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Biomedical subjects

R N Harris

Publications and source records attributed to R N Harris.

At least 19 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↗
PubMed1991

Evaluating FACES III and the Circumplex Model: 2,440 families.

Previous evaluations of the Circumplex Model's curvilinear hypothesis using FACES instruments have yielded conflicting results. A review of the different research procedures and samples used in those investigations revealed that none of the studies had samples large and/or heterogenous enough to test the curvilinear hypothesis adequately. The present study evaluates the curvilinear hypothesis of family functioning and the concurrent validity of FACES III with a sample of optimal size (N = 2,440 families) and diversity. The lack of support for the curvilinear hypothesis in this "greenhouse" sample is explained by different findings for the two FACES III subscales. There was no relationship between the study's measures of well-being and the adaptability subscale and a linear relationship between these measures and the cohesion subscale. Implications of these findings for the continuing use of the FACES III and for the Circumplex Model of Marital and Family Systems are discussed.

Adolescent↗
PubMed1990

Spontaneous regression of anterior pituitary deficits in a woman harboring a persistent hypothalamic mass.

Sellar or parasellar lesions can cause anterior pituitary dysfunction either by direct damage to the anterior pituitary gland or by compression of the pituitary stalk and mediobasal hypothalamus which contain the hypophysiotropic hormones. Without treatment, the pituitary deficits in such cases are not likely to improve. We describe a case in which deficits in anterior pituitary hormones spontaneously remitted in a woman who had a persistent hypothalamic lesion that was not amenable to surgery or radiotherapy. The factors that may predict spontaneous recovery of anterior pituitary function in such cases are discussed.

Adult↗
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↗
PubMed1986

Effects of advanced leukemia on hepatic drug-metabolizing activity in the mouse.

Mice that had received 10(6) P388 leukemia cells IV 8 days previously exhibited a decrease in the components of the hepatic microsomal mixed function oxidase, with a 58% decrease in cytochrome P-450, and up to a 60% decrease in hepatic microsomal metabolism of biphenyl. Liver weight was increased by 49% due to infiltration of the liver with leukemic cells. Changes in liver drug-metabolizing activity and liver weight were not seen 6 days after administration of P388 leukemia. There was a small increase in serum liver enzyme but no increase in total serum bilirubin in tumor-bearing mice. In vivo total-body plasma clearance of cyclophosphamide, a drug metabolized by hepatic cytochrome P-450, was decreased to 53 ml/min/kg in mice that had received P388 cells 8 days earlier, as against 97.2 ml/min/kg in control mice. Cytochrome P-450-independent metabolism of [14C]5-fluorouracil, measured by means of [14C]CO2 in the breath over 3 h, was decreased to 21% of the dose administered by 8 days after tumor cell administration, compared with 31% of the dose in control mice. P388 leukemia cells growing in the ascitic form in the intraperitoneal cavity of mice did not release an inhibitor of 5-fluorouracil metabolism into the ascitic fluid. Total-body plasma clearance of indocyanine green was decreased to 11 ml/min/kg by 8 days after P388 cell administration, compared with 36 ml/min/kg in control mice. The decrease in indocyanine green clearance might reflect a decrease in hepatic blood flow in the tumor-bearing mice. A possible explanation for the decrease in hepatic drug metabolism caused by P388 leukemia is that the hepatocytes are deprived of oxygen and nutrients by the tumor in the liver, coupled with or caused by a physical obstruction of hepatic blood flow.

Animals↗
PubMed1986

The role of uncertain self-esteem in self-handicapping.

In this article, the hypothesis that some individuals confronted with an intellectual evaluation use a lack of preparation as a "self-handicapping" strategy (Jones & Berglas, 1978) was studied. Sex and both level and certainty of self-esteem were examined in regard to the self-handicapping strategy of lack of effort. Subjects were 54 men and 54 women, certain and uncertain, high and low self-esteem college students, who believed that the experiment was designed to update local norms for a nonverbal test of intellectual ability. After subjects' level of state anxiety was assessed, they were instructed in the benefits of practicing for the evaluation. Subsequently, subjects' state anxiety and preparatory efforts (the primary dependent variables) were measured. Subjects' practice, self-protective attributions, and related affect supported a self-handicapping interpretation for uncertain males but not for uncertain females.

