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Biomedical subjects

W Weber

Publications and source records attributed to W Weber.

At least 181 records · Page 10Linked to original sources
PubMed1995

Pharmacokinetics and bioavailability of pentaerithrityl tetranitrate and two of its metabolites.

Two preparations containing 100 mg pentaerithyrityl tetranitrate (PETN, CAS 78-11-5) each were administered to 24 healthy male volunteers in an open randomised two-way cross-over design. The test preparation was a commercially available 50 mg tablet (Pentalong 50 mg Tabletten, 2 tablets per dose), the reference preparation was an aqueous suspension prepared immediately before application from the same 25% PETN/lactose trituration as was used for manufacturing the tablets. Blood samples were withdrawn pre-dose and at 14 time points within 24 h after dosing. The resulting plasma was analysed by a GC/MS method developed on purpose. Since in a pilot study not a single one of 120 plasma samples contained concentrations of unchanged PETN or of its metabolite pentaerithrityl trinitrate (PE-tri-N, CAS 1607-17-6) above the quantification limit of 50 pg/ml, the samples of this study were assayed for the metabolites pentaerithrityl dinitrate (PE-di-N, CAS 1607-01-8) and pentaerithrityl mononitrate (PE-mono-N, CAS 1607-00-7) only. -Mean peak levels of 17 ng/ml and 7.5 ng/ml PE-di-N were reached ca. 3 h after application of tablets or trituration. The plasma elimination half-life was 4-5 h. Average maximum PE-mono-N levels of 79 ng/ml (tablets) and 35 ng/ml (trituration) were observed at 7 h p. appl. They declined with a half-life of 10-11 h. The relative bioavailability of the tablets as determined by means of the AUC of PE-di-N is 280-290%. This high value is explained by the specific properties of drug liberation and dissolution from the preparations used.

Adult↗
PubMed1995

NONMEM analysis in determining the tri-exponential disposition of cefotaxime: a method of evaluating serum and urinary phase I data.

The time above the minimum inhibitory concentration (MIC) is an important surrogate parameter for the efficacy of cephalosporines. In clinical practice cefotaxime (CTX) is usually administered every 8 h or 12 h. Unfortunately the limit of quantification (LOQ) of the available assay is not low enough to detect CTX concentrations in serum later than 6 h after a 2 g i.v. dose. Consequently the time above MIC has to be estimated by extrapolation of the available serum data. Due to the concentrating properties of the kidney, concentrations in urine following a 2 g dose however remain above the LOQ for up to 16 h. It is therefore possible to follow the pharmacokinetics of CTX in urine within a 12 h dosing interval. Due to the linear pharmacokinetics of CTX, serum concentrations, and accordingly the time above MIC, can be estimated by using the measured urinary excretion and the calculated renal clearance. The pharmacokinetics of cefotaxime were studied in 12 healthy subjects who received a single 2 g i.v. dose administered as a short infusion. Blood and fractional urine were collected up to 24 h after dosing. For the characterization of the true terminal half-life only sparse and unbalanced serum and urinary data was available. In such situations, the population approach is the method of choice for estimating the kinetic parameters. The combined analysis of serum and urinary data using NONMEM shows the superiority of a tri-exponential compared to a bi-exponential pharmacokinetics model. As a result, the predicted serum trough levels of cefotaxime following twice daily dosing are about 30-fold higher than those extrapolated from the bi-exponential model. Consequently, the concentrations of CTX- and its metabolite desacetyl-CTX--are above the MIC of many therapeutically relevant pathogens for a longer period of time than previously assumed. In conclusion, a twice daily dosing regimen for cefotaxime is adequate for a number of clinically relevant pathogens. This is supported by the positive outcome in previous clinical trials following this dosing regimen.

Body Weight↗
PubMed1994

[gamma-heavy chain production as an epiphenomenon in non-Hodgkin's lymphoma].

