Tetralogy of Fallot (TOF) assumes its' most severe form when accompanied by pulmonary atresia (PA). Preserving the patent ductus arteriosus to maintain pulmonary blood flow is life-saving for patients with this congenital heart disease. Milrinone, a selective phosphodiesterase III inhibitor, is a potent vasodilator. Here, we report the successful use of milrinone for a newborn infant with TOF and PA for keeping the ductus arteriosus open and thereby maintaining pulmonary circulation. Milrinone is a useful drug because of its inotropic, lusitropic, and pulmonary vasodilating effects, in addition to its ability to keep the ductus arteriosus open and its relatively mild side-effects. Case series and comparative studies will be needed in the future to verify the effectiveness of this drug.
Cyclic Nucleotide Phosphodiesterases, Type 3 ; Ductus Arteriosus ; Ductus Arteriosus, Patent ; Heart Diseases ; Humans ; Infant, Newborn ; Milrinone ; Pulmonary Atresia ; Pulmonary Circulation ; Tetralogy of Fallot

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder with a prolonged clinical course. Since this disorder is considered to be at increased risk of thromboembolism, therapy is mainly focused on the decreased risk of thrombohemorrhagic events by use of cytotoxic agents. Anagrelide is a phosphodiesterase III inhibitor which is utilized in the treatment of ET for the reduction of platelets. However, patients treated with anagrelide might experience cardiovascular adverse effects including myocardial infarction (MI), although these events are rare. Herein, we report a case of a 30-year-old female with well controlled ET by anagrelide, who eventually developed an acute non-ST elevation myocardial infarction (MI). There has no found any cardiovascular risk factors in this ET patient, strongly suggesting that anagrelide might be the cause of MI. Therefore, cardiovascular function should be monitored in those patients prescribed with anagrelide.
Adult ; Blood Platelets ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Cytotoxins ; Female ; Humans ; Myeloproliferative Disorders ; Myocardial Infarction ; Quinazolines ; Risk Factors ; Thrombocythemia, Essential ; Thromboembolism

BACKGROUND AND OBJECTIVES: Cilostazol, a selective inhibitor of phosphodiesterase III (PDE III), prevents inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP) and irreversibly inhibits platelet aggregation and vasodilation. Hence, we performed this prospective randomized study to evaluate the clinical effects of additional cilostazol administration in patients receiving dual antiplatelet therapy after drug-eluting stent (DES) insertion. SUBJECTS AND METHODS: Between December 2003 and June 2006, we enrolled a total 603 consecutive patients who underwent successful percutaneous coronary intervention (PCI) with DES insertion at Dong-A University Hospital. Study patients received dual antiplatelet therapy (aspirin and clopidogrel, n=301) for at least six months or dual antiplatelet therapy (six months) combined with cilostazol medication for one month (triple therapy, n=302) after PCI. We investigated the incidence of major adverse cardiac events (MACE) at one month and six months after the initiation of medical therapy. MACE was defined as a composite of death, myocardial infarction (MI), stent thrombosis, and target lesion revascularization (TLR). Platelet function was evaluated in 66 patients (dual therapy group, n=40; triple therapy group, n=26) using a Chrono-Log platelet aggregometer and the VerifyNow P2Y12 assay system. RESULTS: The MACE rate was 0.66% in the triple therapy group (death only, 0.67%) and 1.67% in the dual therapy group (death, 0.67%; MI, 0.67%; stent thrombosis, 0.99%; TLR, 0.99%) at one month after PCI (p=0.087). At six months, there were no differences in the MACE rate between the two groups (triple group vs. dual group=2.65% vs. 3.99%, p=0.864). In laboratory tests, platelet aggregation induced by agonists of ADP (27.92+/-13.04% vs. 40.9+/-15.78%, p=0.0008), collagen (13.73+/-6.95% vs. 27.43+/-14.87%, p=0.03), and epinephrine (10.38+/-7.82% vs. 15.5+/-10.45%, p=0.0000) were lower in the triple therapy group versus the dual therapy group. However, platelet aggregation induced by agonists of arachidonic acid (3.23+/-1.07% vs. 3.78+/-2.12%, p=0.23) and ristocetin (29.19+/-35.55% vs. 44.78+/-32.65%, p=0.07) and aspirin reaction unit (412.96+/-96.25 vs. 427.93+/-76.24, p=0.48) measured by VerifyNow were not different in the triple group versus the dual group. CONCLUSION: Additional administration of cilostazol did not decrease the MACE rate when compared to dual therapy six months after PCI in patients with DES.
Adenosine Diphosphate ; Adenosine Monophosphate ; Arachidonic Acid ; Aspirin ; Blood Platelets ; Collagen ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Drug-Eluting Stents ; Epinephrine ; Humans ; Incidence ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Platelet Aggregation ; Prospective Studies ; Ristocetin ; Second Messenger Systems ; Stents ; Tetrazoles ; Thrombosis ; Ticlopidine ; Vasodilation

