatment we were able to control the infection in terms of clinical symptoms and laboratory parameters.

Anti-Bacterial Agents↗
PubMed1988

Alterations in insulin clearance and hepatic blood flow during the night do not contribute to the 'dawn phenomenon' in type 1 diabetes.

To assess mechanisms leading to the 'dawn phenomenon' in type 1 diabetes mellitus, overnight insulin clearance, hepatic blood flow and insulin sensitivity of glucose metabolism were determined in 9 type 1 diabetic subjects treated with continuous subcutaneous insulin infusions. Glucose clamp studies were performed twice, once after midnight (from 24.00 to 02.00 h), and once in the early morning (from 06.00 to 08.00 h) during insulin infusion at 15 mU/m2/min. Insulin clearance was 482 +/- 57 ml/m2/min during the first, and 528 +/- 56 ml/m2/min during the second clamp (nonsignificant). Hepatic plasma flow assessed by measuring indocyanine green clearance was 984 +/- 115 and 1,040 +/- 163 ml/min, after the first and after the second clamp, respectively (nonsignificant). Glucose uptake during the two clamps was not significantly different. Since hepatic blood flow is known to influence insulin clearance and hepatic glucose metabolism, the data demonstrate that overnight changes in hepatic blood flow and insulin clearance do not contribute to the previously described early morning increase in insulin requirements in type 1 diabetic subjects (dawn phenomenon).

Adult↗
PubMed1985

Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3 alpha, 4a alpha, 10a beta)-1,2,3,4,4a,5,10,10a- -octahydro-6-hydroxy-1-propyl-3-benzo[g]quinolinyl]sulfamide.

The synthesis and preliminary pharmacological evaluation of the optical antipodes of the title compound (+/-)-1 (CV 205-502) is presented. The dopaminomimetic activity is shown to reside entirely in the (-) enantiomer. Crystallographic analysis has proven that the absolute configuration of the active (-) enantiomer corresponds to that of its ergoline analogue 3 (CQ 32-084) and of apomorphine (5).

Aminoquinolines↗
PubMed1980

[Attitude of psychiatric personnel on the treatment of patients, psychometrics and results].

UNLABELLED: The therapeutic attitude of psychiatric nurses towards inpatients of a mental hospital was studied. Is there a correlation of nurses' attitude and their view of the patients' behaviour, social attractiveness, and prognosis? Are there differences in the therapeutic attitude in regard to different diagnostic groups? A questionnaire was constructed. Probands were 70 female, 40 male nurses. For every proband there was taken a patient: 70 female, 40 male patients (34 schizophrenics, 15 depressive patients, 15 psychogeriatric patients). The data were evaluated by path analysis and analysis of variance. THE RESULTS: Patients with more social interest and more psychotic symptomatology were rated as more socially attractive. The more pathologic patient's behaviour in the wards was judged the worse was the supposed prognosis. Dysphoric-morose patients and patients with low social attractiveness provoke an authoritarian and controlling attitude. Patients held as social competent stimulate nurses' attitude towards promotion of dependence and autonomy. The lower social competence and the worse prognosis is taken the more the attitude is inclined to protective control and isolation. The therapeutic value of personal humane communication and direct social contacts is taken for less important when patients seem to be socially inattractive and incompetent. We did not find any difference in the nurses' attitude in regard to schizophrenic or depressive patients. Schizophrenic patients did stimulate more intentions towards propagation of independence and autonomic activity than psychogeriatric patients do. Between male and female nurses we did not find any difference in their attitudes to the (same sex) patients.

Adult↗
PubMed1979

[Suicidal thoughts, personality structure and social problems in 19-year-old Zuricher adolescents].

A sample of 586 19-year old male adolescents from the canton of Zurich was examined 446 of the adolescents surveyed, i.e. 76.1%, indicated that they had never entertained thoughts of suicide, while 140, i.e. 23.9%, had already thought of commiting suicide. These two groups are compared with regard to various personal und sociographic data, as well as to their personality structure. The significance of important conflicts leading to thought of suicide is discussed.

Adult↗