Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 20 de 41
Filtrer
1.
Bioanalysis ; 16(9): 369-384, 2024.
Article de Anglais | MEDLINE | ID: mdl-38497721

RÉSUMÉ

This study was conducted to compare dissolution profiles of four Jordanian registered sildenafil (SDF) products to the originator. Dissolution samples were analyzed utilizing a validated and stability-indicating HPLC method in human plasma. Validation was performed for specificity, linearity, limit of detection, lower limit of quantification, precision, trueness and stability. SDF was extracted from plasma samples using liquid-liquid extraction. The analysis was performed utilizing isocratic elution on C18 column with 1.0 ml/min flow rate. The regression value was ∼0.999 over 3 days with drug recovery between 86.6 to 89.8%with 10 ng/ml lower limit of quantitation. This method displayed a good selectivity of SDF with improved stability under various conditions. The method was used for SDF quantification in dissolution medium. Similarity factors for local products varied according to the used mediums, but all SDF local products passed the dissolution in vitro test since all of them showed a released of >85% after 60 min at the dissolution mediums.


[Box: see text].


Sujet(s)
Citrate de sildénafil , Citrate de sildénafil/sang , Citrate de sildénafil/composition chimique , Citrate de sildénafil/analyse , Chromatographie en phase liquide à haute performance/méthodes , Humains , Médicaments génériques/composition chimique , Médicaments génériques/analyse , Solubilité , Jordanie , Stabilité de médicament , Limite de détection
2.
Biomed Pharmacother ; 143: 112161, 2021 Nov.
Article de Anglais | MEDLINE | ID: mdl-34537676

RÉSUMÉ

BACKGROUND: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil. METHODS: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response. FINDINGS: The target concentration range (47-500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose. INTERPRETATION: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects. RESEARCH IN CONTEXT: None. SEARCH STRATEGY BEFORE UNDERTAKING THE STUDY: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work. EVIDENCE BEFORE THIS STUDY: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model. ADDED VALUE OF THIS STUDY: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.


Sujet(s)
Aorte/effets des médicaments et des substances chimiques , Circulation extracorporelle , Thérapies foetales , Artère pulmonaire/effets des médicaments et des substances chimiques , Citrate de sildénafil/pharmacocinétique , Vasodilatation/effets des médicaments et des substances chimiques , Vasodilatateurs/pharmacocinétique , Animaux , Aorte/imagerie diagnostique , Aorte/physiopathologie , Pression artérielle/effets des médicaments et des substances chimiques , Âge gestationnel , Perfusions veineuses , Modèles biologiques , Artère pulmonaire/imagerie diagnostique , Artère pulmonaire/physiopathologie , Ovis aries , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Résistance vasculaire/effets des médicaments et des substances chimiques , Vasodilatateurs/administration et posologie , Vasodilatateurs/sang
3.
Anal Biochem ; 631: 114355, 2021 10 15.
Article de Anglais | MEDLINE | ID: mdl-34461080

RÉSUMÉ

This study aimed to develop an LC-MS/MS method for determining sildenafil and its metabolites N-desmethylsildenafil and N1,N4-desmethylsildenafil in human plasma and applying it to a pharmacokinetic study of sildenafil in healthy volunteers. Sildenafil-d8 was used as the internal standard. Plasma samples were pretreated via protein precipitation with acetonitrile. The extractives were then separated on an ACQUITY UPLC BEH C18 (50-mm × 2.1-mm, 1.7-µm) column using gradient elution. The aqueous and organic mobile phases were ammonium formate 2 mM supplemented with 0.1% formic acid in water and acetonitrile, respectively, and the flow rate was 0.3 mL/min. An electrospray ionization source was applied, and multiple reaction monitoring was operated in the positive mode with selective channels at m/z 475.30 â†’ 100.10, 461.20 â†’ 283.30, 483.30 â†’ 108.10, and 449.00 â†’ 283.00 for sildenafil, sildenafil-d8, N-desmethylsildenafil, and N1,N4-desmethylsildenafil, respectively. The linear calibration curves of sildenafil and its metabolites spanned 1.0-1000 ng/mL. The lower limit of quantification was 1.0 ng/mL. The extractive recovery of analytes from the biological matrix was more than 90% and the matrix effect complied with relevant provisions. The intra- and inter-day precisions of sildenafil and its metabolite were <10%. The intra- and inter-day accuracy of sildenafil, N-desmethylsildenafil, and N1,N4-desmethylsildenafil was more than 99%. The method is highly sensitive and selective, and it was successfully applied to the bioequivalence studies of 100-mg sildenafil citrate tablets in 40 healthy Chinese volunteers.


