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Biomedical subjects

J Mühlbacher

Publications and source records attributed to J Mühlbacher.

8 recordsLinked to original sources
PubMed2003

Sorbicillactone A: a structurally unprecedented bioactive novel-type alkaloid from a sponge-derived fungus.

This chapter deals with the discovery of sorbicillactone A, as an illustrative example of the fruitful cooperation within BIOTECmarin--its isolation and chemical characterization, and its biological activities. Sorbicillactone A was isolated from a strain of Penicillium chrysogenum cultured from a sample of the Mediterranean sponge Ircinia fasciculata; it possesses a unique bicyclic lactone structure, seemingly derived from sorbicillin. Among the numerous known sorbicillin-derived structures, it is the first found to contain nitrogen and thus the first representative of a novel type of 'sorbicillin alkaloids', apparently originating from a likewise remarkable biosynthesis. Furthermore, the compound exhibits promising activities in several mammalian and viral test systems, in particular a highly selective cytostatic activity against murine leukemic lymphoblasts (L5178y) and the ability to protect human T cells against the cytopathic effects of HIV-1. These properties qualify sorbicillactone A or one of its derivatives for animal and (hopefully) also future therapeutic human trials.

Alkaloids↗
PubMed2001

New insecticidal rocaglamide derivatives and related compounds from Aglaia oligophylla.

Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product. All isolated rocaglamide, aglain, and aglaforbesin derivatives have a characteristic methylenedioxy substituent linked to C-6 and C-7 or to C-7 and C-8, respectively. Structure elucidation of the new natural products and the determination of the absolute configuration of compound 1 by calculation of its CD spectrum with molecular dynamics simulation are described. All isolated rocaglamide derivatives exhibited strong insecticidal activity toward neonate larvae of the polyphageous pest insect Spodoptera littoralis when incorporated into an artificial diet, with LC(50) values varying between 2.15 and 6.52 ppm.

Animals↗
PubMed2000

Tropane alkaloids from Erythroxylum zeylanicum O.E. Schulz (Erythroxylaceae).

Six tropane alkaloids were isolated from the Sri Lankan endemic plant Erythroxylum zeylanicum O.E. Schulz (Erythroxylaceae) and structurally elucidated by NMR and MS measurements. Three of them, erythrozeylanines A [1R,3R,5S,6R-6-acetoxy-3-(3',4',5'-trimethoxybenzoyloxy)tropane], B [cis-3 beta-(cinnamoyloxy)tropane], and C [cis-6 beta-acetoxy-3 alpha-(cinnamoyloxy)tropane] are new, whereas the others have already been found in other Erythroxylum species. For the first time, the absolute configuration of a tropane alkaloid (erythrozeylanine A) has been determined by quantum chemical CD calculations.

Alkaloids↗
PubMed1995

Amoxicillin concentrations in nasal secretions of patients with acute uncomplicated sinusitis and in paranasal sinus mucosa of patients with chronic sinusitis.

In this prospective randomized clinical study a total of 59 patients of both sexes (above 18 years of age) were enrolled. Thirty patients with acute sinusitis were randomly allocated to two treatment groups, one group receiving 1000 mg amoxicillin every 12 h for 10 days and the other group receiving 500 mg amoxicillin every 8 h for 10 days. The median concentration of amoxicillin in nasal secretions was 2.34 micrograms/ml in the 12-h administration group and 1.95 micrograms/ml in the 8-h administration group. Median bioavailability of antibiotic at 8-24 h did not show any statistical differences between the two treatment schemes [probability (Z) = 0.2]. Twenty-nine patients with chronic sinusitis were then randomly allocated to three groups, with patients receiving 1000 mg amoxicillin at 12, 8 or 6 h before nasal and/or sinus surgery was carried out. The mean amoxicillin concentrations in mucosal tissues removed intraoperatively ranged from 0.69 to 0.99 microgram/g samples. Statistical evaluation by analysis of variance did not show any statistically significant differences among the three treatment groups [probability (F) = 0.1705]. In all cases of acute and chronic sinusitis, amoxicillin concentrations exceeded minimum inhibitory concentration values for pathogens common in sinusitis. Our results indicate that 1000 mg amoxicillin administered twice daily produces tissue concentrations high enough to be clinically effective in patients with either acute or chronic sinusitis.

