Buffering the stomach content enhances the absorption of diflunisal in man

Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p less than 0.05) shortened the time to reach peak plasma concentration (tmax greater than 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration-time curve (AUC greater than 8 per cent). Other pharmacokinetic parameters, including terminal half-life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine. In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half-life of 12.8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89.5 per cent.     

Biocompatibility pattern of a bicarbonate/lactate-buffered peritoneal dialysis fluid in APD: a prospective, randomized study.

BACKGROUND: In chronic ambulatory peritoneal dialysis, bicarbonate-buffered fluids, with their neutral pH and less advanced glycosylation end-products (AGE) and glucose degradation products (GDP), have better biocompatibility than conventional peritoneal dialysis (PD) solutions. That difference may be more beneficial in automated peritoneal dialysis (APD), due to its more frequent exchanges and longer contact times with fresh dialysate. We performed a prospective, randomized study in APD patients to compare the biocompatibility of conventional and bicarbonate/lactate-buffered PD fluids. METHODS: We randomized 14 APD patients to have APD with either conventional or bicarbonate/lactate-based fluids. After 6 months, both groups changed to the other solution. The overall observation period was 12 months. After 1 and 5 months and again after 7 and 11 months, phagocytotic and respiratory burst capacities of effluent peritoneal macrophages were determined. Plasma interleukin (IL)-6 and C-reactive protein (CRP) as well as effluent IL-6, CRP, transforming growth factor (TGF)-beta 1, AGE and CA125 concentrations were measured. Inflow pain was quantified using a patient questionnaire. RESULTS: Respiratory burst capacity remained unchanged and phagocytotic activity increased significantly during APD (P<0.001) with the bicarbonate/lactate fluid. Effluent IL-6 release was significantly lower than with the lactate fluid (P<0.05). While in the effluent TGF-beta 1 was unaffected, AGE concentration was lower after bicarbonate/lactate treatment (P<0.05). Effluent CA125 concentration, an indicator of mesothelial cell integrity, was higher (P<0.05) in neutral effluents. Finally, patients' inflow pain diminished (P = 0.05) when using the neutral fluid. CONCLUSIONS: The use of a neutral PD fluid in APD improved patients' inflow pain as well as biocompatibility parameters reflecting enhanced phagocytotic activity of peritoneal macrophages, reduced constitutive inflammatory stimulation (IL-6), reduced AGE accumulation in the peritoneal cavity and better preservation of the mesothelial cell integrity. From the biocompatibility point of view, a neutral fluid with low GDP content can be recommended as the primary choice for APD.     

Expression of Na+/HCO3− co‐transporter proteins (NBCs) in rat and human skeletal muscle

Aim: Sodium/bicarbonate co‐transport (NBC) has been suggested to have a role in muscle pH regulation. We investigated the presence of NBC proteins in rat and human muscle samples and the fibre type distribution of the identified NBCs. Methods and results: Western blotting of muscle homogenates and sarcolemmal membranes (sarcolemmal giant vesicles) were used to screen for the presence of NBCs. Immunohistochemistry was used for the subcellular localization. The functional test revealed that approximately half of the pH recovery in sarcolemmal vesicles produced from rat muscle is mediated by bicarbonate‐dependent transport. This indicates that the NBCs are preserved in the vesicles. The western blotting experiments demonstrated the existence of at least two NBC proteins in skeletal muscle. One NBC protein (approximately 150 kDa) seems to be related to the kidney/pancreas/heart isoform NBC1, whereas the other protein (approximately 200 kDa) is related to the NBC4 isoform. The two NBC proteins represent the electrogenic isoforms named NBCe1 and NBCe2. Membrane fractionation and immunofluorescence techniques confirmed that the two NBCs are located in the sarcolemmal membrane as well as in some internal membranes, probably the T‐tubules. The two NBCs localized in muscle have distinct fibre type distributions. Conclusions: Skeletal muscle possesses two variants of the sodium/bicarbonate co‐transporter (NBC) isoforms, which have been called NBCe1 and NBCe2.     

Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

Sodium bicarbonate secretion indicated by ultrastructural cytochemical localization of HCO3 −, Cl−, and Na+ ions on rat bile duct brush cells

Brush cells are widely distributed in the digestive and respiratory apparatus, but their function is still unknown. Because brush cells (BC) are found in organs secreting NaHCO₃, it was hypothesized that these cells may secrete NaHCO₃. To test this possibility, rat common bile duct epithelia were examined by ultrastructural cytochemical methods for localizing HCO₃⁻, Cl⁻, and Na⁺ ions. All three ion precipitates were few in or on BCs of rats without stimulation. Lead carbonate precipitates, which localized HCO₃⁻ ions by the lead nitrate-osmium method, increased markedly on the surface of the microvilli (MV) of BCs after secretin or meal stimulation, but similar precipitates were few on the luminal surface of principal cells (PCs). Silver chloride precipitates, which indicate the presence of Cl⁻ ions by the silver-osmium method, increased in the apical cytoplasm and in MV of BCs after secretin or meal stimulation, but they were few in PCs. Sodium pyroantimonate precipitates, which localize Na⁺ ions by the potassium pyroantimonate-osmium method, increased on the surface of the MV, along the basolateral membrane, and in the apical cytoplasm of BCs after secretin or meal stimulation, but they were few in PCs. These results strongly suggest that BCs may be a significant source of NaHCO₃ secretion.     

