Glucose-6-Phosphate Dehydrogenase Deficiency and Coronavirus Disease 2019.

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with glucose-6-phosphate dehydrogenase deficiency had an increased risk of coronavirus disease 2019 (COVID-19) infection and severity, with higher rates of hospitalization and diagnosed long COVID.

Explainable multimodal machine learning model for classifying pregnancy drug safety.

MOTIVATION: Teratogenic drugs can cause severe fetal malformation and therefore have critical impact on the health of the fetus, yet the teratogenic risks are unknown for most approved drugs. This article proposes an explainable machine learning model for classifying pregnancy drug safety based on multimodal data and suggests an orthogonal ensemble for modeling multimodal data. To train the proposed model, we created a set of labeled drugs by processing over 100 000 textual responses collected by a large teratology information service. Structured textual information is incorporated into the model by applying clustering analysis to textual features. RESULTS: We report an area under the receiver operating characteristic curve (AUC) of 0.891 using cross-validation and an AUC of 0.904 for cross-expert validation. Our findings suggest the safety of two drugs during pregnancy, Varenicline and Mebeverine, and suggest that Meloxicam, an NSAID, is of higher risk; according to existing data, the safety of these three drugs during pregnancy is unknown. We also present a web-based application that enables physicians to examine a specific drug and its risk factors. AVAILABILITY AND IMPLEMENTATION: The code and data is available from https://github.com/goolig/drug_safety_pregnancy_prediction.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ultra-processed food (UPF) intake in pregnancy and maternal and neonatal outcomes.

PURPOSE: Ultra-processed food (UPF), as defined by the NOVA classification, is related to lower diet quality, which may adversely affect maternal health and neonatal outcomes. This study aims to describe nutrient intake of pregnant women by the share of UPF in the diet and to identify associations between UPF intake and maternal and neonatal outcomes. METHODS: In this cross-sectional study, pregnant women (n = 206) were recruited upon arrival to the obstetrics ward for delivery, and asked to complete a Food Frequency Questionnaire (FFQ), and questionnaires regarding environmental exposures, and socio-demographic characteristics. Neonatal measurements and clinical data were obtained following delivery. UPF energy intake was expressed as absolute and in terms of percent from total energy. Women with high intake of energy from UPF were compared to those with low intake. RESULTS: Among 206 pregnant women, dietary intake of UPF ranged from 15.6% to 43.4% of total energy in the first and fourth quartiles of UPF consumption, respectively. Women in the fourth quartile of energy from UPF had lower intakes of vitamin C, beta-carotene, vitamin B6, and potassium, which is indicative of inferior diet quality. Percent energy from UPF was associated with maternal obesity (BMI ≥ 30) (OR = 1.06, 95% CI: 1.06, 1.10, p = 0.008) and shorter male infant ano-genital distance (AGD) (B = -1.9, 95% CI: -3.5, -0.24, p = 0.02). CONCLUSIONS: UPF intake during pregnancy is associated with undesirable maternal and neonatal outcomes and more research is needed to confirm these findings.

Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas.

OBJECTIVE: Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. METHODS: Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 µg/ml (10 µmol·L-1 , n = 7) or 10 µg/ml (40 µmol·L-1 , n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 µg/ml, 500 µmol·L-1 , n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. RESULTS: Following a 3-h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 µg/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 µg/ml lacosamide, 83 µg/ml valproate, and 2.5 µg/ml lacosamide, respectively; p < .05). SIGNIFICANCE: Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.

Levetiracetam in lactation: How much is excreted into human breast milk?

