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)

Tramadol is a centrally acting analgesic which is used mainly for the treatment of moderate or severe pain. It is a synthetic opioid in the aminocyclohexanol group that binds weakly to micro-opioid receptors. Since it has been suggested that both opioid and monoaminergic systems play a role in depressive disorders, tramadol has been studied in the forced swimming test (FST). The present study was designed to explore the antidepressant activity of tramadol in rat FST and its possible mechanisms of action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of tramadol was investigated. Treatment with tramadol, given (30 min earlier) by oral route (p.o.) at the doses of 10, 20 and 40 mg/kg, decreased immobility time in the FST. Pretreatment of rats with L-arginine (250 mg/kg, intraperitoneal, i.p., a nitric oxide precursor) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor, PDE5) significantly reversed the reduction in immobility time elicited by tramadol (20 mg/kg, p.o.) in the FST. Treatment of animals with a sub-effective dose of tramadol (5 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine (L-NNA, 3 mg/kg, i.p., an inhibitor of nitric oxide synthase) or with 7-nitroindazole (7-NI, 9 mg/kg i.p., a specific neuronal nitric oxide synthase inhibitor) in the FST. Pretreatment of animals with methylene blue (3.75 mg/kg i.p., an inhibitor of NO synthase and soluble guanylate cyclase - sGC) or (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 2 mg/kg, i.p., a specific inhibitor of sGC) significantly caused a synergistic effect with a sub-effective dose of tramadol (5 mg/kg, p.o.) in the FST. In the present study, different doses of tramadol and the combination with the L-arginine-NO-cGMP pathway modulators had no effect on the locomotor activity of rats in the open-field test. Thus, our findings suggest that the acute administration of tramadol produces antidepressant-like effect in the rat FST by a mechanism that involves the inhibition of L-arginine-NO-cGMP pathway.
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PMID:Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. 1877 34

A hemolysis-linked subphenotype of sickle cell disease (SCD), characterized by pulmonary hypertension, stroke, priapism and leg ulcers, is associated with decreased nitric oxide bioavailability and vasculopathy. Vasculopathy appears to have a multifactorial etiology, including mechanisms primarily that involve deficient nitric oxide (NO) signaling, but also involving altered function of NO synthase related to substrate availability and cooperating factors such as apolipoproteins. Improved understanding of the vascular pathophysiology of SCD has led to new vascular targets for translational research in SCD. This growing vascular therapeutics field in SCD is complementary to the ongoing efforts to reduce the morbidity of vaso-occlusive pain crisis. This presentation will review the current biology and translational clinical development of novel small molecules targeting sickle cell vasculopathy. Strategies targeting the hemeoxygenase-carbon monoxide pathway, the arginine-NO synthase-cGMP-phosphodiesterase 5 pathway, the nitrate-nitrite-NO pathway, and the apolipoprotein A-I pathways will be reviewed. In this context, current clinical trials of inhaled NO, CO, nitrite, sildenafil and apoA-I mimetics will be discussed.
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PMID:Novel small molecule therapeutics for sickle cell disease: nitric oxide, carbon monoxide, nitrite, and apolipoprotein A-I. 1907 79

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.
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PMID:Additive antinociception between intrathecal sildenafil and morphine in the rat formalin test. 1911 49

Spinal sildenafil (phosphodiesterase 5 inhibitor) and clonidine (alpha-2 adrenoceptor agonist) have shown antinociception. The author examined the properties of drug interaction after concurrent administration of intrathecal sildenafil-clonidine, and further clarified the reciprocity of sildenafil and clonidine. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. The formalin test was used as a nociceptive test, which was induced by subcutaneous injection of 50 microl of 5% formalin solution into the hindpaw. The pharmacological interaction was characterized using an isobolographic analysis. Intrathecal sildenafil and clonidine dose-dependently suppressed the flinching response observed during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of sildenafil-clonidine in both phases. Intrathecal yohimbine antagonized the antinociceptive action of intrathecal sildenafil during both phases in the formalin test. However, intrathecal ODQ failed to antagonize the antinociceptive action of intrathecal clonidine. These results suggest that sildenafil and clonidine, and the mixture of the two are effective against acute pain and facilitated pain state at the spinal level. Furthermore, synergism was noted after delivery of sildenafil-clonidine mixture. The antinociception of sildenafil can be modulated by spinal alpha-2 adrenoceptor, while the effect of clonidine is independent on the guanyly cyclase.
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PMID:Synergistic antinociception of intrathecal sildenafil with clonidine in the rat formalin test. 1925 41

