In the recent few years, especially since the introduction of phosphodiesterase-5 inhibitor, sildenafil, most researchers have focused their researches on biochemistry and physiology of erectile function. New progress has been made made in basic and clinic researches on pharmacotherapy for ED. In this article, the putative molecular or cellular mechanism of actions of the available centrally and peripherally acting drugs are reviewed, providing details about the current and most explosive area of drug research and development in erectile dysfunction.
Animals ; Apomorphine ; pharmacology ; therapeutic use ; Erectile Dysfunction ; drug therapy ; Humans ; Male ; Phosphodiesterase Inhibitors ; pharmacology ; therapeutic use ; Piperazines ; pharmacology ; therapeutic use ; Purines ; pharmacology ; therapeutic use ; Rats ; Sildenafil Citrate ; Sulfones ; pharmacology ; therapeutic use ; Yohimbine ; pharmacology ; therapeutic use

Viagra has become the first line drug for the treatment of erectile dysfunction since it was first introduced in 1998. Its efficacy and safety have been sidely acclaimed as being definite. This article presents a brief review about the advances in the studies of Viagra, including its therapeutic effect and safety, its protection of penile health, and its promotion of self-esteem and sexual relationship.
Erectile Dysfunction ; drug therapy ; Humans ; Male ; Penile Erection ; drug effects ; Personal Satisfaction ; Phosphodiesterase Inhibitors ; pharmacology ; therapeutic use ; Piperazines ; pharmacology ; therapeutic use ; Purines ; pharmacology ; therapeutic use ; Sildenafil Citrate ; Sulfones ; pharmacology ; therapeutic use

OBJECTIVETo review and assess the update studies regarding selective serotonin reuptake inhibitors (SSRIs) in the treatment of premature ejaculation (PE) and then provide practical recommendations and possible mechanisms concerning state of the art knowledge for the use of SSRIs in alleviating PE.

DATA SOURCESUsing the Medline, 48 articles published from January 1st, 1996 to August 1st, 2006 concerning the use of SSRIs and their possible mechanisms in alleviating PE were found and reviewed.

STUDY SELECTIONPE, rapid ejaculation, early ejaculation and SSRIs were employed as the keywords, and relevant articles about the use of SSRIs and their possible mechanisms in the treatment of PE were selected.

RESULTSMany kinds of SSRIs, such as fluoxetine, sertraline, paroxetine and citalopram, have widely been employed to treat PE. However, their effects are moderate and there is no a universal agreement about the kind, dose, protocol and duration. Dapoxetine, as the first prescription treatment of PE, may change this bottle-neck situation. SSRIs are suggested to be used in young men with lifelong PE, and acquired PE when etiological factors are removed but PE still exists. Phosphodiesterase 5 inhibitors (PDE(5)-Is) are suggested to be employed alone or combined with SSRIs when SSRIs fail to treat PE or sexual dysfunction associated with SSRIs occurs. The protocol of taking drugs on demand based on taking them daily for a suitable period is proposed to be chosen firstly. The possible mechanisms include increasing serotonergic neurotransmission and activating 5-hydroxytryptamine 2C (5-HT(2C)) receptors, then switching the ejaculatory threshold to a higher level, decreasing the penile sensitivity and their own effect of antidepression.

CONCLUSIONThe efficacies of the current SSRIs are moderate in the treatment of PE and they have not been approved by the FDA, therefore new SSRI like dapoxetine needs to be further evaluated.

Clinical Trials as Topic ; Ejaculation ; drug effects ; Humans ; Male ; Piperazines ; therapeutic use ; Purines ; therapeutic use ; Serotonin Uptake Inhibitors ; adverse effects ; pharmacology ; therapeutic use ; Sexual Dysfunction, Physiological ; drug therapy ; Sildenafil Citrate ; Sulfones ; therapeutic use

Sildenafil increases the cyclic guanosine monophosphate (cGMP) by inhibition of a phosphodiesterase 5, thereby leading to an antinociceptive effect. The increased cGMP may exert the effect on an L-type calcium channel through the activation of protein kinase G (PKG). The purpose of this study was to examine the possible involvement of a PKG-L-type calcium channel on the effect of sildenafil at the spinal level. Catheters were inserted into the intrathecal space of male SD rats. Pain was induced by applying 50 microliter of a 5% formalin solution to the hindpaw. The sildenafil-induced effect was examined after an intrathecal pretreatment of a PKG inhibitor (KT 5823), or a L-type calcium channel activator (FPL 64176). Intrathecal sildenafil produced an antinociceptive effect during phase 1 (0~10 min interval) and phase 2 (10~60 min interval) in the formalin test. Intrathecal KT 5823 and FPL 64176 attenuated the antinociceptive effect of sildenafil during both phases. Sildenafil is effective against both acute pain and the facilitated pain state at the spinal level. In addition, the inhibition of an L-type calcium channel by activation of the PKG may contribute to the antinocieptive mechanism of sildenafil in the spinal cord.
Animals ; Calcium Channel Agonists/pharmacology ; Calcium Channels, L-Type/*physiology ; Carbazoles/pharmacology ; Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/*physiology ; Dose-Response Relationship, Drug ; Male ; Pain/drug therapy/*physiopathology ; Pain Measurement ; Piperazines/*pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Purines/pharmacology/therapeutic use ; Pyrroles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfones/*pharmacology/therapeutic use

PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.
Animals ; Baclofen/analogs & derivatives/pharmacology ; Bicuculline/pharmacology ; Blood Pressure/drug effects ; Dose-Response Relationship, Drug ; Heart Rate/drug effects ; Hemodynamics/drug effects ; Male ; Neuralgia/*drug therapy ; Pain Threshold/drug effects ; Phosphodiesterase Inhibitors/*therapeutic use ; Piperazines/*therapeutic use ; Purines/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A/antagonists & inhibitors/physiology ; Receptors, GABA-B/antagonists & inhibitors/physiology ; Sulfones/*therapeutic use

PURPOSE: The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil. MATERIALS AND METHODS: Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 mininutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined. RESULTS: Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test. CONCLUSION: Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.
Adenosine/metabolism ; Analgesics/*therapeutic use ; Animals ; Cyclic GMP/metabolism ; Dihydroergocristine/pharmacology ; Injections, Spinal ; Male ; Pain/*drug therapy ; Piperazines/*pharmacology ; Purines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P1/*metabolism ; Receptors, Serotonin/*metabolism ; Spinal Cord/*metabolism ; Sulfones/*pharmacology ; Vasodilator Agents/therapeutic use

Erectile response is centrally and peripherally regulated by androgens. The original insights into the mechanisms of action of androgens were that androgens particularly exert effects on libido and that erections in response to erotic stimuli were relatively androgen-independent. It was shown that sexual functions in men required androgen levels at the low end of reference values of testosterone. So it seemed that testosterone was not useful treatment for men with erectile difficulties, particularly following the advent of the phosphodiesterase type 5 (PDE5) inhibitors. However, approximately 50% of those treated with PDE5 inhibitors discontinue their treatment. A number of recent developments shed new light on testosterone treatment of erectile dysfunction (ED) in aging men. (1) A recent insight is that, in contrast to younger men, elderly men might require higher levels of testosterone for normal sexual functioning. (2) Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men, and that testosterone improves the therapeutical response to PDE5 inhibitors considerably. (3) There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, reversible upon androgen replacement. The synthesis of PDE5 is upregulated by androgens, and the arterial inflow into the penis is improved by giving androgen. The above invites a re-examination of the merits of giving testosterone to aging men with ED. The beneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment.
3',5'-Cyclic-GMP Phosphodiesterases ; Aging ; physiology ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Humans ; Male ; Middle Aged ; Penile Erection ; drug effects ; physiology ; Penis ; anatomy & histology ; drug effects ; Phosphodiesterase Inhibitors ; pharmacology ; therapeutic use ; Phosphoric Diester Hydrolases ; physiology ; Piperazines ; therapeutic use ; Purines ; Sildenafil Citrate ; Sulfones ; Testosterone ; blood ; physiology

AIMTo search for new compounds with strong anti-inflammatory activity and low gastrointestinal (GI) side effects.

METHODSA series of alpha-substituted p-(methanesulfonyl) phenyl-propenamides were synthesized. Their anti-inflammatory activities against xylene-induced mice ear swelling and carrageenan-induced rat paw edema were evaluated, and their GI side effects in rats were examined.

RESULTSTwenty-five target compounds (II1-25) were obtained, and their structures were determined by IR, 1H NMR, MS and elemental analysis. Thirteen compounds (II1,3,5,8-13,15,18,19,23) exhibited marked anti-inflammatory activity comparable to diclofenac sodium (DC) and rofecoxib (RC) in xylene-induced mice ear swelling model, and twelve compounds (II1,3,5,7,8,10-12,17,18,20,23) showed remarkable anti-inflammatory activity comparable to DC and RC in carrageenan-induced rat paw edema. Compounds II3,8,10,11,18,20 showed GI side effects less than DC (P < 0.01), and no significant difference compared with RC and CMC-Na (P > 0.05).

CONCLUSIONalpha-Substituted p-(methanesulfonyl)phenylpropenamides showed strong anti-inflammatory activity but few GI side effects and deserve to be further investigated.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; adverse effects ; chemical synthesis ; pharmacology ; therapeutic use ; Carrageenan ; Edema ; chemically induced ; drug therapy ; Mice ; Peptic Ulcer ; chemically induced ; Phenylpropionates ; adverse effects ; chemical synthesis ; pharmacology ; Rats ; Structure-Activity Relationship ; Sulfones ; adverse effects ; chemical synthesis ; pharmacology ; Xylenes