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Biomedical subjects

G Schumann

Publications and source records attributed to G Schumann.

At least 91 records · Page 5Linked to original sources
PubMed1986

Biotransformation of aklanonic acid by blocked mutants of anthracycline-producing strains of Streptomyces galilaeus and Streptomyces peucetius.

Aklanonic acid is an anthracyclinone-related pigment that was found to be an intermediate at an early stage of the biosynthesis of daunomycinone glycosides by Streptomyces griseus. We now isolated anthracycline-negative mutants of other Streptomyces species and used them in feeding experiments with both natural and radioactive aklanonic acid. In cultures of the mutant Streptomyces galilaeus S 727 exogenous aklanonic acid was biotransformed to cinerubin A as the major product. The spectrum of the conversion products was qualitatively comparable to that of the parent strain. In cultures of mutant 21/8 derived from Streptomyces peucetius var. caesius the predominant conversion product was epsilon-rhodomycinone. Daunomycinone glycosides were isolated in small amounts. According to results obtained with the radioactively labelled precursor aklanonic acid was completely incorporated into the molecules of the conversion products. Our findings suggest that aklanonic acid is also a natural intermediate in the biosynthesis of anthracyclines by Streptomyces galilaeus and Streptomyces peucetius. Proposed biosynthetic pathways have been constructed.

Anthracyclines↗
PubMed1986

Enprofylline: pharmacokinetics and comparison with theophylline of acute effects on bronchial reactivity in normal subjects.

In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml X kg-1. h-1, volume of distribution 0.481 X kg-1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV1.0 (PC20). Mean PC20 values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC20S after placebo and theophylline was statistically significant (p less than 0.05). At the time of determination of the PC20, the serum concentration of enprofylline was between 16.5 and 11.8 mumol/l, and that of theophylline was between 78.3 and 61.1 mumol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.

Adult↗
PubMed1986

Influence of 1-double bond and 11 beta-hydroxy group on stereospecific microbial reductions of 4-en-3-oxo-steroids.

The yeast Rhodotorula glutinis and the anaerobic bacterium Clostridium paraputrificum were used for stereospecific reductions of 4-chloro-11 beta-hydroxy-17 alpha-methyl-testosterone and the corresponding 1-dehydro compound to prepare 5 alpha- and 5 beta-H derivatives, respectively. C. paraputrificum was able to 5 beta-reduce both substances, whereas the 5 alpha-reduction by R. glutinis was inhibited by the structure elements 1-en and 11 beta-OH so that the substrate with both structure elements was not 5 alpha-reduced. The microbial conversion of the four steroids with and without 1-en and 11 beta-OH was compared in semiquantitative experiments. A number of new substances are described, 11 beta-hydroxy and 11-oxo derivatives of 5 alpha- and 5 beta-dihydro-4-chloro-17 alpha-methyltestosterone including some 3-OH compounds and characterized by NMR, mass spectrometric and further data.

Clostridium↗
PubMed1985

[Leukaemomycin-blocked mutants of Streptomyces griseus and their pigments. III. 11-Desoxydaunomycinone derivatives from the mutant ZIMET 43699/G44].

The isolation and identification of several anthracyclinones (designated as G44-K4/5, G44-G1, G44-G2) and anthracyclines (G44-A, B, C, D, E, F, G) produced by the mutant strain IMET JA 3933/G44 of the daunomycin-producing Streptomyces griseus strain IMET JA 3933 are described. G44-K4/5 was found to be identical with 7,11-dideoxy-13-dihydrodaunomycinone previously isolated from a mutant strain of Streptomyces coeruleorubidus. Compound G44-G1 was identified as 11-deoxydaunomycinone, the aglycone of the antibiotic 11-deoxydaunomycin. G44-G2 was found to be a stereoisomer of G44-G1. The NMR and CD spectral data suggest strongly that the compound is 7-epi-11-deoxydaunomycinone. Of the 7 isolated G44-glycosides only the major component G44-B could be identified. Comparison with an authentic sample revealed that this compound is 11-deoxydaunomycin which had previously been isolated from cultures of Streptomyces peucetius var. aureus and Micromonospora peucetica. As reported for S. coeruleorubidus, S. peucetius var. aureus, and Micromonospora peucetica the 11-deoxydaunomycinone derivatives described in this paper were isolated from the fermentation broth of a mutant of a daunomycin-producing wild type strain. This suggest that in general the accumulation of 11-deoxydaunomycinone derivatives may be the result of a block of C11-hydroxylation in the normal biosynthetic pathway of daunomycin and its analogues.

