Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of epalrestat. The suggested ability of epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that epalrestat may be a useful drug in an area where there is a need for effective therapy.
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PMID:Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus. 831 78

Liver transplantation poses enormous and complex medical problems. Of the infective complications, bacterial infections are the commonest overall, but the single commonest is cytomegalovirus and the most deadly are the fungal infections. Therapeutic options and possibilities for prophylaxis are improving. Rejection, both acute and chronic, is the other major cause of mortality, and the balance between immunosuppression and infection is difficult. Cyclosporin treatment contributes to renal impairment, hypertension, and multitudinous potential neurological problems. The risk of long-term neoplasia is unclear. Relatively more minor is the potential for osteoporosis and metabolic complications, such as diabetes and hyperlipidaemia. Hepatitis B disease has a sizable risk of recurrence, but the most recent prophylaxis regimes have improved relapse rates. Having survived the physical problems following transplantation, most of which occur in the first 6 months, there are considerable psychosocial adjustments to be made particularly in the case of children where growth and development may have been delayed. Despite all these difficulties, liver transplantation is an expanding and optimistic area with enormous potential.
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PMID:Medical complications of liver transplantation. 833 63

Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease, diabetic renal disease, and in renal transplant recipients with or without cyclosporine therapy. In general, studies in both animal models and humans have demonstrated maintenance or reduction in renal vascular resistance, and preservation or enhancement of renal blood flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well suited for the treatment of patients with hypertensive disease even in the presence of renal impairment.
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PMID:Calcium channel blockers: do they offer renal protection? 834 86

Progressive renal failure is a significant complication of hypertension, a major cause of end-stage renal disease. In hypertensive patients, the markers of impaired renal function are abnormal levels of serum creatinine and microalbuminuria. Serum creatinine measurements, which can be adjusted for age and gender by using a simple formula, are used to estimate creatinine clearance and glomerular filtration rate. Microalbuminuria is an early sign of renal damage found in 20% to 30% of cases of essential hypertension and foretells the development of nephropathy and other complications. Current general guidelines for managing hypertension associated with renal impairment recommend controlling blood pressure, pharmacologically if necessary; adding a diuretic, if initial monotherapy is not effective; and reducing dietary sodium intake. Diuretic drugs remain the cornerstone of antihypertensive therapy for patients with renal failure, whereas beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors have varying effects and continue to be investigated intensively. In a study undertaken by the National Institute of Diabetes and Digestive and Kidney Diseases, the different classes of antihypertensive drugs are currently being evaluated for their ability to slow progressive renal failure.
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PMID:Renal issues in the management of hypertension. 839 8

The association between plasma coagulant activity and the presence of diabetic nephropathy was investigated in 31 patients with Type 1 diabetes, 12 with and 19 without nephropathy, and in 11 healthy subjects. Thrombin generation was assessed by computer assisted chromogenic method and expressed as time (in seconds) to 50% maximal thrombin activity (T50). Factor VIII:C levels related to thrombin activity, glycaemic control, and renal function. Median (IQ) FVIII:C concentration was increased in patients with nephropathy (1590 (1130-1900) IU l-1) compared to those without renal disease and with controls (960 (750-1090); 1020 (810-1100) IU l-1, p < 0.01, respectively). There were no significant differences in T50 values between the groups. FVIII:C correlated with age in all subjects and in the diabetic group (r = 0.33, p = 0.036; r = 0.39, p = 0.031) and inversely with T50 in all subjects and in controls (r = -0.35, p = 0.02; r = -0.62, p = 0.04). In all subjects and in patients, FVIII:C was related to urinary albumin excretion and creatinine clearance. FVIII:C and T50 were not related to HbA1c. The results show that FVIII:C levels are increased in Type 1 diabetes complicated by nephropathy and are related to degree of renal impairment but not levels of glycaemia. No associated enhancement of plasma procoagulant activity was detected.
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PMID:Thrombin generation and factor VIII:C levels in patients with type 1 diabetes complicated by nephropathy. 850 16

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.
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PMID:Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. 852 50

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CL*cr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CL*cr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.
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PMID:Kidney function and age are both predictors of pharmacokinetics of metformin. 862 83

