JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7(th )week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations

Guinea pigs as models for experimental drugs affecting triglyceride metabolism

The purpose of this study was to evaluate guinea pigs as models for triglyceride (TG) metabolism by assessing treatment with a microsomal transfer protein (MTP) inhibitor, a hypolipidemic drug and with rapamycin, a drug prescribed to organ transplant patients, which is known to develop hypertriglyceridemia. ^ Partial inhibition of MTP has been documented to decrease circulating lipid levels leading to fatty liver. JTT-130, an MTP inhibitor targeted towards the intestine, was evaluated. Guinea pigs (10/group) were allocated to a control (no drug) low dose or high dose of JTT-130 for 4 wk following a 3 wk-treatment with a hypercholesterolemic diet. JTT-130 significantly reduced plasma total cholesterol (TC) by 20%, and TG by 30% concentrations compared to controls without causing fatty liver. The activity of hepatic regulatory enzymes of cholesterol synthesis, esterification and catabolism were not affected by drug treatment. These data suggest that JTT-130 has the potential to be used as a lipid-lowering drug in clinical settings. ^ In a second study guinea pigs (10/group) were treated with 0, low or high dose of rapamycin (RAPA) to trace the pathways leading to hyperlipidemia. Increases in plasma TG by 50% without affecting plasma TC values was observed after 3-wk treatment. Plasma glucose (+ 57%), free fatty acids (FFA) (+ 65%), aortic TG (+ 41.7%) and TNF-α (+ 945%) were increased (P \u3c 0.01) in high PAPA groups. Results suggest that RAPA affects VLDL secretion and promotes aortic deposition of TG. Because low-RAPA decreased TC accumulation in liver and aorta and had less of an effect on plasma FFA and aortic TNF-α compared to high-RAPA (P \u3c 0.01), low RAPA treatment could be less detrimental to organ transplant individuals. ^ A third objective of this dissertation was to evaluate the relationship between liver and mononuclear cell\u27s gene expression for target proteins regulating hepatic cholesterol metabolism. RT-PCR, results from HMG-CoA reductase and LDL receptor expression demonstrated a positive correlation between liver and mononuclear cells. These results suggest that mononuclear cells have the potential to be used as an index for liver metabolism to assess diet and drug effects on the expression of these ubiquitously distributed proteins.

Lymphangioma of gingiva: A rare case report

No Abstract

The kaleidoscope of autoimmunity: A report of 10 cases of multiple autoimmune syndrome

Dear Sir, Multiple autoimmune syndrome has been defined as the coexistence of at least three autoimmune disorders in a single patient.[1] Dermatological autoimmune disorders, especially vitiligo, take a special seat in the setting of multiple autoimmune syndrome.[2] There is strong evidence to suggest that the various autoimmune disorders have a common origin and share similar pathophysiological mechanisms. Therefore, the presence of one autoimmune disorder in an individual makes him/her susceptible to the development of other autoimmune disorders.[3] Herein, we report 10 cases of multiple autoimmune syndrome that presented to the dermatology department of our hospital. The patients’ details are shown in [Table 1]. Females made up majority of the cases in our series with seven patients while there were only three male patients. The age of the patients ranged from 19 to 60 years. Seven patients had three autoimmune disorders, two patients had four, and one patient had five coexisting autoimmune disorders. Autoimmune thyroid disease was the most common disorder in our case series which was present in seven patients. The diagnoses of vitiligo, psoriasis, alopecia areata, and lichen planus were confirmed with clinical examination and dermoscopy along with histopathological examination. In addition to these, specific antibody testing was carried out for systemic sclerosis, systemic lupus erythematosus, pemphigus vulgaris, and bullous pemphigoid. Triiodothyronine, tetraiodothyronine, thyroid-stimulating hormone, and antithyroid peroxidase antibody levels were carried out for autoimmune thyroid disease while fasting blood glucose, serum insulin levels, and serum C-peptide levels were measured for type 1 diabetes mellitus. The diagnosis of rheumatoid arthritis was based on clinical, radiological, and immunological testing. Disorders with an autoimmune pathogenesis occur with increased frequency in patients already suffering from another autoimmune disease.[4] The term polyautoimmunity has been proposed for this association of autoimmune disorders. This term also encompasses the probable common origin of these disorders.[5] Multiple autoimmune syndrome showcases the kaleidoscope of autoimmunity with at least three autoimmune disorders being present in a single patient. The presence of one autoimmune disease should alert one to watch for presence or subsequent development of another one. To sum up, this study indicates that autoimmune hypothyroidism, type 1 diabetes mellitus, and rheumatoid arthritis are the most common systemic associations of the autoimmune dermatological disorders. Hence, a patient presenting with features of skin autoimmunity must be investigated for these conditions. Declaration of patient consent Patient’s consent not required as patient’s identity is not disclosed or compromised. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest

