Stimulation by nizatidine,a histamine H_2-receptor antagonist,of duodenal HCO_3^-secretion in rats:relation to anti-cholinesterase activity

AIM To examine whether nizatidine stimulates duodenal HCO_3^- secretion in rats by inhibiting AChE activity. METHODS Under pentobarbital anesthesia,a proximal duodenal loop was perfused with saline,and the HCO_3 secretion was measured at pH 7.0 using a pH-stat method and by adding 10mM HCI.Nizatidine,neostigmine,carbachol or famotidine was administered i.v.as a single injection. RESULTS Intravenous administration of nizatidine(3-30 mg/kg)dose-dependently increased duodenal HCO_3^- secretion,and the effect at 10mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg.This nizatidine action was observed at the same dose range that inhibited acid secretion and enhanced gastric motility,mimicked by i.v.injection of neostigmine(0.03 mg/kg),and significantly attenuated by bilateral vagotomy and prior s.c. administration of atropine but not by indomethacin,a cyclooxygenase inhibitor,or N^G-nitro-L-arginine methyl ester,a NO synthase inhibitor.The HCO_3^- secretory response to acetylcholine(0.001 mg/kg)was significantly potentiated by the concurrent administration of nizatidine(3mg/kg,i.v.).The IC_(50)of nizatidine for AChE of rat erythrocytes was 1.4×10^(-6)M,about 12 times higher than that of neostigmine.Neither famotidine(>10^(-3)M, 30mg/kg,i.v.)nor cisapride(> 10^(-3)M, 3mg/kg,i.v.)had any influence on AChE activity or duodenal HCO_3^- secretion.Duodenal damage induced by acid perfusion(100 mM HCI for 4 h)in the presence of indomethacin was significantly prevented by nizatidine and neostigmine,at the doses that increased the HCO_3^- secretion. CONCLUSION Nizatidine stimulates duodenal HCO_3^- secretion,in both vagal-dependent and atropine-sensitive manners,and the action is associated with the anti-AChE activity of this agent.

A study of the effects of saliva stimulation by nizatidine on dry mouth symptoms of primary biliary cirrhosis

AIM: To elucidate the effect of saliva stimulation by nizatidine on oral symptoms of primary biliary cirrhosis (PBC) by administering it to PBC cases. METHODS: From among 73 cases that had been definitively diagnosed as PBC at our hospital by February 2010, we selected 27 cases of PBC, 4 males and 23 females, as subjects. We obtained subjects' consent after giving them a full explanation of the administration of nizatidine. Nizatidine 150 mg was administered internally twice daily, after morning and evening meals. To observe changes in the quantity of saliva secreted, chewing gum tests were carried out four times: before the initial dose, and after 6 mo, 12 mo and 24 mo of administration. For subjective dry mouth symptoms, a visual analog scale (VAS) method was used to assess their feelings of oral dryness and eating difficulty, five times: before the initial dose, and after 1, 6, 12 and 24 mo of administration in 8 cases. The nutritional condition and the hepatic functional reserve were compared between before and after the nizatidine treatment.RESULTS: The result of a chewing gum test on the subjects before the administration of nizatidine showed that 50% produced less than 10 mL of saliva, i.e. , the standard under which cases are considered to have hyposalivation. The results of these tests showed that the quantity of saliva secreted was 10.5 ± 6.8 mL before administration of nizatidine, 10.9 ± 6.0 mL after 6 mo, 10.6 ± 4.9 mL after 12 mo, and 11.8 ± 6.8 mL after 24 mo administration. Thus, there was a slowly increasing trend in the quantity of saliva in the whole group. The percentage of subjects with saliva production above 10 mL was 45.8% after 6 mo administration of nizatidine, that is, only a slight change from before its administration, but it was 64.3% after 12 mo, that is, a significant increase. The saliva secretion by subject patients was examined before the beginning of administration of nizatidine, 12 mo later, and 24 mo later, and Fisher's combined probability test was used to examine the results for increases in saliva secretion. The analysis yielded P values of 0.51 and 0.53 for 12 mo later and 24 mo later, respectively. Thus, although there was no statistically significant increase, it was confirmed that saliva secretion tended to increase. A VAS method was employed to study the intensities of subjective symptoms of oral dryness and eating difficulty. Almost every case indicated some improvement of subjective oral dryness on the VAS early in the administration, i.e. , one month after. We also studied the effects of the administration of nizatidine on nutritional condition, hepatic functional reserve, and long-term prognosis of PBC. No significant improvements in cholinesterase (ChE) level, albumin (Alb) level, or Child-Pugh score were found during the period of observation from the beginning to the end of administration of nizatidine, nor in comparison with the non-administration group. A comparative analysis between before administration and 24 mo later yielded P values of 0.41 for Alb, 0.56 for ChE, and 0.59 for the Child-Pugh scores. CONCLUSION: It was confirmed that administering nizatidine to cases of PBC with dry mouth increased the secretion of saliva and improved the symptoms.