Antibiotics, Antineoplastic↗
PubMed1985

Induction of tumouricidal leucocytes by the intranasal application of MTP-PE, a lipophilic muramyl peptide.

Single intranasal applications of MTP-PE, a lipophilic muramyl peptide, induce tumouricidal and tumouristatic leucocytes in the lungs of rats. In ex vivo assays the tumouristatic activity was detectable for 8 days after drug administration. By separation of the effector cells on Ficoll-Hypaque gradients, it was shown that both neutrophils and macrophages are responsible for this activity. Using the B16/BL6 melanoma system in mice, there was a high survival rate after repeated intranasal applications of MTP-PE.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Hydrazonopropionic acids, a new class of hypoglycemic substances. 5. Inhibition of hepatic gluconeogenesis by 2-(3-methylcinnamyl-hydrazono)-propionate in the rat and guinea pig.

2-(3-Methyl-cinnamyl-hydrazono)-propionate (MCHP) is a new compound which effectively lowers the blood glucose level in guinea pigs. 0.04 mmol/l MCHP inhibited glucose formation from lactate, pyruvate and alanine, but not from dihydroxyacetone in the perfused guinea pig liver. In the presence of both hexanoic acid and alanine, 0.04 mmol/l MCHP did not effect hepatic gluconeogenesis. Gluconeogenesis was probably reduced by an inhibition of the pyruvate carboxylase: The pattern of hepatic metabolite concentrations indicated a block between pyruvate and the triose phosphates. The intrahepatic concentration of acetyl-CoA was consistently decreased. The decrease of the acetyl-CoA concentration could be explained by an influence of MCHP on the fatty acid oxidations, which occurred at the carnitine palmitoyl transferase (CPT) step. This hypothesis is supported by the fact that a medium chain fatty acid not requiring CPT reversed the inhibition of gluconeogenesis by MCHP. From all results reported it is concluded that transamination and oxidative phosphorylation were not effected to a degree relevant for the inhibition of gluconeogenesis by 0.04 mmol/l MCHP.

Animals↗
PubMed1985

Determination of theophylline in saliva, using fluorescence polarization immunoassay (FPIA).

Theophylline concentrations were determined by fluorescence polarization immunoassay (FPIA) in saliva, serum and serum water of healthy volunteers and outpatients after administration of single theophylline doses, and after the administration of several doses in order to establish a steady state. The FPIA allowed rapid and reliable theophylline determinations in saliva and serum water (between-days coefficients of variation: less than 3%; recovery: 95-03%). Salivary theophylline concentrations measured by FPIA in 30 samples agreed well with those determined by HPLC. Furthermore the results obtained by ultrafiltration for the concentration of unbound theophylline in serum water were in good agreement with those determined by ultracentrifugation. The binding of theophylline by serum protein rose by about 25%, when the pH of the samples was increased from 7.0 to 8.0. After adjusting the pH to 7.4, average values for theophylline binding to proteins at 25 degrees C ranged from 48.5 to 52.2% in serum samples from outpatients and healthy adults. Salivary theophylline concentrations correlated well with total and free serum theophylline concentrations in healthy adults and outpatients (r = 0.90-0.98). The theophylline concentration in saliva was on average about 20-30% higher than the unbound theophylline concentration in serum water. The saliva/serum concentration ratio of theophylline showed some intersubject variation (0.68 +/- 0.08; range: 0.50-0.85). Using the mean saliva/serum concentration ratio of the patient group, steady state serum theophylline concentrations were predicted from salivary levels with a mean error of 7.6% (range: 0.0-26.8%). The salivary theophylline concentration appears to be a suitable parameter for assessment of compliance, for identification of patients with inappropriate dosage, and for consequent dosage adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Isolation and chemical structure of aklanonic acid, an early intermediate in the biosynthesis of anthracyclines.

