Phosphodiesterase 5 inhibitors for pulmonary hypertension

Barnes, Hayley; Brown, Zoe; Burns, Andrew; Williams, Trevor

doi:10.1002/14651858.cd012621

Cited by 29 publications

(51 citation statements)

References 22 publications

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“…Eleven types of this enzyme have been described to date. Some PDEs, namely PDE4, 7, and 8 are specific for cAMP (1)(2)(3), while other, such as PDE5, 6, and 9 for cGMP (4)(5)(6). The remaining family members, i.e., PDE1, 2, 3, 10, and 11 exhibit dual cAMP/cGMP specificity (5,7,8).…”

Section: Introductionmentioning

confidence: 99%

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

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Purpose This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. Methods Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. Results GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC 50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC 50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. Conclusions PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immunerelated diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

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Section: Introductionmentioning

confidence: 99%

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

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“…76,77 Sildenafil citrate use has been verified to exhibit protective effects in pulmonary arterial hypertension cases by suppressing multiple cytokines involved in the neutrophil and mononuclear cell recruitment, including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2a/b, tissue inhibitor of metalloproteinase-1, IL-1a, lipopolysaccharideinduced chemoattractant cytokines chemokine, monokine induced by gamma interferon, macrophage inflammatory protein (MIP)-1a, and MIP-3a. 78,79 Sildenafil has been shown to have positive effects in cases of acute lung injury, 80 by inhibiting the proliferation of regulatory T cells and the production of autoantibodies, proinflammatory cytokines, and modulating platelet activation, angiogenesis, and pulmonary vasoreactivity. Sildenafil use has been validated to reduce the leak of neutrophils into the lung, the release of proinflammatory mediators TNF-a, IL-8, and IL-6.…”

Section: Role Of Daily Phosphodiesterase Type 5 Inhibitors In Preventmentioning

confidence: 99%

COVID-19, Type 2 Diabetes, and Hypogonadism: Lessons for Acute Management and Long-Term Prevention

Hackett

Kirby

2020

Androgens: Clinical Research and Therapeutics

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Despite similar infection rates due to COVID-19 (SARS CoV-2) between men and women, male patients have twice the mortality rate across older age groups compared with women. Studies from China, Germany, and Italy suggest that there is a severe primary hypogonadism associated with acute infection and that the more severe the drop in testosterone, the higher the mortality. The co-morbidities associated with increased mortality, namely age, obesity, type 2 diabetes, chronic obstructive pulmonary disease, and chronic kidney disease are all associated with lower rates of testosterone in the general population. Longitudinal studies of testosterone therapy in these conditions have shown reduced all cause mortality. These findings suggest that screening for low testosterone and treating low levels might reduce all-cause mortality including COVID-19. Paradoxically, some observational studies in prostate cancer patients have reported lower mortality rates in those receiving androgen deprivation therapy (ADT). This has led to studies of ADT to reduce mortality associated with COVID-19 infection and suggestions that testosterone replacement therapy (TRT) should be stopped. This seems ill advised as recent publications suggest that TRT can reverse progression to type 2 diabetes and even lead to complete regression, as well as reducing all-cause mortality. In contrast, ADT has been repeatedly shown to have adverse cardio-metabolic effects with increased rates of depression, suicide and reduced quality of life. We also suggest a potentially important role for daily PDE5 inhibitors based on their established beneficial effect on endothelial dysfunction, pulmonary hypertension, insulin resistance, inflammation and cellular apoptosis.

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“…Patients with PH including PAH and non-PAH patients (e.g. PH due to left sided heart disease) were investigated in four studies [20,34,44,45] while patients with PAH were examined alongside other diseases (e.g. heart failure, prostate cancer) in two studies [46,60].…”

Section: Study Characteristicsmentioning

confidence: 99%

“…In nine studies, drugs targeting one pathway only were investigated: prostacyclins in five studies [40,48,61,63,66] and ERAs in four studies [25,46,60,64]. Fifteen studies [17,20,21,24,25,32,34,35,39,46,60,62,64,65,67] focused on oral treatments only. Besides the approved treatments, non-approved PAH treatments were included in seven studies: imatinib [52,53,56,62], terbogrel [29,62] and aspirin [52].…”

Section: Study Characteristicsmentioning

confidence: 99%

“…The outcomes evaluated included clinical, hemodynamics, health-related-quality-of -life (HRQoL) and safety. Frequently investigated clinical endpoints were 6MWD (as a standalone or within combined events) in 43 studies [17,19,20,[22][23][24][25][26][27][28][29][30][31][32][33] [18-20, 24, 27, 29, 31-33, 35, 37, 40, 42, 44, 45, 47, 48, 55, 57, 59, 60, 63, 65, 67].…”

Section: Study Characteristicsmentioning

confidence: 99%

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Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal

et al. 2020

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Background: The clinical landscape of pulmonary arterial hypertension (PAH) has evolved in terms of disease definition and classification, trial designs, available therapies and treatment strategies as well as clinical guidelines. This study critically appraises published evidence synthesis studies, i.e. meta-analyses (MA) and network-metaanalyses (NMA), to better understand their quality, validity and discuss the impact of the findings from these studies on current decision-making in PAH. Methods: A systematic literature review to identify MA/NMA studies considering approved and available therapies for treatment of PAH was conducted. Embase, Medline and the Cochrane's Database of Systematic Reviews were searched from database inception to April 22, 2020, supplemented by searches in health technology assessment websites. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist covering six domains (relevance, credibility, analysis, reporting quality and transparency, interpretation and conflict of interest) was selected for appraisal of the included MA/NMA studies. Results: Fifty-two full publications (36 MAs, 15 NMAs, and 1 MA/NMA) in PAH met the inclusion criteria. The majority of studies were of low quality, with none of the studies being scored as 'strong' across all checklist domains. Key limitations included the lack of a clearly defined, relevant decision problem, shortcomings in assessing and addressing between-study heterogeneity, and an incomplete or misleading interpretation of results. Conclusions: This is the first critical appraisal of published MA/NMA studies in PAH, suggesting low quality and validity of published evidence synthesis studies in this therapeutic area. Besides the need for direct treatment comparisons assessed in long-term randomized controlled trials, future efforts in evidence synthesis in PAH should improve analysis quality and scrutiny in order to meaningfully address challenges arising from an evolving therapeutic landscape.

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Phosphodiesterase 5 inhibitors for pulmonary hypertension

Abstract: This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To determine the e icacy of PDE-5 inhibitors for pulmonary hypertension in adults and children.

Cited by 29 publications

References 22 publications

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

COVID-19, Type 2 Diabetes, and Hypogonadism: Lessons for Acute Management and Long-Term Prevention

Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal

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