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Milko Radicioni,1 Chiara Castiglioni,1 Andrea Giori,2 Irma Cupone,3 Valeria Frangione,4 Stefano Rovati4 1CROSS Research S.A., Phase I Unit, Arzo, Switzerland; 2IBSA Farmaceutici Italia, Lodi, Italy; 3Bouty S.p.A., Strada Padana Superiore, Cassina De’ Pecchi, Italy; 4IBSA Institut Biochimique S.A., Pambio-Noranco, Switzerland Abstract: A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra®) after single-dose administration to 53 healthy male volunteers (aged 18–51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0–t) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration–time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film formulation can be used interchangeably with the conventional film-coated formulation. Keywords: sildenafil, pharmacokinetics, bioequivalence, orodispersible film, PDE5 inhibitor, N-desmethyl-sildenafil

IntroductionThrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management.MethodsWe present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management.ResultsThe RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0–18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled.DiscussionThe RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.

Objectives: To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 μg/g (T1) and 50 μg/g (T2)) compared to Ovestinon® (estriol 500 μg/0.5 g (R)) and placebo in postmenopausal women.Methods: Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated.Results: Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUCss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good.Conclusions: Estriol 20 and 50 μg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®. [ABSTRACT FROM AUTHOR]

Purpose: Concerns remain on different alveolar deposition of surfactant between LISA and INSURE methods. Ultrasound evaluation of diaphragm kinetics may provide clinical evidence on this issue, as indirect representation of the respiratory system compliance., Methods: This was a prospective-observational pilot study. The inclusion criterion was CPAP-supported infants ≤ 32 weeks with RDS receiving surfactant via minimally invasive technique. 52 patients randomized for surfactant administration via LISA or INSURE methods were enrolled. Right diaphragm (RD) global mean peak velocity (MPV) by Pulsed-Wave Tissue Doppler Imaging (PTDI) was recorded before and two hours after surfactant administration with simultaneous measurements of oxygen saturation (SpO 2 )/fraction of inspired oxygen (FiO 2 ) (SF ratio). Mechanical ventilation ≤ 72 h from birth represented treatment failure., Results: LISA infants had significantly higher gestational age (p = 0.029) and birth weight (p = 0.030) with lower CRIB-II scores (p = 0.030) than INSURE infants. LISA infants showed higher median MPV at baseline RD-PTDI US assessment (p = 0.024), but post-surfactant median MPV and other the investigated variables were similar at the adjusted analysis for gestational age and sedation. 8/52 (15%) infants who failed treatment had a significantly lower SF ratio (p = 0.002) and higher median MPV at RD-PTDI US (p = 0.004) after surfactant administration, despite the higher CPAP support level before (p = 0.007) and after (p = 0.001) surfactant administration. A full course of antenatal steroids was protective against mechanical ventilation (p = 0.038)., Conclusions: Different minimally invasive surfactant administration techniques do not appear to influence diaphragm kinetics evaluated by RD-PTDI US., (© 2023. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Introduction: The aim of our single-center case-control study is to evaluate whether minipuberty occurs in patients with hypoxic ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). We intend to conduct this evaluation by confronting the values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the values of testosterone in males and estradiol in females between newborns with HIE and in subsequent TH and healthy controls., Methods: We enrolled 40 patients (age: 56-179 days; 23 males), of whom 20 met the inclusion criteria for the case group and who underwent TH. A blood sample was taken from each patient at approximately 10 weeks of age to evaluate FSH and LH from the serum samples of all patients and to evaluate 17-beta estradiol (E2) and testosterone levels, respectively, from the serum samples of female and male patients., Results: It was found that minipuberty occurred in the case group patients, with no significant differences reported from the control group and with hormonal serum levels comparable to healthy infants of the control group (FSH 4.14 mUI/ml ± 5.81 SD vs. 3.45 mUI/ml ± 3.48 SD; LH 1.41 mUI/ml ±1.29 SD vs. 2.04 mUI/ml ±1.76 SD; testosterone in males 0.79 ng/ml ± 0.43 SD vs. 0.56 ng/ml ± 0.43 SD; 17-beta estradiol in females 28.90 pg/ml ± 16.71 SD vs. 23.66 pg/ml ± 21.29 SD)., Discussion: The results of the present study may pave the way for further research and the evaluation of more possible advantages of TH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lanciotti, Sica, Penta, Parisi, Argentiero, Radicioni, Di Cara, Di Genova, Verrotti, Troiani and Esposito.)

