Cycloalkyl analogues of Antergan with the basic structure of N, N-dimethyl-N’-cycloalkylmethyl-N’-phenylethylenedi-amlne have been synthesized in good yields. The alkyl group was a butyl-, pentyl-, hexyl-, or heptyl-ring structure. The compounds with the benzyl group of Antergan substituted by a hydrogen or a methyl group were also synthesized in good yields. The general reaction sequence followed was to start with the appropriate cycloalkanecarboxyllc acid and build up to a secondary amine via an acid chloride and an amide. Leung’s methods (1) were followed and checked up to this step. Further reaction sequences were developed during this study. The desired amine was reacted with chloroacetyl chloride, dimethylamine and then reduced to the tertiary diamine analogues. The preliminary antihistamine activity of these analogues was studied and compared with that of Diphenhydramine Hydrochloride Standard Solution. The relative activity of each analogue was also determined. / Pharmaceutical Sciences, Faculty of / Graduate

No description available.

Through wastewater entering aquatic environments, aquatic insects are continuously exposed to pharmaceuticals including neurologically active antihistamines. The antihistamine hydroxyzine has previously been found to lower activity in damselflies and to reach 2000 times the concentration of surrounding water in damselfly tissue. The purpose of this short-term exposure study was to investigate if hydroxyzine also bioaccumulates in dragonflies and if dilute hydroxyzine (362 ± 50, mean ng/l ± SD) have effects on predator-prey interactions between dragonfly Aeshna grandis and damselfly Coenagrion hastulatum larvae, i.e. number of attacks and predation success. Predators and prey were captured and exposed during one, three or five days (with controls) before taking part in predation experiments; Dragonflies were put in separate containers with six damselflies, they were video recorded and attacks and predated damselflies noted during four hours. Tissue concentrations of hydroxyzine were analyzed from all dragonflies and a subsample of the damselflies showing a mean bioconcentration factor (BCF) of 27 and 7 respectively, surprisingly much lower than previous research. There was no difference in attack rate or predation efficiency between controls and exposed dragonflies. However, dragonflies exposed for five days were found to attack more and capture more prey than dragonflies exposed for one day, a change that was not seen in the controls. This confounding factor motivates further studies to clarify if hydroxyzine after a period of exposure can have a sublethal effect altering foraging and/or predator avoidance traits with the net result of increased predation success for dragonflies in the predator-prey interaction between dragonflies and damselflies.

A G protein-coupled receptor with structural characteristics of a biogenic amine GPCR was cloned from Schistosoma mansoni (SmGPCR). SmGPCR was codon-optimized and double-tagged with FLAG and His epitopes at the N- and C-terminal ends, respectively. Immunofluorescence experiments targeting these epitopes revealed that the expression of codon-optimized SmGPCR was highly increased compared to wild-type in mammalian cells. These studies also demonstrated that SmGPCR has a typical GPCR topology, the N-terminus being extracellular and C-terminus intracellular. Functional assays revealed that codon-optimized SmGPCR was responsive only to histamine, which caused a dose-dependent increase in intracellular Ca2+ (EC50 = 0.54 +/- 0.05 muM), but not cAMP, consistent with a Gq pathway of signal transduction. In vitro behavioral studies showed that treatment of S. mansoni cercaria with exogenous histamine caused a dose-dependent increase in the motility of the parasite.

Antergan is one of the ethylenediamine type of antihistamines; in this work ten analogues of it were prepared. That pπ conjugation is essential to antergan's antihistaminic activity has already been established. Six of these analogues (A-l a-d, and B-l and 2, illustrated in Fig. 2 , p. 4 ) were synthesized in order that the significance of pπ conjugation in the antihistaminic properties of antergan molecule may at some future time be investigated. The problem is to find in what way alteration (i. e. , increase or decrease in) electronic density of the pπ -conjugated moiety of the molecule affects antihistaminic activity. The analogues A-l a-d involved ortho-, meta-, and para-methyl, and para-bromo substitution to the aromatic ring which gives rise to pπ conjugation in the antergan molecule; while the ring which gives rise to homo conjugation was replaced by a cyclohexyl moiety to eliminate any possible contribution of homoconjugation to antihistaminic activity. In analogue B-l, the antergan structure was modified so that the aromatic ring which gives rise to pπ, conjugation was removed from the rest of the molecule by a methylene group, i.e. , the phenyl group was replaced by a benzyl moiety. The other ring was left unmodified. Another compound (B-2) relocated the aromatic ring giving rise to pπ conjugation to the adjacent methylene carbon, so that pπ conjugation was eliminated; this compound is the nitrogen analogue of diphenhydramine and thiodiphenhydramine. In order that the importance of homo conjugation to antergan's antihistaminic activity may be established, the aromatic ring which gives rise to pπ, conjugation was replaced by a cyclohexyl moiety (A-3). Two compounds were synthesized in which the aromatic ring giving rise to homoconjugation were replaced by 3-cyclohexyl moieties (A-2a and b); while the aromatic ring which gives rise to pπ, conjugation was left unaltered in one of the compounds (b) and replaced by a cyclohexyl moeity in the other (a). In the tenth compound (A-1 e), both aromatic rings giving rise to both homo- and pπ - conjugation were removed and replaced by cyclohexyl moieties. The resulting analogue of antergan has already been demonstrated to have a very low antihistaminic activity compared to diphenhydramine, but it was felt that it would provide a useful comparison for the antihistaminic activities of the other antergan analogues prepared in this work. Two final intermediates in the synthesis of other analogues of antergan were prepared. In these analogues (C-2a and b) the aromatic ring giving rise to homoconjugation would have been replaced by the 1-cyclohexenyl moiety, while the other aromatic ring which gives rise to pπ conjugation would have been the same in one of the analogues, and replaced by a cyclohexyl moiety in the other. In intermediates of analogues D-l and 2, the ring giving rise to homoconjugation would have been replaced by 2, 5- and 1,4-cyclohexadiene respectively, while the aromatic ring giving rise to Pπ conjugation was replaced by the cyclohexyl moiety. In intermediates D-3 and 4, the aromatic ring giving rise to homoconjugation would have been replaced by cyclohexyl, while the aromatic ring giving rise to pπ, conjugation would have been replaced by 2, 6-dimethylphenyl and 3-cyclohexenyl moieties. / Pharmaceutical Sciences, Faculty of / Graduate

No description available.

