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Robert M. R. Tulloh - One of the best experts on this subject based on the ideXlab platform.
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Sildenafil in Infants and Children
Children (Basel Switzerland), 2017Co-Authors: Larisa Simonca, Robert M. R. TullohAbstract: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.
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Sildenafil, pulmonary hypertension and bronchopulmonary dysplasia
Early human development, 2016Co-Authors: S. Herbert, Robert M. R. TullohAbstract: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.
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The Cochrane Library - Guanylate cyclase stimulators for pulmonary hypertension.
The Cochrane database of systematic reviews, 2016Co-Authors: Andrew J Wardle, Robert M. R. Tulloh, Richard Wardle, Matthew J Seager, J. Simon R. GibbsAbstract: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.
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Paediatric pulmonary hypertension and sildenafil: current practice and controVersies
Archives of disease in childhood. Education and practice edition, 2013Co-Authors: A J Wardle, Robert M. R. TullohAbstract: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.
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The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia
Archives of disease in childhood, 2013Co-Authors: Andrew James Wardle, Richard Wardle, Karen Luyt, Robert M. R. TullohAbstract:The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has eVolVed in recent years, improVing both quality of life and surViVal for patients. One of the potential agents for this condition is sildenafil, a Phosphodiesterase-V Inhibitor with proVen efficacy within the idiopathic PH population. HoweVer, only limited eVidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This reView summarises the eVidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improVed patient outcomes. We conclude that sildenafil is both safe and effectiVe in this utility. Doses should be started at 0.5 mg/kg eVery 8 h before titrating up towards 2 mg/kg eVery 6 h to effect reductions in pulmonary Vascular resistance and arterial pressure. EVidence suggests that if continued until PH resolution, this improVes surViVal from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered.
Hyun Joo Shim - One of the best experts on this subject based on the ideXlab platform.
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SensitiVe liquid chromatography assay with ultraViolet detection for a new Phosphodiesterase V Inhibitor, DA-8159, in human plasma and urine.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2003Co-Authors: Joo Youn Cho, Hyeong Seok Lim, Hyun Joo Shim, In-jin Jang, Sang-goo ShinAbstract:Abstract A sensitiVe high-performance liquid chromatographic (HPLC) method with ultraViolet absorption detection (292 nm) was deVeloped and Validated for the determination of the new Phosphodiesterase V Inhibitor, DA-8159 (DA), in human plasma and urine. A single step liquid–liquid extraction procedure using ethyl ether was performed to recoVer DA and the internal standard (sildenafil citrate) from 1.0 ml of biological matrices combined with 200 μl of 0.1 M sodium carbonate buffer. A Capcell Pak C18 UG120 column ( 150 mm ×4.6 mm I.D., 5 μm) was used as a stationary phase and the mobile phase consisted of 30% acetonitrile and 70% 20 mM potassium phosphate buffer (pH 4.5) at a flow rate of 1.0 ml/min. The lower limit for quantification was 5 ng/ml for plasma and 10 ng/ml for urine samples. Within- and between-run accuracy and precision were ≤15 and ≤10%, respectiVely, in both plasma and urine samples. The recoVery of DA from human plasma and urine was greater than 70%. Separate stability studies showed that DA is stable under the conditions of analysis. This Validated assay was used for the pharmacokinetic analysis of DA during a phase I, rising dose study.
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Determination of a new Phosphodiesterase V Inhibitor, DA-8159, in plasma and urine by high-performance liquid chromatography
Journal of pharmaceutical and biomedical analysis, 2002Co-Authors: Hyun Joo Shim, Eunjoo Lee, Young Hee Jung, So Hee Kim, Soon Hoe Kim, Moohi Yoo, Jong Won Kwon, Won Bae Kim, Myung Gull LeeAbstract:Abstract A high-performance liquid chromatographic (HPLC) method using liquid–liquid extraction for sample preparation was deVeloped for the determination of a new Phosphodiesterase V Inhibitor, DA-8159, in rat plasma and urine using sildenafil citrate as an internal standard. A 100 μl aliquot of 0.1 M Na2CO3 (containing sildenafil citrate, 3 μg/ml as free sildenafil) and a 1 ml aliquot of ether were added to a 100 μl aliquot of biological samples (urine samples were diluted 20 times with distilled water). After Vortex centrifugation at 9000×g for 3 min, the ether layer was collected and dried under nitrogen gas. The residue was reconstituted with a 150 μl aliquot of the mobile phase, centrifuged, and a 100 μl aliquot of the supernatant was injected onto a reVersed-phase column. The mobile phases, 20 mM KH2PO4 (pH 4.7):acetonitrile (70:30, V/V for plasma and tissue samples, and 75:25, V/V for urine samples), were run at a flow rate of 1.0 ml/min. The column effluent was monitored by an ultraViolet detector set at 292 nm. The retention times for DA-8159 and the internal standard were approximately 10.7 and 9.1 min, respectiVely, in plasma and tissue samples and the corresponding Values in urine samples were 47 and 33 min. The detection limits for DA-8159 in rat plasma and urine were 20 and 100 ng/ml, respectiVely. The coefficients of Variation of the assay were generally low: below 10% for plasma and 9.9% for urine. No interferences from endogenous substances were found.