Acute Disease↗
PubMed1991

Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-[3H]emopamil.

(-)-Emopamil ((S)-emopamil, (2S)-2-isopropyl-5-(methylphenethylamino)- 2-phenylvaleronitrile hydrochloride) is a Ca(2+)-antagonistic phenylalkylamine which also blocks serotonin (5-HT2) receptors and has antiischemic properties. The (-)-[3H]emopamil tissue distribution profile of specific binding is in striking contrast to that observed for (+)-[3H]PN 200-110 or (-)-[3H]desmethoxyverapamil: (-)-[3H]emopamil labels membrane fractions from guinea-pig liver much greater than adrenal gland greater than kidney approximately lung approximately ductus deferens approximately brain approximately skeletal muscle. Binding to liver membrane was saturable (KD = 12.8 nM, Bmax = 35 pmol/mg of protein), stereoselective, reversible (K-1 = 0.22 min-1 at 25 degrees C) and inhibited by tetraethylammonium (IC50: 1.8 mM) greater than Li+ (IC50: 12.5 mM) approximately Na+ (IC50: 13.6 mM) and [NH4+] (IC50: 79.3 mM) but not by Rb+, Cs+ or K+. The high-affinity liver membrane binding sites have a pharmacological profile that is distinct from the phenylalkylamine receptor domain of the voltage-dependent L-type Ca2+ channel. Similar sites exist in brain and other tissues, albeit with a lower density. Amiodarone, butoprozine and amiloride derivatives bind with high affinity whereas 1,4-dihydropyridines do not interact at all. It is suggested that the novel phenylalkylamine site is linked to a sodium-dependent carrier or transport system.

Animals↗
PubMedDate not supplied

Antimicrobial activity of josamycin against erythromycin-resistant staphylococci as compared to roxythromycin and clarithromycin.

In an in vitro study 246 clinical isolates of erythromycin-resistant staphylococci from six hospitals in Austria were investigated for susceptibility to josamycin and other, newer macrolide antibiotics, e.g. roxithromycin and clarithromycin. 71 strains of Staphylococcus aureus showed an MIC > or = 4 mg/l and 100 strains of S. aureus showed an MIC > or = 256 mg/l. In addition, 25 strains of coagulase-negative staphylococci resistant to erythromycin at an MIC of > or = 4 mg/l were investigated. At an MIC of 2 mg/l 57% of the erythromycin-resistant strains of S. aureus were inhibited by josamycin, 25% by clarithromycin and 11.6% by roxithromycin. At an MIC of 2 mg/l 13.3% of erythromycin-resistant coagulase-negative staphylococci were inhibited by josamycin, 10.7% by clarithromycin and 9.3% by roxithromycin. This study suggests that josamycin is still active in vitro against more than 50% of erythromycin-resistant strains of S. aureus. This drug is also more active than roxithromycin and clarithromycin against erythromycin-resistant S. aureus.

Clarithromycin↗
PubMedDate not supplied

Web-based cheminformatics and molecular property prediction tools supporting drug design and development at Novartis.

Web-based tools offer many advantages for processing chemical information, most notably ease of use and high interactivity. Therefore more and more pharmaceutical companies are using web technology to deliver sophisticated molecular processing tools directly to the desks of their chemists, to assist them in the process of designing and developing new drugs. In this paper, the web-based cheminformatics system developed at Novartis and currently used by more than thousand users is described. The system allows various molecular modeling and molecular processing tasks, including the calculation of molecular and substituent properties, property-based virtual screening, visualization of molecules, bioisosteric design, diversity analysis, and support of combinatorial chemistry. The methodology to calculate various molecular properties relevant to drug design is described, including the prediction of intestinal absorption, blood-brain barrier penetration, efflux, and water solubility. Information about the web technology used is also provided.

Drug Design↗