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The effect of sucralfate on serum lipids and lipoproteins in normal volunteers [corrected].

Sucralfate is used in the treatment and prophylaxis of peptic ulcer disease. One possible mechanism of action is the binding of bile acids. Because the absorption of dietary fat and cholesterol is dependent on the presence of bile acids in the small intestines, sucralfate therapy may produce changes in serum lipoprotein composition qualitatively similar to bile acid sequestrants, such as cholestyramine, which reduce serum cholesterol levels. Although changes in total serum cholesterol have not been reported in sucralfate efficacy studies, the effect of sucralfate on serum lipoprotein composition has not been specifically addressed. The purpose of this study was to prospectively examine the effect of sucralfate on serum lipids and lipoproteins in normal volunteers. Eight healthy volunteers (six men, two women) were recruited for this 10-week study. Drugs known to affect cholesterol levels were not permitted before or during the study. Diet composition during the study period was unaltered from before the study. Subjects took 1 g sucralfate orally 1 hour before meals and at bedtime (four times a day) for 8 weeks, followed by a 2-week washout period. Fasting blood samples were obtained at baseline and weekly, and were analyzed for serum total and HDL cholesterol and for triglycerides. Levels of LDL cholesterol were estimated. After eight weeks of sucralfate, HDL cholesterol increased from baseline by 2.5 mg/dL (6.6%, from 37.6 +/- 9.5 to 40.1 +/- 8.69 mg/dL), and LDL cholesterol decreased by 7.6 mg/dL (6.4%, from 134 +/- 28.1 to 125.4 +/- 34.1). Total cholesterol decreased by 3.5 mg/dL (1.8%, from 192.9 +/- 34.3 to 189.4 +/- 37.2 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Medical management of antimicrobial-associated diarrhea and colitis.

Gastrointestinal complications, including diarrhea, may occur with virtually all antimicrobial agents. Such diarrhea may represent either a common, nonspecific adverse effect, or it may be one of the manifestations of antimicrobial-associated colitis (AAC), a potentially fatal complication. Clostridium difficile and a cytotoxin neutralized by Clostridium sordellii antitoxin has been isolated from the stools of nearly all patients with antibiotic-associated pseudomembranous colitis, many patients with AAC, and approximately 20% of those with antimicrobial-induced diarrhea. Demonstration that C. difficile is responsible for cytotoxin production has allowed for specific therapy for these disorders. General treatment measures include discontinuation of the causative antimicrobial agent(s), bowel rest, and supportive care with fluids, electrolytes and colloids, if necessary. Antiperistaltic agents and corticosteroids are not recommended. Various antimicrobials demonstrate potential efficacy in treating AAC in humans. Oral vancomycin is the most widely tested and is currently the treatment of choice. It achieves high concentrations in the feces and is very active against C. difficile in doses of 125-500 mg by mouth every six hours. Other potentially useful but inadequately tested antimicrobials include metronidazole (500 mg by mouth every eight hours) and bacitracin (25,000 units by mouth every six hours). Tetracycline has been employed with some success in nonspecific antibiotic-associated diarrhea, although it is as yet untested in humans with AAC and may induce diarrhea itself. Both miconazole and rifampin are highly effective against C. difficile in vitro but have not been evaluated in AAC. Anion-exchange resins bind the cytotoxin found in stools of patients with AAC. Cholestyramine has been used with variable response in oral doses of 4 g every six to eight hours. Since these resins may also bind vancomycin, resulting in lowered vancomycin concentrations in the stool, combination therapy should be used cautiously. With specific therapy directed against the toxin and aggressive supportive therapy, surgical intervention is rarely necessary. More recently, investigations have been directed at using bacterial preparations to suppress C. difficile by restoring the normal flora. The development of immunological agents (i.e., vaccines, toxoids, antitoxins) for the prevention or treatment of AAC would be a significant advance in therapy.

Anion Exchange Resins↗

Brief overview of the mounting evidence that atherosclerosis is both preventable and reversible.

