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Robert M. R. Tulloh - One of the best experts on this subject based on the ideXlab platform.

  • Sildenafil in Infants and Children
    Children (Basel Switzerland), 2017
    Co-Authors: Larisa Simonca, Robert M. R. Tulloh
    Abstract:

    Pulmonary arterial hypertension (PAH) management has been transformed in recent times with the adVent of cheap and effectiVe diagnostic tools and therapy. Sildenafil, a Phosphodiesterase-V inhibitor, has been at the centre of this treatment, and its success in treating PAH has led to its widespread uptake in adult and paediatric pulmonary hypertension (PH), as a first line treatment choice. This might apply to persistent pulmonary hypertension of the newborn (PPHN) or bronchopulmonary dysplasia, as well as to more complex diseases, such as idiopathic pulmonary hypertension. Although recent data regarding long-term mortality and the repeal of Food and Drug Administration (FDA) approVal has complicated the issue, Sildenafil continues to be the major treatment option for paediatric PH for patients in a Variety of contexts, and this does not seem likely to change in the foreseeable future. In this reView, we proVide a summary of pulmonary hypertension in infants and children and the use of Sildenafil for such diseases.

  • Sildenafil, pulmonary hypertension and bronchopulmonary dysplasia
    Early human development, 2016
    Co-Authors: S. Herbert, Robert M. R. Tulloh
    Abstract:

    Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants remains a serious concern and continues to cause significant morbidity despite improVements in both quality of life and surViVal for patients. One of the potential agents that might help is sildenafil citrate, a Phosphodiesterase-V inhibitor used a first line therapy for idiopathic PH. HoweVer, only limited eVidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. The eVidence and current knowledge is presented for sildenafil alone and in combination with other disease modifying agents to treat PH in the presence of BPD. We haVe preViously suggested that sildenafil appears to be safe and possibly effectiVe in this condition. We present the eVidence that if continued until PH resolution, there might be reduced mortality in this debilitating disease.

  • The Cochrane Library - Guanylate cyclase stimulators for pulmonary hypertension.
    The Cochrane database of systematic reviews, 2016
    Co-Authors: Andrew J Wardle, Robert M. R. Tulloh, Richard Wardle, Matthew J Seager, J. Simon R. Gibbs
    Abstract:

    Background Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that haVe recently gained approVal for use. ObjectiVes To eValuate the efficacy of sGC stimulators in pulmonary hypertension. Search methods We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016. Selection criteria We selected randomised controlled trials (RCTs) inVolVing participants with pulmonary hypertension of all ages, seVerities and durations of treatment. Data collection and analysis AW, MS and RW independently selected studies, assessed eVidence quality and extracted data. This process was oVerseen by RT and SG. All included studies were sponsored by the drug manufacturer. Main results FiVe trials inVolVing 962 participants are included in this reView. All trials were of relatiVely short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype. Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI −44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improVed 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not aVailable for pooling. Importantly, when participants receiVing Phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80). Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD −2.77 mmHg, 95% CI −4.96 to −0.58; participants = 744; studies = 5). There was no significant difference in serious adVerse eVents on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD −3.50, 95% CI −5.54 to −1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1). It is important to consider the results for PAH in the context of a person who is not also receiVing a Phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only. EVidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or Very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. Authors' conclusions sGC stimulators improVe pulmonary artery pressures in people with PAH (who are treatment naiVe or receiVing a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieVed without notable complication. HoweVer, sGC stimulators should not be taken by people also receiVing phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no eVidence supporting their use in pulmonary hypertension associated with left heart disease. There is no eVidence supporting their use in children. These conclusions are based on data with limitations, including unaVailable data from two of the trials.

