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1.
Paediatr Anaesth ; 32(3): 436-445, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34878707

ABSTRACT

BACKGROUND: Few randomized studies have assessed recovery from rocuronium- or vecuronium-induced moderate or deep neuromuscular blockade with sugammadex in pediatric participants. AIM: To assess sugammadex for reversal of neuromuscular blockade in pediatric participants. METHODS: This was a randomized, phase IV, active comparator-controlled, double-blind study. Participants aged 2 to <17 years, under moderate or deep neuromuscular blockade, were administered sugammadex (2 or 4 mg/kg) or neostigmine (50 µg/kg; for moderate neuromuscular blockade only). Predefined adverse events of clinical interest, including clinically relevant bradycardia, hypersensitivity, and anaphylaxis, were monitored. The primary efficacy endpoint was time to recovery to a train-of-four ratio of ≥0.9 in participants receiving sugammadex 2 mg/kg versus neostigmine for reversal of moderate neuromuscular blockade, analyzed by analysis of variance adjusted for neuromuscular blocking agent and age. RESULTS: Of 288 randomized participants, 272 completed the study and 276 were included in the analyses. Clinically relevant bradycardia was experienced by 2.0%, 1.6%, and 5.9% of participants in the sugammadex 2 mg/kg, sugammadex 4 mg/kg, and neostigmine groups, respectively. No hypersensitivity or anaphylaxis events were observed. Recovery to a train-of-four ratio of ≥0.9 with sugammadex 2 mg/kg was faster than neostigmine (1.6 min, 95% CI 1.3 to 2.0 vs. 7.5 min, 95% CI 5.6 to 10.0; p < .0001) and was comparable to sugammadex 4 mg/kg (2.0 min, 95% CI 1.8 to 2.3). CONCLUSIONS: Pediatric participants recovered from rocuronium- or vecuronium-induced moderate neuromuscular blockade significantly faster with sugammadex 2 mg/kg than with neostigmine. Time to reversal of deep neuromuscular blockade with sugammadex 4 mg/kg was consistent with that of moderate neuromuscular blockade reversal. No meaningful differences in clinically relevant bradycardia, hypersensitivity, or anaphylaxis were seen with sugammadex vs neostigmine. These results support the use of sugammadex for reversal of moderate and deep rocuronium- and vecuronium-induced neuromuscular blockade in patients aged 2 to <17 years. CLINICAL TRIAL REGISTRATION: NCT03351608/EudraCT 2017-000692-92.


Subject(s)
Anaphylaxis , Anesthetics , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents , Anaphylaxis/chemically induced , Anesthetics/adverse effects , Bradycardia/chemically induced , Child , Humans , Neostigmine , Neuromuscular Blockade/methods , Neuromuscular Nondepolarizing Agents/adverse effects , Rocuronium , Sugammadex/adverse effects , Vecuronium Bromide/adverse effects
2.
BMC Anesthesiol ; 21(1): 62, 2021 02 27.
Article in English | MEDLINE | ID: mdl-33639839

ABSTRACT

BACKGROUND: This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW). METHODS: Adults with BMI ≥40 kg/m2 were randomized to 1 of 5 groups: M-neuromuscular block, sugammadex 2 mg/kg ABW; M-neuromuscular block, sugammadex 2 mg/kg IBW; M-neuromuscular block, neostigmine 5 mg, and glycopyrrolate 1 mg; D-neuromuscular block, sugammadex 4 mg/kg ABW; or D-neuromuscular block, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX®) monitored recovery. Primary endpoint was time to TOF ratio ≥ 0.9 for ABW and IBW groups pooled across neuromuscular blocking agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis. RESULTS: Of 207 patients randomized, 188 received treatment (28% male, BMI 47 ± 5.1 kg/m2, age 48 ± 13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time > 10 min (95% CI of difference: - 4.8 to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences. CONCLUSIONS: ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of neuromuscular block or NMBA used. TRIAL REGISTRATION: Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070 .


Subject(s)
Anesthesia Recovery Period , Body Weight/physiology , Neuromuscular Blockade/methods , Obesity, Morbid/physiopathology , Rocuronium/pharmacology , Sugammadex/administration & dosage , Vecuronium Bromide/pharmacology , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Ideal Body Weight/physiology , Male , Middle Aged , Neuromuscular Nondepolarizing Agents/pharmacology , Time Factors
3.
Clin Transl Sci ; 13(3): 482-490, 2020 05.
Article in English | MEDLINE | ID: mdl-31758661

ABSTRACT

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials.


