WHO classification of pulmonary hypertension

WHO classification of pulmonary hypertension

Source publication
Article
Full-text available
Sildenafil is an orally administered phosphodiesterase type 5 inhibitor that is approved for the treatment of pulmonary arterial hypertension (PAH). The hemodynamic effects of sildenafil are mitigated primarily via potentiating the effects of endogenous nitric oxide, leading to smooth muscle cell relaxation and reductions in pulmonary arterial pres...

Context in source publication

Context 1
... conditions result in development of pulmonary hypertension, but are not characterized as PAH (Table 3). Phase III clinical trials have excluded these patients, and therefore, sildenafil is not FDA approved for treatment in these conditions. ...

Similar publications

Article
Full-text available
Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud’s Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance...
Article
Full-text available
Systemic sclerosis is a connective tissue disease characterized by cutaneous and visceral fibrosis, as well as vascular disease involving arterioles, small and medium arteries of the peripheral circulation. Digital ulcers, defined as necrotic lesions that occur either at distal aspects of digits or over bony prominence, occur in up to 50% of patien...
Article
Full-text available
Background Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH). Methods Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3...
Article
The interaction of sildenafil citrate (Viagra) with DNA was studied by using an electrochemical DNA biosensor. The binding mechanism of sildenafil citrate was elucidated by using constant current potentiometry and differential pulse voltammetry at DNA-modified glassy carbon electrode. The decrease in the guanine oxidation peak area or peak current...
Article
Full-text available
Recent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH. We retrospec...