A 46-year-old woman was found to have localized lymphoplasmocytic lymphoma (low-malignancy non-Hodgkin lymphoma). Repeated recurrences required various chemotherapy courses with different drugs. Gamma heavy chains in serum and urine, as well as in blast cells in bone marrow, were first found 3 years later as part of a follow-up examination. When the lymphoplasmocytic lymphoma subsequently changed into a highly malignant disseminated large-cell lymphoma, the monoclonal gamma heavy chain-producing components no longer occurred. During continuing treatment and presumably selection of different cell clones the now terminal chemotherapy-resistant lymphoma again produced biclonal IgG heavy chains. The gamma heavy chain production added little to the histomorphological characterization of the underlying lymphoma, as well as its treatment and prognosis.

Combined Modality Therapy↗
PubMed1994

The role of alpha 2M receptor/LRP in chylomicron remnant metabolism.

A strong candidate for the long-searched CR receptor might be the alpha 2MR/LRP. Presently, we are overseeing a whole series of in vitro experiments from different laboratories that show that LRP expresses all the features for being such a receptor protein. LRP is localized on the liver cell surface, as well as on most other animal cells. It recognizes apo E-enriched lipoproteins as beta-VLDL and CR. There is evidence that CR contain LPL and it has been demonstrated that LPL binds with high affinity to LRP. This has been shown in cell binding experiments with subsequent cross-linking and in direct assays on purified receptor protein. HL, which is expressed in liver cells and localized at the liver cell surface, is also able to bind to LRP. Moreover, LRP is found in endosomes and can mediate the uptake of beta-VLDL and CR. Further studies are necessary to evaluate its role in vivo as well as its regulation. The interplay between the different ligands of this large multifunctional receptor protein needs to be clarified. It should be emphasized here that, by describing LPL as a new mediator of CR uptake in the liver and by providing evidence for a direct interaction between LPL and LRP, the role of LRP in the remnant catabolism has become even more likely.

Amino Acid Sequence↗
PubMed1994

Protein microheterogeneity and crystal habits: the case of epidermal growth factor receptor isoforms as isolated in a multicompartment electrolyzer with isoelectric membranes.

A purified, soluble form of the epidermal growth factor receptor (sEGFR) was found, by isoelectric focusing in immobilized pH gradients, to consist of three major isoforms (with pI values 6.45, 6.71 and 6.96, respectively) and ca. a dozen minor components. This wild-type sEGFR, while producing crystals, has so far defied any attempt at decoding the structure, due to the very poor diffraction pattern. When the wild-type sEGFR was purified in a multicompartment electrolyzer with isoelectric Immobiline membranes, it yielded the three major isoforms as single-pI components, collected in three separate chambers of the recycling electrolyzer. The pI 6.71 and the pI 6.96 isoforms produced large crystals of apparent good quality. However, while the former produced a high-quality diffraction pattern, which may lead to decoding of three-dimensional structure, the pI 6.96 produced crystals which did not diffract at all. It is concluded that, in the case of "tough" proteins (large size, heterogeneous glycosylation, high water content of crystals), purification to single-charge components might be an essential step for growing proper crystals. The unique advantage of purification via isoelectric membranes is that the protein is collected both isoelectric and isoionic, i.e. uncontaminated by soluble buffers (such as the carrier ampholytes used in conventional focusing).

Animals↗
PubMed1994

[Idiopathic CD4 lymphocytopenia with lethal Salmonella typhimurium sepsis].

