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Biomedical subjects

G R Gale

Publications and source records attributed to G R Gale.

At least 127 records · Page 7Linked to original sources
PubMed1966

Urease activity and antibiotic sensitivity of bacteria.

Gale, Glen R. (Veterans Administration Hospital, Durham, N.C.). Urease activity and antibiotic sensitivity of bacteria. J. Bacteriol. 91:499-506. 1966.-An investigation was made of the responses of certain urease-positive bacteria to various antibacterial drugs in the presence of highly specific urease inhibitors, in a test of the hypothesis proposed by other workers that inhibition of bacterial urease enhances the sensitivity of the cells to antimicrobial agents. Urease inhibitors employed were seven hydroxamic acids (HA). Six of the seven HA reduced the sensitivity of nine Proteus strains to ampicillin and methenamine mandelate. Two HA increased the sensitivity to colistin, and six HA increased the sensitivity to kanamycin. Investigation of the mechanism of action of the synergistic effect between kanamycin and HA led to the tentative conclusion that potentiation was mediated through an initial alteration of cell permeability by the aminoglycoside antibiotic which permitted accumulation of each of the six HA into the cell, at which point each interacted with pyridoxal phosphate. The single HA which failed to yield synergism with kanamycin failed to interact with pyridoxal phosphate in a nonenzymatic system; the other six HA produced alterations of the normal ultraviolet absorption spectrum of the coenzyme.

Ampicillin↗
PubMedDate not supplied

Chirality, charge, and chain branching effects on dithiocarbamate-induced mobilization of cadmium from intracellular deposits in mice.

The effects of three major structural features on the intracellular cadmium mobilizing potency of dithiocarbamates have been examined. These features, the chirality of the groups, the total ionic charge of the chelating agent, and the extent of chain branching, would be expected to affect the pharmacological properties of these chelating agents but to have little effect on the stability constants of the cadmium complexes involved. A total of 25 compounds (including 21 new ones) was prepared and used in animal studies designed to evaluate these effects. These included a series of amphipathic dithiocarbamates of the general type R1N(R2)CS2-Na+, where R1 is a relatively nonpolar organic group and R2 is derived from a reducing hexose. All of the factors examined influenced the potency of dithiocarbamates in the mobilization of cadmium from intracellular deposits. The compounds with R2 = galactose or mannose and R1 = benzyl were both more effective than the corresponding glucose derivatives in inducing the removal of cadmium from the liver and the whole body. Increases in the net negative charge of the chelating agent uniformly decreased the observed potency in the mobilization of hepatic and renal cadmium deposits. The replacement of a normal alkyl group by a branched-chain group of the same molecular weight also led to an increase in potency for the two pairs of compounds examined. Dithiocarbamates which are not amphipathic because of the presence of similar polar substituents for both R1 and R2, such as sodium diarabitylamine carbodithioate, were relatively ineffective as agents for the mobilization of intracellular cadmium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Structure-activity relationships for intracellular cadmium mobilization by N-alkyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioates+ ++.

An examination of a group of dithiocarbamate chelating agents derived from various alkylamines and lactose reveals that the relative potencies in the mobilization of intracellular cadmium from renal and hepatic deposits in mice are highly dependent upon the size and nature of the alkyl groups. For those compounds containing straight-chain alkyl groups, the potency drops off as the number of carbon atoms is increased beyond seven. Branched-chain alkyl groups are more effective in promoting the removal of cadmium than straight-chain alkyl groups with the same number of carbon atoms. The fact that these compounds are effective in the mobilization of intracellular cadmium deposits suggests that the size and shape of the alkyl group are important in the determination of the facility with which the compound can pass through cellular membranes. Straight-chain derivatives with 10 or more carbon atoms were more toxic than those with nine or fewer carbon atoms. Of the new compounds, four (the n-hexyl, n-heptyl, n-octyl, and 2-ethylhexyl derivatives) are more effective than the corresponding benzyl derivative in inducing a reduction of hepatic cadmium levels from animals given cadmium at least 1 week previously. The results obtained indicate that modest modifications in the groups on the basic dithiocarbamate structure can produce agents of significantly enhanced effectiveness for the removal of cadmium from its hepatic deposits.

Animals↗
PubMedDate not supplied

Structure-activity relationships for in vivo cadmium mobilization by dithiocarbamates derived from lactose and maltotriose.