AIMS: In breastfeeding women, anti-epileptic therapy can lead to infant toxicities, even with newer anti-epileptic drugs such as levetiracetam. This study assessed levetiracetam breastmilk excretion and its correlation with the maternal oral dose and serum concentrations. METHODS: Women with epilepsy treated with levetiracetam were recruited to this study and completed a questionnaire. Levetiracetam concentrations were determined in serial breastmilk samples (pre-dose to 12 h post-dose period) and in a single pre-dose maternal serum sample. RESULTS: Twenty breastfeeding women and 21 infants (one woman with twins; 16 fully and five partially breastfed infants) participated in this study. The trough breastmilk/serum ratio of levetiracetam was 0.98 ± 0.20. The infant levetiracetam daily dose was 5.39 ± 1.96 and 2.70 ± 0.98 mg. kg-1. d-1 , and the relative infant dose (RID) was 13.8 ± 3.1% and 6.9 ± 1.6% in the fully and partially breastfed infants, respectively. Substantial correlations between the levetiracetam dose, maternal serum and breastmilk trough concentrations, and breastmilk AUC values were found. Three women reported somnolence in their fully breastfed infants, which resolved shortly after switching to partial breastfeeding. All the infants gained weight according to their age. CONCLUSIONS: Infant levetiracetam exposure via the breastmilk was close to the safety thresholds (trough breastmilk/serum ratio slightly below 1, RID > 10% in fully breastfed infants), and infant somnolescence reports could be related to exposure of the infants to levetiracetam via breastmilk. Further studies are warranted to reveal the short- and long-term safety of levetiracetam in breastfeeding.

Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study.

BACKGROUND: Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns. METHODS: We recruited 975 mother-term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models. RESULTS: Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel. CONCLUSION: By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.

Analysis of 10 urinary BTEX metabolites using LC-MS/MS.

Benzene, toluene, ethylbenzene, and xylene (BTEX) are a group of volatile organic compounds that are ubiquitous in the environment due to numerous anthropogenic sources. Exposure to BTEX poses a health hazard by increasing the risk for damage to multiple organs, neurocognitive impairment and birth defects. Urinary BTEX metabolites are useful biomarkers for the evaluation of BTEX exposure, because of the ease of sampling and their longer physiological half-lives compared with parent compounds. A method that utilizes LC-MS/MS was developed and validated for simultaneously monitoring of 10 urinary BTEX metabolites. During the sample preparation an aliquot of urine was diluted with an equal volume of 1% formic acid; internal standard solution was added, and then the sample was centrifuged and analyzed. The analytes were separated on the Kinetex-F5 column by applying a linear gradient, consisting of 0.1% formic acid and methanol. The method was validated according to the FDA Bioanalytical Method Validation Guidance for Industry. The mean method's accuracies of the spiked matrix were 81-122%; the inter-day precision ranged from 4 to 20%; the limits of quantitation were 0.5-2 µg/L. The method was used for the evaluation of baseline levels of urinary BTEX metabolites in 87 firefighters.

Pregnancy outcomes following gestational exposure to papaverine: An observational comparative study.

AIMS: Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS: A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS: The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P < .001), CS (35.9 vs. 24.1%, P < .001) and lower birth weight (3207 vs. 3246 g, P = .02). Adjustment for treatment indication demonstrated that these remained significant only when given for obstetrical/surgical aetiologies. Comparable rates were observed for the remaining outcomes. CONCLUSIONS: Short-term gestational exposure to papaverine adjusted for indication was not associated with preterm deliveries, CS, lower birthweight, small for gestational age or perinatal death. Rate of major malformations among 46 first trimester exposures was comparable to controls.

The effect of an intervention program on the knowledge and attitudes among medical staff regarding adverse drug reaction reporting.

PURPOSE: Adverse drug reactions (ADRs) are a growing important public health problem; however, underreporting of ADRs is very common. The aim of the current study was to explore the effect of an intervention program on the knowledge and attitudes among physicians and nurses regarding ADRs reporting. METHODS: A multicentre study consisted of three phases: filling out a questionnaire; an intervention program; filling out the same questionnaire again. The intervention program consisted of posters, lectures, and distant electronic learning. The questionnaire contained questions about personal/professional demographic variables, and statements regarding knowledge and attitudes regarding ADR reporting. RESULTS: The data revealed that the intervention program significantly elevated the "Objective knowledge" (P < 0.01) and "Practical knowledge" (P < 0.02) score as compared to the control group, while no significant differences were found regarding "Acquired knowledge" (P = 0.14). Seniority (P = 0.01) and experience in internal medicine (P = 0.05) were demonstrated as significant factors determining the knowledge of the staff. Obligation was the main motive for reporting in 80% of participants. After the intervention, no differences were found in the "Attitude related to the motive for reporting" or "Attitude related to the commitment to report", between the two groups. However, "Attitude related to the need to report" score significantly improved after the intervention (P = 0.04). CONCLUSIONS: The intervention program increased knowledge and attitudes regarding ADRs reports. Seniority had the most effect on the influence of the intervention program. The data from this study encourages the necessity to hold ongoing intervention programs in order to improve ADRs reporting rate.