In April 1991, a then 43-year-old woman fell ill with a systemic cryptococcal infection which responded well to antimycotic treatment. Four months later she was found to have a T-helper cell deficiency (48/microliters, 15%). Since August 1992 she noted an increased tendency towards infections and had recurrent fever bouts over 4 weeks, which led to her hospitalization in January 1993. Repeated HIV tests were negative. During the first 4 days she was free of infection, but developed a temperature of 39.1 degrees C on the fifth day, and within a few hours a fulminant septicaemia with cardiorespiratory failure developed ending fatally the same day. Blood cultures drawn during fever bouts grew Salmonella typhimurium by the time of her death. Lymphocyte differentiation revealed absolute and relative reduction in the number of CD4-lymphocytes (158/microliters; 18%), retrospectively providing the diagnosis of idiopathic CD4-lymphocytopenia.--In cases such as this there is the need of including opportunistic and masked disease entities in the differential diagnosis, even in the absence of HIV infections, and start early treatment.

Adult↗
PubMed1994

Mixed cryoglobulinemia type II in chronic hepatitis B associated with HBe-minus HBV mutant: cellular immune reactions and response to interferon treatment.

The case of a young female patient with chronic active hepatitis B, vasculitic purpura, edema, and circulating immune complexes due to mixed cryoglobulinemia is described. Serum transaminases were elevated. Serological assays showed hepatitis B surface antigen (HBsAg), antibody to hepatitis B e antigen (anti-HBe), and antibody to hepatitis B core antigen (anti-HBc) antibodies but no antibody to hepatitis C virus (anti-HCV) or antibody to hepatitis delta virus (anti-HDV) antibodies. Using hepatitis B virus-polymerase chain reaction (HBV-PCR) and direct sequencing a precore/core (preC/C) mutant unable to synthesize HBeAg was detected in serum. HBV antigens were demonstrated in the circulating immune complexes. Following 1 month of treatment with interferon-alpha 2b3 miu three times weekly, alanine aminotransferases returned to normal levels while cryoglobulins and immune complexes disappeared from serum. In addition, 2 months after the onset of treatment serum HBV-DNA was no longer detectable by PCR. Prior to treatment the analysis of cellular immune reactions of peripheral blood mononuclear cells showed a major proliferative response to HBcAg, preS1Ag and HBxAg and a minor response to HBeAg and HBsAg. One month after conclusion of treatment a decline in T-cell reactivity against all HBV antigens was observed. During clinical response to the therapy, however, a strong proliferative response of T cells to HBcAg and HBeAg was demonstrated. In conclusion, immune complex disease may complicate chronic hepatitis B in patients expressing HBe-minus HBV mutants. Treatment with interferon-alpha was found to be effective in mixed cryoglobulinemia even in the presence of HBe-minus HBV mutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

[Gadolinium-DTPA (Magnevist) as contrast medium for arterial DSA].

16 DSA investigations using intra-arterial Gd-DTPA were performed on 12 patients. The contrast medium was administered either as a 0.5 molar gadolinium solution (commercially available) or diluted with distilled water to a 0.2-0.4 molar gadolinium solution. The injection was made either by pressure injector or by hand. The aortic arch, abdominal aorta and pelvic and lower limb arteries were examined. 14 of the 16 procedures were diagnostically adequate, but compared with iodinated contrast materials, contrast was less marked. There were no cardiovascular, neurological or allergic side effects. Three patients suffered a feeling of heat and one patient had mild pain during the injection. Even large volumes rapidly injected (up to 20 ml/s of the commercially available solution) were well tolerated. DSA with intra-arterial Gd-DTPA seems to be a suitable alternative for vascular imaging if iodine-containing contrast materials are contraindicated.

Angiography, Digital Subtraction↗
PubMed1994

Regulation of epidermal growth factor receptor kinase activity by polyions.