BACKGROUND: Milrinone, phosphodiesterase III inhibitor, has been used effectively in patients with right heart failure, especially resulted from pulmonary hypertension. However, milrinone is often used with alpha- and beta-adrenergic receptor agonist to prevent severe systemic vasodilation and unfavorable hypotension. Furthermore, structural and functional vasacular changes are associated with aging and are greatest in the aorta. We evaluated the vasodilatory effects of milrinone and sodium nitroprusside (SNP) on young and old rat aortic rings preconstricted with various catecholamines. METHODS: Aortic rings of young and old rat were placed in 25 ml organ chamber and preconstricted with epinephrine (EPI, 10(-6) M), norepinephrine (NE, 10(-7) M) , phenylephrine 10(-7) M) , and U46619 (10(-8) M). Cummulative dose-responses to milrinone (10(-9)-10(-5) M) and SNP (10(-9)-10(-5) M) were obtained to characterize vasodilatory effects. RESULTS: Relaxation response to milrinone was markedly enhanced in both young and old aortic rings preconstricted with U46619 compared with other vasoconstrictors. The maximal response of the young rat aortic rings preconstricted with NE is significantly reduced, compared with that of EPI. The maximal vasorelaxant response of SNP in young and old aortic rings are nearly identical. CONCLUSIONS: We conclude that combined use of milrinone and epinephrine may be more useful in prevention and treatment of systemic hypotension.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Adrenergic beta-Agonists ; Aging ; Animals ; Aorta ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Epinephrine ; Heart Failure ; Humans ; Hypertension, Pulmonary ; Hypotension ; Milrinone ; Nitroprusside ; Norepinephrine ; Phenylephrine ; Rats ; Relaxation ; Vasoconstrictor Agents ; Vasodilation

Recently published studies from different populations provide apparently conflicting evidence on the association between the phosphodiesterase 4D (PDE4D) gene and ischemic stroke. The relationship between a representative PDE4D genotype and ischemic stroke was explored in a case-control study of 205 consecutive Korean patients with noncardiogenic ischemic stroke and 103 healthy controls who were neurologically and radiologically proven to be stroke-free. We selected and genotyped a PDE4D single nucleotide polymorphism (SNP 41, rs152312) as a candidate marker for susceptibility to ischemic stroke because SNP 41 has shown the most significant association with stroke in both a meta-analysis and the original Icelandic study of the PDE4D gene. No significant difference was observed between the cases and controls in the distribution of the PDE4D SNP 41 genotypes. The results from the adjusted conditional logistic regression analysis (adjusted for age, hypertension, diabetes and smoking status) showed no significant association between PDE4D SNP 41 genotypes and an increased risk of noncardiogenic ischemic stroke. The PDE4D gene is not a major risk factor for noncardiogenic ischemic stroke in a Korean population, which supports the recent evidence suggesting that the causative genetic variants of ischemic stroke may differ across populations.
Aged ; Asian Continental Ancestry Group/*genetics ; Brain Ischemia/diagnosis/*genetics ; Case-Control Studies ; Cyclic Nucleotide Phosphodiesterases, Type 3/*genetics ; Cyclic Nucleotide Phosphodiesterases, Type 4/*genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Korea ; Magnetic Resonance Angiography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Regression Analysis ; Risk ; Stroke/diagnosis/*genetics

Cilostazol inhibits phosphodiesterase III (PDE III), which is predominantly distributed to and regulates physiologic responses in platelets, cardiac muscle cells, vascular smooth muscle cells, and adipose cells. Clinically, it is well known as an antiplatelet agent that inhibits the platelet aggregation normally induced by collagen, 5'-adenosine diphosphase (ADP), epinephrine, and arachidonic acid. It also has pleotropic effects, including the prevention of restenosis after angioplasty and the promotion of peripheral vascular flow in patients with peripheral vascular diseases. In the drug-eluting stent era, it has emerged as an effective post-intervention anti-atherothrombotic agent and a useful agent for therapy in diabetic patients. The aim of this study was to review the mechanisms of action and clinical trial results associated with cilostazol in cardiovascular disease patients.
Angioplasty ; Arachidonic Acid ; Blood Platelets ; Cardiovascular Diseases ; Collagen ; Coronary Restenosis ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Drug-Eluting Stents ; Epinephrine ; Humans ; Muscle, Smooth, Vascular ; Myocytes, Cardiac ; Peripheral Vascular Diseases ; Platelet Aggregation ; Tetrazoles ; Thrombosis ; Vascular Diseases

