Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Findings coming from autopsies and serum of SARS patients suggest an important immune-inflammatory implication in the evolution to respiratory distress. Conditions such as HIV infection or treatment with immunosuppressors (in cancer or autoimmune diseases) are not among the bad prognosis factors for development of distress. To date, there have been no reported case fatalities in children, probably due to their more immature immune system. Our conclusions follow: (1) The milder form of SARS in children and the apparent protective factor that immunosupression represent rules out a significant viral cytopathic effect (they would be the most affected). (2) The evidence for immune implication in distress strongly supports immunomodulators for therapy: phosphodiesterase inhibitors (due to their down-modulating activity on proinflammatory cytokines); inhaled corticoids (aimed at producing a local immunomodulation); teophylline or nedocromil sodium (which prevents inflammatory cell recruitment into the airway wall). (3) An early immunomodulatory therapy, based on the levels of proinflammatory cytokines and clinical parameters to evaluate the respiratory function such as arterial oxygen saturation, could prevent the occurrence of distress. (4) Vaccine design should consider the immune origin of distress. (5) Physicians should be aware of mildly symptomatic patients (children, immuno-compromised hosts) to avoid transmission to immunocompetent adults.
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PMID:Severe acute respiratory syndrome, a pathological immune response to the new coronavirus--implications for understanding of pathogenesis, therapy, design of vaccines, and epidemiology. 1567 50

Several of the aspartic acid protease inhibitors used to treat HIV infection increase basal lipolysis in adipocytes, but the cellular mechanisms leading to this augmentation are not well understood. We therefore studied the effects of chronic exposure to the HIV protease inhibitor, ritonavir, on the lipolytic cascade in 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with ritonavir for 14 d (during and after differentiation) enhanced basal, isoproterenol (Iso)-stimulated, and cAMP analog-stimulated lipolysis. Enhancement of lipolysis was observed after Iso at concentrations between 0.1 and 10 mum. Despite a significant decrease in cyclic nucleotide phosphodiesterase (PDE)3B activity and protein levels, there were no changes in Iso-stimulated intracellular cAMP, protein kinase A (PKA) expression, or PKA activity. Ritonavir-augmented lipolysis was also observed under conditions that reversed the effect on PDE3B activity via preincubation with 1 mum (-)-N(6)-(2-phenylisopropyl)adenosine. In ritonavir-treated cells, protein expression of the lipid droplet-protective protein, perilipin, was significantly decreased, whereas there was no change in hormone-sensitive lipase. Activation of ERK1/2 by Iso did not play a role in the augmentation. We conclude that ritonavir decreases PDE3B and perilipin protein expression and affects both basal and catecholamine-stimulated lipolysis in 3T3-L1 adipocytes primarily through actions at sites downstream of PKA.
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PMID:Effects of the human immunodeficiency virus-protease inhibitor, ritonavir, on basal and catecholamine-stimulated lipolysis. 1574 Dec 49

Functional anatomy of the human penis involves various parameters: cavernous tissue, covering integument, prepuce foreskin, corpora cavernosa, corpus spongiosum, glans, facia, arterial supply, venous drainage, lymph drainage, musculature, and nerve supply. Several factors affect the expression/degree of erectile dysfunction (ED) endocrine profile, aging/senescence, demyelinating diseases, and surgery. Risk factors of ED are: age, vascular factors, metabolic diseases (diabetes mellitus), neurologic diseases, and HIV/AIDS. Several drugs are associated with ED: antiandrogenic, anticholinergic, antidepressants, antihypertensive, major tranquilizers, anxiolytics, and certain medicines/metabolites. The International Index of Erectile Function (IIEF) is a multidimensional scale for assessment of erectile dysfunction. The main structures mediating erection are the corpora cavernosa or "erectile bodies," which are fused distally for approximately three-quarters of their length. They separate proximally to fuse with each ischial tuberosity of the pelvis. On their ventral surface lies the corpus spongiosum, which surrounds the urethra. Coital dysfunction is classified into "erectile dysfunction" (psychosexual and endocrine/neuro-endocrine) and "ejaculatory dysfunction" (psychosexual, and genitourinary surgery). Vasculogenic impotence was evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Cavernosal, alpha-blockade is a technique used to evaluate and treat ED. Another diagnostic procedure for ED involves color floro and spectural Doppler imaging after papaverine-induced erection in impotent men. Color Doppler and duplex ultrasonography are used to evaluate Peyronie's disease. Sildenafil cilrate (Viagra) is an effective therapy of ED in men. Vardenavil is a highly selective phosphodiesterase 5 (PDE5) inhibitor which improved ED. Prostagland E1, vasoactive intestinal polypeptide (VIP), and phentolamine mesylate (administered by autoinjectors) have been applied to treat ED in patients resistant to other intracavernosal agents. Clinical trials were conducted on self-injection of vasoactive drugs, apomorphine SL, and tadalafil in diabetic men. Medical therapy of ED includes: medicated urethral system for erection (MUSE), intravenous pharmacotherapy, arterial revascularization, vacuum devices, two- and three-component inflatable penile prosthesis, semi-rigid penile prosthesis in situ, and inflatable one-piece penile prosthesis. Surgical therapy include procedures to correct Peyronie's penile deformity and penile deformity, procedures to avoid inevitable shortening accompanying Nesbit's disease, and for penile lengthening.
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PMID:Erectile dysfunction: anatomical parameters, etiology, diagnosis, and therapy. 1576 14

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.
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PMID:The efficacy and safety of PDE5 inhibitors. 1615 23