Sujet(s)
Chromatographie en phase liquide/méthodes , Citrate de sildénafil/sang , Citrate de sildénafil/pharmacocinétique , Spectrométrie de masse en tandem/méthodes , Administration par voie orale , Adolescent , Adulte , Analyse chimique du sang/méthodes , Calibrage , Stabilité de médicament , Humains , Limite de détection , Mâle , Adulte d'âge moyen , Sensibilité et spécificité , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/métabolisme , Équivalence thérapeutique , Jeune adulte
4.
Leg Med (Tokyo) ; 48: 101815, 2021 Feb.
Article de Anglais | MEDLINE | ID: mdl-33264696

RÉSUMÉ

In recent years, there has been an increase in the use of phosphodiesterase type 5 inhibitors (PDE5i) that are purchased from abroad without a doctor's diagnosis via the Internet or other means. We report six cases in which nonprescription use of PDE5i may have led to death. Among the four deceased individuals who were believed to have experienced sudden cardiac death, three (cases 1-3) had a history of cardiovascular disease, which is a contraindication, and the remaining case (case 4) involved combined use of multiple PDE5i. Sildenafil (0.063 µg/mL, 0.087 µg/mL) was detected in two of the four cases of sudden cardiac death. Tadalafil (0.096 µg/mL) was detected in one of the remaining two cases, and tadalafil (0.197 µg/mL) and vardenafil (0.011 µg/mL) were detected in the other case. Sildenafil (0.032 µg/mL), tadalafil (0.062 µg/mL), and ethanol were detected in a traffic accident case with a history of contraindications. In a case of asphyxiation by vomit aspiration, autopsy showed 90% stenosis in the anterior descending branch of the coronary artery, and sildenafil (0.063 µg/mL) was detected. To the best of our knowledge, this is the first report of postmortem blood levels of tadalafil and vardenafil likely contributing to the cause of death. Despite all the warnings about the dangers of using PDE5 inhibitors, cases of PDE5i contributing to death are still identified during autopsies. Therefore, raising public awareness of the risks of the risks associated with the imported drug use by individuals is necessary.


Sujet(s)
Mort subite cardiaque/étiologie , Inhibiteurs de la phosphodiestérase-5/effets indésirables , Comportement sexuel/effets des médicaments et des substances chimiques , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladies cardiovasculaires/complications , Contre-indications aux médicaments , Dysfonctionnement érectile/traitement médicamenteux , Dysfonctionnement érectile/psychologie , Médecine légale , Humains , Mâle , Adulte d'âge moyen , Inhibiteurs de la phosphodiestérase-5/sang , Risque , Citrate de sildénafil/effets indésirables , Citrate de sildénafil/sang , Tadalafil/effets indésirables , Tadalafil/sang , Dichlorhydrate de vardénafil/effets indésirables , Dichlorhydrate de vardénafil/sang
5.
Biol Pharm Bull ; 43(12): 1917-1923, 2020 Dec 01.
Article de Anglais | MEDLINE | ID: mdl-33012742

RÉSUMÉ

This study was performed for a better understanding of the pharmacokinetics of sildenafil (SIL) and N-desmethyl sildenafil (DMS) in 13 children treated in the intensive care unit (ICU). Blood samples were taken periodically after the first oral administration of SIL (0.5 mg/kg). Plasma concentrations were analyzed by tandem LC/MS. Of the 13 patients, apparent peaks in the plasma concentration of SIL were observed in four patients, with the other nine patients showing reduced or delayed drug absorption of SIL. The maximum plasma concentrations of SIL after administration varied in range from 7.8 to 101.0 ng/mL. The parent drug-to-metabolite (SIL/DMS) ratios of the nine patients with reduced or delayed drug absorption of SIL were relatively lower than those in the four patients with rapid absorption of the drug. These observations suggested that the inter-individual variability of intestinal absorption and/or first-pass extraction of SIL was involved in the pharmacokinetic variability of the drug. Next, we evaluated the impact of changes in the gastrointestinal absorption rate on the pharmacokinetics of the drug. That is, SIL (2.5 mg/body) was administered at two different rates in the duodenum of rats. When SIL was administered for 10 min, the Cmax and bioavailability were 3.46 ± 1.65 µg/mL and 23.2 ± 11.1%, respectively. When SIL was administered for 60 min, the Cmax and bioavailability were 0.990 ± 0.352 µg/mL and 9.91 ± 3.79%, respectively. These findings suggest that the drug absorption rate was at least partly responsible for the pharmacokinetic variability of SIL in the ICU children.


