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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male sexual impotence is the symptom of an alteration of central and peripheral mechanism neuropsychoendocrine, vascular and neurological. Nowadays it affects 8-10% of sexually active population. In some diseases, like diabetes and uremia, it can reach very high percentages of incidence. At our Andrology Center 35% of referrals are represented by sexual complaints. In the last years the diagnostic accuracy has increased, narrowing the percentage of unknown causes. Vasculopathy represents the most relevant pathological condition associated with impotence: it can affect both arterial and venous vessels. The new medical technologies and procedures permit an increase of the life span but often affecting the quality of life. Therefore, the iatrogenic causes of impotence, both pharmacological and surgical, are growing. A modern diagnostic approach starts with an accurate clinical history and physical examination, followed by an NPT (nocturnal penile tumescence) test and/or ICI (intracavernosal injection) with a standard dose of PGE1 and Doppler flowmetry of penile arteries. An endocrine evaluation (LH, testosterone and prolactin) is also performed. Further investigation of a vascular dysfunction is represented by more invasive procedures, like arteriography, cavernosography and cavernosometry. A suspect of neurological disease is confirmed by sacral evoked potentials. According to the findings of these examinations, a correct therapeutical approach can be applied in 100% of cases. An endocrine treatment is adequate only when a clear reduction of T plasma level or hyperprolactinemia are present. The treatment of other central disorders causing psychoneuroendocrine impotence is promising, but still under investigation. The intracavernosal injection of vasoactive drugs, apart from having revolutionized the diagnostic approach to the impotent patient, represents a clear standpoint in medical management of impotence, particularly in vascular and neurological diseases. The great advancement in the technology of penile prostheses has allowed the development of valuable and reliable tools to be used in selected cases.
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PMID:[Recent diagnostic and therapeutic aspects in male sexual impotence]. 128 49

Lucigenin-enhanced chemiluminescence was examined as an index of neutrophil superoxide production in four groups of 20 subjects: controls with/without infection and type 1 diabetics with/without infection. At 5 mM glucose there was no significant difference in chemiluminescence output between neutrophils from the four groups (P greater than 0.01). Increasing the in vitro glucose concentration from 5 to 20 mM produced an 8.75% reduction in superoxide in the combined control groups, compared with a 21.45% reduction in the diabetic subjects (P less than 0.01). With the addition of an aldose reductase inhibitor (Statil, ICI) to neutrophils from diabetic subjects, the suppression caused by an increase in glucose concentration to 20 mM was reduced to 4.5%. This value was similar to the controls (P greater than 0.01). Neutrophil aldose reductase activity, measured in 28 diabetic subjects was 0.024 +/- 0.003 U/10(8) cells (mean +/- SE). There was a significant correlation between aldose reductase activity and superoxide suppression (P less than 0.01, r = 0.64). These results suggest that aldose reductase is responsible for reduced superoxide production in diabetic patients and the addition of an aldose reductase inhibitor to the diabetic neutrophil restores superoxide output to control values.
Diabetes Res Clin Pract 1992 Feb
PMID:The influence of aldose reductase on the oxidative burst in diabetic neutrophils. 131 60

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (1) (R1 = OMe) had previously been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 1 (R1 = OH). Amides have been examined to determine whether they have advantages over the ester. In particular, in the rat and dog the half-lives of amides of appropriate potency were no longer than those of the ester. The amide (S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2- methoxyethyl)phenoxyacetamide [S-27, ICI D7114] was selected as having properties consistent with a sustained-release formulation should that prove necessary. Unlike the ester it is resistant to hydrolysis in the gut lumen. Further testing of ICI D7114 has shown that in the rat, cat, and dog it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1- and beta 2-adrenergic receptors in other tissues. Slimming effects were observed in the dog. ICI D7114 may be a selective thermogenic agent in man and may be useful in the treatment of obesity and diabetes.
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PMID:Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 2. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetamides. 135 Mar 10

Although the enhanced activity of the polyol pathway has been detected in diabetic glomeruli, the intraglomerular localization of this pathway has not yet been well defined. In this study, we attempted to identify aldose reductase, a key enzyme of the polyol pathway, in cultured rat mesangial cells and to characterize the properties of this enzyme using enzymological and immunological methods. When the aldose reductase (DL-glyceraldehyde-reducing) activity was analyzed in mesangial cell extract, the Lineweaver-Burk plot showed concave downward curvature, and the Michaelis constant was 0.83 mM DL-glyceraldehyde, and this activity was noncompetitively inhibited by an aldose reductase inhibitor, ICI-128,436. The enzyme activity was enhanced by the addition of sulfate ion and partially suppressed by barbital. The enzyme cross-reacted with the antisera against rat lens and testis aldose reductases on Ouchterlony plate, and migrated to the region of molecular weight of about 36,500 Da on Western blotting. The presence of aldose reductase mRNA was also confirmed by Northern analysis using cDNA for rat aldose reductase, 10Q. From these results, it was concluded that the aldose reductase may exist in rat glomerular mesangial cells and may play a role in the development of diabetic glomerulopathy, though the coexistence of aldehyde reductase(s) may not be fully ruled out.
Diabetes 1992 Sep
PMID:Identification and characterization of aldose reductase in cultured rat mesangial cells. 149 67

Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr, range 25-65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat ICI 128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) greater than 35 V at the great toe or thermal difference thresholds (TTs) greater than 10 degrees C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain, numbness, or paresthesia between ponalrestat and placebo groups, and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 +/- 4.9 m/s at baseline to 33.4 +/- 4.0 m/s at 24 wk (NS) with placebo compared with 37.6 +/- 5.6 vs. 37.2 +/- 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 +/- 6.1 vs. 36.2 +/- 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.
Diabetes 1991 Jan
PMID:Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy. 190 8

This study examines whether an aldose reductase inhibitor (statil, ICI) can enhance neutrophil oxidative killing by diabetic neutrophils. We have examined a radiometric assay of phagocytosis and killing of Candida albicans by neutrophils from 20 controls and 20 subjects with insulin-dependent diabetes under various in vitro glucose concentrations. Glucose was present at 5, 10 and 20 mM in the presence and absence of statil (11 microM). Phagocytosis was unaffected by raised glucose levels in controls and in diabetic subjects. Killing by the diabetic cells was inhibited by increasing concentrations of glucose, killing was 18.9 +/- 2.0, 16.9 +/- 2.4 and 14.8 +/- 2.0% (mean +/- s.e.m.) at 5, 10 and 20 mM glucose, respectively (P less than 0.05). With the addition of statil under the same conditions killing improved to 19.3 +/- 2.0, 23.2 +/- 2.2 and 23.6 +/- 2.4 (P less than 0.01), these values were similar to the controls (P greater than 0.01). We conclude therefore that aldose reductase inhibition restores oxidative killing to normal.
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PMID:The role of aldose reductase inhibition in diabetic neutrophil phagocytosis and killing. 190 27

Many of the complications of diabetes seem to be due to aldose reductase (aldehyde reductase 2, ALR2) catalysing the increased conversion of glucose to sorbitol. Therapy with aldose reductase inhibitors (ARIs) could, therefore, decrease the development of diabetic complications. (2,6-Dimethylphenylsulphonyl)nitromethane (ICI 215918) is an example from a newly discovered class of ARIs, and we here describe its kinetic properties. Preparations of bovine lens ALR2 exhibit biphasic kinetics with respect to glucose and various inhibitors including ICI 215918. The inhibitor sensitive form (ALR2S) has a higher affinity for glucose than does the inhibitor insensitive form (ALR2I). Only ALR2S was characterized in detail because ALR2I activity is very low at physiological levels of glucose and is difficult to measure with accuracy. Aldehyde reductase (ALR1) is the most closely related enzyme to ALR2. Inhibition of ALR1 was, therefore, investigated in order to assess the specificity of ICI 215918. The values of Ki and Kies (dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for ICI 215918 with bovine kidney ALR1 and bovine lens ALR2S have been determined. When glucose is varied, the compound is an uncompetitive inhibitor of ALR2S (Kies = 0.10 microM and Ki is much greater than Kies), indicating that ICI 215918 associates with an allosteric site on the enzyme. These kinetic characteristics would cause a decrease in the concentration required to give 50% inhibition when glucose levels rise during hyperglycaemia. ICI 215918 is a mixed noncompetitive inhibitor of ALR1 (Ki = 10 microM and Kies = 1.8 microM) when glucuronate is varied. Thus, the compound has up to 100-fold specificity in favour of ALR2S relative to ALR1. Therapeutic interest has now centred upon at least three distinct structural types of ARIs: spirohydantoins, acetic acids and sulphonylnitromethanes. Using one representative of each type, we have demonstrated kinetic competition for inhibition of ALR2S. This observation strongly suggests that the different inhibitors use overlapping binding sites.
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PMID:(2,6-Dimethylphenylsulphonyl)nitromethane: a new structural type of aldose reductase inhibitor which follows biphasic kinetics and uses an allosteric binding site. 195 30