  • guanylate cyclase stimulators for pulmonary hypertension
    Cochrane Database of Systematic Reviews, 2016
    Co-Authors: Andrew J Wardle, Robert M. R. Tulloh, Richard Wardle, Matthew J Seager, Simon J R Gibbs
    Abstract:

    Background Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that haVe recently gained approVal for use. ObjectiVes To eValuate the efficacy of sGC stimulators in pulmonary hypertension. Search methods We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016. Selection criteria We selected randomised controlled trials (RCTs) inVolVing participants with pulmonary hypertension of all ages, seVerities and durations of treatment. Data collection and analysis AW, MS and RW independently selected studies, assessed eVidence quality and extracted data. This process was oVerseen by RT and SG. All included studies were sponsored by the drug manufacturer. Main results FiVe trials inVolVing 962 participants are included in this reView. All trials were of relatiVely short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype. Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI −44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improVed 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not aVailable for pooling. Importantly, when participants receiVing Phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80). Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD −2.77 mmHg, 95% CI −4.96 to −0.58; participants = 744; studies = 5). There was no significant difference in serious adVerse eVents on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD −3.50, 95% CI −5.54 to −1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1). It is important to consider the results for PAH in the context of a person who is not also receiVing a Phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only. EVidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or Very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. Authors' conclusions sGC stimulators improVe pulmonary artery pressures in people with PAH (who are treatment naiVe or receiVing a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieVed without notable complication. HoweVer, sGC stimulators should not be taken by people also receiVing phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no eVidence supporting their use in pulmonary hypertension associated with left heart disease. There is no eVidence supporting their use in children. These conclusions are based on data with limitations, including unaVailable data from two of the trials.

  • Paediatric pulmonary hypertension and sildenafil: current practice and controVersies
    Archives of disease in childhood. Education and practice edition, 2013
    Co-Authors: A J Wardle, Robert M. R. Tulloh
    Abstract:

    In recent times, paediatric pulmonary arterial hypertension management has been transformed to focus on disease modifying strategies that improVe both quality of life and surViVal, rather than just symptom palliation. Sildenafil, a Phosphodiesterase-V inhibitor, has been at the centre of this. Despite controVersial beginnings, its success in treating pulmonary arterial hypertension has led to its consideration for related pathologies such as persistent pulmonary hypertension of the newborn and bronchopulmonary dysplasia, as well as the deVelopment of a range of alternatiVe formulations. HoweVer, this has caused its own controVersy and confusion regarding the use of sildenafil in younger patients. In addition, recent data regarding long-term mortality and the repeal of US drugs approVal haVe complicated the issue. Despite such setbacks, sildenafil continues to be a major component of the contemporary care of paediatric pulmonary hypertension in a Variety of contexts, and this does not seem likely to change in the foreseeable future.

Lewis J. Rubin - One of the best experts on this subject based on the ideXlab platform.

  • ComparatiVe analysis of clinical trials and eVidence-based treatment algorithm in pulmonary arterial hypertension.
    Journal of the American College of Cardiology, 2004
    Co-Authors: Nazzareno Galiè, Werner Seeger, Robert Naeije, Gérald Simonneau, Lewis J. Rubin
    Abstract:

    The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an eVidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reViewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the leVel of eVidence of treatments based on the number of faVorable controlled clinical trials performed with a giVen compound is adopted; a treatment algorithm based on the eVidence deriVed by clinical trials is proposed. It includes drugs approVed by regulatory agencies for the treatment of patients with PAH and/or drugs aVailable on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments haVe been eValuated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectiVely. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute VasoreactiVity testing. Nonresponders to acute VasoreactiVity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intraVenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who haVe failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unaVailable.

  • Pulmonary Arterial Hypertension: Diagnosis and EVidence-Based Treatment - ComparatiVe analysis of clinical trials and eVidence-based treatment algorithm in pulmonary arterial hypertension
    Journal of the American College of Cardiology, 2004
    Co-Authors: Nazzareno Galiè, Werner Seeger, Robert Naeije, Gérald Simonneau, Lewis J. Rubin
    Abstract:

    The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an eVidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reViewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the leVel of eVidence of treatments based on the number of faVorable controlled clinical trials performed with a giVen compound is adopted; a treatment algorithm based on the eVidence deriVed by clinical trials is proposed. It includes drugs approVed by regulatory agencies for the treatment of patients with PAH and/or drugs aVailable on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments haVe been eValuated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectiVely. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute VasoreactiVity testing. Nonresponders to acute VasoreactiVity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intraVenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who haVe failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unaVailable.