pH and smooth muscle

In this paper, the control of vascular smooth muscle intracellular pH (pH_i) and the mechanisms of importance for the vasodilation to acidosis are reviewed. The three transport pathways of importance for the control of pH_i are a sodium-coupled bicarbonate transport, a Na,H-exchanger and a Cl,HCO₃^?exchange. While the two latter pathways are present in all smooth muscle cells studied, the sodium-coupled bicarbonate transport may be present in two forms which are either coupled to chloride efflux or are independent of chloride. The chloride-independent pathway seems electroneutral, indicating a 1:1 stoichiometry. All three transporters can be activated by vasoactive hormones and the second messengers involved are under intense investigation. With respect to the mechanisms involved in the vasodilation to acidosis, there seems to be a nitric oxide-dependent pathway as well as a direct effect of acidosis on the smooth muscle cells. In some preparations, prostanoids may also be involved. The direct vasodilator effect of acidosis is probably mediated through reduction of extracellular pH and the acidosis is associated with a reduction of the intracellular calcium concentration, which could explain the reduction of smooth muscle tone.     

Evidence for rheogenic sodium bicarbonate cotransport in the basolateral membrane of oxyntic cells of frog gastric fundus

Ionic conductance properties of the basolateral cell membrane of oxyntic cells were studied in frog gastric fundus in vitro. After mounting the fundus in a modified Ussing chamber the serosal connective tissue was dissected off and individual oxyntic cells were punctured from the serosal surface with microelectrodes. Under resting conditions the membrane potential averaged –56.9, SD±9.5 mV (n=63), cytoplasm negative. Lowering or raising serosal HCO ₃ ^– concentration from 17.8 to 6 or 36 mmol/l respectively at constant depolarized or hyperpolarized the cell membrane by +16.7 or –18.2 mV respectively. Sudden removal of serosal Na⁺ also depolarized the cell membrane (anomalous Nernst response). Since both the HCO ₃ ^– dependent and the Na⁺ dependent potential changes were strongly depressed by the disulfonic stilbene SITS and since the potential response to HCO ₃ ^– was virtually abolished in Na⁺-free solution we conclude that a rheogenic Na⁺ (HCO ₃ ^– ) _n -cotransport system (n>1) is present in the basolateral cell membrane of oxyntic cells. Its possible role in base transfer during HCl-secretion or HCO ₃ ^– secretion remains to be elucidated.This work was supported by grants Nr. 85.0443.04 and 86.00048.04 from Consiglio Nazionale delle Ricerche, Rome, Italy and by grant Nr. I 37736 from Stiftung Volkswagenwerk, Hannover, FRG     

Acid-induced increase in duodenal mucosal alkaline secretion in the rat involves the L-arginine/NO pathway

Duodenal mucosal alkaline secretion increases in response to hydrochloric acid exposure. The tentative role of nitric oxide (NO) in the mediation of this response was investigated. The mucosal alkaline output by a duodenal segment was recorded by in situ titration in chloralose-anaesthetized rats. In some experiments the duodenal blood flow was estimated by laser-Doppler flowmetry. Exposure of the duodenum to acid (0.01 M HCl, 5 min) increased the alkaline secretion by ≈85%. The NO synthase inhibitor N^G-nitro-L -arginine methyl ester (L -NAME, 10 mg kg^?1 intravenously or 0.3 mM intraluminally) blocked the secretory increment after mucosal acid exposure. Mean arterial pressure and basal alkaline secretion were markedly raised, whereas duodenal blood flow was decreased, when L -NAME was given intravenously (i.v.). Intraluminal (i.l.) administration left mean arterial pressure as well as duodenal blood flow unaltered, and the duodenal mucosal alkaline secretion was only slightly elevated. The stereoisomer N^G-nitro-D -arginine methyl ester (D -NAME) had no effect on either basal or acid-induced duodenal alkaline output. In animals receiving L -arginine (10 mg kg^?1 min^?1 i.v., or 3 mM i.l.) and L -NAME, the acid exposure elicited an increase in duodenal mucosal alkaline secretion, similar to that observed in controls. The results suggest that the acid-induced increase in duodenal mucosal alkaline secretion involves NO synthesis, which takes place close to the lumen, probably within the mucosa.