Sevelamer worsens metabolic acidosis in hemodialysis patients.

BACKGROUND: Sevelamer hydrochloride, a major phosphate binder for patients on maintenance hemodialysis (MHD) is associated with reduced serum bicarbonate concentration due to hydrochloric acid release in the gut and to the binding of short chain fatty acids in the large intestine. Since metabolic acidosis can be deleterious, a study was devised to compare the time course of serum bicarbonate concentration during treatment with sevelamer hydrochloride or calcium carbonate. METHODS: Sixteen well nourished patients on MHD who were in excellent clinical conditions and achieving target levels for blood pressure (BP) and hemoglobin (Hb), while on a protein intake of 1.1g/kg body weight (bw), were enrolled in the study. After a 2-week washout period, the patients were divided into two groups, each consisting of eight patients, and randomized either to 24 weeks of sevelamer followed by 24 weeks of calcium carbonate (group A) or to 24 weeks of calcium carbonate followed by 24 weeks of sevelamer (group B). Protein intake, n-protein catabolic rate (nPCR), serum concentrations of calcium, phosphate, calcium x phosphate (Ca x P) product, bicarbonate, intact parathyroid hormone (iPTH) and albumin were monitored. Time course changes in serum bicarbonate concentrations in relation to short and long dialytic intervals (48 vs. 72 hr) were also investigated. RESULTS: Both sevelamer and calcium carbonate effectively controlled serum phosphate and the Ca x P product. During calcium carbonate treatment plasma phosphate concentrations were significantly below those of patients on sevelamer. Plasma bicarbonate concentration fell within target DOQI values during calcium carbonate administration both in group A and in group B, a goal which was not achieved under sevelamer administration. After a long dialytic interval in patients on sevelamer, serum bicarbonate concentration averaged 17.3 +/- 1.1 mEq/L, whereas it averaged 21.1 +/- 0.7 mEq/L in patients on calcium carbonate (p<0.01). Finally, a 24-week sevelamer administration caused a statistically significant (p<0.05) reduction (0.8 g/dL) in serum albumin concentration, without affecting iPTH. Taken together, these results indicate that sevelamer worsens metabolic acidosis, which needs to be corrected.

Intramolecular C-H--O interaction between lactam oxygen and N-alkyl protons.

We report evidence of an unusual C-H--O interaction between an alpha-methylene hydrogen of the alkylamine chain of substituted (N,N-dimethylamino)propyl-azetidinones, substituted (N,N-dimethylamino)propyl-thiazolidinones and substituted (N,N-dimethylamino)propyl-thiazinone and the lactam carbonyl oxygen. NMR analysis results, supported by molecular mechanic predictions, were in agreement with ab initio calculations. The observed interaction shorting the nitrogen-nitrogen distance in the H1-histamine antagonist, 2-(4-methylphenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-one (1) could explain its fitting with the H1-antihistaminic pharmacophoric model and the high antihistaminic activity.

Synthesis and structure-activity relationships of 2-(substituted phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones acting as H1-histamine antagonists.

2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidi n-4- ones (1-15) showed dependence of the potency of the H1-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong pi-interaction. Electron-withdrawing substituents decrease the potency while the electron-donating alkyl substituents, enhancing the aryl HOMO energy, increase the antihistamine activity. The m-substituents with the capability to form hydrogen bonds, seems to share an extra-interaction with hydrogen accepting or donating groups of the histamine receptor and exhibits very high potency.

Alpha-naphthyl acetate esterase activity in human lymphocytes: distribution in lymphocyte subpopulations and in mitogen-activated cells.

The cytochemical demonstration of nonspecific alpha-naphthyl acetate esterase (ANAE) activity in human peripheral blood mononuclear cells was studied. Different staining patterns were found, allowing differentiation of mononuclear cells into macrophages (strong granular cytoplasmic activity), B lymphocytes (negative reaction), Tgamma lymphocytes, i.e. bearing IgG Fc receptors (granular scattered reaction), and T non-gamma lymphocytes, i.e. devoid of IgG Fc receptors (single cytoplasmic ANAE spot). During the early phases of phytohaemagglutinin (PHA)- and concanavalin A (Con A)-induced activation, the reactivity of most lymphocytes became granular and scattered, similar to that found in Tgamma cells. Blast cells generating in successive phases appeared devoid of detectable enzymatic activity. The hypothesis is put forth that T cells showing granular, scattered reactivity represent a population of activated cells and that the redistribution of enzymatic activity could represent a preliminary step leading to secretion (lymphokine-like?) of enzyme from cytoplasm in the course of cell activation.