The fermentation, isolation and structure elucidation of aklanonic acid are described. The compound was isolated from fermentations of Streptomyces strain ZIMET 43,717. Aklanonic acid is a yellow-orange crystalline substance, melting at 203-204 degrees C (dec), having the molecular formula C21H16O8, and possessing UV maxima at 258, 282 (sh) and 438 nm (CHCl3). In dimethyl sulfoxide or pyridine aklanonic acid is unstable and a new compound (aklanone) is formed as a conversion product. The elucidation of the structures has shown that aklanonic acid and aklanone are derivatives of 1,8-dihydroxyanthraquinone.

Anthraquinones↗
PubMed1984

Hydrazonopropionic acids, a new class of hypoglycemic substances, 3. Inhibition of jejunal glucose uptake in the rat and guinea pig.

Recently hydrazonopropionate derivatives have been recognized as a new group of compounds with strong hypoglycemic effects in various laboratory animals. The hypoglycemia probably has several causes of which an inhibition of gluconeogenesis and of intestinal glucose uptake could be identified. In the present report, the influence of phenylethylhydrazonopropionate, cyclohexylethylhydrazonopropionate, methylcinnamylhydrazonopropionate and their corresponding hydrazine derivatives on the glucose uptake of rat and guinea pig jejunum has been compared with the well known effects caused by phenformin. All substances tested inhibited the jejunal glucose uptake, phenelzine, methylcinnamylhydrazine and cyclohexylhydrazonopropionate more effective, the other compounds less effective than phenformin. The hydrazine derivatives appeared more effective than the hydrazone compounds used. The cellular ATP/ADP ratio was not influenced by the hydrazonopropionate compounds.

Adenosine Diphosphate↗
PubMed1984

Hydrazonopropionic acids, a new class of hypoglycemic substances. 4. Hypoglycemic effect of 2-(3-methyl-cinnamylhydrazono)-propionate in the rat and guinea pig.

The hydrazone-compound 2-(3-methyl-cinnamylhydrazono)-propionate (MCHP) significantly lowered the blood glucose concentration in fasted guinea pigs and rats. A significant decrease of blood glucose levels was observed in fasted guinea pigs already after an intraperitoneal injection of 20.5 mumol/kg MCHP, while much higher doses (about 1000 mumol/kg) were necessary to produce a hypoglycemic effect in the fasted rat. After oral administration MCHP (82.0 mumol/kg) significantly decreased the blood glucose concentration in guinea pigs. Furthermore MCHP caused a dose-dependent increase of plasma free fatty acid concentrations in guinea pigs and rats. In addition, MCHP decreased the concentrations of blood ketone bodies, plasma cholesterol and intrahepatic acetyl-coenzyme A in the guinea pig. All of these findings appear to be due to a reduced fatty acid utilization in the presence of MCHP resulting presumably in an intramitochondrial deficiency of acetyl-CoA. At hypoglycemic effective doses the intramitochondrial and cytoplasmatic redox ratios as well as the hepatic ATP/ADP ratio were not influenced by MCHP in fasted guinea pigs. Even at large doses (123 mumol/kg) MCHP decreased the activity of monoamino oxidase in guinea pigs only by less than 15%. Furthermore MCHP showed under our experimental conditions no relevant influence on the activity of various liver enzymes in plasma, the plasma concentration of creatinine, the plasma triglyceride-glycerol level and on the intrahepatic triglyceride-glycerol concentration of fasted guinea pigs. It is concluded that MCHP meets basic requirements for a potential oral antidiabetic agent.

Acetyl Coenzyme A↗
PubMed1984

Monoclonal antibodies recognizing structural components of murine retroviruses including an FMR antigen on protein p12.