Sujet(s)
Absorption intestinale/physiologie , Citrate de sildénafil/métabolisme , Citrate de sildénafil/pharmacocinétique , Animaux , Biodisponibilité , Enfant d'âge préscolaire , Absorption gastro-intestinale , Humains , Nourrisson , Unités de soins intensifs , Mâle , Taux de clairance métabolique , Rats , Rat Wistar , Citrate de sildénafil/sang
6.
Biomed Chromatogr ; 34(10): e4927, 2020 Oct.
Article de Anglais | MEDLINE | ID: mdl-32562289

RÉSUMÉ

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.


Sujet(s)
Chromatographie en phase liquide/méthodes , Citrate de sildénafil/sang , Spectrométrie de masse en tandem/méthodes , Adulte , Humains , Limite de détection , Modèles linéaires , Mâle , Reproductibilité des résultats , Citrate de sildénafil/analogues et dérivés , Citrate de sildénafil/pharmacocinétique , Jeune adulte
7.
Clin Pharmacol Drug Dev ; 9(5): 573-581, 2020 07.
Article de Anglais | MEDLINE | ID: mdl-32463593

RÉSUMÉ

Sildenafil citrate is approved to treat erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate that does not require swallowing or administration with fluids has been developed. The bioequivalence and bioavailability of sildenafil citrate ODT (50 mg) without and with water were compared with conventional sildenafil citrate tablets (50 mg) in an open-label, randomized crossover study. Healthy Chinese male subjects (n = 36) were allocated to 1 of 6 sildenafil citrate treatment sequences under fasted conditions, and plasma samples for determination of sildenafil concentrations were collected predose through 14 hours postdose. Bioequivalence was demonstrated for sildenafil citrate ODT administered without water relative to the sildenafil citrate tablet administered with water; 90%CIs for the ratios of adjusted geometric means for sildenafil AUClast , Cmax , and AUCinf (ratio, 101.41%; 90%CI, 95.49%-107.70%; ratio, 93.55%; 90%CI, 84.15%-104.00%; and ratio, 101.03%; 90%CI, 94.80%-107.66%; respectively) were wholly contained within the bioequivalence acceptance range of 80% to 125%, indicating bioequivalence criteria were met. Relative bioavailability of sildenafil citrate ODT administered with water to the sildenafil citrate tablet (50 mg) administered with water was 97.10%, 91.43%, and 97.09% with respect to sildenafil AUClast , Cmax , and AUCinf , respectively (90%CI, 91.43%-03.12%, 82.25%-101.65%, and 90.90%-103.71%, respectively). Both sildenafil citrate formulations were generally well tolerated in healthy Chinese men. Sildenafil citrate ODT administered without or with water was bioequivalent to or met bioequivalence criteria compared with conventional sildenafil citrate tablets administered with water under fasted conditions in healthy Chinese men, thus offering a convenient alternative method of oral administration.


Sujet(s)
Préparation de médicament/statistiques et données numériques , Dysfonctionnement érectile/traitement médicamenteux , Inhibiteurs de la phosphodiestérase-5/pharmacocinétique , Citrate de sildénafil/pharmacocinétique , Administration par voie orale , Adulte , Aire sous la courbe , Asiatiques/ethnologie , Biodisponibilité , Études croisées , Préparation de médicament/méthodes , Dysfonctionnement érectile/psychologie , Jeûne/physiologie , Volontaires sains/statistiques et données numériques , Humains , Mâle , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/sang , Sécurité , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Comprimés/administration et posologie , Équivalence thérapeutique
8.
Br J Clin Pharmacol ; 85(12): 2824-2837, 2019 12.
Article de Anglais | MEDLINE | ID: mdl-31475367

RÉSUMÉ

AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.


