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The inclusion and exclusion criteria for the 18 studies were the same as mentioned above for the 10 studies.

Efficacy was assessed for patients in the sildenafil and placebo groups who were taking antihypertensive medication or who were not taking any antihypertensive agent using end-of-treatment responses to question 3 (ability to achieve an erection) and question 4 (ability to maintain an erection) of the International Index of Erectile Function (IIEF) 7 and responses to a global efficacy question (“Did the treatment improve your erections?”).

The responses to the two IIEF questions were graded on a scale of 1 (almost never or never) to 5 (almost always or always), with a score of 0 indicating no attempt at sexual intercourse.

Physical examinations and standard laboratory tests were performed throughout the studies. In all studies, investigators recorded all observed and patient-reported adverse events and classified the relationship of the adverse event to the study medication as definitely related, uncertain, or not related. A treatment-related adverse event was defined as any event classified as definitely related, of uncertain relation, or of unspecified relation to the study medication. Adverse events were analyzed for the 2881 patients not taking any antihypertensive medication and for the 1094 patients taking one or more of the following classes of antihypertensive agent: diuretic, ?-blocker, ? 1 -blocker, angiotensin converting viagra pharmacy cost enzyme inhibitor, or calcium channel blocker. The mean responses to the two questions of the IIEF for each of the treatment groups were calculated and the treatment effect was analyzed using an analysis of covariance model, as described previously.

4 Comparisons between mean responses for patients taking versus not taking antihypertensive agents were analyzed using an analysis of covariance model that accounted for the treatment effect. The responses to the global efficacy question were analyzed using a logistic regression model.

4 Intention to treat analyses were performed on all variables, and all statistical tests were two-sided and evaluated at the 5% significance level.

In the 10 double-blind, placebo-controlled studies in which efficacy was assessed, the mean age of the patients was 58 years for those taking antihypertensive medication and 55 years for those not taking any antihypertensive agent. The mean duration of ED in the two groups was 4.7 years and 5.2 years, respectively.

The etiology of ED was 67% organic, 11% psychogenic, and 22% mixed for the patients taking concomitant antihypertensive medication compared with 56% organic, 17% psychogenic, and 27% mixed for those not taking an antihypertensive agent. The characteristics of the patients randomized to treatment in the 18 double-blind, placebo-controlled studies from which safety data were collected were similar to those described above. The mean end of treatment scores for question 3 (achieving an erection) and question 4 (maintaining an erection) of the IIEF were significantly higher for the sildenafil group than for the placebo group for both patients taking and those not taking antihypertensive agents ( P values Table 1). Furthermore, the incidences of the most common adverse events (eg, headache, flushing, and dyspepsia) also were not affected by whether the patients receiving sildenafil were taking antihypertensive medication.

Combined incidence (%) of treatment-related adverse events reported in 18 double-blind placebo-controlled studies of patients with ed receiving sildenafil (Sild) or placebo (Pbo) who were taking or not taking different classes of antihypertensive medication * Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients. 1 Department of Clinical Immunology, Institute of Transplantology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.

Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction.

Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5.

cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis.

PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology.

Positive result of sildenafil treatment is closely connected with viagra pills wholesale its immunomodulatory effects.

Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies.

Sildenafil action in humans and animals appears to be viagra quick delivery different.

Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data fake prescription for viagra on the influence of selective PDE5-Is on the human immune system are limited.

The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals.

This is the first review of the current state of knowledge about the effects of sildenafil on the immune system. Phosphodiesterases (PDEs) are critical components in the cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) and the cyclic guanosine monophosphate/protein kinase G (cGMP-PKG) signaling pathways. Phosphodiesterases decompose the cyclic nucleotides, cAMP and cGMP, to inactivate 5?-AMP and 5?-GMP, respectively. PDE activity is tightly coupled with the activity of adenyl cyclases (AC) and guanyl (GC) which synthesize these cyclic nucleotides: cAMP and cGMP. The cyclic nucleotide-dependent protein kinases (PKA and PKG) control the functional cellular responses such as intracellular calcium level, inflammation, cell proliferation, and transcription. Therefore, cAMP and cGMP are considered as potential new therapeutic targets [1, 2].

The inhibition of action of PDE results in increased level of cyclic nucleotides. Several PDEs have been identified and characterized based on their molecular sequence, kinetics, regulation, and pharmacological characteristics. These enzymes were divided into 11 families (PDE1–PDE11) [3, 4].

PDEs 1, 2, 3, 10, and 11 have affinity to cAMP and cGMP and PDEs 4, 7, and 8 hydrolyze cAMP only, while PDEs 5, 6, and 9 exhibit specificity for cGMP. Increased activity of PDEs has been implicated in a number of clinical conditions including erectile dysfunction (PDE5), cardiovascular diseases (PDEs 3, 4, and 5), pulmonary inflammatory conditions (PDE4), autoimmune diseases (PDEs 3 4, 5, and 7), and cognition and memory disorders (PDEs 1, 2, 3, 4, 7, 9, and 10 A) [5–7].

All PDEs are composed of 3 main domains: the catalytic core (highly conserved), the regulatory N-terminus, and the carboxyl C-terminus.

N-terminal domains are responsible for regulation and subcellular localization of PDEs.

They contain domains involved in ligand binding, PDE oligomerization, kinase recognition, and phosphorylation.

