Evaluación piloto de la reducción de niveles séricos de productos de glicación avanzada (AGEs) sobre la electrofisiología de la visión, en pacientes con diabetes mellitus tipo 2 / Pilot evaluation of the serum levels reduction of advanced glication products (AGEs) on the vision electrophysiology in type 2 diabetic patients

BACKGROUND: Diabetic vascular complications are associated with elevated concentrations of advanced glycation end-products (AGEs). These substances can be originated endogenously by hyperglycaemia and oxidative stress, but also by dietary intake. There is indirect evidence suggesting that these complications can be prevented by lowering AGEs levels by dietary or pharmacological interventions, however its clinical benefits are still not clear enough because this would require long periods of treatment. Specific neuro-ophthalmologic tests like Multifocal Electroretinogram (MFERG) and visual evoked potentials (VEP) can detect retinal and myelinic nerve early changes, and thus could represent good methods to study the results of certain interventions in shorter lapses. The aim of this preliminary study was to evaluate the effects of a pharmacological intervention designed to lower AGEs levels, on these variables. PATIENTS AND METHODS: We included 7 patients with type 2 diabetes (DM2), with more than 5 and less than 10 years of disease, without clinically evident micro and macrovascular disease, without renal failure, hypothyroidism nor vitamin B12 deficiency, whose AGEs dietary intake was moderately elevated or high (according to dietary recalls). Upon admission, a clinical evaluation, urine and blood samples were obtained for routine labs, plus ultrasensitive C Reactive Protein (usCRP) as an inflammatory marker, and carboxymethyl-lysine (CML) as representative of AGEs. Then a complete ophthalmologic evaluation was performed, including fundus, MFERG and VEP. After the initial evaluation, placebo capsules were prescribed (12 daily capsules, 4 with each main meal) during 3 months, repeating the same initial evaluation at completion of this period. Then the active treatment followed, with capsules containing cholestyramine (4 capsules containing 500 mg each, totaling 6 g per day). Patients were cited each month, to register adverse events and repeating the same evaluation after this second 3 months period. RESULTS: The sample was composed of 2 male patients, mean age was 55.1 ± 3.8 years, and diabetes was managed with metformin plus other oral agents or o insulin (4 cases). In addition, 4 patients received lipid lowering and 4 antihypertensive drugs. Metabolic control and lipid levels were variable (ranges of HbA1c 6.2-8.4%, LDL cholesterol 45-141 mg/dL, triglycerides 70-220 mg/dL). AGEs levels represented by CML were highly variable (median 31.7, range min-max 3.4-58.9 ug/uL). Basal usCRP was also variable (median 405.9, range min-max 265.6-490.7 mg/L). The treatment was well tolerated, except for mild constipation associated with cholestiramine intake. No significant changes in electroretinography or evoked potentials were observed when comparing the initial placebo period with cholestyramine treatment. A significant increase in triglyceride levels and decrease of vitamin D levels after cholestyramine treatment was observed. No changes were detected in serum concentrations of CML, usCRP or glycemic control, after treatment. The latter variables were not correlated with neurophthalmologic studies. DISCUSSION: In this preliminary study we did not observe changes in MFERG nor VEP after 6 g/day cholestyramine treatment, which did not induce lowering of CML levels. This could be attributed to the many limitations of a pilot study, such as a small sample size, short duration of treatment, reduced doses. However this design allowed to evaluate the patients´ tolerance to the drug and rule out adverse effects, in order to plan further studies using the necessary doses to obtain lowering of AGEs

High Bile Acid-induced by High-fat Diet Impairs Intestinal Mucosa by Down-regulating Stem Cell Function / 胃肠病学

