Treatment with hOKT3gamma1(Ala-Ala) mitigates the deterioration in insulin production and improves metabolic control during the first year of type 1 diabetes mellitus in the majority of patients. The mechanism of action of the anti-CD3 monoclonal antibody may involve direct effects on pathogenic T cells, the induction of populations of regulatory cells, or both.
BackgroundA formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters.ObjectiveThis trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters.MethodsThe study consisted of three arms: single ascending dose (1500, 3000, 4500 or 6000 mg CBD [n = 6 per group]/placebo [n = 8; 2 per CBD dose group]), multiple dose (750 or 1500 mg CBD [n = 9 per group]/placebo [n = 6; 3 per CBD dose group] twice daily), and food effect (1500 mg CBD single dose [n = 12]). All subjects completed all trial arms and were analyzed as planned.ResultsCBD was generally well tolerated. Diarrhea, nausea, headache, and somnolence were the most common adverse events (AEs) across all trial arms, with an increased incidence of some gastrointestinal and nervous system disorder AEs (most notably diarrhea and headache) apparent in subjects taking CBD compared with placebo. All AEs were of mild or moderate severity; none were severe or serious. There were no deaths or discontinuations in the trial. After single oral doses, CBD appeared rapidly in plasma; time to maximum plasma concentration (tmax) was approximately 4–5 h. The major circulating metabolite was 7-carboxy-CBD, then parent CBD, 7-hydroxy-CBD (active metabolite), and 6-hydroxy-CBD (a relatively minor metabolite). Plasma exposure to CBD [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time t (AUCt)] increased in a less than dose-proportional manner (Cmax slope 0.73; AUCt slope 0.64). Oral clearance of CBD was high (1111–1909 L/h) and apparent volume of distribution was large (20,963–42,849 L). CBD reached steady state after approximately 2 days, with moderate accumulation (1.8- to 2.6-fold) after 750 and 1500 mg CBD twice daily. After 7 days, a twofold increase in CBD dose resulted in 1.6- and 1.9-fold increases in geometric mean Cmax and area under the plasma concentration-time curve over a dosing interval (AUCτ), respectively. CBD elimination was multiphasic; the terminal elimination half-life was approximately 60 h after 750 and 1500 mg CBD twice daily; and effective half-life estimates ranged from 10 to 17 h. Cmax was 541.2 ng/mL and AUCτ was 3236 ng·h/mL after 1500 mg CBD twice daily. A high-fat meal increased CBD plasma exposure (Cmax and AUCt) by 4.85- and 4.2-fold, respectively; there was no effect of food on tmax or terminal half-life.ConclusionCBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.
These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.
Children with special health care needs may be at higher risk for bullying, victimization, and ostracism. Further research is needed to explore this relationship, especially as it relates to child adjustment. Children with special health care needs should be asked about bullying and ostracism experiences and potential effects as part of mental health screening.
Trait disinhibition is associated with problem drinking and alcohol drinking itself can bring about a state of disinhibition. It is unclear however, if expectancies of alcohol-induced disinhibition are unique predictors of problem drinking. Impaired control (i.e., difficulty in limiting alcohol consumption) may be related to disinhibition expectancies in that both involve issues of control related to alcohol use. Data from a prospective survey of undergraduates assessed during freshman (N = 337) and senior year (N = 201) were analyzed to determine whether subscales of the DrinkingInduced Disinhibition Scale and the Impaired Control Scale predicted unique variance in heavy episodic drinking and alcohol-related problems. In Time 1 cross-sectional models, dysphoric disinhibition expectancies predicted alcohol-related problems and impaired control predicted both alcohol-related problems and heavy episodic drinking. In prospective models, Time 1 impaired control predicted Time 2 alcohol-related problems and Time 1 euphoric/social disinhibition expectancies predicted Time 2 heavy episodic drinking. These findings suggest that expectancies of alcohol-induced disinhibition and impaired control predict unique variance in problem drinking cross-sectionally and prospectively and that these phenomena should be targeted in early intervention efforts.
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