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S Almog

Publications and source records attributed to S Almog.

At least 55 records · Page 3Linked to original sources
PubMed1988

On the solubility of calcium deoxycholate: kinetics of precipitation and the effect of conjugated bile salts and lecithin.

In view of the low solubility of calcium deoxycholate and the possible induction of cholesterol precipitation in the gallbladder by calcium insoluble salts, we find it of interest to study the precipitation of calcium deoxycholate and its dependence on other bile components. The findings of these studies were as follows: (i) Precipitation of calcium deoxycholate from mixtures of calcium chloride and monomeric deoxycholate (at concentrations below the critical micelle concentration (CMC] is very slow even at relatively high CaCl2 concentrations (more than 20 days at 50 mM CaCl2). (ii) At higher deoxycholic acid (DOC) concentrations, precipitation of micellar DOC is faster and requires much lower calcium chloride concentrations. For any given calcium concentration, the rate of precipitation is maximal at an optimal DOC concentration. In solutions containing 150 mM NaCl, the maximal rate of precipitation occurs at about 10 mM DOC, almost independent of Ca2+ concentration. At lower ionic strength (10 mM NaCl), the optimal DOC concentration is 30 mM. These observations suggest that the most important factors in determining the rate of Ca(DOC)2 precipitation are (a) the ratio between calcium ions bound to the surface of a DOC micelle, and the [DOC] (the Ca2+/DOC binding ratio) and (b) the concentration of DOC micelles. (iii) In the presence of conjugated deoxycholates, the crystallization of calcium deoxycholate is inhibited. Phosphatidylcholine has a similar, although smaller, inhibitory effect. Upon precipitation of calcium deoxycholate from a mixed micellar system containing sodium deoxycholate, phosphatidylcholine and cholesterol, the latter two components spontaneously form vesicles. The anti-nucleating effect of PC and conjugated bile salts is explained in terms of "poisoning" of the crystallization process. In view of the latter results we conclude that under normal conditions calcium deoxycholate is not likely to precipitate in the gallbladder.

Bile Acids and Salts↗
PubMed1988

Precipitation of calcium palmitate from bile salt-containing dispersions.

Addition of calcium chloride to mixed micellar systems composed of sodium salts of palmitic acid and high concentrations of different bile acids results in precipitation of Ca(palmitate)2 only when the palmitate concentration exceeds a critical value, which is dependent on the concentrations of Ca2+, Na+ and bile salt, and on the type of bile salt used. All these dependencies, as well as the complex and interrelated effects of the various parameters on the kinetics of Ca(palmitate)2 precipitation are consistent with the following mechanism: (i) calcium binds to palmitate-bile salt mixed micelles and promotes their aggregation, at a rate governed by the concentration ratio between bound calcium and micelles (here denoted "binding ratio"). (ii) Ca(palmitate)2 precipitation occurs within the aggregate of micelles only if those micelles include sufficient amounts of Ca2+ and palmitate to allow for the formation of large enough crystal units of Ca(palmitate)2 which can serve as nucleation "seeds". Both the concentrations of micelles and Na+ have dual effects on the rate of precipitation. Increasing micelle concentration, by itself, accelerates aggregation but at the same time leads to a decrease of the binding ratio, thus reducing the rate of precipitation. Na+ which reduces the binding ratio through competitive binding also reduces the surface charge, thus assisting micelle aggregation. Our model also explains the facilitation of precipitation observed when phosphatidylcholine is contained in the palmitate-bile salt mixed micelles and the inhibitory effect of the water soluble bovine serum albumin.

Bile Acids and Salts↗
PubMed1988

Stability of mixed micellar bile models supersaturated with cholesterol.