Many of the complications of diabetes appear to be closely linked to increased conversion of tissue glucose to sorbitol which is catalysed by aldose reductase (aldehyde reductase 2, ALR2). Inhibition of ALR2 could, therefore, lead to a reduction in the development of diabetic complications. Ponalrestat ["Statil" (a trademark, the property of Imperical Chemical Industries PLC), "Prodiax" (a trademark, the property of Merck, Sharp and Dohme), ICI 128436, MK538] inhibits ALR2 from a number of sources. Until now, the mechanism of this inhibition has not been fully elucidated. In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat. Treatment of humans with some ALR2 inhibitors leads to side-effects, some of which may result from interactions with other enzymes. Aldehyde reductase (ALR1) is probably the most closely related enzyme to ALR2. Inhibition of ALR1 from bovine kidney was, therefore, investigated in order to assess the specificity of ponalrestat. The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear fitting of kinetic data. These values indicate that ponalrestat does not compete with binding of glucose of NADPH to ALR2, nor with binding of glucuronate or NADPH to ALR1. Lack of competition and the structural dissimilarity of substrates and inhibitor make it unlikely that ponalrestat will utilize substrate binding sites on other enzymes, and so produce undesirable side-effects via such a mechanism. Ponalrestat is a potent inhibitor (Ki = Kies = 7.7 nM) of ALR2 and follows a pure noncompetitive mechanism with respect to glucose. Efficacy, therefore, will not be decreased by development of hyperglycaemia. The compound is a mixed noncompetitive inhibitor of ALR1 when glucuronate is varied. The values of Ki and Kies are 60 microM and 3 microM, respectively, so that inhibition tends towards uncompetitive. The selectivity of ponalrestat in favour of ALR2, therefore, lies in the range 390 to 7,800-fold, being higher at lower concentrations of glucuronate. The high selectivity of ponalrestat in favour of ALR2 rather than ALR1 suggests that the compound is unlikely to inhibit other enzymes which have less homology with ALR2.
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PMID:Ponalrestat: a potent and specific inhibitor of aldose reductase. 210 33

This study measured sugars and polyols, weight/unit length, and slow component-a of axonal transport (SCa) in dorsal root afferents of the sciatic nerves of control rats and rats with streptozocin (STZ)-induced diabetes of 4-wk duration. The effects of two treatments--aldose reductase inhibition [Statil ("Statil" is a trademark; the property of Imperial Chemical Industries PLC.) ICI 128436 at 25 mg/kg/day, p.o.] and myo-inositol supplementation (650 mg/kg/day, p.o.)--were studied in control and diabetic groups. Inclusion of untreated controls and diabetics gave a total of six groups for the study. The treatments were begun on the day after injection of STZ and were maintained throughout the protocol. The sciatic nerves of the diabetic (untreated) rats showed accumulation of sorbitol and fructose, depletion of myo-inositol, and an 8% increase in weight/unit length. All of these abnormalities were prevented by treatment with Statil. Treatment of diabetic rats with myo-inositol prevented its depletion in the sciatic nerve, but did not affect the accumulation of sorbitol and fructose nor the increase in weight/unit length. Neither treatment exerted any apparent effect on body weight, blood glucose, nerve weight, or nerve sugars and polyols in the control rats. The diabetic rats showed a retardation of the wave of transported-labeled protein (shown as increased leftward skewness of the wave) and a reduction in mean transport velocity (calculated as the mean velocity for all segments contributing to the transport wave: 0.96 +/- 0.09 mm/day in diabetics versus 1.15 +/- 0.07 mm/day in controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Apr
PMID:Slow component-a of axonal transport, nerve myo-inositol, and aldose reductase inhibition in streptozocin-diabetic rats. 242 Jun 64

This study measured the velocity of the fast anterograde axonal transport of [3H]-proline-labelled proteins in sciatic motoneurones of rats with streptozotocin diabetes of 12 weeks duration and in age matched controls. Four groups of diabetic animals were studied. One of these groups remained untreated whilst 2 diabetic groups received a long-acting insulin twice weekly to limit body wasting, but to permit regular hyperglycaemia. One insulin-treated group and one other diabetic group received an aldose reductase inhibitor, "Statil" (ICI 128436) by dietary admixture. Neither diabetes alone nor any of the treatment regimes produced any significant alteration of axonal transport velocity. Sciatic nerve temperature was measured concomitantly. A slight nerve hypothermia was seen in the untreated diabetic rats, but not in either insulin-treated group. It is concluded that 2 aspects of diabetes mellitus, namely persistent hyperglycaemia and polyol pathway activity in nervous tissue are without effect on the velocity of fast orthograde axonal transport of proteins.
Diabetes Res 1986 Nov
PMID:Fast anterograde axonal transport in wasted and non-wasted diabetic rats; effects of aldose reductase inhibition. 243 44


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