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The feasibility of administering a relatively high dose of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix by means of a needle-free injection device, which could be useful in the long-term treatment of sex-steroid-dependent disorders, was evaluated in a randomized, crossover study in 16 healthy females. Local tolerance and pharmacokinetics of ganirelix administered by MediJector versus conventional needle injections were compared. Additionally, the pharmacodynamic effect was evaluated. Two milligrams of ganirelix was administered s.c. once daily for 7 days by Medi-Jector or conventional needle in a randomized sequence, without a washout period. No apparent differences in local tolerance were observed. Most injections (87.5%) gave either no or only a mild reaction. Of the moderate reactions, swelling and redness were reported most frequently (overall 4.9 and 8.5% per injection, respectively). Administration by Medi-Jector was bioequivalent to conventional needle injection with respect to the peak concentration and area under the curve. A profound suppression of luteinizing hormone and follicle stimulating hormone was observed. Serum oestradiol and progesterone concentrations were relatively low prior to treatment and remained low during the entire study period. In conclusion, administration of a relatively high dose of ganirelix by Medi-Jector might be useful for long-term treatment of sex-steroid dependent disorders. [ABSTRACT FROM AUTHOR]

The feasibility of administering a relatively high dose of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix by means of a needle-free injection device, which could be useful in the long-term treatment of sex-steroid-dependent disorders, was evaluated in a randomized, crossover study in 16 healthy females. Local tolerance and pharmacokinetics of ganirelix administered by MediJector® versus conventional needle injections were compared. Additionally, the pharmacodynamic effect was evaluated. Two milligrams of ganirelix was administered s.c. once daily for 7 days by Medi-Jector® or conventional needle in a randomized sequence, without a washout period. No apparent differences in local tolerance were observed. Most injections (87.5%) gave either no or only a mild reaction. Of the moderate reactions, swelling and redness were reported most frequently (overall 4.9 and 8.5% per injection, respectively). Administration by Medi-Jector® was bioequivalent to conventional needle injection with respect to the peak concentration and area under the curve. A profound suppression of luteinizing hormone and follicle stimulating hormone was observed. Serum oestradiol and progesterone concentrations were relatively low prior to treatment and remained low during the entire study period. In conclusion, administration of a relatively high dose of ganirelix by Medi-Jector® might be useful for long-term treatment of sex-steroid dependent disorders. [ABSTRACT FROM PUBLISHER]

