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The side effects and drug interactions of clofibrate, cholestyramine and nicotinic acid are reviewed because these hypolipidemic drugs are given for preventive and only rarely curative reasons and because these drugs have been given for many years and often concomitantly with other drugs.
In the treatment of acute diarrheal disease in infants reinstituting the normal intestinal homeostasis is of primary importance. Prompt rehydration should be accomplished with a well balanced glucose electrolyte solution by parenteral or oral route. From a diet, given after rehydration, lactose and long chain fatty acids must be eliminated. Antibiotics, cholestyramine or elemental diets are to be reserved for special situations.
Methods were developed for the determination of HMG CoA (3-hydroxy-3-methylglutaryl CoA) reductase activity in subcellular fractions of intestinal mucosa and liver of Wistar strain rats. In the liver, reductase activity was located exclusively in the microsomal fraction. In the intestinal mucosa, activity was found in both mitochondrial and microsomal fractions of crypt cells but not of villi. The microsomal HMG CoA reductases of liver and intestinal mucosa had similar kinetic characteristics and pH optima. However, the activity of the hepatic enzyme differed with age and sex of the experimental animals while that of the intestinal crypt cells did not. Cholestyramine treatment enhanced the activity of the microsomal HMG CoA reductase in both liver and intestinal mucosa. Reductase activity of the intestinal crypt cells was elevated in both jejunum and ileum. The greatest stimulation, both relatively and absolutely, was observed in the distal half of the jejunum.
Postvagotomy-diarrhea, a troublesome complication of truncal vagotomy, seems to be caused by an increased concentration of bile acids reaching the colon due to intestinal hurry. Whether a dilatation of the gallbladder may contribute to bile acid malabsorption with its consequences of watery diarrhea cannot be decided at the moment. The beneficial therapeutic effect of cholestyramine or aluminiumhydroxide-containing antacids supports the concept that postvagotomy-diarrhea is induced by bile acids.
HMG CoA reductase activity of rat intestinal mucosa has a diurnal rhythm which coincides with the diurnal variation of the hepatic HMG CoA reductase but has a lower amplitude. The rhythmic variation of the intestinal reductase was present in both jejunal and ileal crypt cell microsomes and was not abolished by cholestyramine administration.
Previous studies have shown that in the absence of dietary lipid, intestinal lymph contains endogenous very low density lipoproteins (VLDL) which are identical to those in plasma in size, flotation rate, composition, and electrophoretic mobility. In order to document that these particles are produced in the mucosa of the small intestine itself, electron microscopic studies of rat and human intestinal mucosa were carried out. Small intestinal absorptive cells from rats fasted and restrained for 48 hr were rich in osmiophilic particles of the size of VLDL (300-1000 A). These particles were present in the endoplasmic reticulum and Golgi apparatus, and in intercellular spaces and lacteals; they were most abundant in mucosa from mid-jejunum. Similar particles were seen in jejunal mucosal biopsy specimens obtained from normal human volunteers after a 40-hr fast. After 6 hr of bile diversion or cholestyramine administration to fasted rats, the VLDL-sized particles virtually disappeared from the mucosa, suggesting that they were produced in the mucosa itself and depended upon the absorption of endogenous intralumenal lipid. These studies provide further evidence for the production of VLDL in absorptive cells of fasting rat and human intestine, and support the concept that the small intestine is a source of endogenous plasma VLDL.
These studies were designed to determine the importance of the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, the amount of chylomicron cholesterol reaching the liver, and the rate of bile acid transport into bile as determinants of the rate of biliary cholesterol output. Female rats that had been subjected to diurnal light cycling, fasting for 48 hr, intravenous administration of chylomicrons, and diets containing either cholestyramine, cholesterol, or bile acid underwent total biliary diversion for 2 hr. The animals were then killed and the rates of hepatic cholesterol synthesis and levels of hepatic esterified cholesterol were measured along with biliary lipid concentrations. Despite a 1000-fold variation in the rate of hepatic cholesterogenesis and a 100-fold variation in the levels of cholesteryl esters, the output and molar percentage of cholesterol in bile remained essentially constant with the exception of an approximate doubling in the output of cholesterol, as well as of bile acid and phospholipid in those animals fed bile acid. However, in this latter group the molar percentage of each component was unchanged. The administration of a bolus of chylomicrons did not alter output or molar percentage of cholesterol. Total biliary diversion for 36 hr and bile acid infusion were used to markedly vary the rate of biliary bile acid output. Cholesterol and phospholipid output remained tightly coupled to bile acid output over almost a 40-fold range. In other experiments it was shown that biliary cholesterol output could be driven by bile acid infusion to a similar extent in rats in which the rate of hepatic cholesterogenesis had been varied over a 26-fold range. It was concluded that the rate of hepatic cholesterol synthesis, the level of hepatic cholesteryl esters, and the amount of cholesterol absorbed from the diet play no role in determining the rate of biliary cholesterol secretion, at least in this species.-Turley, S. D., and J. M. Dietschy. Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.