The major life-threatening events in advanced atherosclerosis are precipitated by the plaque. Thrombosis in the muscular arteries and rupture of the large elastic arteries usually follows rupture of the plaque's fibrous cap. The smooth muscle cell (SMC) participates in many aspects of the atherosclerotic process: lipid uptake, synthesis of plaque components, and cell proliferation. The latter is a particularly significant aspect of the disease. High serum cholesterol levels stimulate proliferation of arterial medial cells; low-density lipoproteins (LDL) from hyperlipidemic plaques induce ingress and storage of cholesterol ester. These effects are inhibited by high-density lipoproteins (HDL). Endothelial injury may be an important part of the pathogenesis of some atherosclerotic plaques because powerful growth factors actively stimulate SMC proliferation, even when other risk factors are absent. Utilization of animal models of atherosclerosis, especially nonhuman primate models, has led to great progress in understanding this disease process. In controlled feeding experiments, severe atherosclerosis has been produced in rhesus monkeys by means of a high fat, high cholesterol diet. Animals then placed on a low fat, low cholesterol diet, or given cholestyramine, or a combination of these two approaches, showed a remarkable decrease in the size of their atherosclerotic plaques. Many epidemiologic studies, as well as more recent prospective intervention studies involving bile acid sequestrants, indicate by imaging techniques that plaque regression takes place in humans.

Arteriosclerosis↗

Safety of oral cyclodextrins: effects of hydroxypropyl cyclodextrins, cyclodextrin sulfates and cationic cyclodextrins on steroid balance in rats.

Derivatives of beta-cyclodextrin differing in the length of a hydroxyalkyl substituent (CH2CH2OH, CH2CHOHCH3, CH2CHOHCH2CH2CH2CH3) or in the electrical charge of the substituents (SO4-, CH2CHOHCH2N(CH3)3+) and hydroxypropyl derivatives (CH2CHOHCH3) of alpha-, beta-, and gamma-cyclodextrin were compared, individually and in mixtures, as solubilizers of cholesterol. The most effective solubilizer proved to be hydroxypropyl derivatives of beta-cyclodextrin; beta-cyclodextrin sulfate (SO4-) was practically devoid of solubilizing activity. Oral administration of these cyclodextrin derivatives, some of which are both nondegradable and effective complexation agents for cholesterol and bile acids, nevertheless did not affect the conversion of [14C]acetic acid to [14C]-cholesterol in rat under the same conditions when another bile acid complexation agent, cholestyramine, increased that conversion. Thus, complexation of cholesterol and of bile acids by cyclodextrin derivatives, which is a significant and well-defined phenomenon in vitro, seems to have limited importance in terms of excretion of cholesterol from the gastrointestinal tract. It is proposed that various untoward effects observed after chronic large oral doses of hydroxypropyl beta-cyclodextrin are administered are not caused by an increased excretion of some vital lipophile or enzyme but are probably caused by solubilization and increased absorption of toxic contaminants of the ingested food.

2-Hydroxypropyl-beta-cyclodextrin↗

Treatment of refractory cholestatic pruritus after liver transplantation with albumin dialysis.

Albumin dialysis has been shown to improve the outcome in patients with cholestatic liver failure caused by chronic liver disease. This study reports 7 liver transplant recipients who were treated with albumin dialysis for intractable pruritus of different origin (ductopenic graft rejection, non-anastomotic strictures, and recurrence of hepatitis C). Treatment with histamine (H1) blockers, opioid antagonists, and cholestyramine had not been effective. The Molecular Adsorbent Recirculating System (MARS; Teraklin, Rostock, Germany) was used for albumin dialysis. All patients presented with numerous scratch marks, 6 of whom had a pronounced icterus. Six patients (86%) responded to 3 consecutive treatments with significant reduction of pruritus. The mean pruritus score, which was quantified by a visual analog scale (VAS), decreased from 9.7 +/- 0.5 to 3.7 +/- 0.8 (SD). The mean duration of 1 treatment was 15.6 hours. The procedure was well tolerated by all patients. The mean total serum bilirubin in patients who responded to therapy declined from 19.11 +/- 16.96 mg/dL (SD) before MARS therapy to 9.24 +/- 3.52 mg/dL after treatment. The mean serum concentration of 3 alpha-hydroxy bile acids decreased from 192.67 +/- 58.12 micromol/L (SD) to 42.33 +/- 31.58 micromol/L (SD). Follow-up in 3 cases showed sustained improvement of pruritus lasting for more than 3 months. In 3 patients, however, pruritus relapsed. One patient, who showed severe pruritus, without relevant elevation of serum bile acids before treatment, did not respond to albumin dialysis. Our data indicate that MARS is an effective therapeutic option for patients with intractable cholestatic pruritus.