Bardet-Biedl syndrome is a rare autosomal recessive disease characterized by dysphormic extremities, retinal dystrophy, obesity, hypogenitalism in males, and renal structural abnormalities. Because the clinical outcome of these patients is not well known, 21 families with Bardet-Biedl syndrome (BBS) were studied to determine the natural history of the disease. In a prospective cohort study, 38 patients with the syndrome and 58 unaffected siblings were identified. Patients were studied in 1987 and again in 1993. Age of onset of blindness, hypertension, diabetes, renal impairment, and death was determined. The prevalence of obesity, gonadal dysfunction, and renal structural abnormalities was assessed. All but 5 BBS patients (86%) were legally blind, 26% being blind by the age of 13 years and 50% by 18 years. Eighty-eight percent were above the 90th percentile for height and weight. Twenty-five (66%) patients had hypertension, 25% of BBS patients by age 26 years, and 50% by age 34 years, whereas in the unaffected group, 25% had hypertension by age 49 years (P < 0.0001). Twelve (32%) BBS patients developed diabetes mellitus, compared with none of the unaffected group. Only 2 patients were insulin dependent. Twenty-five percent of BBS patients had diabetes by the age of 35 years. In 12 women of reproductive age, 1 (8%) had primary gonadal failure. In 10 men, 4 had primary testicular failure. Nine (25%) patients developed renal impairment, with 25% of the BBS group affected by the age of 48 years. Imaging procedures of the kidney were performed in 25 patients with normal renal function. Whereas fetal lobulation and calyceal cysts/diverticula/clubbing were characteristic, occurring in 96% of patients, 20% (n = 5) had diffuse and 4% (n = 1) focal cortical loss. Eight patients with BBS died, 3 with end-stage renal failure and 3 with chronic renal failure. On life-table analysis, 25% of BBS patients had died by 44 years, whereas at that age 98% of unaffected siblings were still alive (P < 0.0001). Bardet-Biedl syndrome has an adverse prognosis, with early onset of blindness, obesity, hypertension, and diabetes mellitus. Renal impairment is frequent and an important cause of death. Survival is substantially reduced.
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PMID:The importance of renal impairment in the natural history of Bardet-Biedl syndrome. 865 Dec 40

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus (NIDDM). Considerable renewal of interest in this drug has been observed in recent years. Metformin can be determined in biological fluids by various methods, mainly using high performance liquid chromatography, which allows pharmacokinetic studies in healthy volunteers and diabetic patients. Metformin disposition is apparently unaffected by the presence of diabetes and only slightly affected by the use of different oral formulations. Metformin has an absolute oral bioavailability of 40 to 60%, and gastrointestinal absorption is apparently complete within 6 hours of ingestion. An inverse relationship was observed between the dose ingested and the relative absorption with therapeutic doses ranging from 0.5 to 1.5 g, suggesting the involvement of an active, saturable absorption process. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identified. The absence of liver metabolism clearly differentiates the pharmacokinetics of metformin from that of other biguanides, such as phenformin. Metformin undergoes renal excretion and has a mean plasma elimination half-life after oral administration of between 4.0 and 8.7 hours. This elimination is prolonged in patients with renal impairment and correlates with creatinine clearance. There are only scarce data on the relationship between plasma metformin concentrations and metabolic effects. Therapeutic levels may be 0.5 to 1.0 mg/L in the fasting state and 1 to 2 mg/L after a meal, but monitoring has little clinical value except when lactic acidosis is suspected or present. Indeed, when lactic acidosis occurs in metformin-treated patients, early determination of the metformin plasma concentration appears to be the best criterion for assessing the involvement of the drug in this acute condition. After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or haemodialysis, both of which favour rapid elimination of the drug. Although serious, lactic acidosis due to metformin is rare and may be minimised by strict adherence to prescribing guidelines and contraindications, particularly the presence of renal failure. Finally, only very few drug interactions have been described with metformin in healthy volunteers. Plasma levels may be reduced by guar gum and alpha-glucosidase inhibitors and increased by cimetidine, but no data are yet available in the diabetic population.
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PMID:Clinical pharmacokinetics of metformin. 874 35

A study of 270 newly presenting, previously untreated, type II diabetic patents revealed that 38 patients (14%) had already developed diabetic retinopathy (DR). Among this group, 26 patients had lesions of background diabetic retinopathy and 12 patients already had maculopathy or preproliferative changes. The aim of this study was to determine the risk factors influencing susceptibility to retinopathy, and to provide an accurate predictive value for diabetic retinopathy from a detailed multiple regression analysis that involved 27 demographic variables and the metabolic and hormonal responses during a meal tolerance test (MTT) at presentation. Compared to the nonretinopaths, the retinopaths had higher fasting plasma glucose levels (FPG) (mean +/- SD) (13.9 +/- 3.1 versus 11.6 +/- 3.2 mmol/L, p < 0.001), lower body-mass index values (BMI) (26.1 +/- 3.8 versus 29.3 +/- 5.0 kg/m2, p < 0.001) and higher plasma urea concentrations (6.0 +/- 1.9 versus 5.3 +/- 1.2 mmol/L, p 0.05). In contrast, gender and levels of blood pressure and other lipid levels did not influence the prevalence of diabetic retinopathy. A multiple regression formula for the prediction of diabetic retinopathy was derived and then used to categorize patients into high-risk and low-risk groups. The retinopaths also had higher HbA1c (p < 0.001), higher plasma glucose are under curve (0-2 h, p < 0.001), lower plasma insulin area under curve (0-22 h, p < 0.001), lower C-peptide area under curve (0-2 h, p < 0.01). They were also leaner (p < 0.001) and older (p < 0.05). However, these variables did not feature significantly in the multiple regression formula. The retinopaths were found to have higher risk probability values (25.1 +/- 11.5 versus 13.1 +/- 10.4%, p < 0.001). In the high risk group, 81.6% of retinopaths were identified. In the low-risk group, 63.8% of nonretinopaths were found. The incidence of diabetic retinopathy in type II diabetic patients at clinical diagnosis was found to be highly related to the degree of hyperglycemia, body-mass index, and to a lesser extent, renal impairment.
J Diabetes Complications
PMID:Dominant risk factors for retinopathy at clinical diagnosis in patients with type II diabetes mellitus. 883 21


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