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)

Our study was undertaken in order to evaluate hemodynamic effects of intravenous administration of Reproterol in patients with chronic obstructive lung disease (COLD). Reproterol is a monomulecolar combination of catecholamine and theophilline. Diastolic pulmonary pressure and wedge pressure decreased 20 minutes after Reproterol while total pulmonary resistances were reduced 10 minutes after drug administration; sistolic pulmonary pressure and cardiac index increased only after 10 minutes; heart rate increased until 15th minute. Reproterol, as a catecholamine-theophylline combination, has an additional site of action over and above the pure catecholamine effect owing to inhibition of phosphodiesterase; so an increase in cAMP content is achieved either by increasing the synthesis or by blocking the breakdown. Our results assess that Reproterol has a beneficial effect on pulmonary hemodynamics in COLD.
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PMID:[The hemodynamic effects of reproterol in patients with chronic obstructive lung disease (author's transl)]. 734 17

The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control- respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55-93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 10(6) cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3-4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions.
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PMID:Cyclic AMP enhancing drugs modulate eicosanoid release from human alveolar macrophages. 751 39

Theophylline, as used for the treatment of asthma and chronic obstructive pulmonary disease, may have several effects, including direct bronchodilation, improvement in diaphragmatic and ciliary function, and possibly immune modulation. In this study, we quantified the capacity for theophylline to inhibit natural killer (NK) cells and investigated the mechanism(s) that mediate this inhibition. Theophylline at 10 micrograms/ml and 20 micrograms/ml inhibited the tumoricidal activity of isolated peripheral blood lymphocytes (PBL) by 19 +/- 5% and 36 +/- 6%, respectively (n = 6). Using fluorescence-activated cell sorting, we purified NK cells from PBL and tested theophylline's effects on the kinetics of tumor lysis (Vmax) and on tumor binding. Theophylline at 20 micrograms/ml reduced Vmax by 40 +/- 9% but had no effect on tumor binding. We compared the effects of theophylline, which is both a phosphodiesterase (PDE) inhibitor and an adenosine receptor (AdR) antagonist, with agents that range from relatively pure AdR antagonists to pure PDE inhibitors. Inhibition of NK activity occurred only with PDE inhibitors. We also extracted lymphocyte PDE and observed a direct correlation (r2 = 0.99) between theophylline's activity as a PDE inhibitor and its capacity to inhibit NK activity. These results suggest that theophylline inhibits NK cytotoxicity through its activity as a PDE inhibitor. The clinical relevance of these findings awaits further study.
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PMID:Inhibition of natural killer cell activity by therapeutic levels of theophylline. 825 97

Theophylline, a drug that has been used for several decades, has several different actions at a cellular level, including inhibition of phosphodiesterase isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and modulation of calcium fluxes. Recently, theophylline was found to have several immunomodulatory and anti-inflammatory properties, and thus interest in its use in patients with asthma has been renewed. The use of theophylline in the treatment of asthma and chronic obstructive pulmonary disease has diminished with the advent of new medications, but theophylline remains beneficial, especially in the patient with difficult refractory symptoms. In the future, theophylline may be used as treatment for bradyarrhythmias after cardiac transplantation, prophylactic medication to reduce the severity of nephropathy associated with intravenous administration of contrast material, therapy for breathing problems during sleep, and treatment for leukemias.
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PMID:Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. 955 39

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.
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PMID:Clinical pharmacokinetics of vasodilators. Part II. 967 32

Preclinical and clinical studies of phosphodiesterase 4 inhibitors have shown that these agents may find utility in a wide range of inflammatory disorders, including asthma, chronic obstructive pulmonary disease, atopic dermatitis, rheumatoid arthritis, multiple sclerosis and various neurological disorders. The future of this class of drugs will depend upon the ability to demonstrate a reasonable safety margin against emesis and other typical phosphodieserase (PDE4) side effects, as well as in identification of the inflammatory disorder(s) most relevant to PDE4 inhibition.
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PMID:Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. 1041 56

Theophylline is commonly used in the treatment of obstructive airway diseases. The identification and functional characterization of different phosphodiesterase (PDE) isoenzymes has led to the development of various isoenzyme-selective inhibitors as potential anti-asthma drugs. Considering the distribution of isoenzymes in target tissues, with high activity of PDE3 and PDE4 in airway smooth muscle and inflammatory cells, selective inhibitors of these isoenzymes may add to the therapy of chronic airflow obstruction. However, initial data from clinical trials with selective PDE3 and PDE4 inhibitors have been somewhat disappointing and have tempered the expectations considerably since these drugs had limited efficacy and their use was clinically limited through side effects. The improved understanding of the molecular biology of PDEs enabled the synthesis of novel drugs with an improved risk/benefit ratio. These 'second generation' selective drugs have produced more promising clinical results not only for the treatment of bronchial asthma but also for the treatment of chronic obstructive pulmonary disease.
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PMID:Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease. 1042 32