Aged↗

Dietary cholesterol, serum cholesterol, and colon cancer: a review.

Observational and case-control epidemiologic data supported by experimental studies indicate that dietary cholesterol may contribute to colon tumorigenesis. A mechanism for this possible relationship is currently under investigation. Additional international epidemiologic data, although not uniformly consistent, indicate an inverse relationship between serum or plasma cholesterol levels and risk for colon cancer. This risk is greatest at serum cholesterol levels of less than 180 mg/dl. It has been suggested but not proven that individuals consuming diets high in dietary fat and cholesterol may have variations in cholesterol dynamics that account for lowered serum cholesterol levels and enhanced risk for colon cancer. Clinical evidence in both men and women indicates that age-sex-adjusted, low serum cholesterol levels may precede the detection of colon cancer by more than 5 years. Preclinical colon cancer is associated with a further decrease in serum cholesterol levels. It is not clear whether progression of the disease before metastatic spread results in continued lowering of serum cholesterol levels. In men with markedly elevated serum cholesterol levels who have been placed on cholesterol-lowering drugs such as clofibrate or cholestyramine, there was no evidence that such regimens increased the risk for colon cancer. It is possible that reductions in serum cholesterol associated with the use of these drugs are insufficient to lower cholesterol levels to a range associated with an increased risk for colon cancer.

Cholesterol↗

Regulation of LDL receptors in vivo.

The information reviewed here indicates that LDL receptor activity in vivo is regulated in normal animals and probably in normal humans. Furthermore, LDL receptor activity is also regulated in patients with heterozygous Familial Hypercholesterolemia. Our experiments in patients with this disease indicate that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in these patients to produce an increased number of LDL receptors. This stimulation can be accomplished by manipulating the intracellular cholesterol pools in the liver with drugs that inhibit HMG-CoA reductase and by maneuvers that result in bile acid depletion. These therapeutic measures are most effective when combined. Such therapy is likely to be beneficial, particularly since the results of the Lipid Research Clinics Primary Intervention Trial using the bile acid sequestrant, cholestyramine, have demonstrated that lowering LDL-cholesterol levels with this drug also lowers the incidence of coronary heart disease. In a broader sense, the success of this regulatory manipulation suggests that other genetic diseases may be treated by manipulation of regulatory signals that control the rates of synthesis of gene products.

Animals↗

Clinical and biochemical evaluation of chitosan for hypercholesterolemia and overweight control.

After providing basic information on enzymes involved in cholesterol homeostasis, and on management of hypertriglyceremia and hypercholesterolemia, with the aid of cholestyramine and fibric acid, this chapter examines the effects of the ingestion of chitosan. Dietary chitosan is effective on serum cholesterol and in atherosclerosis in normal and diabetic mice, and lends itself to the treatment of hypercholesterolemia in humans. It also exhibits antiulcer, antiarthritic, antihypertension and antiuricemic properties. The published human trials, analysed statistically, further indicate that chitosan is effective to control overweight when associated to a diet. This chapter discusses several issues raised against the use of chitosan, namely, depletion of zinc and liposoluble vitamins, as well as advantages such as enhanced absorption of nutrients and competitive inhibition of lipases. It also directs attention to the unexplored areas of fungal and algal chitosans, and the use of chitins instead of chitosans.

