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Biomedical subjects

L S Harris

Publications and source records attributed to L S Harris.

At least 91 records · Page 5Linked to original sources
PubMed1983

Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 2. Non-glycolates.

The 19 esters in Table I were prepared from (+)-2 alpha-tropanol, (-)-2 beta-tropanol, (+/-)-3-quinuclidinol, and a variety of non-glycolic acids in order to compare their central and peripheral activities with those of the glycolates reported in the previous paper. The results (Table II) showed that esters 6 and 17 were approximately equivalent to one another and to atropine, that 8 was equal in both central and peripheral activity to reference glycolates, that 9 and 19 were less active than 8 but 9 had a substantially reduced central activity, and that 10 and 11 were more active than the methoxy analogue reported earlier.

Animals↗
PubMed1983

Zomepirac: preclinical narcotic abuse liability evaluation.

5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate dihydrate (Zomepirac, Zomax) was assessed in a variety of preparations in which narcotic agonists and antagonists have distinctive profiles. Zomepirac failed to displace tritiated etorphine significantly at concentrations up to 200 mumol/l. It was active (3-7 X 10(-5) mol/l) on both the electrically stimulated guinea pig ileum and mouse vas deferens but was less efficacious than morphine; these effects were not reversed by narcotic antagonists. Zomepirac was inactive in some analgesic assays in mice: tail-flick (1-30 mg/kg s.c.); hot plate (1-100 mg/kg s.c.); Nilsen (1-50 mg/kg s.c.); it was also inactive (1-10 mg/kg s.c.) as an antagonist of morphine in the tail-flick assay. It was, however, active in the paraphenylquinone writhing assay; this action was not reversed by naloxone (1-10 mg/kg) Zomepirac (2.5-10 mg/kg s.c.) failed to suppress signs of withdrawal produced by morphine deprivation in dependent rhesus monkeys. The intraperitoneal infusion of high doses of zomepirac (50 mg/kg/24 h or more) in rats produced toxicity. However, lower doses failed to induce narcotic-like dependence over a 6-7-day infusion period. The compound failed to maintain intravenous drug self-administration responding in rhesus monkeys over a range of doses (0.1-3.2 mg/kg) although codeine did so. In rhesus monkeys trained to discriminate narcotic agonists (etorphine or ethylketazocine) from saline, zomepirac (1-10 mg/kg i.m.) failed to produce drug-appropriate responding. Thus, zomepirac appears to possess few, if any, of the characteristic actions of narcotics that are associated with their abuse liability.

Analgesics, Opioid↗
PubMed1983

Antagonist of phorbol ester receptor-mediated chemotaxis in mouse peritoneal macrophages.

Biologically active phorbol ester derivatives displace [3H]phorbol-12, 13-dibutyrate from thioglycollate-elicited mouse peritoneal macrophages in a time-, temperature-, and concentration-dependent manner. Scatchard analysis revealed an apparent Kd of 54.1 nM and 8.0 X 10(5) sites/cell, indicating that these macrophages possess saturable, high-affinity phorbol ester-binding sites. These derivatives also act as chemoattractants for the macrophage at equivalent concentrations. A notable exception to this pattern is phorbol-12,13-diacetate. Phorbol-12,13-diacetate inhibits specific binding of [3H]phorbol-12,13-dibutyrate (concentration required for a 50% inhibition of the maximum specific binding of [3H]phorbol-12,13-dibutyrate, 2.6 microM) and chemotaxis to phorbol-12-myristate, 13-acetate (concentration required for a 50% inhibition of the maximum chemotactic response, 0.39 microM) while exhibiting no activity as a chemoattractant at concentrations up to 10(-5) M. The data indicate that phorbol-12,13-diacetate may be an antagonist for receptor-mediated chemotaxis to phorbol-12-myristate, 13-acetate in the macrophage.

Animals↗
PubMed1983

Antitussive effect of the optical isomers of mu, kappa and sigma opiate agonists/antagonists in the cat.

The optical isomer of mu and kappa opiates, when given i.v., inhibited the cough reflex in the lightly anesthetized cat, the levoisomers being, in general, 2 to 14 times more potent than the dextro-isomers. The optical isomers of the sigma agonist, SKF 10,047, did not show any antitussive activity up to near lethal or lethal doses (5 mg/kg i.v.). Naloxone (1 mg/kg i.v.) did not block or reverse the antitussive effects of (-)- and (+)-codeine but completely antagonized the effects of an ED84 of (-)-, (+)-morphine, (-)-, (+)-methadone, levomethorphan and dextromethorphan. The cough suppressant effects of the kappa opiates were partially blocked by naloxone, (+/-)-ketocyclazocine being more sensitive to the effect of naloxone than (-)-cyclazocine. (-)-SKF 10,047 at 3.0 mg/kg i.v. and the ED16 of (-)-cyclazocine did not inhibit the antitussive effect of codeine but blocked that of morphine, behaving like naloxone. (+)-SKF 10,047 and (+)-cyclazocine did not show in vivo antagonistic effect vs. codeine or morphine. The ED16 of ketocyclazocine partially antagonized codeine but not morphine. The optical isomers of opiates showed good correlation between the in vivo antitussive potencies and their in vitro inhibitory potencies against (-)-codeine binding in homogenates of the guinea-pig medulla. The data confirm the hypothesis that the cough suppressant effects of opiates are mediated by receptors which are less stereoselective and less naloxone-sensitive than the analgesic receptors. The possible involvement of mu and kappa sites as well as their interactions are discussed.