Angiolymphoid hyperplasia with eosinophilia: A report of a rare entity in an elderly male

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon benign proliferation of blood vessels of uncertain etiology. It primarily affects the head-and-neck region. Histologically, it is characterized by the prominent proliferation of plump endothelial cells, and accompanying eosinophilic and lymphocytic infiltration. Herein, we report the case of ALHE in a 65-year-old male

Unusual Sites of Cutaneous Tuberculosis: A Report of Two Cases

Cutaneous tuberculosis (CTB) is an uncommon small subset of extrapulmonary tuberculosis, comprising 1–1.5% of all extrapulmonary tuberculosis manifestations, which manifests only in 8.4–13.7% of all tuberculosis cases. Lupus vulgaris (LV) and tuberculosis verrucosa cutis (TBVC) are forms of reinfection tuberculosis and often occur in presensitized patients, by exogenous inoculation. We report two cases of cutaneous tuberculosis at unusual sites. A 35-year-old female having a forehead lesion for 2 years was diagnosed as having tuberculosis verrucosa cutis and another 16-year-old girl with lesion in left axilla for 10 years was proven to have lupus vulgaris. The delayed diagnosis was possibly due to lower clinical suspicion due to the presentation of CTB at unusual sites. This highlights the importance of keeping TB as an important differential as misdiagnosis or delayed diagnosis of this entity can lead to prolonged morbidity

Validation of using gene expression in mononuclear cells as a marker for hepatic cholesterol metabolism

<p>Abstract</p> <p>HMG-CoA reductase and the LDL receptor are ubiquitously expressed in major tissues. Since the liver plays a major role in regulating circulating LDL, it is usually of interest to measure the effects of drug or dietary interventions on these proteins in liver. In humans, peripheral blood mononuclear cells have been used as a surrogate for liver to assess regulation of these genes, although there is concern regarding the validity of this approach. The purpose of this study was to evaluate the relationship between liver and mononuclear cell expression of HMG-CoA reductase and the LDL receptor in guinea pigs, a well established model for human cholesterol and lipoprotein metabolism. We extracted RNA from liver and mononuclear cells of guinea pigs from a previous study where the effects of rapamycin, an immunosuppresant drug used for transplant patients, on lipid metabolism were evaluated. Guinea pigs were assigned to three different diets containing the same amount of fat (15 g/100 g) and cholesterol (0.08 g/100 g) for a period of 3 weeks. The only difference among diets was the concentration of rapamycin: 0, 0.0028 or 0.028 g/100 g. There were no differences in plasma LDL cholesterol (LDL-C) among groups. Values were 78.4 ± 14.3, 65.8 ± 17.2 and 68.4 ± 45.4 mg/dL (P > 0.05) for guinea pigs treated with 0, low or high doses of rapamycin, respectively. The mRNA abundance for the LDL receptor and HMG-CoA reductase was measured both in liver (n = 30) and mononuclear cells (n = 22) using reverse transcriptase PCR. In agreement with the finding of no changes in plasma LDL-C, there were also no differences for the expression of HMG-CoA reductase or the LDL receptor among groups. However, a positive correlation was found between liver and mononuclear cells for both HMG-CoA reductase (r = 0.613, P < 0.01) and the LDL receptor (r = 0.622, P < 0.01). These correlations suggest that monocytes can be used in humans as an index for liver to assess diet and drug effects on the expression of HMG-CoA reductase and the LDL receptor.</p

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

Abstract Background Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. Methods Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. Results Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P Conclusion These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.</p