Previous studies with fasting rats showed that the intestine produces endogenous very low density lipoproteins (VLDL) which resemble those in the plasma. Intestinal VLDL also were found to be important in lipid transport during absorption of saturated but not of unsaturated fat. These findings depended upon separations of a chylomicron-rich fraction (S(f) > 400) from VLDL (S(f) 20-400) by preparative ultracentrifugation methods based on particle flotation rates. The present studies correlate this method with electron microscopic measurement of lipoprotein particle size. Almost all intestinal lymph lipoprotein particles from fasting rats were less than 750 A in diameter, and could not be distinguished morphologically from plasma VLDL. Cholestyramine administration or bile diversion led to decreased lymph lipid output, correlating with marked reduction in VLDL. This supports the concept that lymph VLDL contain endogenous lipid which is reabsorbed from the intestinal lumen. During exogenous fatty acid absorption, lymph lipoprotein particle sizes were significantly smaller after administration of palmitate than after administration of linoleate, a finding consistent with ultracentrifugal evidence of the importance of VLDL in lipid transport during palmitate absorption. These studies fully confirm and extend earlier observations. Together, they show that the intestine is a source of endogenous VLDL in the fasting animal. In addition, significant quantities of exogenous lipid are transported in VLDL during palmitate absorption, whereas with linoleate absorption nearly all lipid is in chylomicrons. These findings indicate that the small intestine plays a role in lipoprotein metabolism which extends beyond the absorption of dietary fat.
Methods were developed for the assay of hydroxymethylglutaryl-CoA reductase (NADPH) activity in microsomes from rat leukocytes. The activity in freshly isolated leukocytes is low compared to rat liver but can be assayed reliably. The patterns of response of leukocyte reductase in the assay to variation in substrate concentration, protein concentration, and time mimic those of rat liver reductase. Reductase activity in leukocyte microsomes, as in liver microsomes, is depressed by dietary cholesterol and by fasting and is elevated by dietary cholestyramine. Unlike liver reductase, leukocyte reductase activity does not exhibit a detectable diurnal rhythm. We conclude that the assay of reductase in freshly isolated leukocytes holds promise as a technique for detecting the effects of various factors on cholesterol synthesis in vivo.
In a study of the mechanism whereby 5alpha-bile acids are formed from cholestanol, the 7alpha-hydroxylation of cholestanol was investigated in rat liver preparations in vitro. It was found that in the presence of NADPH and oxygen, rat liver microsomes catalyzed the 7alpha-hydroxylation of cholestanol to the same extent as that of cholesterol. The rate of the hydroxylation was enhanced by prior treatment of the experimental rats with cholestyramine (a bile acid sequestrant) or by establishment of bile fistulas-i.e., by partial or complete removal of bile acids from the enterohepatic circulation. The 7-hydroxylation reaction was further stimulated by pretreatment of the animals with phenobarbital, a drug known to produce increased biosynthesis of hepatic endoplasmic membranes. The 7alpha-hydroxylase was inhibited by the reaction product, by sterols with 7-keto or 7beta-hydroxyl groups, and also by mono- and dihydroxy bile acids of the 5beta-series, although cholic acid or taurocholate produced no inhibition unless added in high concentrations. The results of these studies are in accord with the concept that the presence of a Delta(5)-double bond is not required for the enzymatic formation of the 7alpha-hydroxy derivative. The rate of this hydroxylation reaction in vitro appears to depend on the concentration of bile salts in the enterohepatic circulation of the experimental animals from whom the microsomes were obtained.