The Clinical Value of Routine Acetaminophen Level Screening in Pediatric Patients Presenting to the Emergency Department.

BACKGROUND: Acetaminophen is the most common drug involved in pediatric poisonings, both intentionally and accidentally, and is the leading cause of acute liver failure among all age groups. OBJECTIVES: To define the characteristics of patients admitted to a pediatric emergency department (ED) where serum acetaminophen concentrations were measured, and to determine which variables are associated with significant risk of acetaminophen toxicity. METHODS: Acetaminophen serum concentrations were measured, in a retrospective case series, of patients younger than 18 years who had been admitted to the ED at Shamir Medical Center between 1 January 2008 and 31 December 2015. RESULTS: During the study period 180,174 children were admitted to the ED. Acetaminophen serum concentrations were measured in 209 (0.12%) patients. Mean age was 12.4 ± 5.9 years. Elevated liver enzymes were found in 12 patients, 5 of whom had documented acute liver injury. All five were older than 11years.Two cases of acute liver injury were attributable to acetaminophen ingestion. In both cases the cause was intentional overdose. Univariate analysis showed a significant (P < 0.05) correlation between detectable acetaminophen blood level and a positive history of drug or acetaminophen ingestion, and suicide attempt. Not all children with non-severe acetaminophen poisoning had been diagnosed during the study period. A positive history of acetaminophen ingestion was associated with a 28-fold higher risk for detectable acetaminophen blood level. CONCLUSIONS: In the absence of a positive history of acetaminophen ingestion and in young children with accidental intoxication, the risk of hepatotoxicity is relatively low.

Tolerability and efficacy of perampanel in children with refractory epilepsy.

AIM: There are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add-on and mono-therapy in children with refractory epilepsy. METHOD: Computerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed. RESULTS: Twenty-four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified. Adverse events were more common in children aged 12 years or older (89%) compared to younger children (53%), and were mainly behavioural. Ten (42%) children had 50 per cent or higher seizure reduction, two (8%) children had 33 per cent seizure reduction, and seizures were less severe in one (4%) child. Perampanel was discontinued in 13 (54%) children mostly due to adverse events. The mean duration of follow-up in the remaining 11 children was 8.1 months (SD 5.2) (range 1.3-17mo). INTERPRETATION: Perampanel is associated with a relatively high rate of behavioural adverse events mostly in adolescents with refractory epilepsy.

Hyperbaric oxygen treatment and nephrotoxicity induced by gentamicin in rats.

BACKGROUND: Nephrotoxicity is a significant adverse side effect of gentamicin. Previous preclinical studies showed that hyperbaric oxygen treatment (HBOT) may have beneficial effects by attenuating renal damage in rats subjected to renal injury. We evaluated the effect of HBOT on acute renal failure caused by gentamicin. METHODS: Thirty-six rats were divided into four groups. Gentamicin (150 mg/kg for 5 consecutive days) was administered in 30 rats, 10 rats received only gentamicin, 10 rats received 100% oxygen therapy on days 1-5 of the experiment, 10 received daily HBOT on days 1-5 of the experiment, and the remaining six served as a control group. On day 6, renal function tests and renal pathological examinations were performed. RESULTS: Body weight and biochemical parameters were similar in all groups except for higher plasma levels of calcium in the 100% oxygen group (P = 0.03). All the rats in the experimental group showed biochemical parameters compatible with renal failure (high serum levels of urea and creatinine). All the rats in the control group had normal renal function tests. Two rats from the HBOT group died on the fifth day of the experiment. All rats in the control group demonstrated normal renal morphology. All 28 intoxicated rats showed moderate to severe histopathological changes without significant differences between the groups. CONCLUSIONS: Treatment of gentamicin-induced nephrotoxicity with either HBOT or 100% oxygen for 5 days had no beneficial renal effect. Mortality was observed only in the HBOT group.