Solubilities of Nizatidine in Methanol+Water, Ethanol+Water and i-Propanol+Water from 273.15 to 303.15 K

The solubilities of nizatidine in methanol + water, ethanol + water and i-propanol + water mixtures were determined in the temperature range from 273.15 K to 303.15 K at atmospheric pressure by a static analytical method. The general single model was used to correlate the experimental data, which fits the data very well.

Rapid Validated Stability Indicating Method for Nizatidine and Its Impurities Quantification

This research article describes stability indicating fast liquid chromatographic method for determination of chromatographic purity and assay of Nizatidine as a alternate for two different methods for chromatographic purity and assay as given in USP Monograph and Ph.Eur Monograph. Proposed method is developed on Waters symmetry RP18 (50 × 4.6 mm), 3.5 μm stationary phase using gradient elution with combination of Ammonium acetate Diethyl amine buffer, Methanol and Tetrahydrofuran as mobile phase. Favorable results are obtained under developed conditions, which guarantee good separation of studied components. Whereas, data obtained from method validation confirm specificity, high sensitivity, linearity in a range of studied concentrations, repeatability and good accuracy of this method. Considerable degradation observed in oxidation stress condition was detected by this method. Eight impurities are studied among which impurity-5 is found major degradant. The stress samples are assayed against a qualified standard and the mass balance is found close to 99.2%. The developed method can be used for routine samples as well as stability studies.

Quantitative determination of nizatidine in human plasma and urine by high performance liquid chromatography and its pharmacokinetic study in humans

A validated simple and sensitive high performance liquid chromatographic（HPLC） method for the quantitative determination of nizatidine（NIZ） in human plasma and urine is reported.Reverse phase chromatographic separation of NIZ and salicylic acid（internal standard） was achieved on Diamonsil C_（18） column,using acetonitrile-0.05 mol/L K_2HPO_4-triethylamine （17：83：1,v/v/v,pH 6.5） as the mobile phase.Flow rate was 0.9 mL/min and the ultraviolet detector was set at a wavelength of 320 nm.The assay was linear over the range of 0.0117-6 mg/mL for plasma samples and 0.029-50 ug/mL for urine samples. The limit of quantification was 0.0117μg/mL.The intra- and inter-day RSD values were lower than 5.12%and 8.03%,respectively, in plasma,and 6.2%and 6.9%,respectively,in urine.A single dose of 100 mg NIZ and multiple doses of 100 mg NIZ were administered to 10 healthy volunteers through intravenous infusions.The multiple dose regimens were administered every 8 h for 6 consecutive days.The pharmacokinetic parameters were obtained as following：for single-dose,Cmax（2.7±0.6）μg/mL, t1/2（1.4±0.4） h,AUC0-12h（2.45±0.33）μg·h/mL,AUC0-∞（2.46±0.33）μg·h/mL,and the accumulated urine excretion rate in 12 h was 61.2%±9.46%;for multiple doses,Cmax（2.9±0.8）μg/mL,t1/2（l.3±0.2） h,AUC0-12h（2.56±0.52）μg·h/mL,AUC0-∞ （2.56±0.52）μg·h/mL,and the accumulated urine excretion rate in 12 h was 51.3%±9.42%.The statistical analysis of the pharmacokinetic parameters in males and females after single-dose and multiple-dose intravenous infusion of NIZ showed no differences.No drug accumulation after multiple-dose intravenous infusion of 100 mg NIZ was observed.The validated HPLC method was suitable for the pharmacokinetic study of NIZ.