Background: Pediatric adjuvanted seasonal influenza vaccines induce higher immune responses and have the potential to confer better protection against influenza among young vaccine-naïve children. Limited data describe benefits and risks of repeated administration of adjuvanted influenza vaccines in children. Two revaccination studies assess the safety and immunogenicity of repeated exposure to an MF59-adjuvanted quadrivalent influenza vaccine (aQIV; Fluad®) compared to routine non-adjuvanted quadrivalent influenza vaccine (QIV)., Methods: Children previously enrolled in the parent study, who received vaccination with aQIV or nonadjuvanted influenza vaccine (TIV or QIV), were recruited in Season 1 (n = 607) or Season 2 (n = 1601) of the extension trials. Season 1 participants remained in their original randomization groups (aQIV-aQIV or TIV-QIV); Season 2 subjects were re-randomized to either vaccine, resulting in four groups (aQIV-aQIV, aQIV-QIV, QIV-aQIV, or QIV-QIV). All subjects received a single-dose vaccination. Blood samples were taken for immunogenicity assessment prior to vaccination and 21 and 180 days after vaccination. Reactogenicity (Days 1-7) and safety were assessed in all subjects., Results: Hemagglutination inhibition (HI) geometric mean titer (GMT) ratios demonstrated superiority of aQIV revaccination over QIV revaccination for all strains in Season 1 and for A/H1N1, B/Yamagata, and B/Victoria in Season 2. Higher HI titers against heterologous influenza strains were observed after aQIV vaccination during both seasons. Mild to moderate severity and short duration reactogenicity was more common in the aQIV than QIV groups, but the overall safety profiles were similar to the parent study., Conclusion: The safety and immunogenicity results from this study demonstrate benefit of aQIV for both priming and revaccination of children aged 12 months to 7 years., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DS is an employee of Seqirus Australia. JO is an employee of Seqirus Netherlands BV. BZ and IS are employees of Seqirus USA., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives., Objective: To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is equivalent to the originator brand glatiramer acetate (hereafter brand drug) product, as measured by imaging and clinical end points, safety, and tolerability., Design, Setting, and Participants: Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. The setting included academic medical centers and clinical practices. Participants were patients with relapsing-remitting multiple sclerosis 18 to 55 years old with at least 1 relapse in the prior year and 1 to 15 gadolinium-enhancing brain magnetic resonance imaging lesions. They were randomized between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013., Interventions: Participants were randomized 4.3:4.3:1 to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or placebo by daily subcutaneous injection for 9 months., Main Outcomes and Measures: The primary end point was the total number of gadolinium-enhancing lesions during months 7, 8, and 9. Additional end points included other magnetic resonance imaging parameters, annualized relapse rate, and Expanded Disability Status Scale score. Safety and tolerability were assessed by monitoring adverse events, injection site reactions, and laboratory test results., Results: In total, 794 participants were randomized and treated with generic drug (n  = 353), brand drug (n = 357), or placebo (n = 84). The estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo (ratio, 0.488; 95% CI, 0.365-0.651; P < 001), confirming study sensitivity. For gadolinium-enhancing lesions, the estimated ratio of generic drug to brand drug was 1.095 (95% CI, 0.883-1.360), which was within the predefined equivalence margin of 0.727 to 1.375. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups., Conclusions and Relevance: As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability., Trial Registration: clinicaltrials.gov Identifier: NCT01489254.

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation., (Copyright © 2010. Published by Elsevier Inc.)

Background: A concern for new compounds in fertility treatment is the possible risk of perinatal complications or birth defects. To demonstrate long-term safety of ganirelix (GnRH antagonist) treatment in controlled ovarian stimulation (COS), follow-up data on pregnancy and neonatal outcome were analysed for 1000 fetuses (>or=16 gestational weeks)., Methods: Obstetrical and neonatal data on 839 pregnancies, resulting in 969 live born infants after ganirelix treatment were compared with a historical cohort of 753 pregnancies after long GnRH agonist (buserelin) treatment, resulting in 963 live born infants. All treatment cycles were performed in a single fertility centre. The infants were examined at the Universitair Ziekenhuis Brussel using an identical follow-up protocol. Incidence of major malformations (i.e. causing functional impairment or requiring surgical correction) was the primary end-point and was analysed by logistic regression including treatment, age of mother, IVF method and pregnancy type (singleton/multiple) as independent variables., Results: There were no relevant differences in maternal characteristics, fertilization method and pregnancy and delivery complications between the ganirelix and historical GnRH agonist groups. There were relatively more multiple pregnancies in the historical GnRH agonist group (31.9%) than the ganirelix group (18.7%; P < 0.0001). The groups were comparable with respect to pregnancy loss after 16 weeks gestation. The incidence of major congenital malformations in fetuses with gestational age >or=26 weeks was 5.0% in the ganirelix cohort versus 5.4% in the historical GnRH agonist group (odds ratio 0.94, 95% confidence interval, 0.62-1.42)., Conclusion: In terms of neonatal outcome and risk of major malformations, treatment with the GnRH antagonist ganirelix during COS is as safe as traditional GnRH agonists.