The N-terminal domains are flanked by the catalytic core. The catalytic c-domain of PDEs possesses an active pocket composed of 3 helical subdomains: the N-terminal cyclic-fold region, the linker region, and the C-terminal helical bundle.

A deep hydrophobic pocket is formed at the interface of the three subdomains.

The hydrophobic pocket is composed of four subsites: a metal binding site (M), a core pocket (Q pocket), hydrophobic pocket (H pocket), and a lid-region (L region).

At the bottom site is a metal binding domain which probably contains zinc or magnesium ions. Stabilization of the enzyme structure and activation of hydroxide are the presumable roles of metal ions [7, 8].

Substrate specificity of PDEs was suggested to depend on the ability to rotate of one glutamine which forms hydrophobic bonds with cAMP or cGMP [9, 10].

The fixed glutamine orientation allows to bind only one substrate [11].

that Gln-817 is critical for cGMP, sildenafil, and vardenafil affinity. The analogous atoms to substituents at N-1 and C-6 in cGMP form a bidentate H-bond with Gln 817 [11].

PDE5 was first identified in rat lung tissue, followed by numerous other tissues.

The enzyme was first purified and cloned in 1980 [12]. Chemically, sildenafil is a 5-[2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one. The crystallographic examination of

PDE5A

The L region of PDE5A surrounds the methylpiperazine group of sildenafil [3, 7].

Orally dosed sildenafil has an expected onset of action of 30 min, with estimated maximum effect at 1 h and a total duration of effect of 4–6 h.

In blood, approximately 96% of sildenafil is protein-bound with the pick serum concentration ( ) of 440 ng/mL being reached at median time of 60 min following administration of a 100 mg oral dose [13]. Sildenafil increases cellular cGMP levels through competition for the phosphodiesterase binding site with cGMP in that way inhibiting degradation of cGMP to GMP. cGMP through protein kinase G (PKG) plays an important role in the regulation of the activity of various cell populations including immune cells.

PKG is abundant in all smooth muscle cells and platelets, and its low levels occur in renal cells, fibroblasts, leukocytes, and neuronal cells. Biological substrates for PKG include inositol, triphosphate receptor (IP 3 R), G-proteins, dopamine- and cAMP-regulated phosphoprotein (DARP-32), and phospholipase C.

PKG promotes the opening of calcium-activated potassium channels and activates Ca 2+ influx, leading to cell hyperpolarization and relaxation [14].

The level of cGMP is also regulated by nitric oxide (NO). NO exerts multiple modulating effects on inflammation and plays a key role in the regulation of the immune responses.

Both the inducible nitric oxide synthase (iNOS) and the PDEs enzymes are expressed in numerous cell types including macrophages, dendritic cells, T cells, and neutrophils [15, 16]. NO is generated by three nitric oxide synthase (NOS) isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). The nitric oxide is the main activator of soluble guanylate cyclase (sGC), an enzyme which synthesizes guanosine 3?5?-cyclic monophosphate (cGMP). Inhibition of cGMP catabolism by selective PDE5-Is increases NO levels by increasing the ratio of nitrite to nitrate and by stimulating transcription of mRNA for iNOS, as well as eNOS [17]. In addition, nitric oxide increases in tissues and cells the level of heme oxygenase HO-1 which oxidatively degrades heme into equimolar amounts of CO, biliverdin, and iron.

Carbon monoxide activates sGC and elevates cGMP in target tissues, which dilates blood vessels.

Through that stimulation, sildenafil may serve a critical growth of cellular cGMP levels [18]. [17] demonstrated that sildenafil stimulates the expression of HO-1 and iNOS in vascular smooth muscle cells (SMCs) via the reactive oxygen species-nuclear erythroid 2-related factor 2 (ROS-Nrf2) and sGC-cGMP pathways, respectively [17]. Transcription factor Nrf2 is responsible for the induction of phase II enzymes of xenobiotics metabolism. It activates transcription of genes encoding cytoprotective proteins which deactivates electrophiles metabolites and reactive oxygen species and stabilizes the redox potential of the cell. Nrf2 controls antioxidant defense genes including HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), gluthatione reductase (GR), and gluthatione peroxidase (GPx) [18, 19]. [20] indicate direct effect of sildenafil on cells.

Sildenafil treatment of astrocytes prevents and also restores effect of LPS on actin filaments.

Changes in actin stress fibres is a result of overactivation of Ca 2+ signaling by LPS.

proposed that sildenafil directly influences cell integrity through ankyrin B, a protein which is associated with the cytoskeleton, and interacts with Na + /K + -ATP-ase and IP 3 R connecting the pump to the Ca 2+ responses from internal cell stores and to the integrity of the cytoskeleton.

These data show that cGMP is involved in Na + /K + -ATP-ase activity. Sildenafil acting through Na + /K + -ATP-ase could change Ca 2+ waves and stop the inflammatory process. The action of sildenafil is amplified through these mechanisms.

The Effect of Sildenafil on the Immune System of Healthy Experimental Animals.

There is some evidence that immunomodulatory properties of sildenafil are gender-specific.

In healthy mice, a tendency to decrease

the

The percentage of the activated NK cells and T conventional cells was increased in the female population and decreased in males. Sildenafil treatment did not affect the percentage of dendritic cells in the whole mouse population.