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PubMed2004

Treatment of the Pruritus of Cholestasis.

The etiology of the pruritus of cholestasis is unknown. It is inferred that the pruritogen(s) is produced in the liver, excreted in bile, and as a result of cholestasis it accumulates in plasma. It may follow, logically, that the removal of the substance(s) that mediate pruritus leads to its resolution. The problem with this approach, however, is that the substance(s) is unknown; thus, it is not possible to reduce its serum levels specifically. Oral cholestyramine, a resin that is not absorbed, is associated with increased fecal excretion of certain substances, including cholesterol and bile acids. Many patients respond to treatment with cholestyramine with a relief of pruritus, which unfortunately may be temporary, but is well tolerated in general and it seems reasonable to prescribe it as an initial therapy. When pruritus is not relieved by resins, the use of opiate antagonists (eg, naloxone and naltrexone) is supported by data from controlled clinical trials. Butorphanol is an agonist at the kappa opioid receptor and an antagonist at the mu opioid receptor with minimal or absent abuse potential. The use of butorphanol spray in selective patients may be a therapeutic alternative. In uncontrolled observations dronabinol, an agonist at the cannabinoid B1 receptor, and sertraline, a serotonin reuptake inhibitor, have been reported to be associated with the relief of pruritus. The cannabinoidergic and serotoninergic systems participate in the mediation of nociception; therefore, there appears to be a rationale for the use of these drugs to treat pruritus. Data from controlled clinical trials on the use of dronabinol and sertraline, however, are not available at present.

Journal Article↗

PubMed2004

Treatment of Clostridium difficile Infection.

With the introduction of broad-spectrum antibiotics into clinical practice, Clostridium difficile infection has become the most common cause of infectious diarrhea in hospitalized patients. Although mild cases may resolve by discontinuing antibiotics, thus allowing re-establishment of colonic microflora, oral metronidazole or vancomycin is indicated if the process is more severe. Metronidazole may be given intravenously, with intracolonic therapeutic levels achieved by excretion of drug into bile and exudation across inflamed tissue. Vancomycin is preferred treatment of severe cases. Bacitracin given orally is a therapeutic alternative and cholestyramine is a useful adjunct. Most patients with diarrhea or colitis caused by C. difficile respond to initial therapy; however, up to 20% experience relapse when treatment is discontinued. Repeating initial therapy for 10 to 14 days is indicated for first relapse. Multiple relapses require prolonged treatment with vancomycin, which may be supplemented with cholestyramine. Saccharomyces boulardii alone or in combination with vancomycin has been reported to be an effective therapeutic alternative for recurrent infection. Intravenous immunoglobulin can be effective in patients with severe recurrent Clostridium difficile colitis and immune deficiency or low pretreatment levels of serum antitoxin. Surgery is indicated only if recurrent infections are severe and associated with serious complications.

Journal Article↗

PubMed2005

Treatment of Biliary Problems in Inflammatory Bowel Disease.

The most common biliary problem in patients with inflammatory bowel disease is primary sclerosing cholangitis (PSC). The treatment of this disease is multifaceted and frequently requires a multidisciplinary approach involving internists, nutritionists, gastroenterologists, and surgeons. Unfortunately, other than liver transplantation, no therapy that is currently available has been proven to alter the natural history of PSC or prolong survival. Ursodeoxycholic acid is currently the most promising pharmacologic treatment option for slowing disease progression and should be used in higher than usual doses (20 to 30 mg/kg/d). Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins such as cholestyramine or colestipol (which is generally better tolerated than cholestyramine). Endoscopic therapy should be reserved for patients with obstructive jaundice, cholangitis, or symptomatic dominant biliary strictures. We recommend dilation of dominant strictures with graduated or balloon dilators followed by temporary stenting if the postdilation cholangiographic appearance is not improved or adequate biliary drainage cannot be assured. There is indirect evidence that the combination of ursodeoxycholic acid and endoscopic therapy to maintain biliary patency may improve transplant-free survival in patients with PSC, although this remains to be proven. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.

Journal Article↗

PubMed1993

The role of lipids and antioxidative factors for development of atherosclerosis. The Probucol Quantitative Regression Swedish Trial (PQRST).

