Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing
Patent
1994-09-14
1997-03-04
Rollins, John W.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
424 946, 424 9461, 424 9462, 424 9463, 424457, 514198, 540336, A61K 3843, A61K 3846, A61K 3847, A61K 3848
Patent
active
056076711
DESCRIPTION:
BRIEF SUMMARY
The present invention addresses all such antimicrobial therapy in man in which .beta.-lactam antibiotics are the therapeutic agents.
The invention uses oral administration of enzymes to break down the therapeutically detrimental .beta.-lactam antibiotic pool, which accumulates in the gut in conjunction with .beta.-lactam antibiotic therapy, into compounds with little (low) or no antimicrobial activity, thus eliminating or diminishing the adverse microbiological effects otherwise encountered among the beneficial, normal bacterial flora of the body, especially in the gut.
The benefits of the invention can be directly availed of with conventional prevention and treatment regimes for bacterial diseases. The invention also allows higher single doses or prolonged administration of .beta.-lactam antibiotics to be used in cases in which effective treatment has so far been hindered by the microbiological side effects of the antibiotic.
The invention also makes possible local antimicrobial therapy, e.g. for bacterial gastritis, gastric and duodenal ulcers, using oral administration of such .beta.-lactam antibiotics which have so far been limited to the parenteral route of administration. Thus the potent antimicrobial properties of these antibiotics can be more extensively availed of.
.beta.-lactam antibiotics are antimicrobial agents which destroy bacteria sensitive to .beta.-lactam antibiotics. Their common feature is the .beta.-lactam ring in their molecules (I): ##STR1##
The .beta.-lactam ring gives these compounds the antimicrobial property availed of in the treatment of bacterial diseases. All .beta.-lactam antibiotics (henceforth .beta.-LABs, AB for antibiotic) discovered in the period 1940-1970 belong to two structural classes: the penicillins (II), in which the .beta.-lactam ring is fused with a thiazolidine ring, and the cephalosporins (III), in which the .beta.-lactam ring is fused with a dihydrothiazine ring. ##STR2##
The more recently introduced compounds are known as nonclassic .beta.-LABs. These include the carbapenems, in which the sulphur atom in the 1-position of the .beta.-lactam nucleus of the penicillins is replaced by a carbon atom, and the monobactams, in which the .beta.-lactam ring is not fused with any other ring structure at all.
With the exception of benzylpenicillin, which is prepared from natural sources, penicillins intended for clinical use are derived semisynthetically by attaching a desired side chain to the amino group of 6-aminopenicillanic acid, 6-APA (IV) (U.S. Pat. No. 2,941,995, U.S. Pat. No. 3,499,909). One method of penicillin preparation is to extract natural penicillins produced by various moulds and then remove the undesired side chains in the 6-position in these penicillins enzymatically using penicillin amidases (FI 59265) to obtain 6-APA, followed by incorporation of a new side chain in this position (GB 1241 844).
Cephalosporins are manufactured from 7-aminocephalosporanic acid (V) (U.S. Pat. No. 3,239,394), 7-ACA, a compound analogous with 6-APA, by linking requisite radicals to the amino group in the 7-position and sometimes even to the side chain in the 3-position.
The nonclassic .beta.-LABs are isolated from natural microorganisms. ##STR3##
Neither of the above-mentioned compounds, 6-APA and 7-ACA, possess any antimicrobial potency of significance (Korzybski and Kurylowicz 1961, Huber et al. 1972).
The penicillin amidases used in the semisynthetic manufacture of .beta.-LABs are a structurally heterogeneous group of enzymes produced by a wide range of microorganisms (US 3,150,059) and also by mammalian cells (U.S. Pat. No. 3,070,511 ). Their common feature is the ability to quite substrate-specifically hydrolyse the side chain of various penicillins. The side chains hydrolysed include acyl groups in the 6-position of the .beta.-lactam nucleus and, in the case cephalosporins, acyl groups in the 7-position. The remaining compounds are 6-APA and 7-ACA (IV and V) with a an amino group in the 6- or 7-position, respectively. To recapitulate, the reaction is a case of hydr
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