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)

In order to obtain some information about the role of cAMP in the regulation of cell turnover of the intestinal mucosa it was interesting to investigate whether chronic pharmacologically induced changes in the cellular cAMP levels could cause alterations in mucosal growth in the case of a well defined animal modell, involving increased cell proliferation rate, such as chronic experimental diabetes mellitus of the rat. Since it has been suggested that cAMP levels on the one hand are low in cell division and increased cAMP levels on the other hand inhibit cell division, the aim of the study was to induce a suppression of the cell proliferation rate in the intestinal mucosa by chronic theophyllin application, a well known PDE-inhibitor. The following results could be obtained: Chronic theophyllin application induces a hyperplastic alteration of the small intestinal mucosa of the rat, which is similar to that observed in diabetes mellitus. In diabetic animals theophyllin causes a further increase in hyperplasia. The morphological alterations of the intestinal mucosa are more pronounced than the functional changes. In experimental diabetes mellitus the radioimmunologically determined cAMP level in the intestinal mucosa is rather low. Chronic theophyllin application alone or in combination with experimental diabetes mellitus was unable to increase the cAMP-level continuously. This could be a result of an adaptive change of the cAMP regulating enzyme system. Therefore theophyllin induced mucosal alterations are probably due to systemic effects of this drug.
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PMID:[The effect of theophyllin on small intestinal structure and function of the diabetic rat (author's transl)]. 22 97

Low-Michaelis constant cAMP phosphodiesterase (PDE; EC3.1.4.C) activity is inhibited in tissues of rats with type I ketosis-prone diabetes and is restored to normal by insulin treatment. To determine whether the oral hypoglycemic agent glyburide affected tissue cAMP PDE activity in non-insulin-dependent oral agent-treatable diabetes, cAMP PDE activity was measured in the liver and fat of animals rendered diabetic by low-dose streptozocin (STZ-DM) and treated for 3 wk with oral glyburide (360 micrograms/kg). The results were compared with PDE activity in the liver and fat of untreated STZ-DM and normal control rats. At the time of death, low-Km cAMP PDE activity [as maximum velocity (Vmax)] in STZ-DM rats was decreased to 66% of control values in the liver and to 65% in fat (P less than .001). PDE activity was restored toward normal by glyburide treatment: 91% in the liver (P less than .01) and 80% in fat (P less than .05). Calmodulin and calmodulin-like activity (PDE-activator activity) in the liver and fat was decreased in diabetes and restored toward normal after glyburide treatment (P less than .05). These data demonstrate that oral agents as well as insulin can restore the activity of cAMP PDE in the low-dose STZ-DM model, which is in some ways similar to type II diabetes.
Diabetes 1986 Nov
PMID:Cyclic AMP phosphodiesterase in diabetes. Effect of glyburide. 301 8

Platelets appear to be involved in both the maintenance of homeostasis and the regulation of proliferation of vascular smooth muscle cells. Anomalies of platelet function may be responsible in part for the pathogenesis of vascular disease in experimental and human diabetes. In a search for an appropriate animal model, we have studied platelet function and the properties of platelet cyclic NCL-PDE in rats with streptozocin-induced diabetes, spontaneous diabetes, and human insulin-dependent diabetes mellitus (IDDM). It appears that opposite abnormalities in both aggregation and phosphodiesterase activity exist in the two animal models. In human IDDM, similar abnormalities to those seen in the BB model were observed. Vascular smooth muscle cells in culture can be used as a model for studies of the effect of circulating growth factors in animals and humans. A growth inhibitory factor was found in plasma and serum from STZ and human IDDM but not BB. In humans we observed increased growth-promoting activity of diabetic platelets, but this phenomenon was absent in both animal models. It remains to be evaluated whether these differences may account for the fact that diabetic rats appear resistant to development of vascular complications. It also remains to be established which animal model is the best choice for studying growth abnormalities in diabetes.
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PMID:Platelets and vascular smooth muscle: abnormalities of phosphodiesterase, aggregation, and cell growth in experimental and human diabetes. 619 Nov 79