Purpose: To evaluate the reproducibility of the results of the viscoelastic coagulation test (VCT) performed with a new viscoelastic coagulation monitor (VCM™ - Entegrion) on native blood obtained by heel prick blood sampling with two different techniques compared to the standard blood collection in the newborn. Methods: Three blood samples were tested with the VCM analyzer in each of the 67 study subjects admitted to our level 3 neonatal intensive care unit. Standard blood collection (S) was performed by direct puncture of a peripheral vessel or by drawing of blood in a syringe connected to an arterial or venous catheter. Then, two more blood samples were drawn through a single heel prick. The first heel prick blood sample (HP1) was collected in the sample well through the attached metal capillary while the second (HP2) was poured directly into the sample well. Blood samples were automatically drawn into their pre-warmed cartridges and inserted into the VCM analyzers set up for analyses, which ran for one hour. VCT blood variables included clotting time (CT), clot formation time (CFT), angle alpha (α), amplitude at 10 and 20 min (A10 and A20), maximum clot firmness (MCF), and lysis indexes at 30 and 45 min (LY30 - LY45). Agreement was quantified by calculating the mean difference and SD between measurements of VCT blood variables from S, HP1 and HP2 blood samples. The 95% limits of agreement were calculated by the Bland & Altman method, using the upper or lower limit of agreement to interpret the variability of the measurements. The Kendall's τ correlation coefficient evaluated the interdependence between SD and intra-measurement mean. Results: S blood samples were easily obtained in all the study subjects, while mild difficulties were recorded in 3/67 infants (4.5%) with the HP1 blood sampling and in 5/67 infants (7%) with the HP2 blood sampling. Pairwise comparison of test results performed on blood samples drawn with HP1 and HP2 techniques showed moderate agreement for CT and α-angle, strong agreement for CFT, LY30 and LY45 and almost perfect agreement for A10, A20 and MCF. In pairwise comparison of VCM analyses performed on blood samples drawn with S technique vs HP1 and HP2 techniques, Kendall's τ correlation coefficient was significant for CT (S vs HP1 and HP1 vs HP2), CFT (S vs HP1 and S vs HP2), α-angle (S vs HP1) and MCF (S vs HP1). This suggests that the measurement error depends on the extent of the measurement. The overall ICC for blood sampling techniques ranged from 0.289 to 0.879 with best agreement observed for CFT (strong) and for A10, A20 and MCF (almost perfect). The LY30 index was the least repeatable measurement (poor agreement). The VCM analysis performed on the blood sample drawn with the HP1 technique showed the best repeatability compared with that performed with the S blood-sampling technique. Conclusion. VCT test results performed with the VCM analyzer on native blood drawn by heel prick in neonates are comparable to those obtained from standard blood samples. This could allow for a widespread, real-time assessment of the overall bedside haemostasis of these small patients.

