Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke volume index (SV(index)) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SV(index), an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SV(index), an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.
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PMID:A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. 1115 13

Vascular and/or myocardial stiffness is a major problem in ageing, diabetes, hypertension and heart failure. The development of the stiffness is partly due to the formation of glucose-dependent cross-links in the collagen. ALT-711 cleaves these cross-links. In aged-rhesus monkeys, ALT-711 decreases vascular stiffness and this effect is reversible. ALT-711 also decreases myocardial stiffness in the monkeys but this effect is not reversible in 39 weeks. ALT-711 has potential in the treatment of the stiffness associated with diabetes, hypertension and heart failure.
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PMID:ALT-711 decreases cardiovascular stiffness and has potential in diabetes, hypertension and heart failure. 1142 1

Breynia officinalis has the Chinese proprietary name, Chi R Yun, which means dizziness or vertigo for 7 d. In daily practice, it has been used to treat venereal diseases, contusion, heart failure, growth retardation and conjunctivitis in combination with other traditional Chinese medicines. Two hospital-based cases of Breynia officinalis poisoning have been reported to the Poison Control Center. Case 1 was a 43-y-old female who consumed a mixture of 1500 g lower stem and root of Ji Mu Ju in boiled water in a suicide attempt. Her AST reached 264 and ALT reached 2443. Case 2 was a 51-y-old female who consumed 20 pieces of lower stem and root of Ji Mu Ju stewed with meat and 100 ml of wine to treat chronic contact dermatitis. Her AST reached 3815 and ALT reached 6625. In both cases Breynia officinalis was identified as the cause of poisoning. Poisoning in humans involves the neurologic, gastrointestinal, hepatic, urinary and respiratory systems. Hepatotoxic effects have been reported for some Chinese herbal medicines, but not Breynia officinalis: Breynia officinalis poisoning causes hepatocellular liver injury rather than cholestatic liver injury.
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PMID:Hepatotoxicity caused by Breynia officinalis. 1193 10

Hepatic hemangioendothelioma (HE) is a tumor that presents in infancy and toddler. It manifests hepatomegaly, abdominal mass, jaundice, abdominal distention, or high output cardiac failure. We reviewed patients with HE in our hospital in the past 15 years (from July 1986 to June 2001). The diagnosis was made by the histology specimen or various imaging studies. There were thirteen patients (9 males, 4 females) enrolled in our study. Their ages ranged from neonate to 2 years old. The common clinical manifestations included abdominal distention (53%), congestive heart failure (38.5%), abdominal mass (30.8%), jaundice (30.8%), and skin hemangioma (23.1%). Nine patients had serum alanine aminotransferase examination and were abnormal in 2. Anemia was noted in 7 of 13 (53.8%) patients, thrombocytopenia and hyperconsumptive coagulopathy were found in 4 and 5 patients, respectively. Serum alpha-fetoprotein was elevated in 4 of 7 patients. Abdominal ultrasonography (n = 13) showed heterogeneous and hypoechoic lesions in the liver. Computed tomography (n = 11) revealed central hypointensity with peripheral enhancement after contrast of the liver masses. Magnetic resonance imaging studies of the hepatic masses (n = 3) showed decreased signal intensity on T1 images and high signal intensity on T2. Most patients were treated with steroid. Other management included interferon, chemotherapy, embolization and/or surgery. Four patients were managed conservatively. Among the other nine patients, four patients died of sepsis, hepatic failure, disseminated intravascular coagulopathy or tumor rupture with hemorrhagic shock. HE appears to be a histologically benign tumor but may have a poor outcome because of complications. For its management, steroid is a first-line medication. Other methods of treatment were interferon, hepatic artery embolization, chemotherapy and surgery. Long term follow up is needed for the evaluation of treatment response.
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PMID:Hepatic hemangioendothelioma in children: analysis of thirteen cases. 1280 Mar 77

Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.
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PMID:Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. 1560 32

