A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), by the respective PDE subtype(s).

• Non-selective phosphodiesterase inhibitors:

1. the minor stimulant caffeine,
2. the bronchodilator theophylline,
3. IBMX (3-isobutyl-1-methylxanthine): used as investigative tool in pharmacological research

• PDE3-selective inhibitors:

1. enoximone and milrinone: used clinically for short-term treatment of cardiac failure. Clinically these drugs mimic sympathetic stimulation and increase cardiac output.

• PDE4-selective inhibitors:

1. rolipram: used as investigative tool in pharmacological research

PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs especially in airway diseases. They suppress the release of inflammatory signals, e.g., cytokines, and inhibit the production of reactive oxygen species. PDE4 inhibitors have a high therapeutic and commercial potential as non-steroidal disease controllers in inflammatory airway diseases such as asthma, COPD and rhinitis · Amrinone · Cilomilast- ORAL PDE-IV INHIBITOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) · Cilostazol · Enoximone · Milrinone · Olprinone · Roflumilast · Sildenafil · Vardenafil ARIFLO (CILOMILAST) - ORAL PDE-IV INHIBITOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PDE-IV INHIBITION The phosphodiesterases are enzymes responsible for hydrolysis of cyclic adenosine monophosphate (cAMP), a naturally occurring substance that mediates suppression of inflammatory cell activation. PDE-IV is the predominant phosphodiesterase isoenzyme in respiratory tissues and is therefore a suitable target for therapy of inflammatory airways diseases such as COPD. By inhibiting PDE-IV, drugs such as CILOMILAST increase levels of cAMP and reduce inflammatory cell activation in the respiratory tract. Results from pre-clinical investigations with CILOMILAST suggest it may: · Reduce bronchoconstriction · Reduce inflammation and subsequent damage to respiratory tissues · Reduce cough and dyspnea (breathlessness) Selective PDE-IV inhibitors, such as CILOMILAST, have potential to not only target symptoms of the disease but to also ameliorate the underlying components of airway obstruction and inflammation. Thus, they represent a completely new approach to the treatment of COPD Enoximone: "1,3-Dihydro-4-methyl-5-(4-(methylthio)benzoyl)-2H-imidazol-2-one. A selective phosphodiesterase inhibitor with vasodilating and positive inotropic activity that does not cause changes in myocardial oxygen consumption. It is used in patients with congestive heart failure." Mechanism of Action The mechanism of the effects of PLETAL on the symptoms of intermittent claudication is not fully understood. PLETAL and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. PLETAL reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, A.P. collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking PLETAL. After 12 weeks, as compared to placebo, PLETAL 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (@ 10%). Cardiovascular Effects Cilostazol affects both vascular body and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral body than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol.

Papaverine- B.P., ED. Sildenafil, Tadalafil- ED.

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-- PDE 5 Amrinone, Milrinone- CHF Theophylline- Asthma Cilomilast- Inflammatory airway diseases (Asthma, COPD)

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PDE 4

• PDE5-selective inhibitors:

1. sildenafil, tadalafil and vardenafil: selectively inhibit (PDE5), which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used as remedies for erectile dysfunction.

Pharmacologic agents

磷酸二酯酶抑制剂类