Research has shown that many antihistamines produce sedative effects as well as impair psychomotor performance. Performance testing of antihistamines, however, has not produced reliable evidence that there are behavioral effects at therapeutic dose levels. Therefore, the objective of this research was to determine whether a complex cognitive and motor task (memory search and tracking combination) showed a performance deterioration under the influence of two antihistamines (benadry| and hismanal) and to determine if the chosen task was of sufficient sensitivity to register decrements in performance at therapeutic dose levels of either of these two antihistamines. Thirty male subjects were divided into five groups of six subjects each. Each of the five groups was tested one day per week for three consecutive weeks. All Subjects received all three treatments (two antihistamines and a placebo) over the course of the test sessions. Order effect of the drug administration was counterbalanced. Analyses of variance showed that benadryl impaired performance on both components of the task as expected. Performance under hismanal did not vary significantly from the placebo. Post hoc testing further revealed an expected significant effect of benadryl three hours following ingestion for three out of four dependent variables. Again, hismanal effects did not vary significantly from those of the placebo. Hence, the memory/tracking combination task registered an expected performance impairment by benadryl which implies sufficient sensitivity of the task to register decrements. Also, hismanal displayed an expected lower incidence of behavioral effects as measured by response time and tracking error, which implies hismanal's usefulness in facilitating normal performance. / Master of Science

This thesis deals with the preparation of dialkylaminoalkoxy derivatives of p-chlorophenoxyacetic acid and phenylacetic acid.

Previous research has shown that most antihistamines have sedative effects and can lead to deterioration of psychomotor performance. The objective of this research was to determine if two antihistamines (diphenhydramine and astemizole) administered at a therapeutic dose level will affect a subject's visual search capabilities. The results of this research indicate that astemizole did not significantly decrement a subject’s ability to visually search as compared to the performance of that same subject after ingesting a placebo. Diphenhydramine produced significantly poorer visual search results than did astemizole. / Master of Science

The development of a new class of antihistamines, the H2-receptor antagonists, introduced a new era in the treatment of peptic ulcer diseases. Cimetidine, the first clinically effective H2-blocker, was introduced in 1976. Recently ranitidine, a second member approved for clinical use, has been found to be as effective as cimetidine in the management of peptic ulcer diseases. Soon after the introduction of cimetidine several reports of loss of libido, impotence and gynaecomastia were described in male patients who were on normal or high therapeutic doses of cimetidine. A few unsubstantiated reports of loss of libido and gynaecomastia attributed to ranitidine therapy have also appeared in literature. This study was undertaken to examine in detail the effects of acute and subchronic treatment with cimetidine and ranitidine on mating behaviour in sexually active male rats. Motor activity counts were recorded immediately before sexual behaviour observations. The animals were tested on every third day and observations were terminated after the first intromission of the next series of copulations. In the single dose study, mating behaviour tests were commenced 2 hours after treatment; mating tests during the subchronic dose studies were done 4 to 7 hours after the 6hOO dose. The following measures were used in the analysis of data: mount latency, intromission latency, mount frequency, intromission frequency, ejaculation latency, and the postejaculatory intromission latency. At the termination of the subchronic dose studies blood samples were collected by cardiac puncture and the animals were subsequently autopsied. Cauda epididymal sperm counts and motility were determined, testes and accessory sex organs were weighed, and one testis was processed for histological examination. Cimetidine in the low dose, 128.6 mg/kg, significantly shortened the ejaculatory latency and to a lesser extent the postejaculatory intromission latency. At the higher dose, 257.1 mg/kg, cimetidine markedly prolonged the postejaculatory intromission latency and to a lesser extent increased the ejaculation latency. The inhibitory effect of cimetidine on copulatory behaviour at the higher dose level was accompanied by significant depression in motor activity. At the conclusion of the subchronic dose studies marked reductions in serum testosterone levels and decreased testes and accessory organ weights were observed in the cimetidine group. No significant changes in sperm counts were observed, although the sperm counts in the cimetidine group were lower than the control values. Histological examination of testes showed apparently normal spermatogenesis in all three treatment groups. However, in spite of the reduced testosterone levels and decreased testes and accessory sex organ weights in the cimetidine group, no impairment in mating behaviour was observed. In both the acute and the subchronic dose studies, similar to placebo, treatment with ranitidine showed no effect on mating behaviour. On final analysis of the results it is concluded that cimetidine, and not ranitidine, disrupts sexual behaviour in male rats. Furthermore, it is concluded that the effect of cimetidine on sexual behaviour is not related to H2-receptor blockade as equipotent doses of ranitidine did not produce similar effects. The mechanism of cimetidine-induced impairment of sexual performance in the male rat may possibly be attributed to some non-specific, direct or indirect action of cimetidine on some neurotransmitter system responsible for the control of sexual behaviour. It is further suggested that the effect may possibly be mediated by a blockade of central dopamine receptors. However, it must be stressed that further experimentation is necessary to elucidate the mechanism of action of cimetidine on sexual behaviour. / Thesis (M.Sc.)-University of Durban-Westville, 1985.