Adverse Effects of Antiepileptic Drugs in North Indian Pediatric Outpatients

Bansal, Dipika; Azad, Chandrika; Kaur, Manpreet; Rudroju, Neelima; Vepa, Pravallika; Guglani, Vishal

doi:10.1097/wnf.0b013e31829a498d

Cited by 22 publications

(27 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4 Another study in India with a different AED utilisation pattern reported a lower incidence of behavioural effects (5.7%). 38 While valproic acid and carbamazepine were the most commonly prescribed AEDs in this study, about two-third of the patients in the Indian study received phenytoin. We have reported no significant differences in cognitive and behavioural functions during and after AED treatment.…”

Section: Discussionmentioning

confidence: 72%

See 1 more Smart Citation

A prospective study of adverse drug reactions to antiepileptic drugs in children

et al. 2015

View full text Add to dashboard Cite

ObjectivesTo prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour.SettingA single centre prospective observational study.ParticipantsChildren (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit.Primary and secondary outcomesPrimary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes.Results180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR.ConclusionsBehavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children.Trail registration numberEudraCT (2007-000565-37).

show abstract

Section: Discussionmentioning

confidence: 72%

“…There have been few pharmacovigilance studies of AEDs in children. 4 38–40 The main ADRs identified in this study were behavioural problems (12%) and somnolence/sleep problems (10%). These were also the two most common ADRs in a previous study more than 20 years ago.…”

Section: Discussionmentioning

confidence: 78%

A prospective study of adverse drug reactions to antiepileptic drugs in children

et al. 2015

View full text Add to dashboard Cite

show abstract

“…If inhaled and human-metabolized CBD do not convert to Δ 9 -THC, as previous research suggests, 30 and the trace amounts of THC in plant-extracted CBD medications cannot account for the high incidence of somnolence and fatigue in recent studies, 26 , 27 the events may be partially explained by the sedating effects of antiepileptic drugs. 35 , 36 However, these effects may also be a normal response to the psychoactive Δ 9 -THC and Δ 8 -THC released from the nonpsychoactive precursor CBD in the highly acidic gut milieu. Since studies of the effects of simulated gastric juice on CBD have shown that acid degradation also yields at least two hexahydrocannabinols that have been associated with catalepsy, hypothermia, sleep prolongation, and antinociception in mice, 28 additive or synergistic activity at multiple cannabinoid receptors may be involved.…”

Section: Discussionmentioning

confidence: 99%

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

Merrick

Lane

Sebree

et al. 2016

Cannabis and Cannabinoid Research

View full text Add to dashboard Cite

Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF).Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid.Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of −0.031 min−1 (R2=0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic reference standards.Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.

show abstract

“…Phenytoin has a narrow therapeutic index with a large propensity to produce ADRs due to patient interindividual variability. Adverse side effects of phenytoin are common and often include rashes, headache, behavioral changes, Steven-Johnson syndrome, cardiovascular collapse, and arrhythmias, especially with rapid intravenous administration, in both children and adults (Bansal et al, 2013;Polat et al, 2015). Many pediatric patients with severe epilepsy are often treated with polytherapy, and interactions between phenytoin and other AEDs and the resulting adverse effects have been documented; for example, concurrent treatment with phenytoin and valproic acid produced phenytoin toxicity in an adolescent epileptic patient despite adhering to pediatric dosing guidelines for phenytoin (Carvalho et al, 2014).…”

mentioning

confidence: 99%

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

et al. 2018

View full text Add to dashboard Cite

The induction of cytochrome P450 (P450) enzymes in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce therapeutic efficacy and/or cause toxicity. Since most studies on P450 induction are performed in adults, enzyme induction at neonatal, infant, and adolescent ages is not well understood. Previous work defined the postnatal ontogeny of drug-metabolizing P450s in human and mouse livers; however, there are limited data on the ontogeny of the induction potential of each enzyme in response to drug treatment. Induction of P450s at the neonatal age may also cause permanent alterations in P450 expression in adults. The goal of this study was to investigate the short- and long-term effects of phenytoin treatment on mRNA and protein expressions and enzyme activities of CYP2B10, 2C29, 3A11, and 3A16 at different ages during postnatal liver maturation in mice. Induction of mRNA immediately following phenytoin treatment appeared to depend on basal expression of the enzyme at a specific age. While neonatal mice showed the greatest fold changes in CYP2B10, 2C29, and 3A11 mRNA expression following treatment, the levels of induced protein expression and enzymatic activity were much lower than that of induced levels in adults. The expression of fetal CYP3A16 was repressed by phenytoin treatment. Neonatal treatment with phenytoin did not permanently induce enzyme expression in adulthood. Taken together, our data suggest that inducibility of drug-metabolizing P450s is much lower in neonatal mice than it is in adults and neonatal induction by phenytoin is not permanent.

show abstract

Adverse Effects of Antiepileptic Drugs in North Indian Pediatric Outpatients

Abstract: Monotherapy was the preferred treatment. Phenytoin was the most common ADR causative agent. Female sex, symptomatic epilepsy, and older age (> 5 years) were found to be associated with higher probability of ADR development.

Cited by 22 publications

References 16 publications

A prospective study of adverse drug reactions to antiepileptic drugs in children

A prospective study of adverse drug reactions to antiepileptic drugs in children

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

Contact Info

Product

Resources

About