Biomedical subjects

D A Goff

Publications and source records attributed to D A Goff.

9 recordsLinked to original sources

PubMed1991

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 4. Effect of various side-chain substituents on therapeutic activity against anticholinesterase intoxication.

A series of quaternary salt derivatives of 2-[(hydroxyimino)methyl]-1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo for the treatment of anticholinesterase intoxication. Test results in the mouse revealed that the type and location of the side-chain substituent both have a significant influence on the toxicity and antidotal effectiveness of the compounds. Some of the more active examples represent the most potent therapeutics to date against intoxication by the powerful cholinesterase inhibitors soman and tabun. Significantly, the antidotal effectiveness of the compounds was not dependent on the inhibiting agent nor was there any correlation between in vivo efficacy and in vitro reactivation of ethyl (4-nitrophenyl)methylphosphonate inhibited human acetylcholinesterase. These observation suggested that the main mode of antidotal protection by the compounds is something other than enzyme reactivation.

Acetylcholinesterase↗

PubMed1991

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 5. Structure-activity relationships for side-chain nitro-, sulfone-, amino-, and aminosulfonyl-substituted analogues for therapy against anticholinesterase intoxication.

Several quaternary imidazolium oxime derivatives incorporating side chains bearing nitro, sulfone, amino, and aminosulfonyl substituents were prepared and evaluated as treatment therapeutics for anti-AChE intoxication. In vivo test results in the mouse revealed that many of these compounds are highly effective in providing life-saving protection against the extremely toxic cholinesterase inhibitors soman and tabun. Several structure-activity relationships were noted that were characteristic of the side-chain substituent. In vivo test results for additional selected derivatives of some of the more therapeutically active compounds indicated that the quaternary heteroaryl nucleus is essential for activity whereas a nucleophilic moiety (i.e., oxime) is not. In support of previous suspicions, these results afforded additional evidence suggesting that reactivation is not the main mode of antidotal action by the imidazolium oximes. An alternative antidotal mechanism is postulated that is consistent with all data and that involves enzyme protection by the compounds.

Animals↗

PubMed1989

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 2. Preparation and in vitro and in vivo evaluation of 1-(alkoxymethyl)-2-[(hydroxyimino)methyl]-3-methylimida zolium halides for reactivation of organophosphorus-inhibited acetylcholinesterases.

A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methyl-phosphonofluoridate (soman, GD). All new compounds were characterized for (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol-buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivation of EPMP-inhibited AChEs. For GD-inhibited AChEs, maximal reactivation was used to compare compounds since rapid phosphonyl enzyme dealkylation "aging" complicated interpretation of kinetic constants. For comparison, we also evaluated three known pyridinium therapeutics, 2-PAM, HI-6, and toxogonin. In vivo evaluation in mice revealed that when selected imidazolium compounds were coadministered with atropine sulfate, they were effective in providing lifesaving protection against both GD and EPMP challenges. This was a major accomplishment in the search for effective anticholinesterase therapeutics--the synthesis and preliminary evaluation of the first new monoquaternary soman antidotes with potencies superior to 2-PAM. Significantly, there was an apparent inverse relationship between in vitro and in vivo results; the most potent in vivo compounds proved to be the poorest in vitro reactivators. These results suggested that an alternative and possibly novel antidotal mechanism of protective action may be applicable for the imidazolium aldoximes. Selected compounds were also evaluated for their inhibition of AChE phosphorylation by GD and antimuscarinic and antinicotinic receptor blocking effects.

Animals↗

PubMed1989

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 3. Synthesis and evaluation of (alkenyloxy)-, (alkynyloxy)-, and (aralkyloxy)methyl quaternarized 2-[(hydroxyimino)methyl]-1-alkylimidazolium halides as reactivators and therapy for soman intoxication.

A series of structurally related monosubstituted 1-[(alkenyloxy)methyl]-, 1-[(alkynyloxy)methyl]-, and 1-[(aralkyloxy)methyl]-2-[(hydroxyimino)methyl]-3-methyli midazolium halides were prepared and evaluated. All new compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, and octanol-buffer partition coefficient. The alkynyloxy-substituted compounds were also evaluated in vitro with respect to reversible inhibition of human erythrocyte (RBC) acetylcholinesterase (AChE) and kinetics of reactivation of human AChE inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP). In vivo evaluation in mice revealed that coadministration of alkynyloxy-substituted imidazolium compounds with atropine sulfate provided significant protection against a 2 x LD50 challenge of GD. For the alkynyloxy-substituted imidazolium drugs there is a direct relationship between in vitro and in vivo activity: the most potent in vivo compounds against GD proved to be potent in vitro reactivators against EPMP-inhibited human AChE. These results differ from the observations made on the sterically hindered imidazolium compounds (see previous article) and suggest that several antidotal mechanisms of protective action may be applicable for the imidazolium aldoxime family of therapeutics. The ability of the alkynyloxy substituents to provide life-saving protection against GD intoxication was not transferable to the pyridinium or triazolium heteroaromatic ring systems.

