The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy

Differences in clinical pharmacology of the currently marketed phosphodiesterase (PDE)5 inhibitors sildenafil, vardenafil and tadalafil are largely determined by their pharmacokinetic (PK) properties and their PDE5 inhibitory activity profile. This review outlines the basic concepts of pharmacokinetics and pharmacokinetic pharmacodynamic (PK/PD) relationships and their relevance to dose selection and applied pharmacotherapy. It is followed by a detailed comparative discussion on the pharmacokinetics and exposure-response relationship of the currently available PDE5 inhibitors, including known drug-drug interactions and dosage adjustments in special populations. The review is aimed at providing a critical assessment of the pharmacokinetics of PDE5 inhibitors, which may assist clinicians in tailoring drug and/or treatment regimens to the unique needs of each individual patient with erectile dysfunction.     

Oral phosphodiesterase-5 inhibitors and sperm functions

This review aims to elucidate the possible effects of phosphodiesterase-5 (PDE5) inhibitors on sperm functions. PDEs hydrolyze cyclic nucleotides, and together with adenylyl and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, regulate the levels of these second messengers in cells. cGMP-specific PDE5 is one of the PDEs that have been intensively studied because of its fundamental pharmacological relevance, as oral PDE5 inhibitors are used successfully in treating erectile dysfunction. In addition, they have shown diverse beneficial actions in different disease categories. Specific relevance of the cGMP system in reproductive functions has been recently proposed. Its use was shown to be devoid of effects on semen volume, concentration, sperm membrane integrity or sperm penetration assay. Most available studies demonstrated a significant increase in sperm motility and viability both in vivo and in vitro, which seems to be enhanced at low doses and reduced at high concentrations. Also, these molecules showed a role in capacitation and a debated one concerning acrosome reaction. However, due to the relative short period since the launching of oral PDE5 inhibitors, more investigations should be carried out in wider scales to assess their effect(s) on variant sperm function that could be beneficial as potential therapeutic approaches.     

PDE5抑制剂的泌尿男科新用途

5型磷酸二酯酶抑制剂(PDE5i)是治疗勃起功能障碍(ED)一线疗法的经典用药。近来研究发现,它还可以用于治疗下尿路症状(LUTS)、肾缺血-再灌注以及睾丸扭转。本文对PDE5i在这些领域的应用及相关机制研究的新进展进行了综述。     

Effects of phosphodiesterase-5 inhibitors on sperm parameters and fertilizing capacity

The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assi     

The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size

The aim of this study was to determine, in an animal model, the effects of tadalafil on myocardial infarct size (IS), hemodynamics and regional myocardial blood flow after myocardial ischemia and reperfusion. Patients with erectile dysfunction (ED) often have risk factors for coronary artery disease. Tadalafil, a long-acting inhibitor of the enzyme phosphodiesterase-5 (PDE5), is used for the treatment of ED; there are no previous data regarding tadalafil in the setting of coronary artery occlusion (CAO). Sprague-Dawley male rats were treated with tadalafil or vehicle (10 mg/kg, by gastric gavage), 2 h before a 30 min CAO. Heart rate was comparable between tadalafil and control groups. Tadalafil reduced mean arterial pressure (P=0.009), systolic (P=0.035) and diastolic (P=0.009) blood pressures during ischemia/reperfusion. Tadalafil significantly reduced IS (42+/-2%) versus controls (54+/-3%) (P=0.006). For the first time, we showed that the PDE5 inhibitor, tadalafil, was well tolerated and cardioprotective in the setting of an experimental myocardial infarction, by substantially reducing ischemic cell death.     

Molecular mechanisms

The clinically useful and potent distal acting diuretics enhance urinary NaCl excretion by specific inhibition of distinct sodium transport processes in the loop of Henle and distal nephron. When these compounds were first used as diuretics little was known about their cellular mechanisms of action. Physiological investigations over the past 25 years, however, have shown that each class of diuretics inhibits a specific ion transport system in the kidney. Over the past few years, the molecular cloning of the distal diuretic-sensitive Na+ transporters has significantly enhanced our understanding of the mechanism of action of each class of diuretics and has clearly defined the specific protein (and its gene) that is the target for each of these diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by alterations in salt balance has provided unequivocal evidence for roles of the cloned diuretic-sensitive transporters in sodium homeostasis. Many laboratories are actively engaged in defining the structural sites for ion transport and diuretic binding, and the molecular mechanisms of transport regulation. This information may enable the design of new diuretics and provide the basis for improved use of diuretics. This review will focus on this recent molecular information.     

Molecular mechanisms of sepsis

Today a great number of problems in the field of bacterial sepsis remain to be solved. Understanding the molecular mechanisms of one of the most important bacterial products in the pathogenesis of sepsis – endotoxin – may contribute to innovative and more effective therapies. Therefore, this review focuses on the structural and functional elements of endotoxin, its interaction with immune cells, and its biological activity. Finally, other bacterial components and their impact on sepsis are discussed. Received: 18 December 1997     

胆管癌分子机制的研究进展

胆管癌发病率逐年上升,由于缺乏有效的治疗措施,胆管癌的预后极差,这使得临床上对该疾病越来越重视.加深对胆管癌发生及生长机制的理解,有助于我们找到针对这种致死性肿瘤的治疗靶点.本文将近年来对胆管癌发病及生长调节机制方面的研究做一回顾.通过对胆管癌分子机制更好的认识,以找到诊断、治疗及预防这种致死性肿瘤的特异性的策略,进而取得满意的治疗效果.     

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.     

Molecular and basic mechanisms of anaesthesia

This postgraduate issue of British Journal of Anaesthesia isbased on the three-day ‘Sixth International Conferenceon Molecular and Basic Mechanisms of Anesthesia’ (June28–30, 2001 in Bonn, Germany) organized by Keith W. Miller,Chris D. Richards, Sheldon H. Roth and Bernd W. Urban. Thiswas the sixth in the series of International Conferences onMechanisms of Anaesthesia that was started by Raymond Fink (1974and 1979 in Seattle, and 1984,     

Molecular mechanisms of renal development

The biology of renal development has become increasingly complex because technical advances in genetics and cell biology have been used to study this aspect of embryogenesis. The molecular biology and genetics of renal development may seem inconsequential and frustrating to the practicing clinician, but insight into fundamental mechanisms of renal development are necessary to understand clinical breakthroughs that will occur in the future. As a basis for appreciating these concepts, specific paradigms of renal development are illustrated and the investigative strategies used to develop them are summarized in this article.