The maximal equilibrium solubility of cholesterol in mixtures of phosphatidylcholine (PC)1 and bile salts depends on the cholesterol/PC ratio (Rc) and on the effective ratio (Re) between nonmonomeric bile salts and the sum (CT) of PC and cholesterol concentrations (Carey and Small, 1978; Lichtenberg et al., 1984). By contrast, the concentration of bile salts required for solubilization of liposomes made of PC and cholesterol does not depend on Rc (Lichtenberg et al., 1984 and 1988). Thus, for Rc greater than 0.4, solubilization of the PC-cholesterol liposomes yields PC-cholesterol-bile salts mixed micellar systems which are supersaturated with cholesterol. In these metastable systems, the mixed micelles spontaneously undergo partial revesiculation followed by crystallization of cholesterol. The rate of the latter processes depends upon Rc, Re, and CT. For any given Rc and Re, the rate of revesiculation increases dramatically with increasing the lipid concentration CT, reflecting the involvement of many mixed micelles in the formation of each vesicle. The rate also increases, for any given CT and Re, upon increasing the cholesterol to PC ratio, Rc, probably due to the increasing degree of supersaturation. Increasing the cholate to lipid effective ratio, Re, by elevation of cholate concentration at constant Rc and CT has a complex effect on the rate of the revesiculation process. As expected, cholate concentration higher than that required for complete solubilization at equilibrium yields stable mixed micellar systems which do not undergo revesiculation, but for lower cholate concentrations decreasing the degree of supersaturation (by increasing [cholate]) results in faster revesiculation. We interpret these results in terms of the structure of the mixed micelles; micelles with two or more PC molecules per one molecule of cholesterol are relatively stable but increasing the bile salt concentration may cause dissociation of such 1:2 cholesterol:PC complexes, hence reducing the stability of the mixed micellar dispersions. The instability of PC-cholesterol-cholate mixed systems with intermediary range of cholate to lipids ratio may be significant to gallbladder stone formation as: (a) biliary bile contains PC-cholesterol vesicles which may be, at least partially, solubilized by bile salts during the process of bile concentration in the gallbladder, resulting in mixtures similar to our model systems; and (b) the bile composition of cholesterol gallstone patients is within an intermediary range of bile salts to lipids ratio.

Cholesterol↗
PubMed1988

Complex interaction of rifampin and warfarin.

Rifampin is known to lower plasma warfarin concentrations by increasing the rate of warfarin clearance. We have described a patient in whom an additional potentiating influence on warfarin effect was observed during treatment with rifampin and isoniazid. After cessation of rifampin and isoniazid, prothrombin time was maintained within the same range by a 50% reduction of warfarin doses, despite a twofold rise in the plasma warfarin concentration. This rise in warfarin concentrations can be explained by the known mechanism by which rifampin increases warfarin clearance. After cessation of rifampin, warfarin fractional clearance decreased from 15.2 to 4.2 ml/min; however, the unchanged prothrombin time in the face of the increased warfarin concentration can be explained only by the removal of a potentiating effect that had been present during the coadministration of rifampin and isoniazid. It is likely that rifampin is responsible for this additional potentiating interaction, probably not through a change in warfarin binding, but through a differential effect on warfarin stereoisomer metabolism or through an altered dynamic effect. The role of isoniazid in this interaction cannot be completely ruled out.

Adult↗
PubMed1988

Altered erythrocyte and plasma sodium and potassium in hypertension, a facet of hyperinsulinemia.

Red blood cell sodium and potassium, plasma potassium, glucose and insulin responses to oral glucose load, serum urate, and plasma triglycerides were determined in a stratified subsample (n = 89) of a representative population sample (n = 1211), comprising 30 nonobese normotensive subjects with normal glucose tolerance (reference group) and 59 subjects representing each of the seven possible combinations of abnormal glucose tolerance, obesity, and hypertension. Rate of cation imbalance (red blood cell sodium greater than or equal to 7.0 mEq/L, potassium less than 92.5 mEq/L, or plasma potassium greater than or equal to 4.5 mEq/L) was 88.1% in subjects with abnormal tolerance, obesity, or hypertension, as compared with 40.0% in the reference group (p less than 0.001). These subjects were also characterized by significantly greater rates of insulin response: 60- and 120-minute postload levels of 100 mU/L or more (88.1 vs 46.7%), plasma triglycerides of 80 mg/dl or more (89.8 vs 53.3%) and serum uric acid of 5.5 mg/dl or more (61.0 vs 26.7%; p less than 0.001 for all). The rate of cation imbalance was significantly associated with each of these three biochemical correlates: insulin response (p less than 0.01), triglycerides (p less than 0.001), and urate (p less than 0.001). In the total population sample, the rate of untreated hypertension increased from 18% to 35% to 55.3% (p less than 0.001), with an increase in the number of biochemical correlates of cation imbalance in combination with glucose intolerance and obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocytes↗
PubMed1987

Hyperinsulinemia--a link between glucose intolerance, obesity, hypertension, dyslipoproteinemia, elevated serum uric acid and internal cation imbalance.