Background:High-fat diet leads to intestinal mucosa barrier dysfunction,but the mechanism is not clear. High-fat diet can induce increase of bile acid. Aims:To investigate whether the high bile acid induced by high-fat diet could act on intestinal stem cell to disrupt stem cell differentiation and imparing the intestinal mucosa. Methods:Twenty-four rats were divided into 3 groups:fed with regular diet,high-fat diet and high-fat diet + cholestyramine,respectively,for 2 weeks. Serum bile acid was detected by ELISA. Ileal diameter was measured and HE staining was performed to observe histology of intestinal mucosa. Expression of Lgr5 gene was determined by RT-qPCR. Ileal tissue fed with regular diet was cultured with deoxycholic acid(DCA)or DCA + cholestyramine for 24 hours in vitro,expression of Lgr5 gene was determined by RT-qPCR. Results:Compared with control group,serum bile acid was significantly increased(P < 0. 05),ileal diameter was significantly decreased,height of intestinal crypts and villus was significantly decreased(P < 0. 05),and expression of Lgr5 gene was significantly decreased in high-fat diet group(P < 0. 01). All the above-mentioned indices were significantly ameliorated in high-fat diet + cholestyramine group(P < 0. 05). In vitro study showed that expression of Lgr5 gene was significantly decreased in DCA group than in control group(P < 0. 01),and cholestyramine could significantly increase expression of Lgr5 gene(P < 0. 05). Conclusions:High-fat diet induced increasing of circulatory bile acid can cause injury of intestinal mucosa by inhibiting stem cell function,which can be ameliorated by cholestyramine.

A Case of Methimazole-Resistant Severe Graves' Disease: Dramatic Response to Cholestyramine

A 22-year-old woman with severe Graves' disease was referred from a local clinic because of her refractory hyperthyroidism. She presented with exophthalmos, diffuse goiter, and tachycardia. She was treated with a maximal dose of methimazole and a beta-blocker for 2 months. However, her thyroid function test (TFT) did not improve. TFT showed a free T4 level of 74.7 ng/dL and a thyroid stimulating hormone (TSH) level of 0.007 µIU/mL. She was then administered cholestyramine (4 g thrice daily), hydrocortisone (300 mg/day) and methimazole (100 mg/day) which prepared the patient for surgery by reducing the free T4 level (4.7 ng/dL). The patient underwent a total thyroidectomy without experiencing thyrotoxic crisis. This case describes the use of cholestyramine for the first time in Korea in treating Graves' disease and provides limited evidence that cholestyramine can be an effective option.

A Case of Methimazole-Resistant Severe Graves' Disease: Dramatic Response to Cholestyramine

A 22-year-old woman with severe Graves' disease was referred from a local clinic because of her refractory hyperthyroidism. She presented with exophthalmos, diffuse goiter, and tachycardia. She was treated with a maximal dose of methimazole and a beta-blocker for 2 months. However, her thyroid function test (TFT) did not improve. TFT showed a free T4 level of 74.7 ng/dL and a thyroid stimulating hormone (TSH) level of 0.007 µIU/mL. She was then administered cholestyramine (4 g thrice daily), hydrocortisone (300 mg/day) and methimazole (100 mg/day) which prepared the patient for surgery by reducing the free T4 level (4.7 ng/dL). The patient underwent a total thyroidectomy without experiencing thyrotoxic crisis. This case describes the use of cholestyramine for the first time in Korea in treating Graves' disease and provides limited evidence that cholestyramine can be an effective option.

Cholestyramine Use for Rapid Reversion to Euthyroid States in Patients with Thyrotoxicosis

Cholestyramine (CS) is an ion exchange resin, which binds to iodothyronines and would lower serum thyroid hormone level. The use of CS added to conventional antithyroid drugs to control thyrotoxicosis has been applied since 1980's, and several studies indicate that using CS in combination with methimazole (MZ) produces a more rapid decline in serum thyroid hormones than with only MZ treatment. Our recent retrospective review of five patients taking high dose MZ and CS, compared to age-, gender-, initial free thyroxine (T4) level-, and MZ dose-matched 12 patients with MZ use only, showed more rapid decline of both free T4 and triiodothyronine levels without more adverse events. CS could be safely applicable short-term adjunctive therapy when first-line antithyroid medications are not enough to adequately control severe thyrotoxicosis or side effects of antithyroid drug would be of great concern.

Refractory Graves' Disease Successfully Cured by Adjunctive Cholestyramine and Subsequent Total Thyroidectomy

The three major forms of treatment for Graves thyrotoxicosis are antithyroid drugs, radioactive iodine therapy and thyroidectomy. Surgery is the definitive treatment for Graves thyrotoxicosis that is generally recommended when other treatments have failed or are contraindicated. Generally, thyrotoxic patients should be euthyroid before surgery to minimize potential complications which usually requires preoperative management with thionamides or inorganic iodine. But several cases of refractory Graves' disease have shown resistance to conventional treatment. Here we report a 40-year-old female patient with Graves' disease who complained of thyrotoxic symptoms for 7 months. Her thyroid function test and thyroid autoantibody profiles were consistent with Graves' disease. One kind of thionamides and beta-blocker were started to control her disease. However, she was resistant to nearly all conventional medical therapies, including beta-blockers, inorganic iodine, and two thionamides. She experienced hepatotoxicity from the thionamides. What was worse is her past history of serious allergic reaction to corticosteroids, which are often used to help control symptoms. A 2-week regimen of high-dose cholestyramine improved her uncontrolled thyrotoxicosis and subsequent thyroidectomy was successfully performed. In conclusion, cholestyramine could be administered as an effective and safe adjunctive agent for preoperative preparation in patients with severe hyperthyroid Graves's disease that is resistant to conventional therapies.

