Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with diabetic angiopathy until today, no histological nor histochemical evidence has been found to define a specific type of diabetic arteriopathy. Consequently, diabetic arteriosclerosis is considered as a more serious form of atherosclerosis characterized by its premature onset. Hyperglycemia is assumed to be the crucial pathophysiological cause of the development of macro- and microangiopathy in diabetes mellitus. Apparently, hyperglycemia has a direct toxic influence on the arterial wall by increased accumulation of irreversible glycosylation end products, and secondly, it provokes endothelial dysfunction. The frequently occurring ulcerations of the diabetic foot are primarily caused by neuropathy; however, peripheral vascular disease (PVD) is often associated. The risk of suffering from PVD in diabetic patients is approximately four-fold. Usually, the distal segments of the lower leg arteries are concerned, where reconstructive intervention is complicated or even impossible. Diabetes is considered as an independent risk factor for cardio- and cerebrovascular diseases with almost twice as high rates for recurrent myocardial infarction, and a 3.7 fold higher relative risk for stroke in diabetic, compared to non-diabetic patients. This review looks at the correlations between hyperglycemia and arteriosclerosis, but also the treatment options in diabetic patients. Until now, there is no evidence for an association between an optimal control of blood glucose levels and a decrease in the risk of coronary heart disease, stroke, or PVD. In contrast, an attenuation of microvascular lesions is achieved by stringent control of blood glucose levels. Thus, although the development of macroangiopathy may not be significantly influenced, the conduction of a stringent control regimen of plasmatic glucose levels is advisable.
 ...
PMID:[Macroangiopathy in diabetes mellitus]. 1158 46

The ubiquitously found beta-amino acid taurine has several physiological functions, e.g. in bile acid formation, as an osmolyte by cell volume regulation, in the heart, in the retina, in the formation of N-chlorotaurine by reaction with hypochlorous acid in leucocytes, and possibly for intracellular scavenging of carbonyl groups. Some animals, such as the cat and the C57BL/6 mouse, have disturbances in taurine homeostasis. The C57BL/6 mouse strain is widely used in diabetic and atherosclerotic animal models. In diabetes, the high extracellular levels of glucose disturb the cellular osmoregulation and sorbitol is formed intracellularly due to the intracellular polyol pathway, which is suspected to be one of the key processes in the development of diabetic late complications and associated cellular dysfunctions. Intracellular accumulation of sorbitol is most likely to cause depletion of other intracellular compounds including osmolytes such as myo-inositol and taurine. When considering the clinical complications in diabetes, several links can be established between altered taurine metabolism and the development of cellular dysfunctions in diabetes which cause the clinical complications observed in diabetes, e.g. retinopathy, neuropathy, nephropathy, cardiomyopathy, platelet aggregation, endothelial dysfunction and atherosclerosis. Possible therapeutic perspectives could be a supplementation with taurine and other osmolytes and low-molecular compounds, perhaps in a combinational therapy with aldose reductase inhibitors.
 ...
PMID:The role of taurine in diabetes and the development of diabetic complications. 1174 39

Chronic hyperglycaemia contributes to tissue and organ damage retina, kidney and nerves by promoting the formation of advanced glycosylation end products (AGE). The AGE accumulation both in intra and extracellular proteins plays an essential role in the pathogenesis of diabetic complications by production of cross links on extracellular matrix proteins, by interaction with specific cellular receptors and by modification of nucleic acids. Human studies are being conducted to examine the pharmacokinetics efficacy and toxicity of pharmacologic agents that inhibit the AGE formation--aminoguanidine and aminoguandine-like--in order to define its role in the prevention and treatment of retinopathy, nephrology, neuropathy and diabetic atherosclerosis.
 ...
PMID:[Advanced glycosylation in diabetes mellitus. Occurrence of late complications]. 1176 82

Diabetes mellitus has reached epidemic proportions worldwide as we enter the new millennium. The World Health Organization (WHO) has commented there is 'an apparent epidemic of diabetes which is strongly related to lifestyle and economic change'. Over the next decade the projected number will exceed 200 million, possibly reaching 250 million persons. Most will have type 2 diabetes and all are at risk of the development of complications. Better education, improved nutrition, more exercise, early diagnosis and prompt treatment are imperative. Diabetes is a serious disease, subject to the development of many complications affecting large vessels (heart, cerebral and peripheral), small vessels (kidney and retina), nerves and other organs. In type 2 diabetes these complications may precede diagnosis of the disease by many years. The process continues inexorably, with premature mortality and morbidity mainly from the development of vascular disease. Data from the WHO confirm the principal role of non-communicable disease on mortality in developed countries, while mortality in developing countries is rising rapidly, now often exceeding communicable disease. The non-communicable diseases are divided into cancer and degenerative diseases. In the developed world, degenerative diseases are grouped to include ischaemic heart disease, stroke, renal failure, hypertension and other macro- and microvascular diseases. The major complications of diabetes encountered most frequently and with the greatest impact are: 1. Neuropathy, both peripheral and autonomic, with principal manifestations in the lower limbs 2. Microvascular disease, mainly affecting the retina and kidney, resulting in blindness and renal failure 3. Macrovascular disease, presenting with atherosclerosis in the coronary arteries causing ischaemic heart disease, cerebrovascular disease causing stroke and peripheral vascular disease contributing to diabetic gangrene.
 ...
PMID:The economic burden of insulin resistance. 1196 27