Background and Objectives: Exogenous human chorionic gonadotropin (hCG) acts on the final phase of the follicle maturation. Choriomon ® , a highly purified hCG formulation, is approved in many European and extra-European countries for the induction of ovulation after stimulation of follicular development. The present study compares hCG bioavailability of Choriomon ® (Test product) versus a recombinant hCG preparation (Ovitrelle ® ; Reference product)., Methods: In this randomized, two-way cross-over study, 26 healthy women received a single dose of Choriomon ® (10,000 IU) and Ovitrelle ® (250 µg; 6500 IU) by subcutaneous injection. hCG was determined in serum up to 192 h post-dose. Dose-normalized peak concentration (C max ) and area under the concentration-time curve up to the time of the last quantifiable concentration (AUC 0-t ) and extrapolated to infinity (AUC 0-∞ ) were calculated and compared between the two treatments., Results: Serum hCG concentrations increased rapidly with a very similar pharmacokinetic curve for the two products. The test/reference geometric means ratio (GMR) for AUC 0-t and AUC 0-∞ corresponded to 121.31 and 119.81%, and the upper limits of the 90% confidence intervals (CIs) (130.21% and 128.51%, for AUC 0-t and AUC 0-∞ , respectively) exceeded the 125% bioequivalence threshold. C max GMR was 146.89%, indicating a rate of hCG absorption approximately 50% greater for the test product (90% CI 132.30-163.10). Half-life (t 1/2 ) was very similar (36.77 ± 5.11 h and 38.63 ± 6.08 h), whereas time to achieve C max (t max ) significantly differed, with median values of 16 h and 24 h for Choriomon ® and Ovitrelle ® , respectively, (p = 0.0023)., Conclusions: The differences between Choriomon ® and Ovitrelle ® pharmacokinetic parameters can be ascribed to the different raw source of the products and are reflected in the approved dose regimens of the two hCG formulations. The observed lack of bioequivalence between the two compounds at the given doses is not clinically relevant, as results from Phase III studies indicated similar clinical efficacy and safety. The safety data are in line with the known safety profile of the two products., Gov Registration No: NCT03735030., (© 2022. The Author(s).)

Background and Objective: An orally disintegrating film (ODF) formulation of vitamin D3 that dissolves rapidly in the mouth without drinking or chewing may be a worthwhile alternative to currently available drug products for therapeutic vitamin D supplementation. This study aimed to compare the bioavailability of a single dose of a vitamin D3 25000 I.U. ODF with those of a marketed oral vitamin D3 preparation in healthy subjects., Methods: This Phase 1, randomised, parallel-group, open-label study compared the pharmacokinetics of calcifediol [25(OH)D3], the precursor of bioactive vitamin D3, after a single dose of a new vitamin D3 25,000 I.U. ODF with those of a Reference formulation (vitamin D3 25000 I.U./2.5 mL oral solution) in healthy adult subjects using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary objective was bioavailability under fed conditions, defined as maximum plasma concentration (C max ) of 25(OH)D3 and area under the concentration-time curve from time zero to time t, the last quantifiable concentration (AUC 0-t ). The pharmacokinetics of 25(OH)D3 were also evaluated following the ODF administration under fasting conditions. Subjects were randomised to receive a single dose of the vitamin D3 25000 I.U. ODF or the Reference oral solution under fed conditions or the vitamin D3 ODF under fasting conditions., Results: Forty-eight healthy subjects were randomised and completed the study. Overall, the pharmacokinetic profile was very similar across the three treatment groups, and bioavailability did not significantly differ among treatments. Under fed conditions, mean 25(OH)D3 plasma values for C max were 6.68 ± 2.03 versus 6.61 ± 2.62 ng/mL for the Test versus Reference formulations. Corresponding values for AUC 0-t were 2364.80 ± 1336.97 versus 2150.52 ± 1622.76 ng/mL × h. Mean C max was slightly lower (6.68 ± 2.03 vs 7.23 ± 1.48 ng/mL) and the time to reach peak concentration was delayed (144 h [36-312] versus 42 h (2-480]) with the ODF under fed versus fasting conditions (p = 0.0371). The point estimates and 90 % CIs of the Test fed /Reference fed ratios of the geometric means showed that the bioavailability of exogenous 25(OH)D3 was, both in rate and extent of absorption, slightly higher with the vitamin D3 ODF than the vitamin D3 oral solution under the administration conditions recommended for the vitamin D3 oral solution. Palatability and ease of use of the ODF were satisfactory., Conclusion: The new ODF 25000 I.U. formulation provided a valuable alternative to the marketed oral solution for therapeutic vitamin D supplementation, with a bioavailability that was slightly higher than that of the vitamin D3 oral solution administered under the same conditions., Trial Registration: The study was retrospectively registered with the ISRCTN Registry (Registry code: ISRCTN13208948) on 27 November 2020., (© 2022. The Author(s).)