There is a driving need to develop new and effective treatments for COPD. Bronchodilators are now the mainstay of symptomatic therapy and a new long-acting anticholinergic bronchodilator, tiotropium bromide, is now in advanced clinical trials as a once daily dry powder inhaler. Several inflammatory mediators are involved in the chronic neutrophilic inflammation that typifies COPD, including leukotriene B(4) and interleukin 8, for which specific receptor antagonists have been developed. Since the inflammatory process in COPD is essentially steroid resistant, new antiinflammatory treatments are needed. Drugs that may be effective include phosphodiesterase 4 inhibitors, NF-kappaB inhibitors, and interleukin 10. Inhibition of proteases is another approach and inhibitors of neutrophil elastase, cathepsins, and matrix metalloproteases are now in clinical development. Supply of endogenous antiproteases, such as alpha(1)-antitrypsin and secretory leukocyte protease inhibitors as recombinant proteins or by gene transfer, is also being explored. In future drugs that may stimulate alveolar repair might be developed, including retinoid receptor agonists and hepatic growth factor. Future directions will include earlier detection of disease, gene profiling to identify which smokers are at risk of COPD, and the development of noninvasive surrogate markers to monitor disease activity in order to monitor new therapies. Identification of genes that confer a risk for COPD in smokers may identify novel targets for drug development. Barnes PJ. Novel approaches and targets for treatment of chronic obstructive pulmonary disease.
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PMID:Novel approaches and targets for treatment of chronic obstructive pulmonary disease. 1055 74

Current therapy for chronic obstructive pulmonary disease is symptomatic, and no treatments prevent the progression of the disease. Stopping smoking is the only effective approach, and this may be facilitated by nicotine replacement and bupropion. Treatment with short- and long-acting inhaled beta2-agonists and anticholinergics are the mainstay of therapy. Inhaled corticosteroids have no impact on disease progression, and the small reduction in exacerbations may not justify the potential systemic side effects. Supplementary oxygen therapy is indicated for acute exacerbations and chronic hypoxia. Other treatments, including mucolytics, vaccines, and respiratory stimulants are of little value. Nonpharmacological measures that are useful include pulmonary rehabilitation, exercise, good nutrition, and, in selected cases, surgery. Several new classes of drug are now in development, including mediator antagonists (leukotriene B4, interleukin-8 antagonists, and anti-oxidants) and nonsteroid anti-inflammatory drugs, of which phosphodiesterase-4 inhibitors look the most promising. There is a pressing need for a better understanding of the underlying disease process to develop more logical therapies.
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PMID:Nonantimicrobial aspects of therapy. 1074 50

To evaluate the potential inhibitory effect of theophylline on the pulmonary oxidative stress in asthma and chronic obstructive pulmonary disease (COPD), we concomitantly measured the blood levels of theophylline, a non-selective phosphodiesterase (PDE) inhibitor and lipid peroxides as an index of oxidative stress. The plasma levels of lipid peroxides were significantly elevated in patients with asthma (3.48 +/- 0.11 nmol ml(-1); mean +/- SEM; n=21, P<0.01), non- or ex-smoking patients with COPD (3.55 +/- 0.11 nmol ml(-1); n = 20, P<0.01), and current-smoking patients with COPD (3.53 +/- 0.15 nmol ml(-1); n = 15, P<0.01), respectively, as compared to those of non-smoking controls (3.02 +/- 0.08 nmol ml(-1); n = 19). There was a significant negative correlation between the plasma level of lipid peroxides and the forced expiratory volume in 1 sec (FEV1)% of forced vital capacity in these subjects (r = -0.304; n = 75, P < 0.01). In asthmatics, there was a significant negative correlation between the plasma level of lipid peroxides and the serum level of theophylline (r = -0.495; n = 18, P<0.05). These results suggest that there may be increased oxidative stress in patients with asthma and COPD, and indicate that oxidative stress could possibly attribute to the pathophysiology of asthma and COPD in leading to airflow obstruction and that theophylline could potentially inhibit oxidative stress in the process of bronchopulmonary inflammation in asthmatics.
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PMID:Evidence of oxidative stress in asthma and COPD: potential inhibitory effect of theophylline. 1092 64


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