Sujet(s)
Prématuré/sang , Modèles biologiques , Inhibiteurs de la phosphodiestérase-5/pharmacocinétique , Citrate de sildénafil/pharmacocinétique , Administration par voie orale , Études de cohortes , Cytochrome P-450 CYP3A/sang , Cytochrome P-450 CYP3A/génétique , Fluconazole/administration et posologie , Fluconazole/pharmacocinétique , Âge gestationnel , Humains , Hypertension pulmonaire/sang , Hypertension pulmonaire/traitement médicamenteux , Nourrisson , Nouveau-né , Maladies du prématuré/sang , Maladies du prématuré/traitement médicamenteux , Injections veineuses , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/sang , Inhibiteurs de la phosphodiestérase-5/usage thérapeutique , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Citrate de sildénafil/usage thérapeutique
9.
Forensic Sci Int ; 303: 109958, 2019 Oct.
Article de Anglais | MEDLINE | ID: mdl-31542401

RÉSUMÉ

The routine analysis of driver specimens for gamma-hydroxybutyrate (GHB) is rarely performed by toxicology laboratories as the physical and chemical properties of GHB make it unamenable to the screening methods usually employed. The prevalence of the drug in driver populations has therefore only rarely been reported. This study outlines the results of the routine analysis for GHB in the blood of motor vehicle drivers in Queensland, Australia, over an eight-year period (2011-2018). The methodology for GHB analysis was updated over the course of the study; screening for GHB was conducted using GC/FID or GC/MS between 2011 and 2016 and by LC/MS/MS from 2017 onwards. Due to the endogenous nature of GHB, any specimens containing greater than 5mg/kg GHB were subjected to quantitative analysis by either; GC/MS after liquid-liquid extraction and derivatisation with BSTFA+1%TMCS (2011-2016), or by LC/MS/MS analysis after solvent precipitation from 2017 onwards. Of the 15,061 specimens analysed, 160 were positive for GHB (1.1% of all cases, range 0.4-1.8%). GHB positive drivers were 66.9% male (33.1% female) and had an average age of 32 years. The mean GHB concentration identified was 89mg/kg (range 6-354mg/kg). GHB was found to be closely associated with amphetamine type substances (ATS), particularly methylamphetamine. Though GHB was present in only 2.2% of all ATS positive specimens submitted to the laboratory, 91.2% of all GHB positive cases contained an ATS. Other drugs commonly co-administered with GHB were THC, cocaine, benzodiazepines and erectile dysfunction drugs. GHB was found to be more commonly identified in drivers from city areas and a geographical localisation of the use of the drug was identified in the Gold Coast region of Queensland.


Sujet(s)
Amphétamines/sang , Conduite avec facultés affaiblies , Oxybate de sodium/sang , Détection d'abus de substances , Troubles liés à une substance/épidémiologie , Adulte , Australie/épidémiologie , Benzodiazépines/sang , Femelle , Toxicologie médicolégale , Chromatographie gazeuse-spectrométrie de masse , Humains , Mâle , Stupéfiants/sang , Inhibiteurs de la phosphodiestérase-5/sang , Citrate de sildénafil/sang , Troubles liés à une substance/sang , Tadalafil/sang
10.
Ultrasound Obstet Gynecol ; 54(4): 506-516, 2019 Oct.
Article de Anglais | MEDLINE | ID: mdl-31364206

RÉSUMÉ

OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHODS: DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULTS: Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. CONCLUSIONS: Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


Sujet(s)
Hémodynamique/effets des médicaments et des substances chimiques , Hernies diaphragmatiques congénitales/traitement médicamenteux , Poumon/effets des médicaments et des substances chimiques , Inhibiteurs de la phosphodiestérase-5/pharmacologie , Citrate de sildénafil/pharmacologie , Animaux , Autopsie/méthodes , Gazométrie sanguine/méthodes , Femelle , Thérapies foetales/méthodes , Foetus , Hernies diaphragmatiques congénitales/physiopathologie , Poumon/vascularisation , Poumon/physiopathologie , Modèles animaux , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/sang , Grossesse , Prise en charge prénatale , Échanges gazeux pulmonaires/effets des médicaments et des substances chimiques , Ovis , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang
11.
Arterioscler Thromb Vasc Biol ; 39(4): 731-740, 2019 04.
Article de Anglais | MEDLINE | ID: mdl-30841708

RÉSUMÉ

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.


