Pulmonary hypertension

A Daily Dose of Viagra Gave Test Subjects a Valuable Health Benefit

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By sustaining erections where limpness once prevailed, Viagra has vastly improved the sex lives of many people. But the little blue pill, it turns out, may be useful outside the bedroom as well. In March, researchers discovered that the popular erectile dysfunction drug can play a potentially life-saving role in another body part — the colon.

The scientists, publishing their findings in the journal Cancer Prevention Research, showed that a small daily dose of Viagra played a role in preventing colon cancer, at least in mice.

Using mice engineered to be predisposed to growing colon polyps — abnormal cell clumps that can sometimes become cancerous — the scientists tested whether a small daily dose of Viagra could prevent the development of colon cancer in the mice. Specifically, they were looking at the effect of sildenafil, the active ingredient in Viagra, on the rate of polyp formation. The daily dose, administered through the drinking water of the mice, reduced polyp formation and colon inflammation by 50 percent.

viagra
When administered to mice in small doses, Viagra reduced the rate of formation for polyps, cell clumps that could become cancerous.

The study built upon previous work suggesting that Viagra inhibits an enzyme in colon cells that boosts cell proliferation. The more that cells multiply, the more opportunities they have to pick up mutations that can lead to cancer, so suppressing cell proliferation. While the researchers don’t know exactly how Viagra is working its magic in these mice just yet, they know that reducing the rate of polyp formation is one promising way to prevent the development of colon cancer (and prevent the painful rectal bleeding that colon polyps cause, whether they’re cancerous or not).

Viagra, for its part, has proven to be useful in solving other medical problems. It’s used to treat premature babies with pulmonary hypertension, a deadly condition in which blood pressure rises in the lungs, and its been shown to help treat prostate cancer when used in tandem with another cancer-fighting drug.

Not that everything went well for Viagra in 2018. An ongoing problem for United States public health experts is the ongoing popularity of vape liquids that contain erectile dysfunction drugs and the danger they pose to users. Not regulated by any medical authority, these widely available vape liquids contain unknown amounts of sildefanil and taladafil (the active ingredient in the erectile dysfunction drug Cialis), which themselves may be counterfeit. One account even claimed it gave a user a two-day erection.

Pulmonary Hypertension & Viagra: Researchers Discover Novel Mechanisms of Sildenafil for Disease.

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A group of researchers from the University of Pécs, Hungary, have attempted to understand the mechanism by which pulmonary vascular remodeling initiates right ventricular failure and hypoxia, one of the leading causes behind the mortality rates associated with Pulmonary Hypertension (PH).

viagra and PH

Sildenafil, known more commonly by its brand name Viagra, is an inhibitor of phosphodiesterase type 5 (PDE-5), an enzyme found in various tissues and involved in the cardiovascular system, and is frequently used in the treatment of PH, since it can improve exercise capacity, PH symptoms, and haemodynamics. However, the molecular mechanisms behind the protective effect exerted by this drug are not fully understood.

In this study, entitled “Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt”, published in the PLOS ONE journal, the team used a monocrotaline (MCT, a toxic metabolite of plant origin)-induced rat PH model to analyze lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-kB activation, to understand the mechanisms by which sildenafil’s exerts its protective effects in PH.

The authors could observe that sildenafil not only protected lung morphology but it also suppressed several cytokines directly related with neutrophil and mononuclear cell recruitment, such as cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2a/b, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1a, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1a, and MIP-3a.

All of these cytokines induced by MCT treatment are regulated by NF-kB, and as such, through immunoblotting and immunohistochemistry with specific antibodies targeted at this nuclear factor, the authors discovered that MCT treatment caused a massive activation and nuclear translocation of NF-kB, a process significantly decreased upon sildenafil treatment.

Furthermore, sildenafil reduced the amount of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation, enhancing the activation of the cytoprotective Akt pathway in these PH mice.

Based on the results of this study, the authors concluded that, in mice, sildenafil is able to overcome the pathologic remodeling processes induced by MCT treatment, thus decreasing the infiltration of inflammatory cells and reducing edema formation.

Altogether, these data can reveal important clues regarding the novel mechanisms responsible for the beneficial effects of Viagra use in PH patients to reduce inflammation and swelling, moving one step closer to the development of improved therapies targeted at this progressive and incurable disease.

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension.

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Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.

METHODS

We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.

RESULTS

A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.

CONCLUSIONS

Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study.

Source: NEJM

 

Pulmonary hypertension in β thalassaemia.

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Pulmonary hypertension is one of the leading causes of morbidity and mortality in patients with haemolytic disorders and is a frequent finding in echocardiographic screening of patients with β thalassaemia. Substantial progress has been made in understanding of the multifactorial pathophysiology of pulmonary hypertension in β thalassaemia. Haemolysis, reduced nitric oxide bioavailability, iron overload, and hypercoagulopathy are among the main pathogenetic mechanisms. Various disease-directed therapeutic methods, such as transfusion, chelation, and splenectomy, have important roles in the development of pulmonary hypertension in β thalassaemia. Studies investigating the prevalence of pulmonary hypertension in β thalassaemia are mostly based on echocardiographic findings, and are thus limited by the scarcity of information derived from right heart catheterisation. Invasive pulmonary haemodynamic data are needed to clarify the true prevalence of pulmonary hypertension in β thalassaemia, to better understand the underlying pathophysiology and risk factors, and to define the optimum therapy for this devastating complication.

Source: Lancet

A Novel Channelopathy in Pulmonary Arterial Hypertension.

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BACKGROUND

Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes.

METHODS

We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis.

RESULTS

We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082.

CONCLUSIONS

Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation.

Source: NEJM

 

Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.

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BACKGROUND

Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.

METHODS

In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.

RESULTS

By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm–5 in the riociguat group and increased by 23 dyn·sec·cm–5 in the placebo group (least-squares mean difference, –246 dyn·sec·cm–5; 95% CI, –303 to –190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).

CONCLUSIONS

Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.

Source: NEJM

 

Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.

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BACKGROUND

Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.

METHODS

In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.

RESULTS

By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm–5 in the riociguat group and increased by 23 dyn·sec·cm–5 in the placebo group (least-squares mean difference, –246 dyn·sec·cm–5; 95% CI, –303 to –190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).

CONCLUSIONS

Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.

Source: NEJM

 

Pulmonary hypertension in β thalassaemia.

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Pulmonary hypertension is one of the leading causes of morbidity and mortality in patients with haemolytic disorders and is a frequent finding in echocardiographic screening of patients with β thalassaemia. Substantial progress has been made in understanding of the multifactorial pathophysiology of pulmonary hypertension in β thalassaemia. Haemolysis, reduced nitric oxide bioavailability, iron overload, and hypercoagulopathy are among the main pathogenetic mechanisms. Various disease-directed therapeutic methods, such as transfusion, chelation, and splenectomy, have important roles in the development of pulmonary hypertension in β thalassaemia. Studies investigating the prevalence of pulmonary hypertension in β thalassaemia are mostly based on echocardiographic findings, and are thus limited by the scarcity of information derived from right heart catheterisation. Invasive pulmonary haemodynamic data are needed to clarify the true prevalence of pulmonary hypertension in β thalassaemia, to better understand the underlying pathophysiology and risk factors, and to define the optimum therapy for this devastating complication.

Source: lancet