Animals↗
PubMed1982

3'-Hydroxy- and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol: biologically active metabolites of delta 9-tetrahydrocannabinol.

Synthesis of 3'-hydroxy- (7) and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol (11), metabolites of delta 9-THC, is described. Condensation of the monoterpene (+/-)-cis-p-menth-2-ene-1,8-diol (1) and (+/-)-3'-acetoxyolivetol (2) in the presence of fused ZnCl2 in CH2Cl2 gave a mixture from which the delta 9-THC derivative 3, containing small amounts of the delta 8-isomer 4, was isolated after column chromatography. This mixture was separated as their diacetates 5 and 6 by high-pressure liquid chromatography. Alkaline hydrolysis (5% KOH in MeOH) of 5 furnished the metabolite 7. Condensation of (+/-)-8 with 2 in the presence of p-toluenesulfonic acid gave 9a, which was acetylated to 9b. Treatment with HgO/BF3 X Et2O in wet THF gave the aldehyde 10. Reduction with LiAlH4 furnished the metabolite 11. These metabolites were compared with delta 9-THC for their ability to depress spontaneous activity and rectal temperature in mice and for their effects on overt behavior in dogs. 3'-Hydroxy-delta 9-THC was also compared to delta 9-THC in the mouse sympatomatology test and cardiovascular system in dogs. The metabolites produced pharmacological effects similar to those of delta 9-THC in all tests. 3'-Hydroxy-delta 9-THC was 2-3 times more effective than delta 9-THC in the behavioral tests, whereas (+/-)-3',11-dihydroxy-delta 9-THC was approximately 3 times less active than delta 9-THC.

Animals↗
PubMed1982

3H-Codeine binding in the guinea pig lower brain stem.

Saturable binding of (-)-3H codeine was found in the guinea pig medulla (KD = 5.6 x 10(-7) M, Bmax = 1.4 pmol/mg protein), whereas little stereospecific binding was detected (KD = 4.4 x 10(-5) M). The saturable binding of (-)-3H codeine was slightly enhanced by Na+ and by Mg++ but not by Li++ and Ca++. The enhancement appears to be due to an increase in the number of receptor sites. (-)-3H-Codeine binding was displaced by (-)- and (+)-codeine, morphine, (-)- and (+)-methadone but not by barbiturates. Naloxone, at a high concentration (1 x 10(-5) M), inhibits the binding by only 40%. This agrees with our previously published data which shows that the optical isomers of codeine had significant antitussive effects in the cat, these effects not being antagonized by naloxone. A class of opiate antitussive receptors, which are less naloxone-sensitive and less stereoselective than the mu receptors, is implicated.

Animals↗
PubMed1981

Modification of radiation carcinogenesis by marihuana.

Male, female, and ovariectomized female Sprague-Dawley rats were irradiated with 400 rads, 150 rads, or 300 rads, respectively, of 60Co gamma rays when they were between 40 and 50 days of age. The animals were injected three times weekly with either marihuana extract or with alcohol-emulphor carrier. Comparable unirradiated groups were similarly injected. Mean survival time in males was significantly shorter in the 400 rad + marihuana group compared with the three other groups whose mean survival times did not differ. Through the 546 days that the males were observed, the total number of tumors other than fibrosarcomas was significantly greater following radiation and marihuana (22) than radiation alone (6). Fifteen of the tumors were of breast or endocrine tissues. No differences were seen in the unirradiated groups. In the females, which were observed for 635 days, the total number of breast tumors was greater with the combined treatment (38) compared with radiation alone (22). This was entirely due to a marked difference in the adenocarcinoma incidence, which was 21 (radiation + marihuana) compared with four (radiation alone). The number of adenofibromas was similar in the two groups. In the unirradiated female groups the breast adenocarcinoma incidence was eight in the marihuana group and two in the control group. Ovariectomy resulted in a lower breast tumor incidence in all groups. Nonbreast tumors were more frequent in the ovariectomized-irradiated groups. Radiation plus marihuana produced more nonbreast tumors (25) than radiation alone (17) in the ovariectomized females.

Adenocarcinoma↗
PubMed1981

Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer.

The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole)from (+)-nicotine (Ib) via (-) 4,4-dibromocotinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of Ia. However, distribution studies showed that the maximum brain levels of (-)-[3H] nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-micrograms/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.

Animals↗