Résumé
At present scopolamine is the most powerful single anti-motion sickness drug, but with prominent unwanted side effects. Many attempts had been made to decrease the unwanted side effects, but no any approach was considered to be successful. Based on our working hypothesis that central cholinolytic activity of anticholinergics may not be parallel completely to their side effects, a series of alicyclic amino alcohol esters were designed, synthesized and evaluated. One of the best compounds, phencynonate HCl, was obtained by transesteration of methyl α-phenyl-α-cyclopentyl-α-hydroxy acetate with N-methyl-3-azabicyclo(3,3,1)nonan-9α-ol. In animal models it was demonstrated that at equivalent anti-motion sickness dose the side effects of phencynonate were milder than those of two other central anticholinergic anti-motion sickness drugs scopolamine HBr and difenidol HCl. In clinical trials the overall effectiveness rates for prevention of seasickness and carsickness of phencynonate (oral 2-4 mg/person) was very significantly higher than that of placebo, and also significantly higher than that of difenidol (oral 25-50 mg/person). In self controlled rotatory chair experiments in hospital laboratory, the preventive effects of phencynonate and difenidol in reducing the changes in electronystagmus and electrogastrogram were statistically significant. In another self controlled rotation experiment, phencynonate (2-4 mg/person) and scopolamine (0.3-0.6 mg/person) showed significant anti-motion sickness effects in reducing the gastric electric cycles of electrogastrogram and the Graybiel scores of acute motion sickness and significant inhibitory effects on visual-vestibular interaction dose-dependently. The anti-motion sickness effects of phencynonate 2 and 4 mg were correspondent with those of scopolamine 0.3 and 0.6 mg, respectively. Student pilots with high susceptibility to airsickness were stimulated by Coriolis acceleration. The course of desensitization and habituation to airsickness training in phencynonate group (3 mg/person) was significantly shorter than that of placebo. There was no rebounding in sensitivity to Coriolis stimulation after discontinuing phencynonate, which was reported in case of scopolamine. The side effects of phencynonate HCl were mild dry mouth (9.7%) and drowsiness (9.97%). The incidence of drowsiness is significantly lower than that of difenidol. The side effect of drowsiness was only appeared in aboard ship and bus experiments, but not in PhaseⅠ trial in hospital or in laboratory rotation tests. The incidence of drowsiness of phencynonate was also lower than that of dramamine in aboard tank experiment. Phencynonate could effectively control the acute attack of vertigo, especially Meniere′s disease and positional vertigo. In animal models of Parkinson′s disease and parkinsonism, phencynonate showed morepotent antagonistic effects than clinical common used trihexyphendyl. In summary, phencynonate is a new central anticholinergic anti-motion sickness drug with higher efficacy and lower central inhibitory side effect than difenidol and scopolamine in prevention of motion sickness. Phencynonate HCl was approved on Dec 25,1993 by State Food and Drug Administration of China as a Class Ⅰ new drug for the prevention and treatment of motion sickness in the market in China.
Résumé
OBJECTIVE:To establish the Second-order Derivative UV-spectrophotometry for the determination of transdermal osmolality of metoprolol tartrate (MP)in vitro.METHODS:The quantitation of the vibration amplitude (?A)between the characteristic valley and the characteristic peak of MP appeared at 224nm and 234nm in UV-scanning.RESULTS:The linear concentration range of metoprolol tartrate was 5～60?g/ml,the average recovery was 98.89%with average RSD at 2.05%.CONCLUSION:This method can accurately determine the transdermal osmolality of MP in vitro yet without the interference of skin exudates,its operation is simple and fast and the results are accurate and reliable.
Résumé
Objective To investigate the effects of anticholinergic antidote and rhodosin on the brain injury induced by soman intoxication combined with hypobaric hypoxia in rats. Methods A total of 72 Wistar rats were divided into 4 groups: hypoxia control (HC), hypoxia plus soman (HS), hypoxia plus soman plus anticholinergic antidote (HSAA), and hypoxia plus soman plus anticholinergic antidote plus rhodosin (HSAAR). The animals after soman intoxication (72 ?g/kg) were placed in a hypobaric (62 kPa) apparatus for hypoxic exposure for 48 h. Rats were sacrificed for brain tissue detachment at the time points of 12, 24, and 48 h. Evans blue (EB) content and PLA 2 activity were detected biochemically. CaM concentration was determined by radioimmuno assay. Results Compared with the rats in HC, soman induced significant increases of brain EB, PLA 2, and CaM at 12, 24, and 48 h in HS. Elevated EB, PLA 2, and CaM induced by hypoxia and soman intoxication in rats in group HSAA were obviously attenuated by anticholinergic antidote. More significant decreases of brain EB, PLA 2, and CaM were found in rats in group HSAA. Conclusion Both anticholinergic antidote and anticholinergic antidote plus rhodosin have the preventive effect on rat brain damage induced by soman intoxication combined with hypoxia.
Résumé
Objective To investigate the effect of soman on the Janus kinases (JAKs) expression in cell line PC 12 . Methods The PC 12 cell was used in these experiments and treated with soman at a concentration of 20 ?mol/L . RT PCR and Western blotting were employed to detect the mRNA and protein expressions of JAK1, JAK2 and JAK3 at the time points of 0, 6, 12 and 24 h. The products were sequenced by Sanger's double strand DNA sequence determination. Results The expression levels of JAK1, JAK2 and JAK3 mRNAs and proteins increased at 2 h, reached the highest at 12 h and decreased at 24 h, but they were still higher than those of the control. It was shown that the sequences of amplification products by RT PCR were the same to corresponding ones in GenBank. Conclusion Soman intoxication enhances the expression of Janus kinases in PC 12 cells. JAKs genes may play an important role in brain injury due to soman intoxication.
Résumé
Objective To illustrate the features of soman induced signal transducers and activators of transcription (STATs) gene and protein expressions in cell line PC 12 . Methods The expression levels of STAT1, 3 and 5 mRNAs and protein in PC 12 cells were detected by semi quantitative RT PCR and Western blotting. PC 12 cells at 5～8 passages were randomly divided into 5 groups: control, intoxication groups for 2, 6, 12 and 24 h respectively. The products were sequenced by Sanger's double strand DNA sequence determination. Results The expression levels of STAT1, 3 and 5 mRNAs and proteins increased in PC 12 cell at 2 h and reached the highest at 12 h, then decreased at 24 h, but they were still higher than those of the control. The sequences of amplification products by RT PCR were the same to those in GenBank. Conclusion Soman intoxication can enhance the expression of STATs in PC 12 cells. STAT genes may possibly play an important role in brain injury.