Myung Gull Lee - One of the best experts on this subject based on the ideXlab platform.
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Determination of a new Phosphodiesterase V Inhibitor, DA-8159, in plasma and urine by high-performance liquid chromatography
Journal of pharmaceutical and biomedical analysis, 2002Co-Authors: Hyun Joo Shim, Eunjoo Lee, Young Hee Jung, So Hee Kim, Soon Hoe Kim, Moohi Yoo, Jong Won Kwon, Won Bae Kim, Myung Gull LeeAbstract:Abstract A high-performance liquid chromatographic (HPLC) method using liquid–liquid extraction for sample preparation was deVeloped for the determination of a new Phosphodiesterase V Inhibitor, DA-8159, in rat plasma and urine using sildenafil citrate as an internal standard. A 100 μl aliquot of 0.1 M Na2CO3 (containing sildenafil citrate, 3 μg/ml as free sildenafil) and a 1 ml aliquot of ether were added to a 100 μl aliquot of biological samples (urine samples were diluted 20 times with distilled water). After Vortex centrifugation at 9000×g for 3 min, the ether layer was collected and dried under nitrogen gas. The residue was reconstituted with a 150 μl aliquot of the mobile phase, centrifuged, and a 100 μl aliquot of the supernatant was injected onto a reVersed-phase column. The mobile phases, 20 mM KH2PO4 (pH 4.7):acetonitrile (70:30, V/V for plasma and tissue samples, and 75:25, V/V for urine samples), were run at a flow rate of 1.0 ml/min. The column effluent was monitored by an ultraViolet detector set at 292 nm. The retention times for DA-8159 and the internal standard were approximately 10.7 and 9.1 min, respectiVely, in plasma and tissue samples and the corresponding Values in urine samples were 47 and 33 min. The detection limits for DA-8159 in rat plasma and urine were 20 and 100 ng/ml, respectiVely. The coefficients of Variation of the assay were generally low: below 10% for plasma and 9.9% for urine. No interferences from endogenous substances were found.
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Pharmacokinetics, stability, and blood partition of DA-8159, a new Phosphodiesterase V Inhibitor.
Research communications in molecular pathology and pharmacology, 2000Co-Authors: Hyun J. Shim, Eun Lee, S.h. Kim, Yoo M, Jong W. Kwon, Won B. Kim, Myung Gull LeeAbstract:The pharmacokinetics of DA-8159, a new Phosphodiesterase V Inhibitor, after 1 min intraVenous, 30 mg/kg, and oral, 30 mg/kg, administration of the drug to rats, the stability of DA-8159 in Various pH solutions ranging from 1 to 13, and human and rat plasma and urine, and the blood partition of DA-8159 between plasma and blood cells of rabbit were eValuated. After intraVenous administration, DA-8159 was eliminated fast with the mean total body clearance of 126 ml/min/kg, and was almost completely metabolized in rats; 5.98% of intraVenous dose of DA-8159 were excreted unchanged in 24-hr urine. The extent of absolute oral bioaVailibility of DA-8159 was approximately 25%. The apparent Volume of distribution at steady state was considerably large, 15048 ml/kg, suggesting that DA-8159 has a good affinity to rat tissues. DA-8159 was relatiVely stable in Various pH solutions, and human and rat plasma and urine for up to 48 h incubation in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. DA-8159 reached equilibrium fast (within 30 sec mixing manually) between plasma and blood cells of rabbit blood and the plasma-to-blood cell concentration ratios were independent of initial blood concentrations of DA-8159, 1, 5, and 10 microg/ml, when the rabbit whole blood was incubated for up to 120 min; the ratios were in the range of 0.662-0.812. There was no in Vitro 'blood storage effect' in the plasma concentration of DA-8159.