The effect of probucol on the development of atherosclerosis is being investigated in the Probucol Quantitative Regression Swedish Trial (PQRST). Hypercholesterolemic patients are randomized to receive either probucol 0.5 g twice daily or placebo in a double-blind manner, in combination with dietary therapy and cholestyramine 8-16 g daily for a 3-year period. The primary endpoint of the trial is the change in atheroma volume, assessed by annual quantitative angiography involving 20-cm segments of the femoral artery. Data from the open diet and prerandomization phase indicate that probucol added to dietary intervention plus cholestyramine produced highly significant reductions in total (-17%), low-density lipoprotein (LDL; -10%), and high-density lipoprotein (-30%) cholesterol. From a subpopulation, LDL levels were isolated during different stages of the prerandomization phase. LDL was exposed to the oxidant Cu2+ and binding to fibroblasts as well as degradation by macrophages was measured. The generation of thiobarbituric acid-reactive substances (TBARS) was also measured. Probucol prevented degradation of copper-exposed LDL by macrophages and also reduced the formation of TBARS, indicating that probucol protected LDL from oxidation. After the trial concludes in December 1992, statistical models will be used to investigate how much of the change in atherosclerosis is explained by changes in lipoprotein concentrations and how much is explained by probucol's antioxidative effects. Thus, other metabolic factors such as dietary intake and circulating levels of lipid soluble vitamins and fatty acids that may modify the possible antioxidative effects of probucol are also measured and will be related to change in atherosclerosis.

Aged↗

PubMed1993

Bile acid synthesis in hamster hepatocytes in primary culture: sources of cholesterol and comparison with other species.

The synthesis of bile acids by primary hamster hepatocytes in culture has been studied. Measurable rates of bile acid synthesis were obtained from cells prepared from livers of animals fed 2% w/w cholestyramine to induce the synthesis of bile acids through the rate-limiting enzyme cholesterol 7 alpha-hydroxylase. The effects of various sources of substrate for bile acid synthesis in these cultured cells were examined over a period of 24 h and the results compared with published or parallel studies in primary rat hepatocytes or in the human hepatoma cell line, HepG2. In all the cells, bile acid synthesis was stimulated by the addition of 7 alpha-hydroxycholesterol, indicating the rate-limiting role of the cholesterol 7 alpha-hydroxylase. Bile acid synthesis in the hamster hepatocytes was also stimulated by a variety of sources of cholesterol as substrate, mevalonic acid (increasing the production of newly-synthesised cholesterol in the cell), and as an exogenous source, hamster LDL. Similarly, if cholesterol was diverted from intracellular esterification using the ACAT inhibitor Dup128, a further increase in bile acid synthesis could be demonstrated. These results show that hepatocytes obtained from cholestyramine-treated hamsters are deficient in substrate cholesterol for bile acid synthesis. A similar conclusion can be drawn from the published work with rat hepatocytes and is further supported by experiments on the regulation of cholesterol 7 alpha-hydroxylase activity at the mRNA and the protein level, although some in vivo studies in animals and studies in man have led authors to suggest that cholesterol 7 alpha-hydroxylase is saturated with substrate.

Animals↗

PubMed1995

Evaluation of cultured hamster hepatocytes as an experimental model for the study of very low density lipoprotein secretion.

The secretion of triacylglycerol, cholesterol and cholesteryl ester in very low density lipoprotein (VLDL) by cultured hamster hepatocytes was studied, and the results compared with those obtained previously using cultured rat hepatocytes and the human hepatoma cell line HepG2. The hamster cells secreted apolipoprotein B and VLDL triacylglycerol, cholesterol and cholesteryl ester linearly during 24 h in culture, and this time period was used in all experiments. Addition of oleate (1 mM) to the culture medium resulted in increased secretion of triacylglycerol, but cholesterol ester output were unchanged. Triacylglycerol secretion was also increased in the presence of lipogenic substrates (10 mM lactate + 1 mM pyruvate) plus dexamethasone (1 microM), but not with either of these agents alone. Inhibition of cholesterol synthesis in the hamster cells by incubation with mevinolin (2 micrograms/ml) did not change VLDL lipid secretion, but stimulation using mevalonate lactone resulted in decreased triacylglycerol output. Manipulation of the rate of cholesterol esterification in the hepatocytes by inhibiting or stimulating the activity of acyl coenzyme A cholesterol:acyl transferase using the inhibitor Dup128 (25 microM) and 25-hydroxycholesterol (50 microM), respectively, had no effect on the secretion of VLDL lipid. In the presence of 1 mM oleate plus 25-hydroxycholesterol, however, a rise in the output of triacylglycerol and cholesteryl ester was observed. Hepatocytes prepared from hamsters fed 2% cholestyramine secreted significantly less triacylglycerol than those from animals given the control diet, but cholesterol and cholesteryl ester output were unchanged, despite a decrease of about 40% in the total cholesterol content of the cells. These results show that the secretion of lipid in VLDL in hamster hepatocytes differs from that in rat and human liver in its response to dietary cholestyramine, and from rat hepatocytes and HepG2 cells in its response to changes in the rate of lipogenesis and cholesterol synthesis and esterification. Overall, hamster hepatocytes appear to be less susceptible to modification the rate of hepatic VLDL secretion, and should provide a useful additional tool for the investigation of this process.