Animals↗

Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Within the last few years considerable evidence has accumulated which indicates that changes in HMG-CoA reductase are due primarily, if not solely, to changes in enzyme quantity. These include the changes caused by insulin, glucagon, cholesterol, mevalonolactone, cholestyramine, compactin, cyclic monoterpenes and the diurnal rhythm. Investigations of whether these changes in enzyme quantity primarily represent changes in rates of enzyme synthesis or degradation are just beginning. Regulation of reductase activity by reversible phosphorylation seems unlikely when all the available data are critically examined.

Animals↗

A survey of pediatric management of dyslipidemias in New England.

We recently surveyed physicians attending the New England Pediatric Preventive Cardiology Society. Sixteen physicians who actively evaluated children with dyslipidemia completed questionnaires; at least one representative from six of the seven medical schools in New England was included. The survey elicited responses to five hypothetical cases of childhood dyslipidemia which were representative of the types of lipid problems commonly referred to pediatric lipid specialists. Diet modification was the initial treatment of choice of all participants. For any set of lipid values, postpubertal age increased the proportion of respondents who would have prescribed medication. When pharmacologic intervention was elected, resin binders (cholestyramine or cholestipol) and niacin were most commonly prescribed. The responses of the physicians showed considerable variation in the threshold for beginning medications. In summary, this survey suggests substantial variation in the approach to pharmacologic management of pediatric dyslipidemias in the New England region.

Adolescent↗

Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: a review.

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

Adult↗

[Therapeutic problems in alkaline reflux esophagitis].

Alkaline reflux esophagitis occurs most frequently after gastric surgery, especially after total gastrectomy. Anastomoses causing this disease are esophagoduodenostomy or esophagojejunostomy end-to-side. As in the stomach bile, pancreatic juice and small bowel contents cause erosions and ulcers of the esophageal mucosa. For symptomatic treatment aluminium-hydroxide-antacids or cholestyramine can be tried. A definite cure of alkaline esophagitis can only be reached by reversing the anastomosis, creating an interposition of the jejunum between esophagus and duodenum of 50 to 60 cm in length or a Roux-Y-esophagojejunostomy, the minimum length of the loop being 40 cm.

Anastomosis, Roux-en-Y↗

Treatment of pruritus of primary biliary cirrhosis with rifampin.

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P less than 0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.

Adult↗

Blood exchange and transfusion therapy for acute cholestasis in protoporphyria.

Acute cholestasis is a rare complication of EPP with a high mortality rate despite extensive treatment with corticosteroids, cholestyramine, and antioxidants. A single survivor, reported in the literature, was treated with blood exchange transfusions. We treated two EPP patients with blood exchange and additional blood transfusions which resulted in full clinical and biochemical recovery from the cholestasis and accompanying hepatitis. Recurrences of the cholestasis and hepatitis could repeatedly be corrected by additional blood transfusions.

Acute Disease↗

Loss of absorptive capacity for sodium chloride as a cause of diarrhea following partial ileal and right colon resection.

Previous studies have emphasized the role of bile acid and fat malabsorption as the cause of the diarrhea that may follow ileal and right colon resection; unabsorbed bile acids and fat are believed to reduce sodium chloride and water absorption in the remaining colon. In this paper we report studies in eight patients with severe postresection diarrhea, in search of a more basic defect in sodium chloride absorption, ie, a loss of sodium chloride absorptive capacity as a direct consequence of resection of sodium chloride absorption sites. First, we determined whether or not diarrhea persisted during a 48-hr fast; in all patients diarrhea and large fecal electrolyte losses continued during a fast. Second, we measured sodium chloride and water absorption rates during total gut perfusion with a balanced electrolyte solution; compared to normal controls, the patients absorbed 23-31% less water, sodium, and chloride. In three patients who could be studied further, the absorptive defect was markedly accentuated when the perfusing solution was such that sodium chloride absorption had to take place against a concentration gradient. These observations indicate that postresection diarrhea patients have a reduced capacity to absorb sodium chloride, particularly when there is a concentration gradient between lumen and plasma. Although all of these patients had malabsorption of radiolabeled taurocholic acid, there was only a modest and statistically insignificant reduction in daily stool weight during treatment with large doses of cholestyramine, suggesting that bile acid malabsorption was not responsible for a major part of their diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Prevention of further recurrences of Clostridium difficile colitis with Saccharomyces boulardii.