The proportion of errors in medical prescriptions and their executions among hospitalized children before and during accreditation.

OBJECTIVE: To evaluate the rate of medication related errors in the pediatric ward and pediatric emergency department (PED), before and after implementing intervention strategies according to the Joint Commission International (JCI) accreditation program. DESIGN: A retrospective cross-sectional study that included chart review. SETTING: A university affiliated pediatric ward and PED. PARTICIPANTS: Children 0-18 years old admitted on February 2013 (before the JCI program) and February 2014 (during implementation of the JCI program). INTERVENTION(S): A training program designed to meet the JCI official standards on medication prescribing. MAIN OUTCOME MEASURE(S): The number of prescribing and medication administration errors in the 2 years. RESULTS: We collected 937 valid prescription orders and 924 administration orders (1861 medical orders) from February 2013, and 961 valid prescription orders and 958 administration orders (1919 medical orders) from February 2014. There was a significant reduction in prescribing errors from 6.5 to 4.2% between years 2013 and 2014 (P = 0.03). There was no significant difference in administration error rates between the two periods (104 (11.3%) in the first period and 114 (11.9%) in the second; P = 0.61). CONCLUSIONS: The errors rate we found was within the range described in the literature. Quality assurance interventions can significantly reduce medication prescribing errors.

Propofol Use in Israeli PICUs.

OBJECTIVES: In Israel, the recommendation for the use of propofol is age limited. Furthermore, procedural sedations involving propofol must be performed only by anesthesiologists. Propofol is frequently used in the PICUs in Israel. DESIGN: Questionnaire survey. SETTING: PICUs in Israel. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Physicians from 13 PICUs (86.6%) responded to the questionnaire. Propofol was used for induction, procedural sedation, and ongoing ICU sedation in 100%, 70%, and 12% of cases, respectively. Eighty-eight percent of the participants limited the duration of propofol infusion to 24 hours at a dose of less than or equal to 4 mg/kg/1 hr, but 40% administered propofol as needed without specifying an upper dose limit. Twenty-five percent encountered adverse effects such as apnea, desaturation, and bradycardia, but only two of the participants suspected propofol infusion syndrome, each in one patient. All the participants agreed to expand the indications for propofol use in the pediatric age group. Ketamine was the drug mostly used instead of propofol (50%), followed by fentanyl (30%), midazolam (30%), and remifentanil (5%). Apart from anesthesiologists, PICU physicians support the use of propofol by physicians who have the technical skills for rapid-sequence intubation and advanced airway management. CONCLUSIONS: Off-label use of propofol is an accepted practice in Israeli PICUs. Propofol has a unique profile that makes it an attractive sedative agent in many clinical settings. PICU physicians may want to prescribe it, at least for short periods and at low doses.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

Importance: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01984697.

Anal fissure in children: a 10-year clinical experience with nifedipine gel with lidocaine.

BACKGROUND: We aimed to evaluate efficacy and safety of the use of nifedipine gel with lidocaine in the treatment of acute anal fissures in children by reviewing the cases of 106 children with acute anal fissure treated conservatively by nifedipine gel with lidocaine between the years 2003-2012. METHODS: The patients included in this study were 48 males and 58 females. Their clinical presentation consisted of constipation, rectal bleeding, anal pain, perianal itching, abdominal pain, irritability and rectal prolapse. Posterior, anterior, both anterior and posterior, multiple, both posterior and lateral locations were the main physical findings in 65, 23, 10, 7, and 1 cases. RESULTS: Ninety-nine patients completed the 4-week treatment course of nifedipine gel with lidocaine successfully (93.40%), with complete healing of the fissure. The recurrence rate observed was very low (6.60%). CONCLUSIONS: Topical 0.2% nifedipine with lidocaine appears an efficient mode of treatment for anal fissures in children, with a significant healing rate and no side effects.