Monoclonal antibodies were prepared from mice and rats immunized with Friend leukaemia virus and BALB/c xenotropic virus. By immunoprecipitation of 125I-labelled and [35S]methionine-labelled viruses and by protein blotting, ten antibodies were found to react with the viral components p12, p15, p30, gp70 and p15E/p12E. A dot-immunobinding assay was found to be a reliable method to type the antibody reactivity with different murine leukaemia viruses (MuLVs). When tested on a panel of ecotropic and xenotropic MuLVs the antibodies revealed the following antigenic specificities: ecotrop-specific on p15E/p12E; xenotrop-specific on p15E; group-specific on p30 and p15E; FM-specific on gp70; FR-specific on gp70 and p15. Of particular interest is a cytotoxic antibody recognizing an FMR determinant localized on p12.

Animals↗
PubMed1983

Influence of a 9-double bond on stereospecific microbial 4,5-reductions.

By stereospecific microbial reduction with Rhodosporidium rubrum or Rhodotorula glutinis, 17 alpha-cyano-methyl-4-estren-17 beta-ol-3-one was metabolized to 17 alpha-cyanomethyl-5 alpha-estrane-3 beta,17 beta-diol (50%) and 17 alpha-cyanomethyl-5 alpha-estrane-3 alpha,17 beta-diol (30%). By Clostridium paraputrificum the same substrate was reduced stereospecifically to 17 alpha-cyanomethyl-5 beta-estrane-3 alpha, 17 beta-diol (70%). When the corresponding 9-dehydrogenated compound 17 alpha-cyanomethyl-4,9-estradien-17 beta-ol-3-one (STS 557, a new progestagen) was fermented, yeasts failed in 5 alpha-reducing the 4-double bond. Still Clostridium paraputrificum formed the expected 5 beta-reduced metabolite 17 alpha-cyanomethyl-5 beta-estr-9-ene-3 alpha,17 beta-diol (60%). Structures were elucidated by n.m.r. and mass spectra and partly by circular dichroism. By oxidation of the metabolites, the corresponding 3-oxo compounds 17 alpha-cyanomethyl-5 alpha-estran-17 beta-ol-3-one, 17 alpha-cyanomethyl-5 beta-estran-17 beta-ol-3-one and 17 alpha-cyanomethyl-5 beta-estr-9-en-17 beta-ol-3-one were prepared. The evident influence of the 9-double bond on reduction of the 4-en-3-oxo compound STS 557 preventing 5 alpha-reduction but permitting 5 beta-reduction is discussed in view of the distinctly diminished metabolism of this progestagen in mammals.

Clostridium↗
PubMed1983

Studies on biotransformation of STS 557.

Transformation of STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) by female rat liver microsomes demonstrates a lower transformation rate in comparison with the analogous compound without 9-double bond: 17 alpha-cyanomethyl-19-nortestosterone, and the basic substance: 19-nortestosterone. 17 alpha-Cyanomethyl-estra-1, 3, 5(10), 9(11)-tetraene-3, 17 beta-diol, 17 alpha-cyanomethyl-11 beta, 17 beta-dihydroxy-estra-4, 9-dien-3-one, and tentatively 17 alpha-cyanomethyl-6 alpha, 17 beta-dihydroxy-estra-4, 9-dien-3-one were identified as metabolites. Microbial model investigations with species known to hydrogenate the 4-double bond in 4-en-3-oxo steroids stereospecifically to 5 alpha H- or 5 beta H-metabolites indicate 5 alpha-hydrogenation to be prevented in STS 557 by the 9-double bond, whereas 5 beta-hydrogenation is not affected. Isolation and characterization of metabolites from beagle dog and rat urine following administration of 3H-STS 557 revealed the following pathways of biotransformation: Hydroxylation in different positions of the steroid molecule, aromatization of ring A, hydrogenation of a double bond, simultaneous hydroxylation and hydrogenation, and alteration of the 17 alpha-side chain with loss of nitrogen.

Animals↗