We aimed to test the diagnostic accuracy in predicting continuous positive airway pressure (CPAP) failure in premature infants with respiratory distress syndrome (RDS) by integrating oxygen saturation (SpO 2 )/fraction of inspired oxygen (FiO 2 ) (SF ratio) with the measurement of peak velocity of the right diaphragmatic excursions (RD-PV), during the inspiration (I-Peak) and expiratory (E-Peak) phases, performed by pulsed-wave Tissue Doppler imaging. This is a prospective, observational pilot study conducted over a 2-year period. Neonates at ≤ 32 weeks gestation supported by early CPAP were eligible. Natural surfactant was delivered via a minimally invasive technique. We performed serial measurements of SF ratio and RD-PV during the early post-natal hours to test the accuracy in predicting surfactant administration as well as invasive ventilation support within 72 h from birth because of the RDS worsening. Of 56 preterm infants enrolled, 34 (61%) failed CPAP support. SF ratio showed a significant inverse relationship with both Silverman-Andersen score at birth (rho = - 0.417; P = .001) and RD-PV [E-Peak] (rho = - 0.361; P = .007). We achieved a high accuracy in predicting CPAP failure (AUC = 95%; 95% CI, 89-100%) by integrating gender, SF ratio, and RD-PV [E-Peak] at the restricted, multivariate analysis.Conclusions: SF ratio and RD-PV, as measured by pulsed-wave Tissue Doppler, may help physicians to improve their confidence in optimizing therapeutic options in preterm infants with RDS. What is Known: • Continuous positive airway pressure is the recommended first-line treatment for respiratory distress syndrome in preterm infants, but failure rates remain unacceptably high. • Choosing the optimal treatment in terms of non-invasive ventilation effectiveness and timeliness of surfactant administration for these patients is often challenging, also due to our inability to identify a worsening respiratory failure. What is New: • The integration of oxygen saturation, as measured by SpO 2 /FiO 2 , with right diaphragm peak motion velocities, as measured by pulsed-wave tissue Doppler, allows for high prediction accuracy of non-invasive ventilation support failure in premature infants at risk of respiratory distress syndrome. • These measurements may help physicians in providing optimal supportive therapy for these patients.

Introduction: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals., Methods: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study., Results: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants., Conclusions: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.

This study evaluated the effect of 3 doses of a trazodone hydrochloride 6% oral drops solution on the QT interval of healthy volunteers. Subjects were randomly assigned to receive a single dose of trazodone 20 mg, 60 mg, and 140 mg, moxifloxacin 400 mg, and trazodone-matched placebo in 5 periods separated by 7-day washouts, according to a double-blind, crossover study design. Subjects were monitored continuously, and triplicate ECGs were extracted from baseline (predose) until 24 hours postdose. Blood samples for trazodone and moxifloxacin analyses were collected at the same time points. The concentration-QTc relationship assessed on placebo-adjusted change from baseline for Fridericia-corrected QT (ΔΔQTcF) was the primary end point. ΔΔQTcF values of 4.5, 12.3, and 19.8 ms for the 20-, 60-, and 140-mg doses were observed at the corresponding trazodone peak plasma concentrations. The upper bound of the 90%CI exceeded 10 ms for the 60- and the 140-mg doses. Time-matched analysis results were in line with these findings. No significant trazodone effect on heart rate or PR or QRS intervals and no clinically significant new morphological changes were present. In this moxifloxacin-validated ECG trial, trazodone had a modest, dose-dependent effect on cardiac repolarization, with no QTc prolongation observed with the 20-mg dose and an effect exceeding the values set in E14 guideline with the 60- and 140-mg doses. The effect on cardiac repolarization is unlikely to represent a clinical risk for ventricular proarrhythmia, but caution should be used with concomitant use of other medications that prolong QT or increase trazodone exposure., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Purpose: Ability to survive the digestive process is a major factor in determining the effectiveness of a probiotic. In this study, the ability of the probiotic L. casei DG ® (Lactobacillus paracasei CNCMI1572) to survive gastrointestinal transit in healthy children was investigated for the first time., Methods: Twenty children aged 3-12 years received L. casei DG ® as drinkable solution of 1 × 10 9 colony forming units (CFU), once daily for 7 consecutive days. Recovery in faecal samples was evaluated at baseline and at different time-points during and after administration. Defecation frequency, faeces consistency, digestive function and product safety were also assessed., Results: Nineteen (95%) of the 20 enrolled children presented viable L. casei DG ® cells in their faeces at least once during the study, with a maximum count (mean 4.3 log 10 CFU/g ± 2.3) reached between day 4 and 6 from the beginning of consumption. Notably, for 11 (57.9%) of the 19 children with viable cells, L. casei DG ® survived in faecal samples up to 3 days after treatment end. Defecation frequency, faeces consistency and digestive function did not change considerably during or after study treatment. Safety of the study product was very good., Conclusions: This study showed for the first time that L. casei DG ® survives the gastrointestinal transit when ingested by children with a paediatric probiotic drinkable solution containing 1 × 10 9 CFU, and persists in the gut up to 3 days after the end of product intake, demonstrating resistance to gastric juices, hydrolytic enzymes and bile acids.