Sujet(s)
Retard de croissance intra-utérin/induit chimiquement , Lésions prénatales/induit chimiquement , Citrate de sildénafil/toxicité , Vasodilatateurs/toxicité , Acétylcholine/pharmacologie , Animaux , Poids de naissance/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Encéphale/embryologie , Débit cardiaque/effets des médicaments et des substances chimiques , Circulation cérébrovasculaire/effets des médicaments et des substances chimiques , Femelle , Sang foetal/composition chimique , Développement foetal/effets des médicaments et des substances chimiques , Retard de croissance intra-utérin/physiopathologie , Guanylate cyclase/analyse , Mâle , Muscles lisses vasculaires/effets des médicaments et des substances chimiques , Muscles lisses vasculaires/enzymologie , Monoxyde d'azote/physiologie , Nitroprussiate/pharmacologie , Taille d'organe/effets des médicaments et des substances chimiques , Placenta/vascularisation , Placenta/effets des médicaments et des substances chimiques , Grossesse , Lésions prénatales/physiopathologie , Ovis , Citrate de sildénafil/sang , Vasodilatation/effets des médicaments et des substances chimiques
12.
ASAIO J ; 65(5): 530-532, 2019 07.
Article de Anglais | MEDLINE | ID: mdl-30299299

RÉSUMÉ

We compared maximal plasma concentrations (Cmax) of sildenafil and metabolite n-desmethyl sildenafil in 12 inpatients with left ventricular assist devices (LVADs) on sildenafil (60 mg/day) to the reference range. Sildenafil Cmax (156.8 ± 124.5 ng/ml) was elevated in 66% of patients, with a two to fivefold increase over the upper limit of the reference range in 25% of patients. Metabolite Cmax (133.3 ± 102.0 ng/ml) was elevated in 75% of patients, with a three to sevenfold increase over the upper limit of the reference range in 40% of patients. Patients with heart failure and LVADs are at increased risk of concentrated-related sildenafil adverse events.


Sujet(s)
Dispositifs d'assistance circulatoire , Inhibiteurs de la phosphodiestérase-5/sang , Inhibiteurs de la phosphodiestérase-5/pharmacocinétique , Citrate de sildénafil/sang , Citrate de sildénafil/pharmacocinétique , Humains , Mâle , Adulte d'âge moyen
13.
Clin Pharmacol Drug Dev ; 8(3): 404-410, 2019 04.
Article de Anglais | MEDLINE | ID: mdl-29947474

RÉSUMÉ

An orally disintegrating film formulation of sildenafil 50 mg (CL Pharm Co, Ltd) was used in this study and compared to the market-available product film coated tablets (Viagra® , Pfizer, Mexico). The objective was to compare the pharmacokinetic properties of these products after a single-dose administration to 47 healthy male volunteers (aged 19-48 years) in a randomized, open-label, 2-way crossover study. Each subject received a single oral dose of 50 mg of sildenafil test or reference product administered under fasting conditions at each of the 2 study periods according to a crossover design. There was a 3-day washout period between drug administrations. Blood samples for pharmacokinetic analysis were collected predose and at different times postdosing. The maximum plasma concentration and area under the curve from administration to last observed concentration time of test and reference products were compared. Pharmacokinetic parameters shown to be within the confidence interval 80% to 125% for log-transformed data and Shuirmann and Anderson Hauck tests showed a high probability that area under the curve values for the test product were within 80% to 125% (P < .05). Adverse events occurred at similar rates for the 2 formulations (8 for each product), headache being the most prevalent. The results suggest that the 2 sildenafil formulations, orally disintegrating films and film-coated tablets, are similar in terms of bioavailability, making the test product a good alternative to treat erectile dysfunction and improving dosing convenience.


Sujet(s)
Muqueuse de la bouche/métabolisme , Inhibiteurs de la phosphodiestérase-5/pharmacocinétique , Citrate de sildénafil/pharmacocinétique , Administration par voie orale , Adulte , Aire sous la courbe , Biodisponibilité , Études croisées , Libération de médicament , Humains , Mâle , Mexique , Adulte d'âge moyen , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/sang , Inhibiteurs de la phosphodiestérase-5/composition chimique , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Citrate de sildénafil/composition chimique , Comprimés , Équivalence thérapeutique , Jeune adulte
14.
Article de Anglais | MEDLINE | ID: mdl-30583015