A representative sample (n = 1211) of the Jewish population in Israel age 40-70 (excluding known diabetics), underwent a glucose tolerance test. Insulin response was found to be independently and positively associated with the GOH conditions--glucose intolerance (p less than 0.001), obesity (p less than 0.001), and hypertension (p less than 0.01) and with elevated serum uric acid (p less than 0.001) after accounting for the effects of sex, age, serum creatinine and use of antihypertensive medications. In a representative subgroup of 542 individuals, total VLDL and LDL fractions were estimated by standardized values (based on the reference group--individuals free of the GOH conditions), of their cholesterol and triglyceride components. Hyperinsulinemia was characterized by jointly elevated VLDL and LDL with reduced HDL. The risk ratio for this pattern (adjusted for the effects of age, sex, smoking and presence of any of the GOH conditions) was 3.4 (p less than 0.001). There was no further association of this disturbed lipoprotein profile with the GOH conditions. Cation concentrations were determined in a stratified subsample (n = 89) of the study group. The subsample comprised 30 individuals in the reference group, and 59 representing each of the seven possible combinations of abnormal glucose tolerance, obesity and hypertension (GOH group). Rate of cation imbalance defined as presence of at least one of three cation concentration--red blood cell sodium greater than or equal to 7.0 mEq/l, red blood cell potassium less than 92.5 mEd/l or plasma potassium greater than or equal to 4.5 mEq/l was 88.1% in the GOH, compared to 40.0% in the reference group (p greater than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

The negative impact of biological variation in the effect and clearance of warfarin on methods for prediction of dose requirements.

Within-individual variation over time in the clearance (Cl) and effect (PT%) of warfarin, was measured in 25 inpatients (group I) studied after standard single or individualized split loading doses and 1-3 times (n = 16) 8-16 weeks later during maintenance. Mean Cl (2.5 +/- 0.9 ml/min) was similar in both phases but significant changes occurred in 6/16 patients, exceeding those expected from within-individual variation alone (defined by its 95% tolerance limits -24% to +62%). Initial PT% (21 +/- 5) was unaffected by dosing schedule, total or free plasma warfarin, varying between patients by only 18-24%. Mean initial and maintenance dose-PT% ratios (8.2 mg/d: 21% and 4.1 mg/d: 40%) were similar but significant changes in sensitivity to warfarin occurred in 4/16 patients. In group I and 64 other outpatients on maintenance therapy, between-individual variability was 36-52% for Cl and 49-56% for effect. PT% correlated best (r = 0.56) with free and total plasma warfarin but poorly with dose (r = 0.29), with only 30% of PT% variance explained at best, due to high between patient variability. Warfarin dose prediction whether based on extrapolation from initial effects to the maintenance phase, or on iterative methods not allowing for between- or within-patient variation in warfarin clearance or effect which may occur independently over time, have not improved on empirical therapy. This, due to the elements of biological variability as well as the intricacy of the warfarin-prothrombin complex interaction not captured by any kinetic-dynamic model used for prediction to date.

Biological Availability↗
PubMed1986

Kinetic and structural aspects of reconstitution of phosphatidylcholine vesicles by dilution of phosphatidylcholine-sodium cholate mixed micelles.

Dilution of mixed micellar dispersions of egg phosphatidylcholine (PC) and sodium cholate beyond a critical value results in formation of cholate-containing PC vesicles. The structure of the resultant vesicles and some mechanistic aspects of this process have been investigated by the use of light scattering and nuclear magnetic resonance techniques. The main findings and conclusions are the following: Both the state of aggregation (micellar or vesicular) and the apparent equilibrium size distribution of micelles or vesicles obtained by dilution of the PC-cholate mixed micellar dispersions are a function of the cholate to PC molar ratio in the mixed aggregates (micelles or vesicles). When this effective ratio (Re) is higher than 0.4, the dispersion is micellar, and the size of the mixed micelles increases with decreasing Re; when Re less than 0.3, the dispersion is essentially vesicular, and the mean hydrodynamic radius of the vesicles is an increasing function of Re; in dispersions with 0.3 less than Re less than 0.4, mixed micelles and vesicles coexist. Addition of cholate to vesicular dispersions, to Re values below 0.3, results in vesicle size growth through a concentration-independent lipid-exchange mechanism. Addition of cholate to higher Re values results in micellization (solubilization) of the vesicles. On the other hand, dilution of vesicular dispersions does not affect the size of the vesicles. Apparent equilibration of a mixed micellar dispersion following dilution to Re values below 0.3 is slow (many hours). The overall process involves a series of three subsequent categories of steps: (i) a rapid (approximately 1-2 min) prevesiculation equilibration of micellar sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholic Acid↗
PubMed1985

Mechanism of warfarin potentiation by amiodarone: dose--and concentration--dependent inhibition of warfarin elimination.

Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.

Adult↗
PubMed1985

Hyperinsulinemia. A link between hypertension obesity and glucose intolerance.