Citations

... Sildenafil's methods of action break down cyclic guanosine monophosphate, causing smooth muscle relaxation via the NO pathway. [1][2][3] Sildenafil is a drug that is prescribed for erectile dysfunction, pulmonary hypertension, and premature ejaculation. [1][2][3][4][5] Sildenafil is water insoluble and has a high membrane permeability, making it a biopharmaceutical categorization system Class II substance. ...
... [1][2][3] Sildenafil is a drug that is prescribed for erectile dysfunction, pulmonary hypertension, and premature ejaculation. [1][2][3][4][5] Sildenafil is water insoluble and has a high membrane permeability, making it a biopharmaceutical categorization system Class II substance. Despite the fact that the traditional sildenafil product was produced as a citrate salt to boost water solubility (4.1 mg/mL), it still has a low oral bioavailability (40%) and a slow onset of action. ...
Article
Sildenafil is a specific inhibitor of the phosphodiesterase type 5 (PDE-5) enzyme that protects cyclic guanosine monophosphate from breakdown by PDE-5. It is a biopharmaceutical categorization system Class II medication with low bioavailability because it is almost insoluble in water. The objectives of this study were to prepare sildenafil cocrystals with co-former molecules including aspirin (acetylsalicylic acid [ASA]), fumaric acid (FMA), and benzoic acid (BZA) to improve the water solubility of sildenafil. The cocrystals were prepared by antisolvent addition (AA) and slow solvent evaporation (SE) methods. The stoichiometric ratios of sildenafil and co-former molecules were varied. The obtained crystals were characterized by stereomicroscope, Fourier transformed infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), and powder X-ray diffraction (PXRD). The water solubility of sildenafil cocrystals was compared with sildenafil base. In the AA method, the crystals only form in sildenafil-ASA reaction. These crystals were not cocrystals between sildenafil and ASA because they were formed to new substances that were confirmed by single-crystal X-ray diffraction. In the SE method, the cocrystals were successfully prepared in the reaction of sildenafil with ASA, FMA, and BZA which use acetone or ethyl acetate as a solvent. The obtained crystals are irregular shapes and their FT-IR, NMR, and PXRD results exhibited the characteristics of sildenafil and its co-former. The stoichiometric ratios of sildenafil and co-formers after cocrystallization were different from an initial of crystallization. The sildenafil cocrystals with ASA, FMA, and BZA by SE method had higher water solubility than sildenafil base. The sildenafil-FMA cocrystals had the highest water solubility and increased up to five times when compared with sildenafil base.
... On the other hand, it has been twenty years since the Federal Drug Administration of the United States as the first oral agent to treat erectile dysfunction approved sildenafil citrate (Viagra ® , Pfizer). Sildenafil acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow to the penis (Ramani & Park, 2010) Both, in blood and seminal plasma, Sildenafil citrate concentration reaches a maximum at about 90 minutes after administration (Al-Ghazawi et al., 2007) However, the drug remains in micromolar concentrations several hours after its administrations (Al-Ghazawi et al., 2007;Gupta et al., 2005). This pharmacokinetic feature led us to investigate the possible effects of this drug on sperm function. ...
... Remarkably, some years later after the approval of this indications, it was repurposed as a treatment for pulmonary hypertension (Ramani and Park, 2010). ...
Chapter
Drug repurposing involves exploring new medical uses for existing drugs, including approved, discontinued, shelved and investigational therapeutics. As the new indication is built on already available safety, pharmacokinetic and manufacturing data, drug repurposing represents an expedited way to develop innovative medications, and has found especial interest in the fields of rare and neglected conditions. It is estimated that about one third of recent approvals correspond to repurposing examples, and different public initiatives have been launched to foster the exploration of repurposing opportunities. The present chapter reviews classical and recent examples of off-label use, drug rescue and drug repositioning at different stages of the drug development process, from sildenafil to aspirin, from thalidomide to adalimumab, among many others. It also discusses challenges and opportunities of drug repurposing, from commercial and legal obstacles to expansion of the drug repurposing horizons in the context of precision medicine and polypharmacology. At last, modern approximations to explore repurposing prospects in a systematic manner are summarized.
... Sildenafil and tadalafil are phosphodiesterase-5 inhibitors, resulting in vasorelaxation by enhancing the downstream effects of nitric oxide (NO) [29]. NO triggers a conversion from guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), leading to vasodilation [30]. ...
... Sildenafil is the first commercially available oral phosphodiesterase 5 inhibitor [5,29]. It was initially approved for the treatment of erectile dysfunction in 1998 and obtained approval in 2005 to treat PAH in adults [39,40]. ...
Article
Full-text available
Introduction:Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects. Areas covered: We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics. Expert opinion: Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.
... [7] Nitric oxide (NO) is endogenously synthesized from L-arginine through NO synthase. [8,9] Vasodilation action of NO is mediated by downstream signaling molecules such as soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate (cGMP) [9][10][11] which is a key mediator in NO/sGC/cGMP signaling, whose action is mediated by cGMP dependent protein kinase G (PKG) and cGMP gated channels. [9] Cyclic nucleotide phosphodiesterases (PDEs) are a group of enzymes having at least 11 isoforms, which degrade the phosphodiester bond in cAMP and cGMP. ...
... [14] Therefore, PDE5 inhibitors such as sildenafil and tadalafil have demonstrated brilliant outcomes for the treatment of SSc related pulmonary arterial hypertension (PAH) and digital ulcers. [10,11,15] In addition, recently, it has been observed that NO/sGC/ cGMP signaling exerts anti-fibrotic activities [16][17][18][19] through stimulation of sGC, which thereby leads to increase in cGMP levels, resulting in reversing of fibrotic phenotype in SSc. [7,20,21] Henceforth, PDE5 inhibitors have also been reported to have anti-fibrotic effects in models of various fibrotic disorders. ...
