Bioequivalence study of rabeprazole sodium on healthy human volunteers.

The newly developed proton pump inhibitor rabeprazole sodium is expected to have beneficial effects in the treatment of peptic ulcer. The pharmacokinetic parameters (C(max), AUC(o-t), t(max)) of this drug have been evaluated to compare the single dose (20 mg) bioavailability of rabeprazole sodium with the standard reference. High performance liquid chromatography (HPLC) coupled with UV detector set at 280 nm has been used to determine plasma concentration of 12 human volunteers as per Drugs Controller General of India (DCGI) guidelines. The method has been validated over a linear range of 20-480 ng/ml from plasma. The minimum quantifiable concentration was set at 10 ng/ml [co-efficient of variance (CV) < 10%]. By comparing AUC(o-t) the relative bioavailability of test preparation has been found to be 100.88% of that of reference preparation.

Significance of Non-erosive Minimal Esophageal Lesions in Gastro-esophageal Reflux Disorder

BACKGROUND: Non-erosive reflux disorder, which represents more than 60% of gastro-esophageal reflux disorders, lacks objective parameters for diagnosis. The purpose of this study was to evaluate the correlation between non-erosive minimal lesions at the lower esophagus and gastro-esophageal reflux disorder. METHODS: Patients were asked to answer a symptom questionnaire. The endoscopic findings were either graded by LA classification or recorded as non-erosive minimal lesions. Patients with minimal lesions were treated with rabeprazole or a placebo and responses were evaluated at weeks 1 and 4. RESULTS: In 8 centers, 3454 patients were screened. In patients with heartburn or acid regurgitation as the most bothersome symptom, 23.7% had endoscopy negative reflux disorder, 40.1% showed minimal lesions, and 36.2% had mucosal break esophagitis. Thirty-four percent of patients with minimal lesions and 39.1% of patients with LA 'grade A' mild esophagitis reported typical reflux symptoms as their main symptom. In patients with minimal lesions, medication with rabeprazole reduced symptoms significantly at weeks 1 and 4, but not with the placebo. CONCLUSION: Patients with non-erosive minimal esophageal lesions had similar reflux symptoms comparable to those with mild erosive reflux esophagitis, and reflux symptoms were improved with a short-term proton pump inhibitor. Thus, non-erosive minimal esophageal lesion constitutes a great part of gastro-esophageal reflux disorder.

Role of metal ions in coupling between chemical catalysis and conformational changes in ATP synthase.

Isolated chloroplast ATP synthase (CF0F1) was used for determination of the structure-function relation by measuring the effect of divalent metal ions on the properties of ATPase. Mg2+ ions were more efficient catalysts than Ca2+ ions as indicated by Kcat/Km of 55.2 and 5.4, respectively. Other activity parameters related to binding, such as the Km of MATP and Ki of MADP, indicated a stronger binding in the presence of Mg2+ as seen from a Mg2+/Ca2+ ratio of 2.8 and 3.8, respectively. Strong binding of Ca2+ ions with a Kd of 0.03 +/- 00.6 microM-1 was detected only in the presence of ADP probably because of the positive interactive effect of CaADP as indicated in the inhibition properties. Mg2+ ions were more efficient catalysts also in other forms of the enzyme such as in the thylakoid membrane, in isolated CF0F1 and in CF1. The Mg2+/Ca2+ ratio of Kcat/Km was 5.3, 10.2 and 1.5 for the thylakoid membrane enzyme, the isolated CF0F1 and the soluble CF1 respectively. This indicated that Ca2+ ions became less efficient catalysts in the more intact and integrated enzyme while Mg2+ ions were as efficient in all forms of the enzyme. Unlike Mg2+, Ca2+ ions also did not support proton-coupled ATP synthesis and ATP driven proton pumping. It is suggested that the differences in the ligand structure of these two ions might be the reason for the differential function. An average 0.3 A shorter bond length of octahedral first coordination in Ca2+ ions caused a weaker binding of CaATP than that of MgATP. The effect of differential binding is discussed in relation to the binding of the transition state intermediate and to the rate of product release.

Mechanism of cAMP-induced H(+)-efflux of Dictyostelium cells: a role for fatty acids.

Aggregating Dictyostelium cells release protons when stimulated with cAMP. To find out whether the protons are generated by acidic vesicles or in the cytosol, we permeabilized the cells and found that this did not alter the cAMP-response. Proton efflux in intact cells was inhibited by preincubation with the V-type H(+) ATPase inhibitor concanamycin A and with the plasma membrane H(+) ATPase blocker miconazole. Surprisingly, miconazole also inhibited efflux in permeabilized cells, indicating that this type of H(+) ATPase is present on intracellular vesicles as well. Vesicular acidification was inhibited by miconazole and by concanamycin A, suggesting that the acidic vesicles contain both V-type and P-type H(+) ATPases. Moreover, concanamycin A and miconazole acted in concert, both in intact cells and in vesicles. The mechanism of cAMP-induced Ca2(+)-fluxes involves phospholipase A2 activity. Fatty acids circumvent the plasma membrane and stimulate vesicular Ca2(+)-efflux. Here we show that arachidonic acid elicited H(+)-efflux not only from intact cells but also from acidic vesicles. The target of regulation by arachidonic acid seemed to be the vesicular Ca2(+)-release channel.

Effect of bafilomycin on proximal bicarbonate absorption in the rat

To evaluate the relative importance of the V-type H(+)-ATPase in proximal bicarbonate reabsorption in vivo, proximal tubules of male and female Wistar rats (180 to 260 g) were perfused with bicarbonate-Ringer solution with and without the addition of 2 microM bafilomycin A1. Bafilomycin significantly increased stationary pH from 6.75 +/- 0.05 (N = 39) to 6.86 +/- 0.03 (N = 82), the stationary concentration of bicarbonate from 5.24 +/- 0.62 to 6.33 +/- 0.46 mM and the half-time of acidification from 3.72 +/- 0.22 to 4.65 +/- 0.25 s, and significantly decreased net bicarbonate reabsorption from 3.17 +/- 0.21 to 2.55 +/- 0.15 nmol s-1 cm-2, that is, by 20 per cent . Since bafilomycin is considered to be a specific inhibitor for V-type H(+)-ATPase, these data establish 1) the existence of this type of transport in the rat proximal tubule and 2) that approximately a fifth of the total proximal bicarbonate reabsorption is due to this mechanism of transport