The relationships between chemical structure and the relative ability to mobilize cadmium in vivo from its aged renal and hepatic deposits have been examined in a series of newly synthesized dithiocarbamates derived from lactose and maltotriose. The results suggest that, in the selection of hydrophobic groups to counter the hydrophilicity contributed by the disaccharides, aromatic groups provide compounds which have a superior efficacy to compounds containing aliphatic groups. The compounds derived from trisaccharides are much less effective than those derived from disaccharides, suggesting that there is a practical size limit to the hydrophilic groups which can be used in the structures of such compounds. With both di- and trisaccharides, aliphatic derivatives with straight chains containing more than eight carbon atoms tend to be less effective than the ones with seven or fewer carbon atoms in the alkyl chain. The three compounds prepared from lactose which contain a benzyl or a methyl-substituted benzyl group are the most effective compounds reported to date for the reduction of whole-body cadmium levels.

Animals↗
PubMedDate not supplied

Design of in vivo cadmium-mobilizing agents: synthesis and properties of monobenzyl meso-2,3-dimercaptosuccinate.

A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.

Administration, Oral↗
PubMedDate not supplied

Combination and individual antitumor effects of hyperthermia, cisplatin, and selected dithiocarbamates.

The antitumor effects produced by combinations of cisplatin (Pt), substituted dithiocarbamates (dimethyldithiocarbamate [DmDTC] and sodium N-methyl-D-glucamine dithiocarbamate [NMGDTC]) and hyperthermia (H) were measured and compared to those produced by single agents alone in C3H/HeN mice bearing the transplantable radiation-induced fibrosarcoma, RIF-1, in one or both hind feet. The average tumor volumes of control and treatment groups were compared periodically after treatment with H. Combinations of H and Pt completely resolved established foot tumors in 10/13 mice. However, evidence of long-term nephrotoxicity and gastrointestinal (GI) toxicity became evident causing death of these mice within 120 to 122 days after tumor inoculation. Hyperthermia plus DmDTC resolved tumors in heated and non-heated feet in 3/8 mice, thus demonstrating both ipsilateral and contralateral anti-tumor activity. Furthermore, H-Pt-NMGDTC produced complete tumor resolution in 7/13 mice; these mice survived and were tumor-free 180 days post inoculation and autopsies revealed no appreciable nephro- or GI toxicity. In addition, 4/8 mice underwent complete tumor resolution in heated left feet plus dramatic retarding of tumor growth in unheated right feet (ipsilateral and contralateral anti-tumor effects). Five heat-treated left foot tumors resolved in the H-Pt-DmDTC group with one mouse demonstrating resolution of tumor in both feet. Advanced foot tumors were treated with H-DmDTC and H-Pt-DmDTC. Hyperthermia and Pt were administered on day 0 of the experiment and DmDTC on days 0 through 3; dramatic tumor shrinkage continued through day 6 for a total of 75 to 80 percent reduction of tumor volume in both groups. The concurrent administration of DmDTC or NMGDTC with H and Pt prevented or greatly reduced nephrotoxicity and GI toxicity in all experiments without retarding anti-tumor efficacy.

Animals↗
PubMedDate not supplied

Diethyldithiocarbamate in treatment of acute cadmium poisoning.

An insoluble complex was synthesized by the reaction of sodium diethyldithiocarbamate trihydrate (DDTC) with CdCl2 X 2.5 H2O (Cd). Elemental analyses of the product yielded a percent composition of each element which was consistent with the postulated structure of two mole equivalents of (DDTC)- and one mole equivalent of Cd++. The DDTC formed a complex with 11 other metal ions tested, but not with Ca++ or Mg++. The complex with Cd was highly insoluble in water, 0.1 N HCl, 0.1 N NaOH, human serum, and carbon tetrachloride, but it was soluble in pure dimethyl sulfoxide. The DDTC protected mice from a greater than LD100 dose of Cd. This protective effect was more pronounced when DDTC treatment was delayed at least 30 min after i.p. administration of Cd. More than 98 percent of mice treated with 500 mg per kg of DDTC 30 min to five hrs after Cd administration survived, and 50 percent survived when treatment wad delayed for eight hrs. Administration of DDTC prior to or immediately after Cd gave less protection. The lowest (DDTC)-/Cd++ molar dose ratio which resulted in 100 percent survival following the otherwise lethal dose of Cd was 7.6, which was less than four times the theoretical stoichiometric molar ratio for formation of the complex. The LD50 of the complex in mice wa approximately 650 mg per kg of the i.p. route, indicative of a low degree of dissociation in vivo.

Acute Disease↗