Animals↗

PubMed1995

Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity.

Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, human fibroblasts, hamster hepatocytes and hamster liver, by inhibiting the cytochrome P450 enzyme lanosterol 14 alpha-demethylase. When administered orally to hamsters fed regular chow, RS-21607 (50 mg/kg/day) lowered serum cholesterol in a dose-dependent manner (ED50 = 62 mg/kg) in a period of 1 week. It preferentially lowered low density lipoprotein (LDL) cholesterol and apo B relative to high density lipoprotein (HDL) cholesterol and apo A-1. It also lowered plasma cholesterol levels in hamsters fed a high saturated fat and cholesterol diet. RS-21607 inhibited hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity in hamsters in a dose-dependent manner (ED50 = 31 mg/kg), and this was highly correlated with serum cholesterol lowering (r = 0.97). Cholesterol lowering by azalanstat and cholestyramine was additive, and the increase in HMG-CoA reductase brought about by cholestyramine was attenuated significantly by azalanstat. In vitro studies with HepG2 cells indicated that this modulation of reductase activity was indirect, occurring at a post-transcriptional step, and it is proposed that a regulatory oxysterol derived from dihydrolanosterol (or lanosterol) may be responsible for this regulation. Azalanstat does not appear to lower circulating cholesterol in the hamster by up-regulation of the hepatic LDL receptor, suggesting that other mechanisms are involved. Orally administered azalanstat (50-75 mg/kg) stimulated hepatic microsomal cholesterol 7 alpha-hydroxylase activity by 50-400% in hamsters, and it is postulated that this may result from modified cholesterol absorption and bile acid synthesis.

Acetates↗

PubMed1988

Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial.

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

Antipyrine↗

PubMed1993

Negative feedback regulation of the ileal bile acid transport system in rodents.

BACKGROUND: Active transport of conjugated bile acids by ileal enterocytes is a key mechanism for conservation of the bile acid pool. Experiments were performed to determine whether such transport is regulated by substrate load. METHODS: Using anesthetized biliary fistula guinea pigs or rats, the ileum was perfused with ursodeoxycholyltaurine at a concentration causing maximal ileal transport of this bile acid; absorption was assessed by biliary recovery. Before ileal perfusion, animals ingested one of three diets: chow, chow with added conjugated bile acid, or chow with added cholestyramine. RESULTS: In the guinea pig, ingestion of a taurocholate-enriched diet resulted in a 75% decrease in the absorption rate of ursodeoxycholyltaurine. Similar results were obtained with cholylsarcosine (a deconjugation-dehydroxylation resistant analogue) or with chenodeoxycholylglycine, the endogenous bile acid of the guinea pig. In contrast, cholestyramine ingestion caused an increase in ursodeoxycholyltaurine absorption. In the rat, cholyltaurine or cholylsarcosine ingestion also caused decreased ileal transport. In the guinea pig, maximal down-regulation of active ileal bile acid transport occurred after 2-3 days of bile acid feeding; up-regulation required 3-4 days. CONCLUSIONS: Bile acid metabolism is regulated by feedback inhibition of active ileal transport in addition to the well-established feedback inhibition of bile acid biosynthesis in the liver. Together, these two regulatory mechanisms ensure constancy of bile acid secretion.

Animals↗

PubMed1978

The effects of plasma exchange on cholesterol metabolism.

