Synthesis and investigation of novel shelf-stable, brain - specific chemical delivery system

A 1,4-dihydropyridine - pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors [MAOIs] were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier [BBB], and to be oxidized biologically into their corresponding quaternary compounds. 1-[Ethoxy-carbonylmethyl]-3,5-bis[N-[2-fluoro-benzylideneamino] carbamoyl]-1,4-dihydropyridine [31] proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-[ethoxycarbonylmethyl]-3,5-bis [N-[2-fluorobenzylideneamino] carbamoyl] pyridinium bromide [20]. Stability studies of the synthesized chemical delivery systems [CDSs] at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale design

Effect of valproic acid on food intake and nociception in morphine dependent mice

The anorectic and antinociceptive effects or valproic acid [VPA] were studied in morphine-dependent rnice in comparison with normal ones. For this purpose, the food intake of animals deprived of food for 24 hours and the hot plate reaction time, were studied. Morphine-dependency was induced by i.p. injections of morphine HC1 [40 mg /kg; twice daily for 3 days]. Morphine-dependent animals showed a significant decrease in food intake [p < 0.05], when compared with control mice [non-morphinized]. Acute administration of VPA [100, 200 and 300 mg /kg, i.p.] significantly potentiated the anorexia observed in morphine-dependent mice. VPA [200 and 300 mg /kg, i.p.] alone produced a significant decrease in food intake [p < 0.05] in non-morphinized animals, in the study of antinociception, a significant increase [p < 0.001] in hot-plate latency was observed in morphine-dependent animals, as compared to control mice. Treatment with VPA alone produced a significant increase [p < 0.05] in hot-plate latency in saline-pretreated animals in comparison with saline-pretreated control group. However, the administration of VPA [100 and 200 mg /kg, i.p.] to morphine-dependent animals significantly decreased [p < 0.05] their hot-plate latency as compared to the control group, in conclusion, VPA exhibited anorectic and antinociceptive activities in mice. VPA potentiated the anorexia seen in mice, which were rendered dependent to morphine, whereas the drug inhibited the antinociceptive activity observed in these mice. It seems from the present study that VPA is probably toxic in morphine-dependent subjects, since it might potentiate the anorectic and inhibit the analgesic effects

Reproductive, cytological and biochemical toxicity of Yohimbe in male Swiss albino mice / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To study the effect of Corynanthe Yohimbe (Yohimbe) on germ cells in Swiss albino mice.</p><p><b>METHODS</b>Adult male mice were orally (gavage) treated with different doses (188, 375 and 750 mg/[kg x day]) of aqueous suspension of Yohimbe for 90 days. The following parameters were evaluated: (i) reproductive organ weight, (ii) motility and count of sperm, (iii) study on rate of pregnancy and mean implants, (iv) spermatozoa morphology, (v) cytology of the testes chromosomes, and (vi) biochemical study on estimation of proteins, RNA, DNA, malondialdehyde, nonprotein sulfhydryl (NP-SH) and hormones.</p><p><b>RESULTS</b>The treatment caused significant increase in the weight of seminal vesicles, motility and count of spermatozoa, pre- and post-implants. Male fertility was decreased. These results are confirmed by our data on spermatozoa abnormalities and chromosomal aberrations. The data on biochemical parameters showed increase of malondialdehyde and depletion of NP-SH, proteins, RNA and DNA in the testicular cells.</p><p><b>CONCLUSION</b>Our results elucidated the role of free radical species in cytological and reproductive changes, possibly, under the influence of yohimbine (principal constituent of Yohimbe) on neurotransmitters, including norephinephrine. These data warrant careful use of Yohimbe.</p>

Antinociceptive activity of vigabatrin in mice

Vigabatrin [an inhibitor of GABA catabolism] was examined for its antinociceptive activity, changes in locomotor activity and body temperature in mice after acute treatment over a period of 24 hours. Vigabatrin [125 and 500 mg/kg i.p] resulted in rapid antinociception within 15 min. At the low dose of vigabatrin this effect returned to normal after-45 min but persisted more than 12 hours at the high dose. With the same dose regimen, the locomotor activity declined significant, with persistence up to 24 hour of the treatment. The effect of this treatment on body temperature was dose related being significantly reduced at 15 min. It returned to normal after 6 hours of treatment with vigabatrin 500 mg/kg. Treatment with bicuculline [a specific GABA A-receptor antagonist] was found to be minimally effective to avert locomotor or body] temperature changes induced by vigabatrin. Picrotoxin [a GABA Aand GABA gated-chloride ion channel blocker] was also ineffective on the hot-plate latency, locomotion or body temperature. However, picrotoxin slightly though significantly [p<0.05] reversed the changes in locomotion and rectal temperature only at first observation [15 min]. On the other hand, naloxone did not antagonize the effect of vigabatrin on body temperature but caused a significant decline in hot-plate latency at 45 min, perhaps because of hepotentiation of naloxone by vigabatrin in the induction of hyperalgesic response. These effects are thought to be a result of neuromediator interactions with the probable involvement of GABA receptor mediated processes and a possible direct effect of drug

Protective effect of thymoquinone and aminoguanidine against paraquat induced cardiotoxicity: possible role of nitric oxide synthase

Paraquat induced cardiotoxicity is due to oxidative damage produced by free radicals generations. The present study was undertaken to investigate whether inhibition of nitric oxide synthase by aminoguanidine, an inhibitor of nitric oxide [NO] synthase, can protect against paraquat-induced cardiomyopathy and to investigate whether thymoquinone, a potent superoxide radical scavenger, can protect against paraquat-induced cardiotoxicity in rats. Administration of paraquat, 50 mg/kg I P induce cardiotoxicity as indicated by a significant increase in the level of lipid peroxide, significant depletion of the reduced glutathione in heart tissue and significant decrease in the activity of antioxidant enzymes glutathione peroxidase [EC 1.11.1.9] and catalase [EC 1.11.1.6]. Oral administration of aminoguanidine [50 mg/100 mL in drinking water] or thymoquinone [5 mg/100 mL in drinking water] for 5 days before 2 days after single injection of paraquat [50 mg/kg, IP] leads to return of lactate dehydrogenase [EC 1.1.1.27] and creatine phosphokinase [EC 2.7.3.2] to normal values