We investigated polyionic agents with regard to their effects as modulators of epidermal growth factor receptor (EGF-R) kinase activity. Many synthetic polypeptides containing glutamine as well as casein were phosphorylated, while polycationic compounds with tyrosine residues were not phosphorylatable and thus inhibited the EGF-R activity. Polyarginine, protamine sulfate, spermidine, heparin, and poly-L-lysine with a chain length of < 20.5 kDa triggered the phosphorylation of poly(Tyr1, Glu4). On the other hand, dextran sulfate and poly-L-lysine with chain lengths of > 20.5 kDa inhibited the EGF-R kinase activity. Alteration of the state of autophosphorylation of EGF-R is not in agreement with the activity of EGF-R kinase towards poly(Tyr1, Glu4). Casein and histone H1 both increased the autophosphorylation of EGF-R in a concentration-dependent manner, but only casein increased the activity of the enzyme towards an exogenous substrate. The compounds enhancing the EGF-R activity, such as poly-L-lysine, protamine, and poly-L-arginine, down-modulated the autophosphorylation reaction. We discuss the consequences of these effects as to in vivo conditions.

Amino Acid Sequence↗
PubMed1994

Colorectal cancer: lessons for genetic counselling and care for families.

Cancers of the colon and the rectum are the second leading cause of malignancy in European countries with similar incidence rates for men and women and, therefore, one of the major health concerns. Emphasis is placed on the early detection of a developing neoplasm in order to improve the life expectancy of patients and their quality of life. Colorectal cancer (CRC) is an excellent model for studying the etiology and pathogenesis of a common malignancy and the complex multistage process of carcinogenesis. Abundant clinical and pathological evidence suggests that CRC arises from benign adenomas that proceed through a series of steps to metastatic carcinomas. Following the discovery of oncogenes and, more importantly tumor suppressor genes, Fearon & Vogelstein (1990) proposed a scheme of genetic events which are associated with colorectal tumorigenesis. Genetic linkage studies have recently identified another type of gene for colon cancer susceptibility that seems to act by destabilising the genome.

Adult↗
PubMed1994

Increased plasma concentrations for type I and II tumor necrosis factor receptors and IL-2 receptors in cancer patients.

Using enzyme-linked immunoabsorbent assays for the soluble tumor necrosis factor (TNF) receptors type I (p55) and type II (p75) and IL-2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors plasma levels of TNF receptor p75 and IL-2 receptor were not significantly different from the controls.

Adult↗
PubMed1994

Caloporoside, a new inhibitor of phospholipases C from Caloporus dichrous (Fr.) Ryv.

A new salicylic acid derivative, caloporoside, was isolated from fermentations of Caloporus dichrous. Its structure was elucidated by a combination of chemical and spectroscopic methods. Caloporoside exhibits weak antibacterial and antifungal activities and is a quite selective inhibitor of phospholipase C isolated from pig brain (Ki 12, 3 microM).

Animals↗
PubMed1994

Crystallization of the EGF receptor ectodomain on US space mission STS-47.

Although biochemists working in the field of biological signal transduction have characterized cell surface receptors for numerous growth factors within the past ten years, none of the three-dimensional structures could be obtained for these important proteins which represent major components of the cells' growth control system. Now, the extracellular ligand binding domain of the EGF receptor was crystallized in the presence of EGF under microgravity on US Shuttle mission STS-47. In 8 out of 9 experiments prepared under different conditions crystal growth was observed. One of these space-grown crystals showed higher diffraction quality than all crystals previously obtained in the laboratory. It allowed, for the first time, evaluation of the real space group by partial data collection.

Crystallization↗
PubMed1994

Study on the influence of food on the absorption of theophylline from a controlled-release preparation.

The possible influence of food and fat content of meals on the bioavailability and pharmacokinetics of a 350 mg sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was investigated after single-dose oral administration to 18 volunteers in a randomized 3-way cross-over design. The treatments investigating an administration of the test preparation in a fasting state, after a standard meal and after a high-caloric fat evening meal, according to the commonly applied rules, could be shown to be equivalent with respect to the amount of bioavailability (AUC) and the observed maximal concentrations (Cmax). Pharmacokinetic parameters describing sustained-release characteristics were not changed either to any relevant degree. As expected, the co-administration of food resulted in a physiologically determined delay in absorption, which probably is not therapeutically relevant during long-term administration.

Adult↗