A drug will not function unless it is bound to a receptor: a longstanding confusion in basic pharmacology.

The disparity between the general definition of a ‘drug’ and the wide-spread mechanism of actions of receptor-dependent drugs may often mislead to believe that a drug-receptor interaction is always indispensable for a drug to exert its action. This short review is intended to rectify this basic misconception in pharmacology with the aid of a list of examples of several receptor-independent drugs in context to their mode of actions.

Anti – Atherogenic Activity of Ethanol Extract of Buccholzia coriacea Seeds on Hypercholesterolemic Rats.

To scientific determine the phytochemical constituents of ethanol extract of B. coriacea (EEBC) powdered seeds and its effects on the serum lipid profile, serum atherogenic index, and lipid peroxidation in the serum of hypercholesterolemic rats. Study Design: Twenty male albino rats were used for the experiment. They were divided into four groups, 5 rats in each. The administration is as follows: GROUP 1 (Normal control): 0.3ml of corn oil only, GROUP 2 (experimental control): 40 mg/kg body weight of cholesterol only, GROUP 3 (standard drug treatment): 40 mg/kg body weight of cholesterol and 260mg/kg body weight of cholestyramine, GROUP 4 (extract treatment): 40 mg/kg body weight of cholesterol and 250mg/kg body weight of EEBC. Place and Duration of Study: Department of Biochemistry, University of Ibadan, Nigeria for eight weeks. Methodology: At the end the 6 weeks of administration, the animals were kept fasting overnight. They were then made unconscious by cervical dislocation and dissected. The blood was then collected into clean vials. The Lipid profile, malondialdehdye levels were measured in the serum of the rats in the four groups while the atherogenic index was calculated. The qualitative phytochemical screening of EEBC seeds powder was performed. Data were statistically analyzed by one way ANOVA followed by post hoc Duncan multiple range comparison tests. Results: EEBC powdered seeds contains tannins, carbohydrates, saponins, flavonoids, saponins, terpenoids and alkaloids. The level of serum total cholesterol, triglyceride, LDL – cholesterol, atherogenic index significantly decreased (P=.05) by 29.5%, 41.5%, 39.2%, 77.4% respectively in the extract – treated group compared with experimental group. Whereas the experimental group showed a significant (P=.05) increase compared with normal control. There was a significant (P=.05) increase of 67.9% in the serum HDL - cholesterol of the extract – treated group compared with the experimental group. Whereas the experimental group showed a significant (P=.05) decrease in comparison with the normal control. A significant (P=.05) decrease of 36% in the amount of serum malondialdehyde was produced in the extract – treated groups compared with the experimental control which showed a significant (P=.05) increase compared with the normal control. Conclusion: EEBC seed powder has potent anti- atherogenic properties.

Diarrea crónica postcolecistectomía / Chronic diarrhea post cholecistectomy

En el presente artículo se trata sobre la alta frecuencia del antecedente de colecistectomía como factor determinante de diarrea crónica y su control con colestiramina.

In the present article presents the high frequency of previous cholecystectomy as determinant factor of chronic diarrhea and its control with cholestyramine.

Cholestyramine resin for erythropoietic protoporphyria with severe hepatic disease: a case report / 대한간학회지

Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis caused by mutations in the gene encoding the enzyme ferrochelatase. In EPP, deficient ferrochelatase activity leads to the excessive production and biliary excretion of protoporphyrin (PP). The major clinical features of EPP are photosensitivity and hepatobiliary disease that may progress to severe liver disease, that are caused by the toxicity of PP. EPP-related liver disease has been treated medically or surgically including liver transplantation. We described a 20-year-old male with severe liver disease who was diagnosed with EPP based on clinical and laboratory findings. He was treated with cholestyramine resin. Six months after the treatment, he was doing well without any abdominal pain or photosensitivity.