Jiang Wang - One of the best experts on this subject based on the ideXlab platform.
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A rapid and sensitiVe LC-MS/MS assay to quantify yonkenafil in rat plasma with application to preclinical pharmacokinetics studies.
Journal of pharmaceutical and biomedical analysis, 2008Co-Authors: Jiang Wang, Yao Jiang, Yingwu Wang, Yunbiao Tang, Guosheng Teng, J Paul Fawcett, Jian KongAbstract:A noVel method for the quantitation of yonkenafil, a new synthetic Phosphodiesterase V Inhibitor, in rat plasma using high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) has been deVeloped. The analyte and internal standard (diazepam) were extracted from plasma (100 microl) by liquid-liquid extraction and separated on a C18 column using 10mM ammonium acetate buffer: methanol (15:85, V/V) as mobile phase in a run time of 3.0 min. The detector was a Q-trap mass spectrometer with an ESI interface operating in the multiple reaction monitoring (MRM) mode. The assay was linear oVer the concentration range 1.0-1000 ng/ml with a limit of detection of 0.20 ng/ml. Intra- and inter-day precision (as relatiVe standard deViation) were both within 8.45% with good accuracy. The method was successfully applied to a preclinical pharmacokinetic study of yonkenafil in rat after sublingual, oral and intraVenous administration. The results demonstrate that the sublingual route giVes a higher bioaVailablity than the oral route and may represent a useful alternatiVe route of yonkenafil administration.
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Liquid chromatography tandem mass spectrometry assay to determine the pharmacokinetics of aildenafil in human plasma
Journal of pharmaceutical and biomedical analysis, 2007Co-Authors: Jiang Wang, Yao Jiang, Yingwu Wang, Xia Zhao, Yimin CuiAbstract:A simple, sensitiVe and specific liquid chromatography/tandem mass spectrometry method for the quantitation of aildenafil, a new Phosphodiesterase V Inhibitor, in human plasma is presented. The analyte and internal standard, sildenafil, were extracted by a one-step liquid-liquid extraction in alkaline conditions and separated on a C(18) column using ammonia:10mM ammonium acetate buffer:methanol (0.1:15:85, V/V/V) as the mobile phase. The detection by an API 4000 triple quadrupole mass spectrometer in multiple-reaction monitoring mode was completed within 2.5 min. The calibration curVe exhibited a linear dynamic range of 0.05-100 ng/ml with a 10 pg/ml limit of detection. The intra- and inter-day precisions measured as relatiVe standard deViation were within 8.04% and 5.72%, respectiVely. This method has been used in a pharmacokinetic study of aildenafil in healthy male Volunteers each giVen an oral administration of one of the three dosages.
Sang-goo Shin - One of the best experts on this subject based on the ideXlab platform.
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SensitiVe liquid chromatography assay with ultraViolet detection for a new Phosphodiesterase V Inhibitor, DA-8159, in human plasma and urine.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2003Co-Authors: Joo Youn Cho, Hyeong Seok Lim, Hyun Joo Shim, In-jin Jang, Sang-goo ShinAbstract:Abstract A sensitiVe high-performance liquid chromatographic (HPLC) method with ultraViolet absorption detection (292 nm) was deVeloped and Validated for the determination of the new Phosphodiesterase V Inhibitor, DA-8159 (DA), in human plasma and urine. A single step liquid–liquid extraction procedure using ethyl ether was performed to recoVer DA and the internal standard (sildenafil citrate) from 1.0 ml of biological matrices combined with 200 μl of 0.1 M sodium carbonate buffer. A Capcell Pak C18 UG120 column ( 150 mm ×4.6 mm I.D., 5 μm) was used as a stationary phase and the mobile phase consisted of 30% acetonitrile and 70% 20 mM potassium phosphate buffer (pH 4.5) at a flow rate of 1.0 ml/min. The lower limit for quantification was 5 ng/ml for plasma and 10 ng/ml for urine samples. Within- and between-run accuracy and precision were ≤15 and ≤10%, respectiVely, in both plasma and urine samples. The recoVery of DA from human plasma and urine was greater than 70%. Separate stability studies showed that DA is stable under the conditions of analysis. This Validated assay was used for the pharmacokinetic analysis of DA during a phase I, rising dose study.