In eligible patients, cardiac transplantation has become the definitive treatment for end-stage heart failure. The initial posttransplantation course is marked by many potential difficulties, including renal insufficiency, hemodynamic instability, and perioperative bleeding. It is important to prevent early rejection; calcineurin inhibitors, such as tacrolimus or cyclosporine, are integral parts of such management. However, these drugs are associated with renal toxicity in some patients. Previous work suggests that limiting the increase in tacrolimus levels is associated with less renal insufficiency. The hypothesis of the current study was that a combination of clinical or laboratory variables could identify patients at risk for rapid changes in tacrolimus target levels. No single variable was strongly associated with high resultant trough levels following a standard 1-mg oral "test dose" of tacrolimus. However, the combination of 2 indices of liver metabolism (alanine aminotransferase and total bilirubin) along with serum creatinine did identify patients who tended toward elevated levels of tacrolimus (> or =4.5 ng/dL). Other variables, such as demographics, and even functional variables, such as right ventricular function by echocardiography, did not enhance the predictive value of this simple scoring system.
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PMID:Can initial tacrolimus trough levels be predicted from clinical variables? 1562 Nov 57

Chronic cardiac hepatopathy is a common entity in patients evaluated for heart transplantation (HTX). Hepatic injury is caused by severe heart failure resulting from prolonged recurrent congestion and/or impaired arterial perfusion. No data are available on the reversibility of cardiac hepatopathy in patients undergoing HTX. Data of 56 consecutive adult patients undergoing HTX during 2000-02 at the University Hospital of Innsbruck were analysed retrospectively. The following parameters were evaluated at the time of listing and 3, 6 and 12 months after HTX. Plasma levels of gamma-glutamyl transferase (gamma-GT), alkaline phosphatase (AP), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and total plasma protein. When listed for HTX, only 12% of all patients analysed had physiological values throughout the seven laboratory parameters assessed. Elevated levels of gamma-GT, AP, bilirubin, AST, ALT, LDH and total plasma protein were detected in 66.6%, 29%, 50%, 16.7%, 10%, 40% and 18% of all patients respectively. Accordingly, median plasma levels of gamma-GT, bilirubin and LDH were elevated, whereas the mean plasma level of AP was at the upper normal range. In contrast, median plasma level of AST and mean plasma levels of ALT and total plasma protein were within the normal range: gamma-GT (median, 109.0; range, 634.0 U/l; n = 36), AP (mean, 120.2 +/- 78.9 U/l; n = 29), bilirubin (median, 1.3; range, 16.1 mg/dl; n = 32), LDH (median, 226.0; range, 2355.0 U/l; n = 33), AST (median, 29.0; range, 145.0 U/l; n = 36), ALT (mean, 28.3 +/- 20.8 U/l; n = 36) and total plasma protein (mean, 7.2 +/- 1.1 g/dl; n = 25). Within 3 months after HTX, elevated parameters except LDH significantly ameliorated: gamma-GT (median, 59.0; range, 1160.0 U/l; P = 0.011), AP (92.2 +/- 75.2 U/l; P = 0.016), bilirubin (median, 0.9; range, 8.1 mg/dl; P = 0.004), LDH slightly increased (median, 281.0; range, 543.0 U/l; P = 0.039), but there was a delayed improvement of this parameter after 6 and 12 months post-HTX. End-stage heart failure is characterized by a cholestatic liver enzyme profile with elevated plasma levels of gamma-GT and bilirubin. These parameters significantly improve within 3 months after HTX. Therefore, chronic cardiac hepatopathy seems to be a benign, potentially reversible disease.
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PMID:Cardiac hepatopathy before and after heart transplantation. 1591 Feb 96