Adolescent↗
PubMed1986

Enhancing the prediction of self-handicapping.

Levels of test anxiety, Type A and Type B coronary-prone behavior, fear of failure, and covert self-esteem were studied as predictors of self-handicapping performance attributions for college women who were placed in either a high- (N = 49) or low- (N = 49) evaluative test or task situation. We hypothesized that test anxiety. Type A or Type B level, and their interaction would account for reliable variance in the prediction of self-handicapping. However, we also theorized that underlying high fear of failure and low covert self-esteem would explain the self-handicapping claims of test-anxious and Type A subjects. The results indicated that only high levels of test anxiety and high levels of covert self-esteem were related to women's self-handicapping attributions.

Adolescent↗
PubMed1985

Effect of doxorubicin-enhanced hydrogen peroxide and hydroxyl radical formation on calcium sequestration by cardiac sarcoplasmic reticulum.

This study investigated the effect of doxorubicin-related oxygen radical formation on Ca2+ uptake by rat heart sarcoplasmic reticulum vesicles. Enzymatic activation of doxorubicin by cardiac NADH dehydrogenase produced a dose-related inhibition of Ca2+ uptake that was enzyme- and cofactor-dependent and that was inhibited by catalase, various hydroxyl radical scavengers, and the iron chelator deferoxamine. Furthermore, inhibition of Ca2+ uptake paralleled the production of the hydroxyl radical by NADH dehydrogenase after doxorubicin treatment. These results suggest that doxorubicin-stimulated reactive oxygen metabolism can alter Ca2+ transport by cardiac sarcoplasmic reticulum and may represent one pathway involved in the cardiac toxicity of this potent antineoplastic agent.

Animals↗
PubMed1984

Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study.

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.

Animals↗
PubMed1984

Structure-activity relationships for reactivators of organophosphorus-inhibited acetylcholinesterase: quaternary salts of 2-[(hydroxyimino)methyl]imidazole.

A series of 1,3-disubstituted-2-[(hydroxyimino)methyl]imidazolium halides were prepared and evaluated in vitro with respect to their ability to reactivate acetylcholinesterase inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methylphosphonofluoridate (GD). The compounds conform to the general formula N(CH3)C(CHNOH)N(CH2OR)CHCH+ X Cl-, where R = CH3, (CH2)3CH3, (CH2)7CH3, CH2C6H5, CH2C10H7, (CH2)3C6H5, CH(CH3)2, CH2C(CH3)3, and CH(CH3)C(CH3)3. For comparison we also evaluated three known pyridinium reactivators, 2-PAM, HI-6, and toxogonin. The imidazolium aldoximes exhibit oxime acid dissociation constants (pKa) in the range 7.9-8.1, bracketing the value of 8.0, believed to be optimal for acetylcholinesterase reactivation. With imidazolium compound in excess over inhibited enzyme, the kinetics of reactivation are well behaved for EPMP-inhibited AChE and depend on the nature of the alkyl ether group R. For GD-inhibited AChE, maximal reactivation was used to compare compounds because rapid phosphonyl enzyme dealkylation and enzyme reinhibition complicate interpretation of kinetic constants.

Acetylcholinesterase↗
PubMed1984

Postmenopausal ureteral endometriosis with atypical adenomatous hyperplasia following hysterectomy, bilateral oophorectomy, and long-term estrogen therapy.

Endometriosis of the ureter is rare. The authors describe a case of ureteral endometriosis presumed on clinical and radiologic grounds to be a primary ureteral malignancy. The unique feature of the present case is the development, after long-term estrogen therapy, of postmenopausal ureteral endometriosis with extensive atypical adenomatous hyperplasia. The present case demonstrates that reactivation of endometriosis and the development of atypical hyperplasia may occur after menopause with prolonged estrogen therapy.

Age Factors↗