... Effect of sildenafil and SB204741 on TGF-β1 induced anti-fibrotic genes mRNA expression: (a-c) HADFs were cultured with only media (bar 1) and with TGF-β1 (bar 2). HADFs were pre-treated with TGF-β1 (10 ng/ml) for 1 hour followed by co-culture with TGF-β1 (10 ng/ml) and10 µM dose of sildenafil (bar 3) and (1 µM) dose of SB204741 (bar 4) respectively for 24 hours. HADFs were pre-treated with 10 µM dose of sildenafil (bar 5) and (1 µM) dose of SB204741 (bar 6) respectively for 1 hour and later incubated with TGF-β1 (10ng/ml) only for 24 hours. ...
... Moreover, being a clinically applied drug, chronic sildenafil treatment is a potential pharmacologic strategy to reduce the risk of CVDs during aging or in progeria. The safety profile of sildenafil in older men that regularly use this drug for erectile dysfunction and in patients with pulmonary hypertension has been well described for chronic use [26,30]. Sildenafil is well tolerated, and adverse events were mostly transient and mild to moderate in severity. ...
Article
Full-text available
Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO–cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO–cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO–cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
... Its onset of action is estimated after 30-60 min, with a duration of up to 12 h and pharmacokinetics affected by fatty food (Goldstein et al., 1998;Moncada et al., 2004). Apart from ED (Hatzimouratidis et al., 2019), sildenafil has been used for treating pulmonary hypertension (Ramani and Park, 2010) and as an off-label medication with unclear role for vasospasm related to other pathologies such as recurrent priapism (Tzortzis et al., 2009), and Raynaud's syndrome (Roustit et al., 2018). Tadalafil was launched in 2003 with a similar onset of action but the prolonged duration of effects lasting up to 36 h. ...
Article
Highlights •Contrast-induced nephropathy is determined by disturbances in oxidant/antioxidant balance. •TAC, GSH and CAT levels decrease while TABRS and PROTC levels increase in CIN. •Sildenafil and tadalafil reduce CIN risk. •Sildenafil and tadalafil increase TAC, GSH and CAT levels. •Sildenafil and tadalafil decrease TBARS and PROTC levels. Abstract The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.
... The selective cyclic guanosine monophosphate (cGMP) phosphodiesterase subtype 5 (PDE5) inhibitor sildenafil citrate was approved for management of erectile dysfunction in 1998 (Giuliano et al. 2010) and pulmonary arterial hypertension in 2005 (Ramani and Park 2010). Sildenafil Abstract Mattapallil et al. described that vendor lines for C57BL/6 N mice may carry the rd8 mutation that leads to an ocular phenotype, which could be mistaken for an induced retinal degeneration. ...
Chapter
Leber congenital amaurosis (LCA) caused by AIPL1 mutations is one of the most severe forms of inherited retinal degeneration (IRD). The rapid and extensive photoreceptor degeneration challenges the development of potential treatments. Nevertheless, preclinical studies show that both gene augmentation and photoreceptor transplantation can regenerate and restore retinal function in animal models of AIPL1-associated LCA. However, questions regarding long-term benefit and safety still remain as these therapies advance towards clinical application. Ground-breaking advances in stem cell technology and genome editing are examples of alternative therapeutic approaches and address some of the limitations associated with previous methods. The continuous development of these cutting-edge biotechnologies paves the way towards a bright future not only for AIPL1-associated LCA patients but also other forms of IRD.
... The recently released Endocrine Society clinical practice guideline on pediatric obesity notes that, given its limited efficacy, metformin is not considered an appropriate agent for treatment of obesity (39). Similarly, sildenafil has been in extensive clinical use for 20 years with no evidence of independent effects on weight (40)(41)(42)(43), and administration of leucine at the dose used in NS-0200 to adults with overweight and obesity increased fat oxidation but did not result in weight loss in the absence of caloric restriction (44). These data indicate that the individual components of NS-0200 have little or no independent therapeutic potential in weight management, supporting the appropriateness of a fixed-dose combination. ...
Article
Objective Leucine was previously demonstrated to allosterically activate mammalian sirtuin 1 and synergize with other sirtuin 1/AMP‐activated protein kinase/nitric oxide pathway activators to modulate energy metabolism. The objective of this study was to evaluate the effects of a triple combination of leucine, metformin, and sildenafil (NS‐0200) on body weight and obesity comorbidities in a phase 2 randomized trial. Methods A total of 91 subjects with obesity were randomized to placebo, low dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil), or high dose (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) twice daily for 16 weeks. Seventy subjects completed the trial and met all a priori compliance criteria. Hypertensive (n = 35) and hypertriglyceridemic (n = 22) subcohorts were also analyzed. Results NS‐0200 dose‐responsively reduced weight; high dose reduced weight by 2.4 and 5.0 kg in the full and high‐triglyceride cohorts, respectively (P < 0.0001). High‐dose NS‐0200 treatment also decreased blood pressure (−5.5 mm Hg diastolic pressure; P = 0.011), with greater effects among hypertensive subjects. NS‐0200 also significantly reduced triglycerides and hemoglobin A1c. Significant improvement in ≥ 2 comorbidities was exhibited by 54% of subjects in the high‐dose arm versus 5% of placebo subjects (P = 0.0009). Treatment‐emergent adverse events did not significantly differ among groups. Conclusions These data support further study of NS‐0200 as a therapy for obesity and associated comorbidities.
... Cialis ® , for example, is popular as a "Weekend-pill," because of its long half-life time, Levitra ® is popular because of its rapid onset of effect and Spedra ® because it is highly selective. All PDE-5-inhibitors have similar sideeffects, like flush, dizziness and a congested nose [2][3][4][5][6]. Epistaxis as an undesired side-effect has so far only been described in connection with Viagra ® and Cialis ® [3][4][5][6]. ...
Article
Full-text available
Reports about Sildefanil (Viagra®) and Epistaxis are anecdotal. This review could identify only three reports in world literature with a total number of four patients. In a 20 year period since the Viagra® approval by the FDA in 1998, this seems to be a rather low number of cases. All persons developed Epistaxis secondary to Viagra intake, two persons had also taken Cialis®. None had Erectile Dysfunction, all had consumed the PDE-5-inhibitors to enhance their sexual performance, the undesired side-effects therefore rather affect consumers than patients. On the other hand this may be an indication that Viagra® is a very safe substance, since no reports about multimorbid patients and Viagra-related Epistaxis have been published so far.