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Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ 9 -tetrahydrocannabinol (THC): CBD up to 10–12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (C ss, Min ) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10–12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. C SS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. C SS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, C SS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

We hypothesized that enteral doxapram would effectively treat apnea of prematurity without the appearance of major side effects. Of 16 infants, 10 (BW 1,520 ± 102 g) received doxapram alone and 6 (BW 1,020 ± 35 g) received doxapram plus theophylline. Apneas decreased from 16.7 ± 1.9 to 2.1 ± 0.6 in infants receiving doxapram alone, and from 38.2 ± 4.4 to 7.9 ± 2.2 apneas/24 h in those receiving doxapram plus theophylline. This was associated with an increase in alveolar ventilation, a shift of the ventilatory response to CO₂ to the left, and no change in the immediate ventilatory response to 100% oxygen. Side effects included premature teeth buds corresponding to the lower central incisors, prevalence of occult blood in stool and necrotizing enterocolitis. The findings suggest that doxapram effectively controls apnea when given enterally, but should be used cautiously because of potentially harmful side effects.

BackgroundInitial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.MethodsTwenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects.DiscussionThis paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.Trial registrationhttp://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827

We report on two Aboriginal patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Both presented with acute hepatic failure with severe hypertransaminasemia and coagulopathy, prompting evaluation for emergent liver transplantation. The diagnosis of HHH syndrome was based on the presence of typical metabolic abnormalities. A protein-restricted diet and L-arginine or L-citrulline supplementation were immediately started, with rapid normalization of liver function test results and other biochemical abnormalities. Molecular analysis of the SLC25A15 gene showed that the two patients were homozygous for the common French Canadian mutation (F188Delta). The diagnosis of HHH syndrome should be considered in patients with unexplained fulminant hepatic failure. There does not appear to be a genotype-phenotype correlation for this presentation, inasmuch as the only other reported patient presenting with this picture had two different point mutations. Early identification and prompt treatment of these patients is crucial to avoid liver transplantation and can be life saving.

To evaluate the effect of intratracheal administration of N-acetylcysteine (Mucomyst) on the clinical status, pulmonary function and gas exchange in premature infants with chronic lung disease, we conducted a randomized, placebo-controlled, crossover trial. Ten mechanically ventilated infants (gestational age 27 +/- 1 week; postnatal age 22 +/- 6 days) with clinical and radiological evidence of chronic lung disease and increased airway secretion were enrolled in the study. Each infant received tracheal administration of 5% N-acetylcysteine for one week and saline placebo every 4 h for another week. N-acetylcysteine was associated with a 59 +/- 26% increase in total airway resistance by the third day of treatment (p less than 0.01). A two-fold increase in airway resistance associated with an increased frequency of bradycardia and cyanosis spells was seen in two of the infants following three days of N-acetylcysteine administration, with a rapid improvement in their condition when subsequently switched to saline. Overall, N-acetylcysteine administration had no effect on the variables measured. We conclude that intratracheal administration of N-acetylcysteine to liquefy airway mucus neither improves the clinical condition nor hastens recovery in premature infants with chronic lung disease and its administration may lead to increased total airway resistance and cyanotic spells. The present data do not support the use of N-acetylcysteine as a mucolytic agent in premature infants with chronic lung disease.

Women seeking ART and being treated with metformin still show a very high rate of GD or IGT after achieving pregnancy by ART. Therefore in women undergoing ART screening for GD should be performed as soon as pregnancy is confirmed to avoid miscarriages due to overlooked uncontrolled glucose metabolism.

For patients who fail conventional therapies, ability to access medical Cannabis may offer a therapeutic alternative that addresses their unmet clinical need. However, a paucity of clinical trial evidence has led to ambiguous pediatric dosing guidelines for medical Cannabis, a situation further complicated by the impact of developmental maturation of the pharmacokinetic (PK) and pharmacodynamic (PD) processes governing drug effect and dosing requirements. The pediatric population is very heterogeneous, and dissimilar developmental trajectories result in important differences in the rate and extent of cannabinoid absorption, distribution, elimination, and response both between and within pediatric age group classifications. These developmental changes will require the prescribing caregiver to consider age-specific dosage regimens that may demand continual modification as the child ages. The chapter that follows emphasizes the impact of agerelated changes in PK and PD processes as important considerations in pediatric dosing recommendations for medical Cannabis.