Experimental diabetes was produced in rats by administrations of streptozotocin (STZ) or alloxan (ALX). Some of the diabetic rats were started on daily insulin (NPH) therapy insufficient to control blood glucose. Rats were sacrificed one week or four weeks after confirmation of diabetes along with age-matched control rats. Analyses of cyclic nucleotide levels and of cyclic nucleotide phosphodiesterase activities in samples of kidney cortex revealed the following: cyclic AMP levels and activity of cyclic AMP phosphodiesterase were unaffected in all diabetic animals; cyclic GMP levels and cyclic GMP phosphodiesterase activity were unaffected in STZ-diabetic animals but were altered in ALX-diabetic animals. The data suggest that the altered cyclic GMP levels and degradation was due to a direct nephrotoxic action of ALX that is unrelated to the diabetic state.
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PMID:Cyclic nucleotides and cyclic nucleotide phosphodiesterases in kidneys from rats with experimental diabetes. 627 81

Interleukin (IL)-12, interferon (IFN)-gamma, and other inflammatory cytokines play an important role in the pathogenesis of autoimmune insulitis and diabetes in NOD mice, and inhibition of these cytokines is likely to be beneficial. In this study, we found that Pentoxifylline (PTX) and Rolipram (phosphodiesterase [PDE] inhibitors that induce increased intracellular cAMP) can block inflammatory cytokine production. Inhibition of IL-12 and IFN-gamma secretion was demonstrated in macrophages activated with lipopolysaccharide or T-cells stimulated through the CD3/T-cell receptor complex, respectively. Moreover, strong inhibition of IL-12 was demonstrated in vivo in superantigen-immunized mice. Rolipram was inhibitory at concentrations as low as 10(-8) to 10(-7) mol/l, and on a molar basis, it was 100-fold more effective than PTX. Tumor necrosis factor-alpha was also inhibited, but IL-4 was less sensitive to suppression. In NOD mice, both PTX and Rolipram reduced the severity of insulitis and prevented diabetes, with or without cyclophosphamide administration (which precipitates onset of disease). This protection of NOD mice was still apparent over 10 weeks after withdrawal of the drug treatment. It appears that blocking the activity of type IV PDE is sufficient to mediate the effects reported in this study, since Rolipram inhibits only this isoform, unlike PTX (a general inhibitor). PTX and Rolipram may be effective in the treatment of autoimmune diabetes or other conditions characterized by excessive production of inflammatory cytokines.
Diabetes 1998 Apr
PMID:The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice. 956 89

Type 3 cyclic nucleotide phosphodiesterase (PDE-3) isoforms exhibit a high affinity ("low K(m)") for cAMP and are specifically inhibited by cGMP and a number of pharmacological agents, which increase myocardial contractility, inhibit platelet aggregation, and increase smooth muscle relaxation. The PDE-3 family consists of at least two isozymes, PDE-3A (cardiac type) and PDE-3B (adipocyte type), with distinct tissue-specific distributions. PDE-3A mRNA is highly expressed in the cardiovascular system, whereas PDE-3B mRNA is primarily expressed in adipocytes and hepatocytes. Toward understanding potential roles of PDE-3 in diabetes mellitus, we have established a specific and sensitive RNase protection assay (RPA) for quantitating PDE-3A and PDE-3B mRNA in rat diabetic models. In fatty Zucker diabetic (ZDF) rats, PDE-3A mRNA, but not PDE-3B mRNA, was expressed in heart, whereas liver and white and brown fat tissues predominantly expressed PDE-3B mRNA. Unexpectedly, PDE-3B mRNA expression was approximately 2.5 times higher than PDE-3A mRNA in aorta from both ZDF and Sprague-Dawley (SD) rats. In contrast, expression levels of PDE-3A mRNA in heart were similar in both species. With this RPA, we were thus able to compare PDE-3A and -3B mRNA levels in different tissues as well as in different rat species.
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PMID:Cyclic nucleotide PDE-3. Quantitation of PDE-3A and -3B mRNAs in rat tissues by RNase protection assay. 963 Dec 38