The cases of Monozygotic twin girls suffering from benign recurrent familiar intrahepatic cholestasis are reported. So far both children had six icteric episodes due to this disease. These episodes occurred during times of severe emotional stress therefore, it may be assumed that a latent enzyme deficiency in the metabolism of bile acids, which is determined genetically, could be influenced by psychosomatic mechanisms. During the acute phases phenobarbital and cholestyramine succesfully reduced serum bilirubin levels.
Tritiated digitoxin (0.25 mg) was i.v. administered to a control group of 5 patients as well as to 5 patients with a T-tube quantitatively draining the bile fluid. During the initial 24 h after injection, 10% of the dose administered, on the second and third days 5 and 3,5%, respectively, were biliarily excreted. The amount biliarily excreted did not influence the course of the blood level as compared to the controls. Also charcoal given perorally in a sufficient amount (50 g) did not affect the blood level of radioactive digitoxin and/or its metabolites. As obtained from in vitro experiments the absorptive potency of cholestipole and cholestyramine for digitoxin and its metabolites in human bile fluid is similar to that of charcoal.
Intestinal transport of pteroylglutamate and amethopterin, a folate antagonist, was further characterized in everted sacs of rat jejunum. The system is composed of two distinguishable processes: active, pH-dependent, carrier-mediated transport and diffusion. The active process is specific for the pteroylglutamate molecule and requires sodium. When active transport is blocked completely by cyanide, iodoacetate, p-chloromercuriphenylsulfonate, the absence of sodium or high concentrations (50-100 microM) of the substrate, 20 to 30% of the total substrate available is transported by diffusion. In contrast to the active process, the diffusion component is not pH-dependent. Sulfasalazine inhibits pteroylglutamate (Ki congruent to 112 microM and amethopterin K congruent to 70 microM) transport competitively and reduces the quantity of pteroylglutamate converted to 5-methyltetrahydrofolate during intestinal transport. Studies using identical concentrations of amethopterin covalently bound to albumin and free drug indicate that the covalently bound amethopterin is transported 18% as well as free drug by jejunal and ileal sacs. Ethanol (3g/dl) has a mild inhibitory effect on pteroylglutamate and amethopterin transport. Cholestyramine (20 mg) adsorbs 95% of pteroylglutamate or amethopterin (100 micrograms) in vitro. These studies further clarify the mechanisms of intestinal folate transport and describe drug interactions which influence the transport process.
Initially liver morphology of chronic destructive non-suppurative cholangitis (CDNC) is rather atypical. Therefore, early morphological diagnosis is difficult. First symptoms are severe pruritus and an increase of IgM, AP and gamma-GT. Own investigation of 101 CDNC patients showed that antimitochondrial antibodies (AMA) are generally later present than the increase of the a/m enzymes. Also remarkable is the fact that among 101 patients are 13 men generally observed during the last 3 years. The most difficult problem is the treatment of CDNC. Here we have to differentiate between symptomatic basic treatment and so-called specific treatment. As basic treatment, ammonia-reducing amino acids, phenobarbital and finally cholestyramine are administered in order to diminish the severe pruritus. The diet must be rich on pectine. Lactulose and bifidum milk improve the diminished detoxication function of the liver. As specific treatment prednisolone and/or azathioprin have disappointed. D-penicillamine can influence CDNC at least temporarily. Because of the frequent side-effects D-penicillamine should be administered only in low doses (100-200 mg daily together with 300 mg vitaminee B6). Until not it is uncertain if the extremely bad prognosis of CDNC can be improved by medical treatment of its early stages.
Microsomal cholesterol 7 alpha-hydroxylase (EC 1.14.13.7) in rat liver was assayed by a single-isotope-incorporation method, and factors influencing its activity were studied. Crude cytosol contained a non-catalytic activator which was heat-stable and on-dialyzable. This activator enhanced cholesterol 7 alpha-hydroxylase catalytic activity. The stimulatory property of this cytosolic activator was not altered by cholestyramine feeding, and was retained after fractionation by ammonium sulfate of saturation up to 65%. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) stimulated hydroxylase activity at concentrations up to 90 micro M. ATP at concentration greater than 1.2 mM inhibited hydroxylase activity. NaF was stimulatory at concentrations up to 50 mM with a maximum stimulatory effect at 10 mM, and was antagonistic in effect to ATP. HMG-CoA and ATP at the above inhibitory concentrations and higher abolished the activating effect of the cytosolic factor.
