The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition... Show moreThe aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. Show less
Introduction: Nonprescription sildenafil was introduced to the United Kingdom in 2018 as the first pharmacy service concerning sexual function, an important but often ignored factor for quality of... Show moreIntroduction: Nonprescription sildenafil was introduced to the United Kingdom in 2018 as the first pharmacy service concerning sexual function, an important but often ignored factor for quality of life.Aim: This study aimed to evaluate pharmacists' views on providing nonprescription sildenafil, their perceptions of the barriers and facilitators to provide this service and strategies to overcome potential barriers, using a theory-based approach.Methods: Community pharmacists were purposefully sampled in Northern Ireland, followed by snowball sampling. Face-to-face interviews were conducted between October 2019 and January 2020. The semi-structured interviews used a piloted topic guide based on the 14-domain Theoretical Domains Framework (TDF). All interviews were audio-recorded, transcribed verbatim and anonymized. Transcripts were analyzed deductively in NVivo 13, utilizing the TDF domains as coding categories. Within each domain, content analysis was utilized to identify barriers and facilitators.Main Outcome Measure: Barriers and facilitators within the TDF domains for pharmacists to provide nonprescription sildenafil.Results: Ten pharmacists were interviewed to reach data saturation. Eight pharmacists had experience with dispensing nonprescription sildenafil. They valued nonprescription sildenafil as an additional service ("Social/professional role and identity"). Training, concise product guidelines, and private consultation areas were important facilitators ("Environmental context and resources"). The service required trusting clients ("Optimism"), with concerns about abuse and men not visiting their GP. From experience gained, pharmacists became more confident dealing with difficult situations such as patients being vague about their medical history or alcoholism or mental problems as causes for erectile disfunction (ED) ("Skills" and "Beliefs about capabilities"). Pharmacists considered lifestyle and medication causes of ED important but preferred to focus on safe supply. In general, pharmacists were satisfied with the perceived professional recognition, using their clinical knowledge or helping patients resume sexual relationships ("Beliefs about consequences").Conclusion: Pharmacists welcomed nonprescription sildenafil to enhance their role as easily accessible healthcare providers for patients. Copyright (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine. Show less
Three-dimensional (3D) printing of pharmaceuticals has the potential to revolutionise personalised medicine but is as yet largely unexplored. A proof-of-concept study of a novel heated, piston... Show moreThree-dimensional (3D) printing of pharmaceuticals has the potential to revolutionise personalised medicine but is as yet largely unexplored. A proof-of-concept study of a novel heated, piston-driven semi-solid extrusion 3D printer was performed by producing furosemide and sildenafil tablets for paediatric patients. The average weight of the tablets was 141.1 mg (RSD 1.26%). The acceptance values of the content uniformity were 4.2 & ndash;10.6 (concentration RSD 0.41 & ndash;0.63%), 4.8 & ndash;8.9 (concentration RSD 0.76 & ndash;0.97%) and 6.6 & ndash;9.2 (concentration RSD 0.94 & ndash;1.44%) for furosemide 2 mg, 10 mg and sildenafil 4 mg, respectively. The dissolution rate limiting step was the dissolving and eroding of the tablet matrix and showed an immediate release. The tablets complied to the requirements of the European Pharmacopoeia (EP) for uniformity of mass (EP 2.9.5), content uniformity (EP 2.9.40) and conventional release (EP 2.9.3). While they complied, not all of these quality tests for tablets might be suitable for 3D printed tablets due to the layering of the tablets and the small batch production. To assess adequate layer adhesion adjusted friability (EP 2.9.7) and resistance to crushing (EP 2.9.8) tests are proposed. Show less
Christensen, C.E.; Younis, S.; Lindberg, U.; Koning, P. de; Tolnai, D.; Paulson, O.B.; ... ; Ashina, M. 2021
The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence,... Show moreThe middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks. Show less
Christensen, C.E.; Younis, S.; Lindberg, U.; Boer, V.O.; Koning, P. de; Petersen, E.T.; ... ; Ashina, M. 2019
BackgroundSildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0tesla (T) MR angiography. Here we hypothesized that an... Show moreBackgroundSildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.MethodsFive subjects completed two sessions at respectively 3.0T and 7.0T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design.ResultsStandard deviations of arterial circumference revealed no difference between 3.0T and 7.0T measurements (p=0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p<0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0T and 7.0T.ConclusionsOur findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies.Trial registrationThe study is part of a parent study, which is registered at ClinicalTrials.gov (NCT03143465). Show less