Four patients heterozygous for familial hypercholesterolaemia were treated by repeated plasma exchange with or without lipid-lowering drugs. Repeated plasma exchange without drug therapy in 3 patients was associated with a significant 18--28% decrement in plasma cholesterol level, comparing control with plateau values observed 3 weeks after exchange. Further decrements in plateau values followed the addition of lipid-lowering drugs used in combination, clofibrate--nicotinic acid or clofibrate--nicotinic acid--cholestyramine (range of total decrement 39--50%). Plasma exchange was associated with an increased excretion of endogenous faecal steroids, but this increase was completely abolished by the subsequent administration of clofibrate--nicotinic acid. This therapy prevented any increase in bile acid excretion with concomitant use of cholestyramine resin. Plasma exchange with drug therapy was associated with a sustained rise in plasma cholesterol specific radioactivity. In a fourth patient, clofibrate--nicotinic acid was administered prior to plasma exchange and led to a 24% fall in plasma cholesterol. Subsequent plasma exchange in this patient produced no sustained change in plasma cholesterol plateau level. In two patients, withdrawal of drugs allowed plasma cholesterol to return to pre-exchange control levels. These observations suggest that plasma exchange probably produced an increase in endogenous cholesterol synthesis and a mobilisation of tissue cholesterol. In relation to plateau cholesterol values 3 weeks after an exchange, the data suggested that the reduction in plasma cholesterol level with plasma exchange and drug therapy could have been achieved by intensive drug therapy alone.

Adult↗

PubMed1995

Cloning and functional expression of the cDNA encoding rat lanosterol 14-alpha demethylase.

Lanosterol 14 alpha-demethylase (LDM) is a cytochrome P-450 enzyme in the biosynthetic pathway of cholesterol. As such, it represents a target for cholesterol-lowering drugs. Rat LDM (rLDM) has been purified from the livers of rats treated with cholestyramine. The purified protein was used to generate tryptic fragments which were then sequenced. The amino acid (aa) sequences were used to design oligodeoxyribonucleotide primers and a DNA fragment was generated by RT-PCR to probe a phagemid library. A clone encoding rLDM was isolated from the livers of cholestyramine-treated rats. The clone contains an open reading frame encoding a polypeptide of 486 aa and a predicted molecular mass of 55 045 Da. The deduced aa sequence shows a high degree of identity to the yeast LDM sequences, as well as sequences which match typical P-450 sequence motifs. When produced in a baculovirus/insect cell culture system, LDM activity was detected and inhibited by the specific inhibitor azalanstat with an IC50 value of less than 2 nM. The isolation of this full-length coding sequence should facilitate research into understanding the direct and indirect effects of LDM in the regulation of cholesterol biosynthesis and the search for cholesterol-lowering drugs.

Amino Acid Sequence↗

PubMed1985

Levothyroxine ingestions in children: an analysis of 78 cases.

A series of 78 cases of accidental levothyroxine ingestion in children (less than 12 years old) with treatment limited to ipecac-induced emesis and a single oral dose of activated charcoal is presented. No patient received any form of dialysis or hemoperfusion, propylthiouracil, cholestyramine, steroids, or serial doses of oral activated charcoal. Propranolol was used in one case despite the absence of clinical manifestations of toxicity. Only four children developed symptoms, limited to modest fever (38.3 degrees C), supraventricular tachycardia (120-176 beats/min), lethargy, irritability, vomiting, diarrhea, and abdominal pain. Peak T4RIA values in three patients were 32.8, 30.0, and 26.4 micrograms/dl, respectively, and two of these patients remained asymptomatic. Initial therapy for acute levothyroxine ingestions in children can be safely limited to routine gastrointestinal decontamination. Hospitalization or prophylactic treatment with propranolol, propylthiouracil, corticosteroids, cholestyramine, or extracorporeal detoxification are unnecessary in the early asymptomatic phase.

Charcoal↗

PubMed1991

In vitro binding of estrogens by dietary fiber and the in vivo apparent digestibility tested in pigs.