A patient with six documented episodes of recurrent Clostridium difficile colitis over an eight-month period is described. Relapses of colitis occurred despite treatment with vancomycin, metronidazole, bacitracin, and cholestyramine. Each recurrence appeared to begin successively closer to the end of the previous course of treatment. Four episodes were sufficiently severe to require hospitalization for rehydration. Saccharomyces boulardii, a nonpathogenic yeast, was begun prior to discontinuing vancomycin therapy for the last recurrence and was continued for three months. Serial stool cultures and assays for C. difficile showed persistence of the organism but rapid reduction of high titers of cytotoxin. No further recurrences of diarrhea or colitis were encountered while the patient was taking Saccharomyces boulardii and for 18 months of follow-up after the yeast was discontinued.

Aged↗

Cerebrotendinous xanthomatosis: a review of biochemical findings of the patient population in The Netherlands.

This study gives a review of the results obtained from biochemical investigations of 20 patients in The Netherlands suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis. Diagnosis can best be established by determining the excretion of urinary bile alcohols, in particular 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,23,25-pentol, in urine by means of capillary gas chromatography. Measurement of serum cholestanol levels or serum cholestanol/cholesterol ratios, commonly used for establishing cerebrotendinous xanthomatosis, are not reliable. The effectiveness of the different therapies, i.e. administration of bile acids, can be evaluated by monitoring the urinary excretion of bile alcohols. From such investigations it was concluded that cholic acid especially, but also chenodeoxycholic acid are the therapies of choice for the treatment of cerebrotendinous xanthomatosis. All patients, until now diagnosed in The Netherlands were not discovered before the third or fourth decade of life because the characteristic signs only then become manifest clearly. Unfortunately, because sterol storage is almost irreversible, therapy only results in minor improvements of the patient's condition. Therefore early detection of the presence of cerebrotendinous xanthomatosis is desirable so that treatment can start before extensive storage of sterols is a fact. We developed some laboratory assays with the purpose of early detection. One consists of the detection of cerebrotendinous xanthomatosis carriers by subjecting them to oral cholestyramine administration and monitoring the urinary excretion of the bile alcohol 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol before and after treatment. Secondly, a relatively simple screening test for cerebrotendinous xanthomatosis was developed based on an enzymatic assay of 7 alpha-hydroxylated steroids in urine. After suitable modification this assay in principle allows the screening of large populations for the existence of cerebrotendinous xanthomatosis and thus to detect the disease at an earlier stage of life.

Bile Acids and Salts↗

Treatment of hypercholesterolemia with the HMG CoA reductase inhibitor, simvastatin.

We report the results of a two center study on the use of the HMG Co A reductase inhibitor, simvastatin, in 44 patients suffering from familial hypercholesterolemia or from primary hypercholesterolemia of unknown etiology. The study included two separate phases: Phase I was part of a multicenter, 4-week, placebo-controlled trial; phase II was a 6-month, open extension trial, the object of which was to reduce low density lipoprotein (LDL) cholesterol levels to below the 50th percentile by increasing the dose of simvastatin, by the use of additional lipid-lowering medication, or both. Our phase I results were commensurate with those reported for the entire international cohort of 272 patients, indicating a clear dose-response relationship, with approximately 75% of the maximum reduction in LDL-C levels being achieved with 20 mg/day and over 90% of the maximum being achieved with 40 mg of simvastatin per day. In the open extension trial, the results from the 2 centers were essentially similar. Total cholesterol fell by 29% on the 20 mg/day dose and by 34% on the full dose of 40 mg/day. LDL-C levels were reduced by 40% on the 40 mg/day schedule, and triglycerides also fell to between 20% and 40% below baseline values. HDL-C concentration rose by 14% and 17.6%. The effects of simvastatin were uniform, both within and between the two cohorts. The addition of cholestyramine caused a further substantial reduction in LDL-cholesterol to below 55% of the initial value in four patients, whereas bezafibrate further enhanced the fall in triglycerides and the increase in high-density lipoprotein cholesterol, but had only a slight effect on LDL-C levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