Activation of the trigeminovascular pain signalling system, including cerebral arteries, meninges, trigeminal ganglion, and brain stem, is involved in migraine. Furthermore, stimulation of cyclic nucleotide (cAMP and cGMP) production as well as inhibition of phosphodiesterases (PDEs) induces headache and migraine. In order to investigate the possible role of PDE in the pain pathway of migraine, expression of the most recently discovered PDE subtypes (9A, 10A and 11A) in cerebral arteries, dura mater, and trigeminal ganglion and nucleus was examined. The presence of mRNA and protein in the middle cerebral artery, basilar artery, meninges, trigeminal ganglion, and spinal trigeminal nucleus of male Sprague-Dawley rats were investigated using real-time PCR, Western blot, and immunohistochemistry. The results were compared to two peripheral arteries: aorta and mesenteric artery, as well as neocortex and cerebellar cortex. Real-time PCR and Western blotting showed that PDE9A, PDE10A and PDE11A are expressed in components of the rat trigeminovascular pain signalling system including middle cerebral artery, basilar artery, meninges, trigeminal ganglion and spinal trigeminal nucleus. Aorta and mesenteric artery as well as cerebral neocortex and cerebellar cortex also showed expression of PDE9A, PDE10A and PDE11A. Immunohistochemistry revealed that PDE9A, PDE10A and PDE11A are localised in the cytosol of nerve cell bodies of the trigeminal ganglion. We here present, for the first time, the expression of PDE9A, PDE10A, and PDE11A in the trigeminovascular system. The functional implications are yet unknown, but their localisation indicates that they may have a role in the pain pathway of migraine as well as trigeminal neuralgia and trigeminal autonomic cephalalgias.
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PMID:PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system. 1944 8

Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women and there are few treatment options. FSD is more typical as women age and is a progressive and widespread condition. Common symptoms associated with FSD include diminished vaginal lubrication, pain and discomfort upon intercourse, decreased sense of arousal and difficulty in achieving orgasm. Only a small percentage of women seek medical attention. In comparison to the overwhelming research and treatment for erectile dysfunction in males, specifically with the development of phosphodiesterase type 5 inhibitors, significantly less has been explored regarding FSD and treatment is primarily limited to psychological therapy. Several cardiovascular diseases have been linked with FSD including atherosclerosis, peripheral arterial disease and hypertension, all of which are also pathological conditions associated with aging and erectile dysfunction in men. Using animal models, we have expanded our understanding of FSD, however a tremendous amount is still to be learned in order to properly treat women suffering from FSD. The aim of this review is to provide the most current knowledge on FSD, advances in basic science addressing this dysfunction, and explore developing therapeutic options.
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PMID:Female sexual dysfunction: therapeutic options and experimental challenges. 1953 61

(1) Intermittent claudication is usually a sign of generalised vascular atheroma, with prognosis mainly depending on the degree of coronary and cerebral involvement. Treatment is based on smoking cessation and regular exercise. Vasodilators have a purely symptomatic effect, modest at best, in increasing walking distance; (2) Cilostazol, a phosphodiesterase III inhibitor, is licensed in France (after 20 years on the market in Japan) as a treatment intended to increase walking distance in patients with intermittent claudication; (3) A double-blind placebo-controlled trial in 1439 patients showed no reduction in mortality after 3 years of treatment; (4) Cilostazol has been compared with pentoxifylline, another vasodilator with uncertain efficacy, in 3 clinical trials. No tangible difference in efficacy was observed; (5) A meta-analysis of 7 double-blind placebo-controlled trials in a total of 1579 patients showed that cilostazol increased the pain-free walking distance by about 30 metres and the maximum walking distance by about 50 metres; (6) There is some evidence that cilostazol causes a dose-dependent increase in mortality, although the data are not statistically significant. However, excess mortality has been documented with other phosphodiesterase III inhibitors, especially in patients with heart failure; (7) Cilostazol can provoke dose-dependent cardiac arrhythmias, and sometimes haemorrhage (due to its antiplatelet effect); (8) Cilostazol is extensively metabolised by cytochrome P450 isoenzymes CYP 3A4 and CYP 2C6, creating a high risk of pharmacokinetic interactions with other drugs and with food; (9) In practice, patients with intermittent claudication should not be given cilostazol; they should instead be prescribed an antiplatelet drug and encouraged to stop smoking and to exercise regularly.
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PMID:Cilostazol: new drug. Intermittent claudication: too little efficacy, too many risks. 1958 17