RÉSUMÉ

In the field of drug safety research, electroretinography (ERG) is commonly conducted according to the international standard method propounded by the International Society for Clinical Electrophysiology of Vision (ISCEV) in recent years. However, various ERG methods other than the ISCEV standard method are also utilized depending on the intended purpose of the evaluation. In this study, we investigated the availability of a multistep light stimulus method for evaluation of rod function in Long-Evans rats using sildenafil, which is known to inhibit phosphodiesterase 6 (PDE6) in phototransduction and induce visual dysfunctions in humans. Sildenafil was orally administered to female Long-Evans rats at doses of 15, 50, and 150 mg/kg, and ERG was recorded at 1.5 h after treatment. In addition to a - 2.0 log cd·s/m2 stimulus corresponding to dark-adapted 0.01 ERG in the ISCEV standard method, light stimulus intensities of -4.5, -4.0, -3.0, -1.0, 0.0, and +1.0 log cd·s/m2 were applied for multistep ERG recording. The amplitude and implicit time of the a-wave were decreased and prolonged, respectively, at doses of ≥50 mg/kg. The amplitude and implicit time of the b-wave were decreased and prolonged, respectively, at all doses. However, the b-wave at 15 mg/kg was only diminished or attenuated at ≤ - 3.0 log cd·s/m2, as weaker stimuli than dark-adapted 0.01 ERG in the ISCEV standard protocol. These findings suggest that sildenafil triggers visual dysfunctions through PDE6 inhibition, and indicate that the multistep light stimulus method is highly sensitive for detection of phototransduction abnormalities in retinal rod cells.


Sujet(s)
Électrorétinographie/effets des médicaments et des substances chimiques , Électrorétinographie/méthodes , Citrate de sildénafil/pharmacologie , Troubles de la vision/diagnostic , Animaux , Femelle , Rats , Rat Long-Evans , Rétine/effets des médicaments et des substances chimiques , Rétine/métabolisme , Rétine/physiologie , Citrate de sildénafil/sang , Troubles de la vision/induit chimiquement , Troubles de la vision/métabolisme , Troubles de la vision/physiopathologie , Vision/effets des médicaments et des substances chimiques
15.
Trials ; 19(1): 524, 2018 Sep 27.
Article de Anglais | MEDLINE | ID: mdl-30261903

RÉSUMÉ

BACKGROUND: Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans. METHODS: This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0-32.6) and at term (sub-study 2; weeks: 36.6-40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured. DISCUSSION: This is the first study evaluating in-vivo transplacental passage of sildenafil in humans. TRIAL REGISTRATION: EU Clinical Trials Register 2016-002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.


Sujet(s)
Antihypertenseurs/administration et posologie , Hernies diaphragmatiques congénitales/traitement médicamenteux , Hypertension pulmonaire/prévention et contrôle , Prise en charge prénatale/méthodes , Citrate de sildénafil/administration et posologie , Adulte , Antihypertenseurs/sang , Antihypertenseurs/pharmacocinétique , Belgique , Essais cliniques de phase I comme sujet , Essais cliniques de phase II comme sujet , Femelle , Hernies diaphragmatiques congénitales/complications , Hernies diaphragmatiques congénitales/diagnostic , Hernies diaphragmatiques congénitales/physiopathologie , Humains , Hypertension pulmonaire/diagnostic , Hypertension pulmonaire/étiologie , Hypertension pulmonaire/physiopathologie , Échange foetomaternel , Circulation placentaire , Grossesse , Deuxième trimestre de grossesse/sang , Troisième trimestre de grossesse/sang , Essais contrôlés randomisés comme sujet , Citrate de sildénafil/sang , Citrate de sildénafil/pharmacocinétique , Jeune adulte
16.
Am J Obstet Gynecol ; 219(6): 619.e1-619.e10, 2018 12.
Article de Anglais | MEDLINE | ID: mdl-30194048