Objective: To assess maximal volume reduction of leiomyomas and uterus and the duration of treatment required to reach these reductions with daily GnRH antagonist treatment., Design: Prospective, open-label study., Setting: Large teaching hospital in The Netherlands., Population: Premenopausal women with symptomatic fibroids, who were scheduled for surgery., Methods: Twenty women were treated with daily 2 mg of subcutaneous ganirelix. Prior to the first injection and weekly during treatment, the volume of leiomyomas and the uterus were assessed by ultrasound (USS) and serum hormones were measured. Prior to treatment and when maximal size reduction was observed by USS, the volume of the leiomyomas and the uterus were also assessed by magnetic resonance imaging (MRI)., Main Outcome Measures: Leiomyoma and uterine size reduction, time to maximal reduction., Results: One woman was excluded from the study due to incorrect administration dose of ganirelix. Data on the remaining 19 women (average age 39 years) with subserosal (n= 9), submucosal (n= 7), intramural (n= 10) and transmural (n= 1) leiomyomas were evaluated. Baseline leiomyoma volumes ranged from small (3-4 mL) to large (>1000 mL). The median duration of treatment up to maximal leiomyoma size reduction was 19 days (range 1-65 days). The maximal size reduction in leiomyomas measured by USS was -42.7% (-77.0% to 14.1%) and -29.2% (-62.2% to 35.6%) by MRI. Comparable uterine size reductions of -46.6% (-78.6% to -6.1%) and -25.2% (-63.6% to 28.9%) were observed by USS and MRI. During the first three weeks of treatment, 8 out of 19 women reported adverse events related to the induced hypoestrogenic state. Most of these events resolved within one week after treatment was discontinued., Conclusion: Daily treatment with 2 mg of ganirelix results in rapid reduction of leiomyoma and uterine volume in premenopausal women with minor side effects. If longer-acting GnRH antagonists become available, pretreatment with GnRH antagonist should be preferred over GnRH agonists prior to surgery.

Increasing depth of sleep corresponds to an increasing gain in the neuronal feedback loops that generate the low-frequency (slow-wave) electroencephalogram (EEG). We derived the maximum-likelihood estimator of the feedback gain and applied it to quantify sleep depth. The estimator computes the fraction (0%-100%) of the current slow wave which continues in the near-future (0.02 s later) EEG. Therefore, this percentage was dubbed slow-wave microcontinuity (SW%). It is not affected by anatomical parameters such as skull thickness, which can considerably bias the commonly used slow-wave power (SWP). In our study, both of the estimators SW% and SWP were monitored throughout two nights in 22 subjects. Each subject took temazepam (a benzodiazepine) on one of the two nights. Both estimators detected the effects of age, temazepam, and time of night on sleep. Females were found to have twice the SWP of males, but no gender effect on SW% was found. This confirms earlier reports that gender affects SWP but not sleep depth. Subjectively assessed differences in sleep quality between the nights were correlated to differences in SW%, not in SWP. These results demonstrate that slow-wave microcontinuity, being based on a physiological model of sleep, reflects sleep depth more closely than SWP does.

Objective: To assess the dose-proportionality and pharmacodynamic properties of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands)., Design: Randomized, parallel, pharmacokinetic, and pharmacodynamic study., Setting: Phase I clinical research unit., Patient(s): Three groups of 15 healthy female volunteers of reproductive age., Intervention(s): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2 concentrations., Main Outcome Measure(s): Pharmacokinetic parameters and hormone suppression., Result(s): Steady-state levels were reached between days 2 and 3. Peak concentrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean values for the area under the curve over one dosing interval (24 hours) were 33 ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25-mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after injection, respectively). Serum hormone levels returned to pretreatment values within 2 days after the last injection., Conclusion(s): The pharmacokinetics of ganirelix were dose-proportional within the dose range studied. Multiple injections resulted in immediate suppression of gonadotropins, which was rapidly reversed after treatment discontinuation.

Objective: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection., Design: Randomized, crossover, pharmacokinetic study., Setting: Phase I clinical research unit., Patient(s): Nineteen healthy female volunteers of reproductive age., Intervention(s): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored., Main Outcome Measure(s): Pharmacokinetic parameters., Result(s): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean (+/- SD) peak concentration and time of occurrence after SC administration were 14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives after IV administration and SC administration were highly similar (12.7+/-3.7 hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/-6.7%. Both treatments were well tolerated., Conclusion(s): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of >90%.

Background and Objective: Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect., Methods: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated., Results: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters., Conclusion: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.