BACKGROUND: Macrovascular disease in diabetes mellitus is a multifactorial process resulting in part from accelerated atherosclerosis and increased thrombosis. The resultant cardiovascular mortality is up to five times that of an age-matched non-diabetic population. Recently, cell adhesion molecules (CAMs) have been demonstrated in atherosclerotic plaques and implicated in the initiation and development of atherosclerosis. METHODS: To assess circulating CAMs as potential predictors of the development of macrovascular disease in diabetes mellitus, we carried out a 5-year prospective study in 28 diabetic patients without manifest macrovascular disease at entry. Circulating CAMs [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin and E-selectin] were measured at baseline and at follow-up. RESULTS: Except for neuropathy, no patient had other microvascular diabetic complications (retinopathy or nephropathy) or clinically manifest macrovascular disease. Eleven patients developed macrovascular disease at follow-up (seven coronary heart disease, two cerebrovascular disease, two peripheral vascular disease). At baseline, systolic blood pressure and serum creatinine were higher (but within normal range) in patients developing macrovascular disease. Baseline ICAM-1 was significantly higher in the patients who developed macrovascular disease than in those who did not, and it remained so even after adjusting for age, systolic blood pressure, creatinine and glycaemic control (P=0.0007). However, baseline VCAM-1, P-selectin and E-selectin were not found to be associated with macrovascular disease. The risk of developing macrovascular disease was associated with increasing baseline concentrations of ICAM-1 [odds ratios 1.04 (95% CI 1.01-1.07); P=0.01]. No correlation was seen between ICAM-1, HbA(1) and cholesterol. CONCLUSION: This study suggests that ICAM-1 may predict development of macrovascular disease in diabetes mellitus.
 ...
PMID:Circulating cellular adhesion molecules ICAM-1, VCAM-1, P- and E-selectin in the prediction of cardiovascular disease in diabetes mellitus. 1202 Jun 26

Two principal theories for the pathogenesis of glaucomatous optic neuropathy (GON) have been described--a mechanical and a vascular theory. Both have been defended by various research groups over the past 150 years. According to the mechanical theory, increased intraocular pressure (IOP) causes stretching of the laminar beams and damage to retinal ganglion cell axons. The vascular theory of glaucoma considers GON as a consequence of insufficient blood supply due to either increased IOP or other risk factors reducing ocular blood flow (OBF). A number of conditions such as congenital glaucoma, angle-closure glaucoma or secondary glaucomas clearly show that increased IOP is sufficient to lead to GON. However, a number of observations such as the existence of normal-tension glaucoma cannot be satisfactorily explained by a pressure theory alone. Indeed, the vast majority of published studies dealing with blood flow report a reduced ocular perfusion in glaucoma patients compared with normal subjects. The fact that the reduction of OBF often precedes the damage and blood flow can also be reduced in other parts of the body of glaucoma patients, indicate that the hemodynamic alterations may at least partially be primary. The major cause of this reduction is not atherosclerosis, but rather a vascular dysregulation, leading to both low perfusion pressure and insufficient autoregulation. This in turn may lead to unstable ocular perfusion and thereby to ischemia and reperfusion damage. This review discusses the potential role of OBF in glaucoma and how a disturbance of OBF could increase the optic nerve's sensitivity to IOP.
 ...
PMID:The impact of ocular blood flow in glaucoma. 1215 Sep 88