Pulmonary hypertension is a severe life-limitating disease often affecting younger patients. The connection between HIV infection and the development of pulmonary hypertension is well documented. The underlying pathobiology still remains unclear. Given that the prognosis of HIV infection has been improved by highly active antiretroviral therapy (HAART), severe pulmonary hypertension is becoming a life-limiting factor.HIV patients suffering from exercise-induced dyspnea should be tested for pulmonary hypertension, if other pulmonary or cardiac disorders (e. g., restrictive or obstructive ventilation disorders, pneumonia, coronary heart disease) can be excluded. The incidence of pulmonary hypertension is 1,000 times higher in HIV patients as compared to the general population. Estimated numbers of unreported cases are not included.A suspected diagnosis of pulmonary hypertension can be substantiated by noninvasive diagnostic methods (e. g., echocardiography), however, right heart catheterization remains the diagnostic gold standard. As new therapeutic options with prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors are now available, early and accurate diagnosis is essential.
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PMID:[HIV-associated pulmonary hypertension ]. 1617 Jun 78

Premature ejaculation is a common male sexual dysfunction. Treatment modalities as recommended by the British Association of Sexual Health and HIV include behavioural therapy, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and local anaesthetic creams. We audited the clinical cohort from our dedicated sexual dysfunction clinic to determine the success of prescribed treatment and co-existing prostatitis/male pelvic pain, erectile dysfunction, phosphodiesterase-5 (PDE5) inhibitor use and anxiety. The use of SSRIs was successful in the treatment of premature ejaculation with or without the use of local anaesthetic cream. Co-existing prostatitis/male pelvic pain, erectile dysfunction, PDE5 inhibitor use and anxiety were high.
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PMID:Pharmacological treatment for premature ejaculation. 1621 22

The discovery that inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cGMP, allowing erectile function to occur by relaxation of penile smooth muscle, represents a revolutionary approach or the treatment of erectile dysfunction (ED). Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) are clinically available at this time, and extensive drug design efforts are registered for finding agents with a better activity, enhanced selectivity and reduced side effects. Many classes of such compounds have been reported, belonging to diverse chemical entities. The drug design has been very much facilitated after the report of the X-ray crystal structure of the PDE5 catalytic domain in complex with the three clinically used derivatives. PDE5 inhibitor therapy, has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. The duration of action of sildenafil and vardenafil is of about 4 hours, whereas that of tadalafil is of about 36 hours, and the overall safety of the treatments is good. There is a risk of hypotension if nitrates are given concurrently with the PDE5 inhibitors. Common side-effects include headache, facial flushing, nasal congestion, dyspepsia and transient visual impairment. There are pharmacological interactions between these drugs and other medications metabolized by the cytochrome P450 (P3A4 isoform), such as the azole antifungals, erythromycin and the HIV protease inhibitors.
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PMID:Phosphodiesterase 5 inhibitors--drug design and differentiation based on selectivity, pharmacokinetic and efficacy profiles. 1701 39

Symptomatic HIV-associated pulmonary artery hypertension (PHT) is a thousand times more frequent than idiopathic PHT and has a clearly worse prognosis. Using echocardiographic criteria the prevalence of PHT in HIV-positive patients, including all degrees of clinical severity, is about 7.5 %, half of those affected being asymptomatic (NYHA class I). The only available data are from just one controlled trial of drug treatment of HIV-associated PHT (BREATH-4-Trial), in which the endothelin-receptor antagonist bosentan was found to bring significant improvement in clinical parameters (NYHA functional class, walking distance). Further trials are required to test other therapeutic options such as prostanoids and phosphodiesterase-5-inhibitors.
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PMID:[Pulmonary hypertension in HIV patients]. 1713 96

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RARalpha is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.
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PMID:Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. 1718 84

Erectile dysfunction (ED) and hypogonadism are increasingly recognized conditions, however, the prevalence and etiologies of these conditions among HIV-infected men remain unclear. We studied 300 HIV-infected men who completed standardized questionnaires regarding sexual function and hypogonadal symptoms. An early morning testosterone test was performed; patients with a low serum testosterone level (defined by <300 ng/dL), underwent additional blood tests to determine the etiology of the hypogonadism. The participants' mean age was 39 years (range, 19-72); 61% were Caucasian; 24%, African American; 9%, Hispanic; and 5% other. Participants had been HIV-positive for a mean of 9 years (range, 0.5-20) with a mean CD4 count of 522 cells/mm(3) (range, 1-1531). Sixty percent were receiving antiretroviral therapy. ED was reported by 61.4%; of those with ED, 32% did not have a rigid enough erection for penetration, and 46% were unable to sustain an erection for the completion of intercourse. In the multivariate analysis, increasing age (odds ratio [OR] 1.4 for a 5-year increment, p < 0.001) and depression (OR 2.64, p < 0.0001) were associated with ED. A higher current CD4 count was protective (OR 0.80 for each 100 cells/mm(3), p = 0.004). Only 25% of patients with ED had utilized a phosphodiesterase-5-inhibitor for treatment. Seventeen percent of the 300 men were hypogonadal; there was no correlation between hypogonadism and ED. Increasing age and a higher body mass index (BMI) were positively associated with hypogonadism, while smoking was negatively associated (OR 0.44, p = 0.02). All patients with low testosterone had secondary hypogonadism. There was no association between ED or hypogonadism with the current, past, or cumulative use of HIV medications.
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PMID:Erectile dysfunction and hypogonadism among men with HIV. 1726 54


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