Six cases of oral intoxication with lindane-solvent mixtures are reviewed. The ingested doses of lindane (mean dosage 120 mg/kg +/- 86 mg/kg) and benzene (mean dosage 366 mg/kg +/- 93 mg/kg) exceeded the toxic level. Symptoms (vomiting, dizziness and hyperreflexia) occurred within 30 min and all patients had epileptiform seizures. Two patients suffered from pulmonary edema and one of them had a severe rhabdomyolysis. Diazepam was sufficient to control convulsions in five cases. Gastric lavage was performed in five patients and activated charcoal, liquid paraffin with saline cathartic, and cholestyramine were used as adsorbents. Recovery was complete in all patients.
Chlorpromazine or aspirin alone, when given to rats parenterally, reduced intestinal fluid secretion induced by cell-free preparations of enterotoxigenic organisms including Escherichia coli, Aeromonas hydrophila, Staphylococcus pyogenes, and Salmonella typhimurium. A combination of chlorpromazine-aspirin given parenterally caused much more marked reduction of fluid secretion. Indomethacin also had significant antisecretory effects against a range of bacterial enterotoxins, while loperamide was effective against heat-labile toxin (LT)-positive E. coli and A. hydrophila. Nicotinamide increased net fluid absorption in the presence of E. coli LT, A. hydrophila, and S. typhimurium. Of the adsorbents tested, aluminum hydroxide showed a positive effect only with E. coli LT and A. hydrophila, while cholestyramine affected net fluid flux only with E. coli ST (heat-stable toxin). Charcoal was effective against all microorganisms tested but only when premixed with the perfusate before the experiments. Aspirin and chlorpromazine probably act at multiple sites to decrease intestinal secretion, and the combination of low doses of these drugs with possibly different sites of action may have advantages over a single agent used in high dosage.
These studies were done in the rat to correlate the ability of low and high density lipoproteins of rat (rLDL and rHDL) and human (hLDL and hHDL) origin to bind in vivo to specific tissues with the rates at which these same lipoprotein fractions were cleared from the circulation. The adrenal gland and liver manifested the greatest amounts of rLDL binding in vivo, but activity also was found in spleen, lung, kidney, ovary, and intestine. In contrast, little or no such binding was found utilizing either methyl-rLDL or hLDL. rHDL containing E apoprotein bound to the same group of tissues although in lesser amounts, except in the case of ovary and adrenal gland which bound disproportionately greater amounts of rHDL than rLDL. In keeping with these marked differences in tissue binding, the clearance of rLDL from the plasma equaled 847 +/- 36 microliters/h/100 g of rat while that of methyl-rLDL and hLDL was only 368 +/- 8 and 363 +/- 11 microliters/h/100 g of rat, respectively. When the steady state plasma level of rLDL was raised 2.5-fold, the clearance decreased slightly to 705 +/- 20 microliters/h/100 g of rat. The clearance of hLDL remained constant, however, at about 350 microliters/h/100 g of rat even when the plasma hLDL level was raised to very high values. The clearance of rHDL and hHDL equaled 644 +/- 16 and 408 +/- 13 microliters/h/100 g of rat, respectively, reflecting the more similar rate of binding of rHDL and hHDL to the tissues of the rat. Rates of whole animal sterol synthesis were lowered from 28 mumol/h to 8.8 mumol/h or 13 mumol/h by fasting and cholesterol feeding, respectively, and stimulated to 71 mumol/h by cholestyramine treatment. Under these same conditions, hepatic cholesterol synthesis could be lowered from the normal rate of 15 mumol/h to 4.2 mumol/h and raised to 50 mumol/h. None of these treatments, however, affected the plasma clearance of rLDL and rHDL. In contrast, treatment with ethinyl estradiol increased by 3-fold both the hepatic binding and the whole animal plasma clearance of rLDL. Following resection of approximately two-thirds of the liver under carefully controlled metabolic conditions, there was no change in the rate of hepatic cholesterol synthesis or rLDL binding in the remaining liver, but the clearance of chylomicrons, rLDL, and rHDL diminished by 67%, 26%, and 17%, respectively, suggesting that in the rat the liver was responsible for the degradation of approximately 97%, 39%, and 27%, respectively, of these lipoprotein fractions.