The effect caffeine elicits on endurance performance is well founded. However, comparatively less research has been conducted on the ergogenic potential of anaerobic performance. Some studies showing no effect of caffeine on performance used untrained subjects and designs often not conducive to observing an ergogenic effect. Recent studies incorporating trained subjects and paradigms specific to intermittent sports activity support the notion that caffeine is ergogenic to an extent with anaerobic exercise. Caffeine seems highly ergogenic for speed endurance exercise ranging in duration from 60 to 180 seconds. However, other traditional models examining power output (i.e. 30-second Wingate test) have shown minimal effect of caffeine on performance. Conversely, studies employing sport-specific methodologies (i.e. hockey, rugby, soccer) with shorter duration (i.e. 4-6 seconds) show caffeine to be ergogenic during high-intensity intermittent exercise. Recent studies show caffeine affects isometric maximal force and offers introductory evidence for enhanced muscle endurance for lower body musculature. However, isokinetic peak torque, one-repetition maximum and muscular endurance for upper body musculature are less clear. Since relatively few studies exist with resistance training, a definite conclusion cannot be reached on the extent caffeine affects performance. It was previously thought that caffeine mechanisms were associated with adrenaline (epinephrine)-induced enhanced free-fatty acid oxidation and consequent glycogen sparing, which is the leading hypothesis for the ergogenic effect. It would seem unlikely that the proposed theory would result in improved anaerobic performance, since exercise is dominated by oxygen-independent metabolic pathways. Other mechanisms for caffeine have been suggested, such as enhanced calcium mobilization and phosphodiesterase inhibition. However, a normal physiological dose of caffeine in vivo does not indicate this mechanism plays a large role. Additionally, enhanced Na+/K+ pump activity has been proposed to potentially enhance excitation contraction coupling with caffeine. A more favourable hypothesis seems to be that caffeine stimulates the CNS. Caffeine acts antagonistically on adenosine receptors, thereby inhibiting the negative effects adenosine induces on neurotransmission, arousal and pain perception. The hypoalgesic effects of caffeine have resulted in dampened pain perception and blunted perceived exertion during exercise. This could potentially have favourable effects on negating decreased firing rates of motor units and possibly produce a more sustainable and forceful muscle contraction. The exact mechanisms behind caffeine's action remain to be elucidated.
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PMID:Caffeine and anaerobic performance: ergogenic value and mechanisms of action. 1975 60

Female sexual dysfunction (FSD) incorporates various sexual disorders including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic and sexual pain disorders. Although many strategies have been formulated for the treatment of male sexual problems, FSD remains an area that warrants further research and trial studies to identify the most efficacious treatment options. Research has highlighted numerous pharmacological interventions that have been trialled and found to exhibit positive effects. These include hormonal therapies, prostaglandins, dopaminergic agonists, phosphodiesterase type-5 (PDE-5) inhibitors and melanocortin agonists.
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PMID:Review of drug treatment for female sexual dysfunction. 1981 9

Ibudilast is a relatively nonselective phosphodiesterase inhibitor which has been marketed for almost 20 years in Japan for treating asthma. More recently it has been found to have anti-inflammatory activity in both the peripheral immune system and in the CNS via glial cell attenuation. This CNS-directed anti-inflammatory activity is of potential use in the treatment of multiple sclerosis, neuropathic pain, and in the improved efficacy and safety of opioids by decreasing opioid tolerance, withdrawal and reinforcement. Its suitable pharmacokinetics and generally good tolerability make it a promising potential treatment for these conditions.
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PMID:Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. 1992 8


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