Within the framework of experiments related to the association between dietary fiber and breast cancer an in vitro test system was used to study the binding of estrogens to various fibers (e.g. cholestyramin, lignin and cellulose) and fiber sources (e.g. wheat bran, cereals, seeds and legumes). Furthermore, the in vivo apparent digestibility of the different fiber sources was tested using a mobile nylon bag technique in intestine-cannulated pigs. Estradiol-17 beta (E2) bound more strongly to the various fibers than did estrone (E1), estriol or estrone-3-glucuronide. At increasing pH (greater than 7) binding of both E1 and E2 to wheat bran decreased significantly. Cholestyramine and lignin bound almost all estrogens present in the medium. Linseed (91%), oats (83%), barley chaff (88%) and wheat bran (82%) are other excellent binders of E2. Corn, rye and white wheat flour showed lower binding capacity with a relatively low affinity. Cereals with the highest percentage of lignin in the fiber (greater than 3%) were also the fiber sources with the lowest apparent digestibility. Estrogens bound with the highest affinity (relative to bovine serum albumin) to these fiber sources. Together with wheat bran and lignin, oats, linseed and soybean seem to be products with good perspectives for in vivo evaluation of the lowering effect of dietary fiber on estrogen exposure of estrogen-sensitive tissues.

Animals↗

PubMed2005

150 kDa glycoprotein isolated from Solanum nigrum Linne enhances activities of detoxicant enzymes and lowers plasmic cholesterol in mouse.

This study was carried out to investigate the modulation of detoxicant enzyme activity and plasma lipidemic levels by 150 kDa glycoprotein isolated from Solanum nigrum Linne (SNL), which has been used as a hepatoprotective and anticancer agent in folk medicine. Our results in this study showed that SNL glycoprotein has a band with 150 kDa on the 10% sodium dodecyl sulfate polyacrylamide gel, and that it has a strong scavenging activity against lipid peroxyl radicals. We also evaluated the lipidemic levels of SNL glycoprotein, based on lipoproteins and activities of detoxicant enzymes in treatment with Triton WR-1339 or corn oil in vivo. When mice were treated with either Triton WR-1339 or corn oil in the absence of SNL glycoprotein, the number of plasma lipoproteins [triglyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL)] increased. However, when the mice were treated with either Triton WR-1339 or corn oil in the presence of SNL glycoprotein, the plasma lipoprotein levels (TG, TC and LDL) were significantly reduced. Similar results of SNL glycoprotein treatment were also produced in the activities of detoxicant enzymes. Namely, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were remarkably increased after treatment with SNL glycoprotein. In addition, the activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was reduced by SNL glycoprotein in cholestyramine-treated mice. For example, we found that it inhibits the activity of cholestyramine-induced hepatic HMG-CoA reductase at 40 microg head body weight g(-1) SNL glycoprotein. Collectively, these results pointed out that SNL glycoprotein can enhance the activities of detoxicant enzymes and bring about the inhibition of HMG-CoA reductase activity in vivo. Therefore, we speculate that SNL glycoprotein can be used as a cholesterol-lowering agent even at low concentrations.

Animals↗

PubMed1997

Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Adult↗

PubMed1998

The lipoprotein and coronary atherosclerosis study (LCAS): lipid and metabolic factors related to atheroma and clinical events.

Studies of lipid-lowering therapy are usually conducted in patients with severely elevated cholesterol levels. However, most individuals who develop clinically significant coronary artery disease (CAD) have total cholesterol levels <240 mg/dL and low-density lipoprotein (LDL) cholesterol levels similar to individuals who do not develop significant CAD. The Lipoprotein and Coronary Atherosclerosis Study (LCAS) was conducted to determine whether lipid-lowering therapy with fluvastatin would reduce the progression or induce the regression of coronary atherosclerotic lesions and/or reduce new lesion formation in patients with CAD and mildly to moderately elevated LDL cholesterol. The LCAS was the first angiographically monitored trial of this 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. All 429 men and women (mean age, 58.8 years) had angiographic evidence of CAD and LDL cholesterol levels of 115-190 mg/dL (mean 145.6 mg/dL). Patients were randomized to fluvastatin 20 mg twice daily or placebo. Patients whose prerandomization LDL cholesterol was > or = 160 mg/dL also received open-label cholestyramine. Lipid-lowering therapy with fluvastatin significantly slowed CAD progression. After 2.5 years, the mean LDL cholesterol decreased by 23.9% in all fluvastatin-treated patients (+/-cholestyramine) and by 22.5% in patients treated with fluvastatin monotherapy. There was significantly less lesion progression in fluvastatin versus placebo-treated patients (p <0.01). There also were fewer clinical events in fluvastatin-treated patients. Findings suggest that fluvastatin may improve arterial and arteriolar function within a few weeks of beginning therapy.

