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Biomedical subjects

A Sjoerdsma

Publications and source records attributed to A Sjoerdsma.

At least 73 records · Page 4Linked to original sources
PubMed1982

Restriction of bacterial growth by inhibition of polyamine biosynthesis by using monofluoromethylornithine, difluoromethylarginine and dicyclohexylammonium sulphate.

Bacterial growth was measurably slowed by a combination of drugs which inhibit polyamine-biosynthetic enzymes. Addition of DL-alpha-monofluoromethylornithine, which was shown to inactivate irreversibly ornithine decarboxylase extracted from Escherichia coli (Ki = 0.36 mM) and Pseudomonas aeruginosa (Ki = 0.30 mM), DL-alpha-difluoromethylarginine and dicyclohexylammonium sulphate to cultures of E. coli or P. aeruginosa resulted in a 40 and 70% increase in generation times (decreased growth rates) respectively, which was completely reversed by the addition of 0.1 mM-putrescine plus 0.1 mM-spermidine to the medium. Decreased intracellular polyamine concentrations correlated with increased generation times; putrescine concentration was decreased by 70% in E. coli and 80% in P. aeruginosa, while spermidine concentration was decreased by 50% in E. coli and 95% in P. aeruginosa. Subsequent investigation of the inactivation of the ornithine decarboxylase by monofluoromethylornithine indicated that it was active-site directed, as the normal substrate ornithine slowed the rate of inhibition. Specific interference with polyamine biosynthesis may be a viable approach to control of some bacterial infections.

Arginine↗
PubMed1982

Methyldopa.

Explore the source record for details and available documents.

Animals↗
PubMed1982

Curative effect of alpha-difluoromethylornithine on fatal Trypanosoma congolense infection in mice.

The curative effect of alpha-difluoromethylornithine (DFMO) on fatal T. congolense infection in mice was investigated using various concentrations administered orally in drinking water. Permanent cure was achieved in mice receiving 4% for 3 days or 2% for 5 days. Mice receiving less became parasitemic again but then, without any further treatment, resisted death due to trypanosomes for an average of 34.5 days, while untreated controls were dead within 8 days after trypanosomes were first seen in their blood.

Animals↗
PubMed1982

alpha-Difluoromethylornithine: a promising lead for preventive chemotherapy for coccidiosis.

alpha-Difluoromethylornithine (DFMO; RMI 71,782) given in drinking water in concentrations as low as 0.0625% inhibited infections of Eimeria tenella and minimized the development of lesions in chickens. It had approximately the same activity as a currently used anticoccidial drug, amprolium, and also had the advantage of being relatively nontoxic in chickens. Body weight gains were not reduced in chickens given 0.0635% DFMO or less for 14 days starting 8 days before they were inoculated with oocysts, but were reduced in chickens given drinking water containing 0.125 and 0.25% DFMO. The anticoccidial activity of DFMO was completely reversed by injection (intraabdominal) of putrescine hydrochloride (300 mg/kg of body weight/day), indicating that the drug may act by blocking putrescine biosynthesis. Inoculated chickens, in which coccidial lesion development was suppressed by DFMO, resisted subsequent challenge exposure with E tenella, as did nontreated infected control birds which had recovered from infection.

Animals↗
PubMed1981

Further studies on difluoromethylornithine in African trypanosomes.

DL-alpha-Difluoromethylornithine (DFMO), a specific enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC) was previously shown to cure mice infected with Trypanosoma brucei brucei, a parasite of game and cattle in Africa and Trypanosoma brucei rhodesiense, a human African Sleeping Sickness pathogen. Our studies now indicate that DFMO blocks ornithine decarboxylase and lowers trypanosome polyamine levels in vivo. Polyamine uptake in T.b. brucei also resembles that previously described for mammalian cells. The therapeutic potential of DFMO can now also be extended to another human pathogen, Trypanosoma brucei gambiense. Finally, DFMO acts synergistically with another drug, bleomycin, to cure acute trypanosome infections, and furthermore, this same drug combination provides a new approach to the treatment of trypanosomal infections of the central nervous system.

Acute Disease↗
PubMed1981

Potentiation of the antitumor therapeutic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor.

alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with various single doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to treat animals bearing murine glioma 26 and rat 9L gliosarcoma intracerebral tumors. Used as a single agent, DFMO has little or no effect against these tumors. However, in both intracerebral tumor models, pretreatment with DFMO p.o. before i.p. administration of BCNU potentiates the effect of BCNU without increasing toxicity. The effects of DFMO administered p.o. after BCNU or before and after various doses of BCNU indicate that DFMO may also effectively slow the repopulation of these tumors after BCNU therapy.

Animals↗
PubMed1980

Polyamine metabolism: a potential therapeutic target in trypanosomes.

alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.

Animals↗
PubMed1980

L-Ornithine decarboxylase:an essential role in early mammalian embryogenesis.

The highly selective, enzyme-activated, irreversible inhibitor of L-ornithine decarboxylase, DL-alpha-difluoromethylornithine, suppresses the increase in uterine L-ornithine decarboxylase activity associated with early embryogenesis in the mouse and arrests embryonic development at that stage. Contragestational effects were confirmed in the rat and rabbit. An increase in L-ornithine decarboxylase activity that leads to a rapid increase in putrescine concentration appears to be essential during a critical period after implantation for continued mammalian embryonal growth.

Adenosylmethionine Decarboxylase↗
PubMed1980

Further studies on the inhibition of monoamine synthesis by monofluoromethyldopa.

1 alpha-Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme-activated irreversible inhibitor of aromatic L-amino acid decarboxylase produces a substantial and long-lasting decrease in the catecholamine content of mouse brain, heart and kidney. 2 Single doses of MFMD reduce the 5-hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration. 3 In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.

Animals↗
PubMed1979

Effects of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor or ornithine decarboxylase, on testosterone-induced regeneration of prostate and seminal vesicle in castrated rats.

1. Castration of adult rats markedly decreases the amounts of polyamines (putrescine, spermidine and spermine) and of RNA and DNA in the ventral prostate and the seminal vesicle. 2. Daily injections of testosterone propionate to rats castrated 7 days previously increase polyamine and nucleic acid contents more rapidly in the seminal vesicle than in the ventral prostate. 3. After 7 days of androgen treatment, polyamine and nucleic acid contents of the seminal vesicle are significantly higher than those of intact animals. Nucleic acid, but not polyamine, contents return to normal values during the next 4 days of continued treatment. In the prostate, androgen treatment increases polyamine and nucleic acid contents to, but not above, normal values. 4. Repeated doses of alpha-difluoromethylornithine, a potent enzyme-activated irreversible inhibitor of ornithine decarboxylase, totally blocked the testosterone-induced increase of putrescine and spermidine in the ventral prostate and of putrescine in the seminal vesicle. They slowed significantly the accumulation of spermine in the ventral prostate and of spermidine in the seminal vesicle. alpha-Difluoromethylornithine also retarded the testosterone-induced accumulation of RNA in the ventral prostate. However, no clear correlation was apparent between accumulation of polyamines and of nucleic acids in the two organs. 5. alpha-Difluoromethylornithine markedly slows the testosterone-induced weight gain of the prostate, but not of the seminal vesicle. Cytological studies suggest that this effect on the prostate is due to inhibition of the androgen-induced restoration of the secretion content of prostatic acini.

Animals↗