Background: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-β-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis ® /Dicloin ® ), was further developed for intravenous (i.v.) bolus administration., Objectives: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products., Methods: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation., Results: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC 0-t ) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC 0-∞ ). The maximum observed plasma concentration (C max ) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus., Conclusions: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.

Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions. Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated. With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group. Methylene blue blood concentrations reached a peak (C max ) in a median time (T max ) of 12 h with 100 mg and 16 h with 200 mg. AUC 0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose. The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sildenafil was the first selective drug available on the market as oral therapy for erectile dysfunction (ED). A novel sildenafil orodispersible film (ODF) for ED treatment, containing sildenafil citrate, has recently been marketed., Objectives: Study objective was to investigate sildenafil bioavailability of the novel ODF formulation after sublingual and supralingual administration., Methods: In this randomised, two-way cross-over study, 12 healthy male volunteers received a single 50 mg sildenafil dose by the sublingual and supralingual administration routes. Plasma sildenafil was determined up to 12 h post-dose. Peak concentration (C max ) and area under concentration-time curve (AUC 0-t ) were calculated and compared between the two administration routes by analysis of variance (ANOVA)., Results: Sublingual and supralingual administration can be claimed equivalent regarding the extent of sildenafil exposure since AUC 0-t 90 % CIs corresponded to 94.90-110.58% and were within the pre-specified acceptance range. C max 90% CIs (79.92-125.57%) were only slightly outside the 80.00-125.00% limits, due to the small sample size, while the time to achieve C max did not differ between treatments (p = 0.9277). Rate of exposure of the two administration routes was therefore similar. Reported treatment-related adverse events were mild to moderate headache (33.3% of subjects) and vomiting (8.3%)., Conclusions: In healthy men, sublingual and supralingual administration of sildenafil ODF resulted in a remarkably similar pharmacokinetic profile and confirmed the safety of both study treatments. The recently marketed sildenafil ODF, administered by both investigated routes, can provide a valuable alternative to the marketed solid oral forms (tablets) in ED treatment.