One of the keys to achieving glycemic control in animals with diabetes mellitus is the appropriate selection and interpretation of analytic monitoring tests. Diabetic animals are subject to many of the same problems described in human diabetics. Diabetics are more susceptible to infection, and wound healing is often impaired. Decreased insulin promotes lipolysis and moderate hyperlipidemia, which can lead to falsely lowered fructosamine levels, impaired renal circulation, and atherosclerosis. Hyperglycemic, hypoinsulinemic animals continue to lose weight despite an increased appetite and an increased intake because they are not able to use glucose. Many unregulated diabetic animals will present with vomiting and diarrhea that can exacerbate electrolyte abnormalities seen with the osmotic diuresis present in an uncontrolled state. Canine diabetics are prone to cataract formation secondary to sorbitol accumulation in the lens. Cats, on the other hand, can present with diabetic distal neuropathy, which may be reversible with appropriate treatment. With all of these potential complications, it is important to monitor these animals regularly; this is the only way that glycemic control can be properly maintained over time. This article reviews the monitoring parameters available to the modern practitioner and outlines the benefits of each test, as well as caveats, in their interpretation.
 ...
PMID:Monitoring techniques for diabetes mellitus in the dog and the cat. 1221 18

Many types of adverse ocular reactions to oral contraceptives (OCs) have been reported, but the role of OCs has not always been confirmed. Neuroophthalmologic complications may result from cerebral vascular accidents responsible for visual field deficits, accidents affecting the cerebral trunk, ischemic accidents resulting from obstruction of the internal carotid artery. The role of OCs in cerebral vascular accidents is controversial. Most reports concern older formulations containing high doses of estrogen. In the current state of knowledge it is generally agreed that OCs may induce an increased thromboembolic risk in women over 35, those who smoke, and those with risk factors for atherosclerosis. It is agreed that occurrence of a transient ischemic cerebral vascular accident requires immediate termination of OC use. OCs have been implicated occasionally in retrobulbar optic neuropathy, but the condition in young women appears more likely to be the 1st manifestation of a sclerosis. OCs appear to increase the incidence of benign intracranial hypertension, manifested by headaches, papillary edema endangering the optic nerve, and the absence of visible anomalies on the scanner. It is also recognized that migraines are induced or aggravated by OCs. Migraines are known to be linked to hormonal factors. Ophthalmic migraines belong to the subgroup of vascular migraines. Retinal vascular diseases such as occlusion of the central retinal artery, intraocular hemorrhage, and more rarely macular edema have been reported retrospectively but their documentation has been insufficient to permit determination of causality. The prognosis for retinal emboli is mediocre. Problems in color vision initially affecting blue have been described in OC users and may be a function of the duration of use. The condition is especially prevalent in diabetes. Pregnancy appears to accelerate the loss of visual field in some women with pigmentary retinopathy. For that reason some ophthalmologists recommend that they avoid OCs. Other ocular problems have been observed in OC users but no link has been proven and the only evidence is anecdotal. It has been suggested that OCs decrease tolerance for contact lenses, but prospective studies have not demonstrated a link. All contraindications to OC use should be scrupulously respected. Use should be terminated immediately in case of transient ischemic accident, appearance of sudden severe headaches, vertigo, or vision problems such as papillary edema or retinal hemorrhage.
 ...
PMID:[Adverse ocular reactions to oral contraceptive use]. 1231 84

Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.
 ...
PMID:Squalene epoxidase as hypocholesterolemic drug target revisited. 1246 39

Despite of dramatic improvement in diagnostic procedures and treatment of diabetic patients, cardio-vascular complications are still the most frequent causes of death in these patients. Diabetes influences myocardial and coronary vessels function by coexisting macroangiopathy, microangiopathy, metabolic disturbances and autonomic nervous system neuropathy. All these factors result in diastolic and systolic dysfunction of the heart. Cardiomyopathy, congestive heart failure and serious arrhythmias are the end stage of diabetic complications. Macroangiopathy demonstrates accelerated atherosclerosis (involving coronary arteries), which consequences can be observed in 1 type diabetes patients at around the age of 30. Causes of increased risk of macroangiopathy in type 1 diabetic patients are not clear. There are not many clinical, prospective trials which can allow for etiology determination of the increased incidence of atherosclerosis and mortality due to coronary artery disease in this population. Adding to traditional risk factors of atherosclerosis like genetic factors, hypertension, dyslipidemia, obesity, smoking and improper diet, other important risk factors are observed in diabetic patients. Only few clinical trials suggest that hyperglycemia, glycation, glycoxidation of proteins, lipoproteins, changes in their composition, microalbuminuria, coagulation, fibrinolytic disturbances are additional risk factors of endothelium dysfunction and atherosclerosis. Prevention and treatment of accelerated coronary artery disease and it's consequences are more complicated in the diabetic population than in others. Some of the clinical trials suggest that even improved glycemic control does not eliminate the elevated risk of coronary artery disease in type 1 diabetic patients.
 ...
PMID:[Myocardial and coronary vessel dysfunction in diabetes I patients]. 1251 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>