Studies on the lipid peroxidation and antioxidant changes and their significance during myocardial injury have provided a new insight into the pathogenesis of heart disease. The heart failure subsequent to myocardial infarction may be associated with an antioxidant deficit as well as increased myocardial oxidative stress. The present study was designed to evaluate the effect of the combination of ferulic acid and ascorbic acid on antioxidant defense system and lipid peroxidation against isoproterenol (ISO)-induced myocardial infarction in rats. Induction of rats with isoproterenol (150 mg/kg body weight daily, i.p.) for 2 days resulted in a marked elevation in lipid peroxidation, serum marker enzymes (LDH, CPK, GOT, and GPT), and a significant decrease in activities of endogenous antioxidants (SOD, GPx, GST, CAT, and GSH). Pre-co-treatment with the combination of ferulic acid (20 mg/kg body weight/day) and ascorbic acid (80 mg/kg body weight/day) orally for 6 days, significantly attenuated these changes when compared to the individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. Thus, ferulic acid and ascorbic acid significantly counteracted the pronounced oxidative stress effect of ISO by the inhibition of lipid peroxidation, restoration of antioxidant status, and myocardial marker enzymes levels. In conclusion, these findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on lipid peroxidation and antioxidant defense system during ISO-induced myocardial infarction and associated oxidative stress in rats.
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PMID:Synergistic interactions of ferulic acid with ascorbic acid: its cardioprotective role during isoproterenol induced myocardial infarction in rats. 1644 96

Recent studies have raised questions about the long-term health risks for individuals with mutations in the HFE gene, although previous studies may have been plagued by selection bias or lack of population-based comparison groups. We examined cardiovascular disease risk factors and iron and liver biomarkers, as well as morbidity and mortality associated with the C282Y and H63D variants of HFE in the Atherosclerosis Risk in Communities (ARIC) study, which is a population-based cohort of nearly 16,000 U.S. white and black men and women who were 45-64 years old at baseline. Subjects were followed for an average of 15 years for death, incident coronary heart disease, stroke, and heart failure, and an average of 8 years for incident diabetes. The prevalence of C282Y homozygosity was 0.42% (45/10,800) in whites, which is similar to other North American population-based studies. C282Y homozygotes had significantly lower mean low-density lipoprotein (LDL) cholesterol and fibrinogen as well as higher mean levels of iron (ferritin, transferrin saturation) and liver biomarkers (alanine aminotransferase, Hepascore) compared with HFE wild-type subjects. Rates of all-cause mortality, cardiovascular disease, and diabetes were similar across HFE genotypes. These prospective, population-based data indicate higher serum iron indices and possible mild liver dysfunction or disease in some C282Y homozygotes, but they provide little evidence that HFE C282Y or H63D mutations are related to all-cause mortality, cardiovascular disease, or diabetes. Reduced LDL in C282Y homozygotes may be because of effects of excess iron on cholesterol metabolism and lipoprotein formation in the liver.
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PMID:HFE C282Y homozygotes have reduced low-density lipoprotein cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study. 1859 31

Tailoring graft size to small paediatric recipients is a challenge. We have developed a reduced left lateral segment as an alternative to monosegment transplantation for small size recipients. Since November 2000, 89 children have been transplanted with 100 deceased donor liver grafts in our unit. Our median patient and graft survival is 89% and 88% respectively. Four of these cases were performed using a new technique of creating a small donor graft by reducing the left lateral segment. The median weight of the reduced liver graft was 264 g (range: 165-390 g). The median blood transfusion requirement was 101 mL/kg body weight (range 69-167 mL/kg). The median values of peak ALT were 1473 IU/L, INR 2.2 and bilirubin 293 micromol/L in the first two wk following surgery. One neonatal recipient died five days after transplantation from a massive intracranial haemorrhage despite satisfactory graft function. Another recipient with excellent graft function died 10 months later from primary pulmonary hypertension and secondary cardiac failure. Hepatic artery thrombosis occurred in one patient with successful revascularization but he was retransplanted three months later for chronic rejection. No biliary or venous outflow complications occurred in this group. This technique of reduced left lateral segment liver transplantation is an alternative to the monosegment graft and allows small recipients to be successfully transplanted with few technical complications related to graft preparation.
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PMID:The reduced left lateral segment in pediatric liver transplantation: an alternative to the monosegment graft. 1878 70


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