BACKGROUND AND PURPOSE: Cilostazol, a phosphodiesterase III inhibitor, is known to be a useful antiplatelet agent that inhibits the progression of atherosclerosis in ischemic stroke. This study investigated the effects of combining cilostazol with aspirin on the expressions of P-selectin and PAC-1 on activated platelets in acute ischemic stroke. METHODS: We analyzed 70 patients with acute ischemic stroke (<72 hrs of an ischemic event). The daily intake was 100 mg of aspirin in 37 patients and 100 mg of aspirin plus 200 mg of cilostazol in 33 patients. The expressions of P-selectin and PAC-1 on activated platelets were measured on the day of admission and 5 days later. We also evaluated the clinical progression using the National Institutes of Health Stroke Scale (NIHSS) at the same times. RESULTS: After 5 days the extent of PAC-1 expression on activated platelets was significantly lower for combined aspirin and cilostazol treatment (61.0+/-19.3%, p=0.008; mean+/-standard deviation) than the baseline level (70.9+/-12.9%), but did not differ between aspirin alone (66.0 +/-19.0%) and baseline (70.1+/-15.7%). The expression of P-selectin did not differ between combined aspirin and cilostazol treatment and baseline. The clinical progression did not differ between the two groups, as indicated by the absence of significant changes on the NIHSS in the acute period. CONCLUSIONS:This study found that the combined regimen of aspirin and cilostazol exerts the beneficial effect of reducing PAC-1 activity on activated platelets in acute ischemic stroke. However, the clinical outcome of this regimen was no better than that of the aspirin-only regimen. Therefore, further detailed studies of the possible clinical benefits of cilostazol in acute ischemic stroke are needed.
Aspirin ; Atherosclerosis ; Blood Platelets ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Humans ; National Institutes of Health (U.S.) ; P-Selectin ; Stroke ; Tetrazoles

OBJECTIVETo evaluate whether mRNA levels of Pde4d and Alox5ap were associated with hypertensive stroke and hypertension in stroke-prone renovascular hypertensive rats (RHRSP) which could simulate human being's hypertensive cerebral stroke.

METHODSFive groups were established: normotensive group, gradient hypertensive groups I, II and III(with contractive pressure of 140-159 mmHg, 160-179 mmHg and 180-199 mmHg respectively) and spontaneous stroke group. RNA from leukocytes in peripheral blood of each rat underwent real time PCR after reversed.

RESULTSThe mRNA levels of Pde4d and Alox5ap of spontaneous stroke group were statistically higher than that of the other groups. Expression of Pde4d of hypertensive group I was a bit higher than that of normotensive group and hypertensive groups II and III; as for Alox5ap, there was no statistical difference between normotensive group and all gradient hypertensive groups.

CONCLUSIONAnimal experiments come to conclusions that over-expression of Pde4d and Alox5ap are associated with hypertensive stroke but not with hypertension. Therefore, the two genes confer the risk of hypertensive stroke independent of traditional risk factors. It is speculated that over-expression of Pde4d and Alox5ap can motivate onset of hypertensive cerebral stroke by participating in inflammation of arterial walls.

5-Lipoxygenase-Activating Proteins ; Animals ; Carrier Proteins ; genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; genetics ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Gene Expression Regulation ; Hypertension ; complications ; genetics ; Membrane Proteins ; genetics ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Inbred SHR ; Stroke ; complications ; genetics

Current available treatment options for erectile dysfunction (ED) are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 (PDE5) inhibitors (i.e. sildenafil, tadalafil and vardenafil) has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure "on demand" without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. Gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined (lacunar) spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.
3',5'-Cyclic-GMP Phosphodiesterases ; antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Erectile Dysfunction ; drug therapy ; genetics ; therapy ; Gene Transfer Techniques ; Genetic Therapy ; adverse effects ; Humans ; Male ; Phosphodiesterase Inhibitors ; therapeutic use ; Vasodilator Agents ; therapeutic use

The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.
3',5'-Cyclic-GMP Phosphodiesterases ; antagonists & inhibitors ; Administration, Oral ; Angiography ; Blood Flow Velocity ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Enzyme Inhibitors ; administration & dosage ; therapeutic use ; Erectile Dysfunction ; diagnosis ; drug therapy ; Humans ; Injections ; Male ; Penis ; blood supply ; diagnostic imaging ; Phosphodiesterase Inhibitors ; therapeutic use ; Vasodilator Agents ; therapeutic use