Animals↗

PubMed1988

Nasopharyngeal carriage of antibiotic-resistant pneumococci by children in group day care.

We compared rates of antibiotic resistance in strains of Streptococcus pneumoniae recovered from nasopharyngeal secretions of a group of children studied longitudinally in a research day care center between 1978 and 1985 and recovered from usually sterile body fluids of patients at a tertiary care hospital between 1981 and 1985. The prevalence of trimethoprim-sulfamethoxazole (TMP-SMZ) resistance was 11.5% in isolates from the hospital, whereas 30.0% of episodes of nasopharyngeal carriage of S. pneumoniae studied in day care children included TMP-SMZ-resistant isolates. The proportion of episodes of colonization with TMP-SMZ-resistant isolates in the day care study increased from 5.4% before 1981 to 39% between 1981 and 1985. Isolates of S. pneumoniae relatively resistant (MIC greater than or equal to 0.125 micrograms/mL) to penicillin G, amoxicillin, or cefuroxime accounted for 8% of isolates from the hospital and 11.9% of episodes of nasopharyngeal colonization in children in day care. Pneumococci with reduced susceptibility to either TMP-SMZ or a beta-lactam antibiotic were recovered from 68% of 72 children in the day care study.

Amoxicillin↗

PubMed1984

Amebic prostatitis.

A man with persistent prostatitis despite antibiotic therapy was found to have amebas compatible with Entamoeba histolytica in his urine after prostatic massage. Two indirect hemagglutination titers for E histolytica were negative. The patient had a prompt response to metronidazole therapy. Prostatitis due to amebic infection should be considered in patients who do not respond symptomatically to standard antibiotic therapy.

Adult↗

PubMedDate not supplied

Substituted 2-iminothiolanes: reagents for the preparation of disulfide cross-linked conjugates with increased stability.

Much attention has been focused recently on the stability of immunotoxin (antibody-toxin) conjugates linked by a disulfide bridge. Conflicting reports have appeared regarding the in vivo stability of such conjugates prepared with the two most commonly used cross-linking reagents, SPDP and 2-iminothiolane. We have developed (i) a series of reagents based on 2-iminothiolane substituted at the 4- and/or 5-positions (X2ITs) which, based on model studies with simple amines, should show enhanced disulfide stability when conjugated with antibodies or other proteins and (ii) a real-time method for monitoring the rate and extent of conjugation of these reagents with amino groups. Depending upon the substituent, the stability of model-activated disulfides relative to unsubstituted 2-iminothiolane was increased from 5- to 4000-fold as measured by glutathione-induced release of thionitrobenzoic acid. This family of cross-linking reagents should allow the construction of disulfide cross-linked toxin, drug, or enzyme conjugates with enhanced stability in vivo.

Chemical Phenomena↗

PubMedDate not supplied

Development and validation of an instrument to measure physicians' attitudes toward the clinical pharmacist's role.

A scale to measure physicians' attitudes toward clinical pharmacy was developed and validated. Based on physician-clinical pharmacist interactions, statements were written and edited into tentative subscales. A preliminary test resulted in a reduction in the number of items and subscales. The final field test, based on responses from 166 physicians, after factor analysis, yielded 23 items in 5 subscales, with a scale reliability of 0.94. As additional measures of validity, physicians' responses showed significant differences in attitudes between subscales and differences by specialty. Differences also were demonstrated by physician status and age. No differences were shown by amount of exposure to clinical pharmacists. Reliability and validity of the scale have been supported and additional research into the concurrent validity of the scale is suggested.

Age Factors↗

PubMedDate not supplied

Absorption characteristics of three phenytoin sodium products after administration of oral loading doses.

The absorption characteristics of three phenytoin sodium products given orally as loading doses in five healthy men were studied. Extended phenytoin sodium capsules, prompt phenytoin sodium capsules, and phenytoin sodium injection were administered in a randomized, crossover trial as single 18-mg/kg doses and as divided doses of 6 mg/kg every three hours for three doses. Each dose was given with 200 ml of water, and a two-week washout period followed each treatment. The maximum plasma concentration (Cmax), time to reach maximum plasma concentration, time to reach the lower end (10 mg/liter) of the therapeutic range, time to reach a plasma concentration greater than 15 mg/liter, and time within the therapeutic range were determined for each loading-dose regimen. Prompt phenytoin sodium capsules (prompt PHT) given in divided doses produced a mean Cmax of 22.0 mg/liter, which was significantly higher than that observed with any of the other loading-dose regimens. In addition, all subjects receiving prompt PHT in divided doses had plasma phenytoin concentrations of 10 mg/liter within six hours; only this treatment produced plasma concentrations greater than 15 mg/liter at nine hours in all subjects. Plasma concentrations remained within the therapeutic range (10-20 mg/liter) for 81 and 78% of the first 24-hour period for prompt PHT in divided and single doses, respectively. Adverse effects were minimal in all regimens. The prompt-release phenytoin sodium capsules used in this study may provide an alternative means for rapidly achieving therapeutic phenytoin concentrations in situations where i.v. administration is not indicated or practical.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