Background: Cerebral sinovenous thrombosis is unusual in the asphyxiated cooled infants, but reliable data regarding the incidence of this comorbidity are lacking. We assessed the incidence of sinovenous thrombosis in a population of asphyxiated cooled infants by performing routine brain magnetic resonance venography., Methods: All asphyxiated infants who underwent therapeutic cooling at our institution completed brain magnetic resonance venography after rewarming. Assessing the incidence of cerebral sinovenous thrombosis was the primary goal. Secondary analyses included group comparisons for laboratory tests and monitored parameters, relationship between variables, logistic regression models, and receiver operating characteristic curve for cerebral sinovenous thrombosis prediction., Results: Cerebral sinovenous thrombosis was detected in 10 of 37 infants (27%), most commonly affecting the superior sagittal sinus (eight of ten). These infants manifested higher blanket (P < 0.001) and lower esophageal temperatures (P = 0.006), lower platelet counts (P = 0.045), and received more red blood cell transfusions (P = 0.038) than the cooled infants without thrombosis. Blanket temperature was independently associated with cerebral sinovenous thrombosis (P = 0.049), and 32°C/hour was the optimal cutoff value to predict the event (sensitivity, 90%; specificity, 88.5%)., Conclusions: High incidence or cerebral sinovenous thrombosis in neonates treated with therapeutic hypothermia suggests that magnetic resonance venography may be reasonable in many of these children. High blanket temperature may be one variable that helps identify patients at higher risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The effects on scalp and serum dihydrotestosterone (DHT) of different doses of a novel topical solution of 0.25% finasteride (P-3074), a type 2 5α-reductase, were investigated in men with androgenetic alopecia., Methods: Two randomized, parallel-group studies were conducted. Study I: 18 men received 1 mL (2.275 mg) P-3074, applied to the scalp once a day (o.d.) or twice a day (b.i.d), or 1 mg oral tablet o.d. for 1 week. Study II: 32 men received P-3074 at the dose of 100 (0.2275 mg), 200 (0.455 mg), 300 (0.6285 mg), or 400 (0.91 mg) μL or the vehicle o.d. for 1 week. Scalp and serum DHT and serum testosterone were evaluated at baseline and treatment end., Results: Change from baseline in scalp DHT was -70% for P-3074 o.d. and approx. -50% for P-3074 b.i.d. and the tablet. Serum DHT decreased by 60 - 70%. The doses of 100 and 200 μL P-3074 resulted in a -47/-52% scalp DHT reduction, similar to the 300 and 400 μL doses (i.e., -37/-54%). A -5.6% inhibition was observed for the vehicle. Serum DHT was reduced by only -24/-26% with 100 and 200 μL P-3074 and by -44/-48% with 300 and 400 μL P-3074. No relevant changes occurred for serum testosterone., Conclusions: The novel finasteride 0.25% solution applied o.d. at the doses of 100 and 200 μL results in an appropriate inhibition of scalp DHT potentially minimizing the untoward sexual side-effects linked to a systemic DHT reduction.

Objective: To delineate thromboelastographic profiles of the premature infants with and without intracranial hemorrhage during the first 21 days of life., Methods: In this study, 49 premature infants (24 female; 25 male) were consecutively admitted at our neonatal intensive care unit during a 6 months period were subject to thromboelastography and standard coagulation assessments at birth and weekly up to 21 days. Sixteen out of 49 infants developed intracranial hemorrhage at birth., Results: The test results of 127/196 were considered eligible for analysis. Overall significant changes of the main thromboelastographic parameters were observed shortly after birth. Newborns with intracranial hemorrhage showed increased thromboelastogram-defined thrombin generation (shorter R and time to maximum amplitude times) from birth onward, suggesting a hypercoagulable state. No significant differences concerning thromboelastographic and coagulation assays parameters were found at birth between infants with and without intracranial hemorrhage, except for higher plasma D-Dimer concentration (p = 0.002) in the former infants. Finally, a positive correlation between clot lysis time and gestational age (Spearman's rho = 0.502, p = 0.002) was observed., Conclusions: Thromboelastographic profiles of the premature infants suggest an effective hemostatic function during the first post-natal weeks. Further study is needed to determine whether thromboelastography may be more useful than coagulation assays to reflect the bleeding risk of the premature infants.

Objective: Finasteride, a selective inhibitor of type 2 5-α reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT., Methods: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined., Results: After multiple doses, mean (± SD) finasteride C(max) and AUC(0-t) corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred., Conclusions: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).