Subject(s)
Clinical Decision-Making/methods , Migraine Disorders/drug therapy , Pyridines/administration & dosage , Pyrroles/administration & dosage , Adolescent , Adult , Aged , Clinical Trials, Phase III as Topic , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Migraine Disorders/diagnosis , Models, Biological , Pain Measurement , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Time Factors , Treatment Outcome , Young Adult
4.
Workplace Health Saf ; 61(6): 237-42, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23738570

ABSTRACT

A 2012 American Association of Occupational Health Nurses, Inc. (AAOHN) web-based membership survey of 5,138 members was designed to identify occupational health and safety issues facing members. A total of 2,123 members responded to the survey (41% response rate). Of the AAOHN members who responded to this survey, 61% reported health risk appraisal (HRA) priorities for 2012. HRA priority areas are identified among various subgroups of the AAOHN responders in this article. The top three HRA priority areas identified were weight management/nutrition/healthy eating, physical activity, and mental health/stress management. These priority areas were consistent across three industry sectors, three occupational health nurse job titles, and the smallest and largest employers. These results suggest that occupational health nurses should consider prioritizing their employee wellness efforts in these areas.


Subject(s)
Health Care Surveys , Health Priorities/statistics & numerical data , Health Priorities/trends , Occupational Diseases/epidemiology , Occupational Health Nursing , Societies, Nursing , Humans , Occupational Diseases/nursing , Risk Assessment , United States/epidemiology
5.
Genetics ; 171(1): 211-25, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15972457

ABSTRACT

Using quantitative trait locus (QTL) mapping, we studied the genetic basis of the difference in pigmentation between two sister species of Drosophila: Drosophila yakuba, which, like other members of the D. melanogaster subgroup, shows heavy black pigmentation on the abdomen of males and females, and D. santomea, an endemic to the African island of São Tomé, which has virtually no pigmentation. Here we mapped four QTL with large effects on this interspecific difference in pigmentation: two on the X chromosome and one each on the second and third chromosomes. The same four QTL were detected in male hybrids in the backcrosses to both D. santomea and D. yakuba and in the female D. yakuba backcross hybrids. All four QTL exhibited strong epistatic interactions in male backcross hybrids, but only one pair of QTL interacted in females from the backcross to D. yabuka. All QTL from each species affected pigmentation in the same direction, consistent with adaptive evolution driven by directional natural selection. The regions delimited by the QTL included many positional candidate loci in the pigmentation pathway, including genes affecting catecholamine biosynthesis, melanization of the cuticle, and many additional pleiotropic effects.


Subject(s)
Quantitative Trait Loci/genetics , Skin Pigmentation/genetics , Animals , Chromosome Mapping , Crosses, Genetic , Epistasis, Genetic , Female , Genes, Insect/genetics , Genetic Variation , Genotype , Haplotypes , Hybridization, Genetic , Male , Species Specificity
6.
Genetics ; 167(3): 1265-74, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15280240

ABSTRACT

Sexual isolating mechanisms that act before fertilization are often considered the most important genetic barriers leading to speciation in animals. While recent progress has been made toward understanding the genetic basis of the postzygotic isolating mechanisms of hybrid sterility and inviability, little is known about the genetic basis of prezygotic sexual isolation. Here, we map quantitative trait loci (QTL) contributing to prezygotic reproductive isolation between the sibling species Drosophila simulans and D. mauritiana. We mapped at least seven QTL affecting discrimination of D. mauritiana females against D. simulans males, three QTL affecting D. simulans male traits against which D. mauritiana females discriminate, and six QTL affecting D. mauritiana male traits against which D. simulans females discriminate. QTL affecting sexual isolation act additively, are largely different in males and females, and are not disproportionately concentrated on the X chromosome: The QTL of greatest effect are located on chromosome 3. Unlike the genetic components of postzygotic isolation, the loci for prezygotic isolation do not interact epistatically. The observation of a few QTL with moderate to large effects will facilitate positional cloning of genes underlying sexual isolation.


Subject(s)
Drosophila/genetics , Polymorphism, Genetic , Quantitative Trait Loci , Sexual Behavior, Animal/physiology , Animals , Chromosome Mapping , Crosses, Genetic , DNA Primers , Drosophila/physiology , Female , Male , Microsatellite Repeats/genetics , Reproduction/genetics , Species Specificity
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