The incidence of erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, increases with age and with risk factors for vascular disease, including smoking, diabetes and hypertension. Penile erection results from an arousal-induced synthesis of nitric oxide (NO) in nonadrenergic-noncholinergic nerves (NANC), endothelial cells and cavernosal smooth muscle cells (SMCs). Vasodilation and relaxation of cavernosal SMCs engorges the corpora cavernosa with blood at arterial pressure. The subcellular mechanism by which tumescence occurs involves NO-induced activation of soluble guanylate cyclase, increased cyclic guanosine monophosphate (cGMP) levels and activation of cGMP-dependent protein kinase (PKG). PKG phosphorylates numerous ion channels and pumps, each promoting a reduction in cytosolic calcium. In particular, PKG activates high-conductance Ca2+(-)sensitive K+ (BKCa) channels, which hyperpolarize the arterial and cavernosal SMC membranes, causing relaxation. This mechanism appears to be compromised with age and with vascular disease, leading to ED. Thus, increasing cavernosal nitric oxide synthase (NOS) expression, cGMP levels and/or BKCa channel expression is an effective therapy for experimental ED. Future therapies may involve augmenting K+ channel expression by gene transfer or increasing channel function through the use of Type 5 phosphodiesterase (Type 5 PDE) inhibitors or phosphatase inhibitors.
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PMID:Potassium channels and erectile dysfunction. 1237 24

In Spain, based on the IIEF, 19% of males between 25 and 70 years old present some degree of erectile dysfunction (ED). Therefore, around 2,000,000 Spanish men present this condition and could require medical attention for it. Here, we present an up-date of the most important aspects of erectile dysfunction (pathophysiology, diagnosis and treatment). We review, in detail, the oral treatments and future drugs that are presently in the premarketing experimental phase. Diagnostic and therapeutic management of the patient with erectile dysfunction should be individualized, taking into account the goals of each patient. It is highly recommendable to carry out a basic assessment (comprehensive clinical history, physical examination, recommended lab testing). If previously undiagnosed diseases are discovered (diabetes, arteriosclerosis, etc.) these should be treated and modifiable risk factors should be corrected. There are numerous therapeutic options for the treatment of erectile dysfunction. Replacement therapy with testosterone should only be used in males with ED and low levels of this hormone, under medical supervision. At present, first line treatment consists of the administration of oral drugs (sildenafil, apomorphine). There are two new PDE 5 inhibitors (tadalafil and vardenafil) that will be released on the market 2003, which will provide better selectivity. Moreover, several drugs for oral administration are in the initial phases of research that will facilitate erection via a direct penile action. When oral drugs are contraindicated, are not effective or when they are unpopular with the patient, the second line of treatment is intracavernous injection. Prostaglandin E1 is the initial drug of choice in patients using intracavernous autoinjection for the first time and has a high efficacy. Implantation of a penis prosthesis and penile revascularisation are appropriate for highly selected patients. Psychotherapy can be an option for men with ED of psychogenic origin, either as a monotherapy or combined with sildenafil or apomorphine.
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PMID:[Erectile dysfunction]. 1250 60

Diagnostic procedures for erectile dysfunction (ED) are still mandatory because ED can be the presenting symptom for a variety of diseases such as diabetes mellitus, coronary artery disease, atherosclerosis, hypertension and hyperlipidemia. Invasive testing for ED has decreased due to the high responder rate for oral PDE-5 inhibitors.
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PMID:[Diagnosis of erectile dysfunction--what is still needed today?]. 1456 79

Erectile dysfunction (ED) often is caused by endothelial dysfunction and may be a sign that a patient has vascular disease elsewhere in the body. Risk factors for coronary artery disease such as lipid abnormalities, smoking, diabetes, and hypertension also are risk factors for ED. Oral therapy for ED, such as sildenafil, inhibits phosphodiesterase-5 (PDE-5) and the breakdown of cyclic guanosine monophosphate. PDE-5 inhibitors have been shown to be safe and effective for the therapy for ED, but remain contraindicated in patients receiving organic nitrates. These agents are mild vasodilators and are being investigated for their treatment potential for patients with pulmonary hypertension, heart failure, and endothelial dysfunction.
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PMID:Erectile dysfunction in the cardiac patient. 1462


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