RÉSUMÉ

BACKGROUND: Sildenafil already is administered during gestation in patients with pulmonary hypertension and is under evaluation as a treatment for several pregnancy complications, such as preeclampsia and intrauterine growth restriction. Animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature, and airway phenotype. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required. OBJECTIVE: We quantified transplacental passage of sildenafil in the ex vivo dually perfused cotyledon model. STUDY DESIGN: Six placentas that were collected after term delivery from healthy volunteers were cannulated and perfused dually. Sildenafil citrate was added to the maternal circulation at 2 different concentrations: 500 ng/mL, which represented the maximum tolerated concentration (n=3), and 50 ng/mL, which represented the therapeutic concentration (n=3). Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150, and 180 minutes; the concentrations of sildenafil and its metabolite desmethyl-sildenafil were determined with the use of high performance liquid chromatography. The fetal/maternal concentration ratio was calculated for each timepoint. Transfer clearance was calculated as the rate of maternal to fetal passage/maternal concentration. RESULTS: Sildenafil crossed the placenta at both maximal and therapeutic concentrations. Maternal and fetal levels reached a plateau at 90-120 minutes. Transfer clearance was the highest during the first hour of perfusion: 3.15 mL/min (range, 2.14-3.19 mL/min) for the maximum tolerated concentration and 3.07mL/min (range, 2.75-3.42 mL/min) for the therapeutic concentration (not significant). The fetomaternal concentration ratio significantly increased over time, up to 0.91±0.16 for the maximal concentration and 0.95±0.22 for the therapeutic concentration at the end of the perfusion (not significant). Desmethyl-sildenafil was not detected in any sample. CONCLUSION: Sildenafil crosses the term placenta at a relatively high rate ex vivo, which suggests that there is sufficient placental transfer to reach clinically active fetal drug levels at the currently used maternal doses.


Sujet(s)
Antihypertenseurs/pharmacologie , Placenta/effets des médicaments et des substances chimiques , Citrate de sildénafil/pharmacologie , Antihypertenseurs/sang , Antihypertenseurs/pharmacocinétique , Femelle , Humains , Hypertension pulmonaire/traitement médicamenteux , Échange foetomaternel , Modèles biologiques , Placenta/métabolisme , Grossesse , Complications cardiovasculaires de la grossesse/traitement médicamenteux , Citrate de sildénafil/sang , Citrate de sildénafil/pharmacocinétique
17.
Int J Mol Sci ; 19(8)2018 Jul 24.
Article de Anglais | MEDLINE | ID: mdl-30042317

RÉSUMÉ

Erectile dysfunction (ED) is a disorder found in males throughout the world, which negatively affects relationships with partners with advancing age. Hence, in this study, we tested a combined novel treatment of electro-acupuncture (EA) and sildenafil citrate against ED. In addition to EA therapy, the sildenafil citrate, a phosphodiesterase 5 inhibitor, is a widely recognized drug that has achieved considerable success in the treatment of ED. However, the combined effect of both the EA and sildenafil has not yet been investigated. Hence, we aimed to examine the effect of EA on the pharmacokinetics and pharmacodynamics of sildenafil in rat plasma. The pharmacokinetic parameters were determined using ultra performance liquid chromatography (UPLC) after EA and sildenafil administration (10 mg/Kg). Following this, the pharmacodynamics was studied via blood flow pattern using developing Doppler images of the lower body and penis. The pharmacokinetic studies demonstrated that sildenafil significantly increases by administration of low-frequency EA. Further, the pharmacodynamic studies using Doppler imaging revealed an elevated blood flow in rat penis compared with lower body during combined treatment of sildenafil and low-frequency EA. These data indicate a synergistic therapeutic effect of EA and sildenafil for the treatment of ED.


Sujet(s)
Électroacupuncture , Dysfonctionnement érectile/traitement médicamenteux , Pénis/vascularisation , Inhibiteurs de la phosphodiestérase-5/pharmacocinétique , Citrate de sildénafil/pharmacocinétique , Vasodilatateurs/pharmacocinétique , Administration par voie intraveineuse , Analyse de variance , Animaux , Aire sous la courbe , Cathétérisme , Mâle , Érection du pénis , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/sang , Rats , Rat Sprague-Dawley , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Vasodilatateurs/administration et posologie , Vasodilatateurs/sang
18.
Urologiia ; (1): 159-162, 2018 Mar.
Article de Russe | MEDLINE | ID: mdl-29634153

RÉSUMÉ

The experience in the management of erectile dysfunction shows that taking even the most effective medications in tablet form may be inconvenient due to the need for natural settings for intimacy. The phosphodiesterase type 5 inhibitor sildenafil, presented in the orally disintegrating film formulation (Dynamic Forward), differs from all forms of the drug for the treatment of erectile dysfunction available in the Russian pharmaceutical market. The drug in the form of a film makes it possible to realize a pathogenetic approach to treating ED without changing the patients habitual way of life.