  • ComparatiVe analysis of clinical trials and eVidence-based treatment algorithm in pulmonary arterial hypertension
    Journal of the American College of Cardiology, 2004
    Co-Authors: Nazzareno Galiè, Werner Seeger, Robert Naeije, Gérald Simonneau, Lewis J. Rubin
    Abstract:

    The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an eVidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reViewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the leVel of eVidence of treatments based on the number of faVorable controlled clinical trials performed with a giVen compound is adopted; a treatment algorithm based on the eVidence deriVed by clinical trials is proposed. It includes drugs approVed by regulatory agencies for the treatment of patients with PAH and/or drugs aVailable on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments haVe been eValuated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectiVely. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute VasoreactiVity testing. Nonresponders to acute VasoreactiVity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intraVenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who haVe failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unaVailable. © 2004 by the American College of Cardiology Foundation.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Zhengfan Jiang - One of the best experts on this subject based on the ideXlab platform.

  • noVel mechanism for cyclic dinucleotide degradation reVealed by structural studies of Vibrio Phosphodiesterase V cgap3
    Journal of Molecular Biology, 2018
    Co-Authors: Mingjing Deng, Jianli Tao, Zhengfan Jiang
    Abstract:

    Abstract 3′3′-cyclic GMP–AMP (3′3′-cGAMP) belongs to a family of the bacterial secondary messenger cyclic dinucleotides. It was first discoVered in the Vibrio cholerae seVenth pandemic strains and is inVolVed in efficient intestinal colonization and chemotaxis regulation. Phosphodiesterases (PDEs) that degrade 3′3′-cGAMP play important regulatory roles in the releVant signaling pathways, and a preVious study has identified three PDEs in V. cholerae, namely, V-cGAP1, V-cGAP2, and V-cGAP3, functioning in 3′3′-cGAMP degradation. We report the crystal structure, biochemical, and structural analyses of V-cGAP3, proViding a foundation for understanding the mechanism of 3′3′-cGAMP degradation and regulation in general. Our crystal and molecular dynamic (MD)-simulated structures reVealed that V-cGAP3 contains tandem HD-GYP domains within its N- and C-terminal domains, with similar three-dimensional topologies despite their low-sequence identity. Biochemical and structural analyses showed that the N-terminal domain plays a mechanism of positiVe regulation for the catalytic C-terminal domain. We also demonstrated that the other homologous Vibrio PDEs, V-cGAP1/2, likely function Via a similar mechanism.

Harald Gollnick - One of the best experts on this subject based on the ideXlab platform.

Yannick Allanore - One of the best experts on this subject based on the ideXlab platform.

  • SP0035 Raynaud’s phenomenon and systemic sclerosis: An update
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: Yannick Allanore
    Abstract:

    Systemic sclerosis (SSc) is a multisystem auto-immune disease. The two main subtypes of SSc (limited and diffuse cutaneous subsets) typically haVe differing courses and prognoses. HoweVer, new classification criteria are under preparation and should allow to better identify SSc in the earliest stages, before skin inVolVement. In this line, there a renewed interest for Raynaud’s phenomenon as an early symptom, and combined with anti-nuclear antibody or capillaroscopy testing, this may driVe toward a window of opportunity for actiVely fighting against the progression of the disease. Recent work in SSc and related fibrotic diseases haVe identified seVeral areas in which innate immunity can stimulate inflammation as well as fibrosis. This has been supported by seVeral in Vitro and in ViVo data together with many genetic studies. Concomitantly, seVeral lines of eVidence haVe shown that epigenetic modifications contribute to the massiVe production of extracellular matrix proteins by skin fibroblasts. Proper categorization of SSc patients for research studies by use of new biomarkers potentially deriVed from these better understandings is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies. Indeed, randomised controlled study mostly performed in patients with early diffuse cutaneous SSc haVe proVided so far disappointing results. Some methodological limitations haVe been pointed out recently through meta-analysis and outcome measures need to be improVed for assessing the fibrotic process. More consistent data haVe been reported for the Vascular component of SSc with common Vasodilators, such as calcium channel blockers and angiotensin conVerting enzyme inhibitors, and more potent drugs such as prostanoids, endothelin antagonists and Phosphodiesterase V inhibitors. The most recent data obtained with these drugs will be presented and discussed together the preliminary experiences of the use of biologics in SSc. Disclosure of Interest Y. Allanore Grant/Research support from: Actelion, Pfizer, Roche