Adult↗

PubMed1999

Relationship among cholesterol, superoxide anion and endothelium-dependent relaxation in diabetic rats.

The purpose of the present study was to investigate the time course of changes in plasma low-density lipoprotein (LDL) cholesterol, tissue lipid peroxidation, the expression of hepatic LDL-receptor mRNA and aortic superoxide dismutase, and the relaxation response to acetylcholine in streptozotocin-induced diabetic rats. Plasma cholesterol and LDL levels were significantly increased in both 4- and 10-week diabetic rats. The tissue malonic dialdehyde content in aortas was increased in 10-week compared to 1- or 4-week diabetic rats. The expression of mRNA for LDL receptor mRNA in the liver showed a decrease in both 4- and 10-week diabetic rats. Hepatic LDL-receptor binding activity decreased significantly in 10-week diabetic rats, and decreased binding activity in diabetic rats was improved by the chronic administration of cholestyramine. The relaxation responses to acetylcholine in helical strips of the aorta precontracted with noradrenaline were significantly decreased in 10-week, but not in 1- or 4-week streptozotocin-induced diabetic rats. The decreased relaxation response to acetylcholine was improved by chronic cholestyramine. Both the expression of Mn-superoxide dismutase mRNA and the activity of superoxide dismutase in the aorta were decreased in 10-week, but not in 4-week diabetic rats. From time-course studies, our data suggest that not only increased LDL cholesterol but also decreased activity of superoxide dismutase are responsible for the decreased relaxation response induced by acetylcholine.

Acetylcholine↗

PubMed1998

The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters.

The hypocholesterolemic and anti-atherogenic properties of sulfamic acid ((2,4,6-tris (1-methylethyl) phenyl) acetyl) 2,6-bis(1-methylethyl) phenyl ester, the ACAT inhibitor, CI-1011, was tested in 120 male F1B hamsters fed a hypercholesterolemic chow-based diet containing 10%, coconut oil and 0.05% cholesterol plus: (i) no drug treatment (HCD); (ii) 3 mg/kg per day (HCD+3): (iii)10 mg/kg per day (HCD+10); (iv) 30 mg/kg per day (HCD+30) of CI-1011; or (v) 500 mg/kg per day of cholestyramine (CSTY). Plasma samples were collected at 8 and 10 weeks for measurement of total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). For the progression studies, animals were euthanized after 10 weeks for aortic fatty streak area and hepatic cholesterol analysis. For the regression study, a cohort of the HCD was treated with 30 mg/kg per day of CI-1011 (regression) for an additional 8 weeks. The HCD+3, HCD+10, HCD+30 and CSTY lowered plasma TC (25, 32, 34 and 32%, respectively), VLDL-C (62, 74, 71 and 75%, respectively), LDL-C (25, 38, 47 and 46%, respectively) and TG (48, 47, 42 and 45%, respectively). All treatments resulted in a significant lowering of aortic fatty streak area (68, 86, 93 and 94%, respectively) and reduction in hepatic cholesteryl esters (57, 65, 67 and 70%, respectively). Regression of aortic fatty streak area was 90% after 8 weeks of HCD+30 treatment. Also during the regression phase, plasma TC, LDL-C and TG were lowered 23, 33 and 47%, respectively, as well as, hepatic cholesteryl esters (76%). Significant correlations between plasma LDL-C concentration and aortic fatty streak area (r=0.62, P < 0.004) in the HCD+10 group, suggest that CI-1101 altered aortic lipid infiltration primarily by its effect on plasma lipids. However the 30 mg/kg per day dose of CI-1011 which additionally reduced aortic fatty streak area by 51% relative to the 10 mg/kg per day dose was only associated with a 14% further decrease in plasma LDL-C. Finally the 10-fold regression of aortic fatty streak area was associated with only a 35% reduction in plasma LDL-C. These exceptions to the lipid-lesion relationship raise the possibility of additional effects of CI-1011, which may occur independent of or in concert with lipoprotein cholesterol lowering. It is concluded that in hypercholesterolemic hamsters, CI-1011 is approximately 50 times more potent than cholestyramine in cholesterol-lowering, reduction and regression of aortic fatty streak area.

Acetamides↗