Sujet(s)
Dysfonctionnement érectile/traitement médicamenteux , Inhibiteurs de la phosphodiestérase-5/administration et posologie , Inhibiteurs de la phosphodiestérase-5/usage thérapeutique , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/usage thérapeutique , Administration par voie orale , Humains , Mâle , Inhibiteurs de la phosphodiestérase-5/sang , Citrate de sildénafil/sang , Comprimés/administration et posologie , Comprimés/pharmacocinétique
19.
Curr Drug Saf ; 13(1): 12-20, 2018.
Article de Anglais | MEDLINE | ID: mdl-29359677

RÉSUMÉ

INTRODUCTION: Due to the chaos in the legislation in the Middle East, male enhancement nutraceuticals may be sold without any registration or evaluation. These products need to be evaluated with respect to safety and efficacy. Furthermore, cultural and social considerations in the Middle East prevent the use of international evaluations schemes for erectile dysfunction. AIM: Evaluating the safety and efficacy parameters of generic and nutraceutical products for erectile dysfunction in the Middle East through a custom-designed, representable and simple system tailored to the regional culture. METHODS: 74 healthy male volunteers were enrolled into a comparative, simple randomized, single dose, double blind, and crossover clinical study incorporated with a tailored-designed questionnaire. Safety assessment included laboratory analysis for liver functions and measuring blood pressure. MAIN OUTCOME MEASURES: Subjective data regarding safety and efficacy were assessed from the validated questionnaire. Blood pressure was measured. Blood samples were collected to assess the drug/adulterants concentration and liver and kidney functions. RESULTS: All tested nutraceuticals showed undeclared Sildenafil citrate in patients. Questionnaire results showed high inter-patient variability with respect to efficacy and comparable safety profile compared to Viagra®. CONCLUSION: The validated tailored-designed questionnaire effectively assessed the efficacy and safety of male enhancement products. The male enhancement nutraceuticals, sold in Egypt, claimed to be 100% natural are adulterated and of questionable safety profile.


Sujet(s)
Compléments alimentaires/analyse , Contamination de médicament , Médicaments génériques/analyse , Dysfonctionnement érectile/sang , Dysfonctionnement érectile/épidémiologie , Citrate de sildénafil/analyse , Adulte , Études croisées , Méthode en double aveugle , Contamination de médicament/prévention et contrôle , Médicaments génériques/métabolisme , Médicaments génériques/usage thérapeutique , Égypte/épidémiologie , Dysfonctionnement érectile/traitement médicamenteux , Humains , Mâle , Adulte d'âge moyen , Inhibiteurs de la phosphodiestérase-5/analyse , Inhibiteurs de la phosphodiestérase-5/sang , Inhibiteurs de la phosphodiestérase-5/usage thérapeutique , Citrate de sildénafil/sang , Citrate de sildénafil/usage thérapeutique , Résultat thérapeutique
20.
J Vet Pharmacol Ther ; 41(3): 457-462, 2018 Jun.
Article de Anglais | MEDLINE | ID: mdl-29352474

RÉSUMÉ

Basic information related to the pharmacokinetics of sildenafil in dogs is scarce. This study aimed to describe the pharmacokinetic properties of oral sildenafil and determine the effect of feeding and dose proportionality. The effect of feeding on pharmacokinetics of sildenafil (1 mg/kg) was investigated using a crossover study with six dogs. In addition, the dose proportionality of sildenafil ranging 1-4 mg/kg was evaluated using five dogs in the fasted states. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil administrations were well tolerated in all studies. Feeding reduced the area under the curve extrapolated to infinity (AUCinf ) and the maximum plasma concentration (Cmax ) significantly. The elimination half-life (T1/2 ) did not differ between the fasted and the fed states. For dose proportionality, nonproportional increases in AUCinf and Cmax at 1-4 mg/kg doses were detected by a power model analysis.


Sujet(s)
Chiens/sang , Interactions aliments-médicaments , Citrate de sildénafil/pharmacocinétique , Vasodilatateurs/pharmacocinétique , Administration par voie orale , Animaux , Études croisées , Relation dose-effet des médicaments , Citrate de sildénafil/administration et posologie , Citrate de sildénafil/sang , Vasodilatateurs/administration et posologie , Vasodilatateurs/sang
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE
...