The usage of low dose of cholestyramine in the preoperotive preparation in hyperthyroidism / 重庆医科大学学报

Objective:To investigate the effect of lowdose of cholestyramine in the preoperotive preparation in hyperthroidism(HT).Methods:Sixty-seven patients with HT were randomly and double blindedly divided into group A and group B,the former were give low dose of cholestyramine and thioureas,the latter were given tapazole(MMI)and Logul's liquid.Four weeks later,the level of TH and basic metabolism rate(BMR)were comparised between two groups.Results:The level of FT3,FT4,BMR,and the preoperotive preparation time were significantly priorier than those of group B(P0.05).Conclusion:It suggests that lowdose of(cholestyramine is beneficial for the preoperotive preparation in HT.

Clinical trial comparing the efficacy of ursodeoxycholic acid and cholestyramine on idiopathic neonatal hepatitis.

common cause of neonatal cholestasis is idiopathic neonatal hepatitis. Several agents have been proposed to counteract the effects of accumulated toxic bile acid such as phenobarbital and cholestyramine. Ursodexycholic acid ( UDCA) is a choleretic agent used in chronic intrahepatic cholestasis. The aim of this study is to compare the efficacy of ursodeoxycholic acid and cholestyramine on hepatic function in idiopathic neonatal hepatitis. Twenty patients were enrolled in this study. The patients were randomized to receive UDCA or cholestyramine orally. There were ten patients in each group. The doses of UDCA and cholestyramine were 15 mg/ kg / day and 350 mg / kg/ day respectively. The duration of the study was 8 weeks. Conventional liver function tests were done initially and at 1,2,4, and 8 weeks. Any side effects of these medications were noted. The ursodeoxycholic acid group showed a significant improvement in levels of total bilirubin, direct bilirubin, and alkaline phosphatase ( P< 0.05). The cholestyramine group showed a significant improvement in levels of total bilirubin, and direct bilirubin ( P< 0.05). There was no significant difference on liver function tests between the groups at any time ( P> 0.05). No side effects were observed. The results showed that both drugs improved cholestasis resulting from idiopathic neonatal hepatitis. The results of this study suggest that UDCA would be an alternative choleretic agent in treatment of idiopathic neonatal hepatitis.

Effect of Oral Administration of Dioctahedral Smectite and Cholestyramine with Phototherapy in the Treatment of Neonatal Hyperbilirubinemia

PURPOSE: Dioctahedral smectite is an alumina silicate of phyllitic structure and absorbs bile acid in the intestine, forming a non-absorbable complex preventing enterohepatic circulation. The purpose of this study is to clarify the value of dioctahedral smectite and the adequate dosage, in combination with phototherapy, as well as to confirm whether it shortens the duration of hospitalization and to compare dioctahedral smectite with cholestyramine. METHODS: Total 45 full-term neonate with a total bilirubin level greater than 12 mg/dl were studied. The neonate were randomly divided into three groups : 1) Only phototherapy group (A) 2) 3.0 g/day dioctahedral smectite with phototherapy group (B) 3) 1.0 g/kg/day cholestyramine with phototherapy group (C). RESULTS: The mean serum bilirubin level of group B and C decreased significantly compared to group A at 48, 72 and 96 hours after the beginning of the study. The duration of phototherapy and hospitalization significantly decreased in group B and C. CONCLUSION: The data revealed that oral administration of dioctahedral smectite not only increased the efficacy of phototherapy, but also shortened the duration of phototherapy and can substitute for cholestyramine.

Effect of cholestyramine on the formation of pigment gallstone in high carbohydrate diet-fed hamsters

This study was designed to investigate the effect of cholestyramine on the formation of pigment gallstones in high carbohydrate diet-fed hamsters and whether that effect occurred because of cholecystokinin action. Forty seven hamsters were divided into three groups: group I(n = 16) was fed on normal rodent chow(43% carbohydrate), group II(n = 14) was fed on a high CHO diet(65% carbohydrate), group III(n = 17) was fed on a high CHO diet containing 4% cholestyramine. Gallstones developed in 0% of group I, 42.9% of group II and 5.9% of group III(P 0.05). In gallbladder bile analysis, there was also no significant difference between group II and group III in cholesterol, phospholipid, total calcium, total bilirubin and bile acid levels. In conclusion, cholestyramine decreases the frequency of pigment gallstone formation in high CHO diet-fed hamsters, but it is not clear whether the mechanism of cholestyramine decreasing the gallstone formation is due to the action of cholecystokinin.