Roxithromycin Pharmacokinetics in Hospitalized Geriatric Patients: Oral Administration of Whole Versus Crushed Tablets.

BACKGROUND: Drug administration as tablets to debilitated elderly patients in crushed form can modify the pharmacokinetic characteristics of the active components. Only scarce information is available on the pharmacokinetics when administered in such form. The aim of this study was to evaluate the pharmacokinetics of roxithromycin administered in crushed form and to compare it with the pharmacokinetics of a group of geriatric patients receiving it in the conventional tablet form. METHODS: Twenty patients from the acute ward of the Shmuel Harofeh Geriatric Medical Center in stable, clinical, and hemodynamic condition were studied. Patients in group 1 (n = 10) received medications orally in tablet form. Group 2 (n = 10) included age- and disease-matched patients from the same department, who received oral roxithromycin in crushed tablet form. The mean daily dose was the same in both groups: 300 mg (150 mg twice daily). The patients received the drug for 3 days before the initiation of the study. Blood samples for determination of the roxithromycin concentration were taken at the baseline, 1 hour before the drug administration, and at 1, 3, 4, 6, 8, and 10 hours after drug administration. Roxithromycin concentration was measured by a liquid chromatography-tandem mass spectrometry method. RESULTS: Pharmacokinetic parameters of roxithromycin were significantly different between the 2 groups: the Cmin and Cmax were significantly higher, the tmax significantly longer, AUC0-10 larger, and CL/F smaller in group 2. CONCLUSIONS: Roxithromycin pharmacokinetic parameters were significantly different between the 2 patient groups resulting in higher drug serum concentrations in the crushed tablets group. The impact of the increased drug exposure is unclear.

Codeine should not be prescribed for breastfeeding mothers or children under the age of 12.

UNLABELLED: Medical regulatory authorities, including the Food and Drug Administration and European Medicine Agency, have published restrictions regarding the use of codeine in paediatric patients and breastfeeding mothers. This review explored the various parameters that are involved in the metabolism and toxicology of codeine in these two populations. CONCLUSION: The growing volume of data on potential serious adverse events and questionable efficacy indicates that codeine should not be prescribed for children under 12 years of age and breastfeeding mothers.

CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study.

AIM: To evaluate the association between cytochrome P450 2D6 (CYP2D6) phenotypes in paediatric patients with autistic spectrum disorders (ASD) treated with risperidone, adverse drug reactions (ADRs), and drug efficacy. METHOD: An observational cohort study of 40 children (34 males, six females; median age 7y range 3-18y) with autistic disorder, pervasive developmental disorder not otherwise specified, or Asperger syndrome diagnosed using the Autism Diagnostic Interview-Revised and treated with risperidone for at least 3 months. Charts were reviewed for demographic and clinical information, response to treatment was assessed by parents and the treating neurologist on a three-point scale, and information about ADRs was collected. Trough plasma levels of risperidone and its metabolites were determined and CYP2D6 genotyping was performed. RESULTS: Twenty-six patients responded to therapy and 11 patients exhibited ADRs. CYP2D6 genotyping showed two patients to be poor metabolizers, two ultra-rapid metabolizers, seven intermediate metabolizers, and 29 extensive metabolizers. Both ultra-rapid metabolizer patients were non-responders and had no ADRs. In contrast, both poor metabolizer patients were responders but experienced ADRs. No correlation was found between risperidone dosage and either risperidone or drug metabolite plasma levels. There was no difference in risperidone or metabolite plasma levels when comparing responders to non-responders, or when comparing patients with or without ADRs. INTERPRETATION: In patients with ASD treated with risperidone, a CYP2D6 phenotype may be associated with response to treatment and development of ADRs.