Hypertension and glucose intolerance, determined in a random population sample (n = 2,475), showed a highly significant (P less than 0.001) association from the mildest levels of both conditions, independent of the confounding effects of age, sex, obesity, and antihypertensive medications. Summary rate ratios for hypertension were 1.48 (1.18-1.87) in abnormal tolerance and 2.26 (1.69-2.84) in diabetes compared with normal tolerance. Altogether, 83.4% of the hypertensives were either glucose-intolerant or obese--both established insulin-resistant conditions. Fasting and post-load insulin levels in a representative subgroup (n = 1,241) were significantly elevated in hypertension independent of obesity, glucose intolerance, age, and antihypertensive medications. The mean increment in summed 1- and 2-h insulin levels (milliunits per liter) compared with nonobese normotensives with normal tolerance was 12 for hypertension alone, 47 for obesity alone, 52 for abnormal tolerance alone, and 124 when all three conditions were present. The prevalence of concentrations (milliequivalents per liter) of erythrocyte Na+ greater than or equal to 7.0, K+ less than 92.5, and plasma K+ greater than or equal to 4.5 in a subsample of 59 individuals with all combinations of abnormal tolerance obesity and hypertension was compared with those in 30 individuals free of these conditions. Altogether, 88.1% of the former vs. 40.0% of the latter group presented at least one of these three markers of internal cation imbalance (P less than 0.001). We conclude that insulin resistance and/or hyperinsulinemia (a) are present in the majority of hypertensives, (b) constitute a common pathophysiologic feature of obesity, glucose intolerance, and hypertension, possibly explaining their ubiquitous association, and (c) may be linked to the increased peripheral vascular resistance of hypertension, which is putatively related to elevated intracellular sodium concentration.

Adult↗
PubMed1985

Effect of alpha-methyldopa excreted in human milk on the breast-fed infant.

A nursing infant whose mother took alpha-methyldopa (alpha-MD) was followed for 3 months. Analysis of maternal serum and milk as well as the infant's serum and urine for alpha-MD revealed that the drug was excreted into maternal milk, absorbed by the infant and excreted in her urine, but no adverse clinical effects were noted during the follow-up period. alpha-MD is excreted in human milk in concentrations that probably do not harm the breast-fed infant.

Adult↗
PubMed1985

Prevalence of chlorpropamide alcohol flush in Jewish Israeli diabetics. The role of serum chlorpropamide concentrations.

Among 53 patients with noninsulin-dependent diabetes (NIDD), chlorpropamide alcohol flushing (CPAF) was more prevalent than among 18 patients with insulin-dependent diabetes (64 vs. 28%, respectively). Among the former, chronic users of chlorpropamide (CP) had a higher prevalence of CPAF than those challenged once with the drug (86 vs. 56%, respectively). Serum CP concentrations were much higher in CP-treated patients, but levels were not different in CPAF-positive compared with CPAF-negative subjects, regardless of the length of their exposure to the drug. Our data confirm the association between CPAF and NIDD in a Jewish Israeli diabetic population and the effect of serum CP levels on the prevalence of this phenomenon.

Adult↗
PubMed1984

Hyperinsulinaemic hypoglycaemia due to chlorpropamide-induced nesidioblastosis.

A 25 year old woman suffering from recurrent attacks of hypoglycaemia underwent a laparotomy for suspected insulinoma. No tumour was found, but histology showed islet cell hyperplasia and nesidioblastosis. Although these changes have been reported as a cause of hypoglycaemia in infants, they are only rarely the cause of hypoglycaemia in adults; in the present case they were found to be the result of covert sulphonylurea administration. The fact that sulphonylureas can cause nesidioblastosis is not well recognised by either physicians or pathologists and it should be considered before "cryptogenic nesidioblastosis" is deemed the cause of hypoglycaemia in adults.

Adult↗
PubMed1982

Components of variability in serum theophylline concentrations during maintenance therapy with a sustained release formulation.

Fifteen adult chronic asthmatic patients were studied on 6 consecutive days of the second week of treatment with a new sustained release theophylline formulation, and 8 were again studied after three months on the same dosing regimen (375 mg b.i.d.). Serum theophylline concentrations were maintained in the therapeutic range (peak - 19.7 +/- 5.0 micrograms/ml; trough - 13.0 +/- 3.2 micrograms/ml) throughout the 12 hour dosing interval, and were greater than 75% of the peak concentration over 8.6 +/- 2.9 h. A degree of drug accumulation was evident in that the 1-h and 5-h levels rose from 12.2 +/- 4.1 and 4.5 +/- 4.8 micrograms/ml during the second week to 16.9 +/- 4.6 and 18.4 +/- 4.5 micrograms/ml, respectively, at three months. Between-patient differences accounted for 61%-71% of the total variation in steady state theophylline concentrations. After accounting for differences due to sampling time and assay error, unexplained random, within-individual variability amounted to 11%-18% of the total. Quantitative estimation of these components of variability may be incorporated into dosage forecasting methods based on single determinations of serum concentration.

Administration, Oral↗