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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.forsciint.2009.04.004 Byline: F. Garcia-Bournissen (a), M. Moller (a), M. Nesterenko (a), T. Karaskov (a), G. Koren (a) Keywords: Hair analysis; Cocaine; Half-life Abstract: Methods that employ detection of drugs of abuse in hair are important for monitoring compliance with drug abstinence. Understanding the mechanisms and timeline of drug disappearance from hair is critical for clinical and forensic application of hair testing. We aimed to evaluate the kinetics of disappearance of cocaine and its metabolite, benzoylecgonine (BE), from hair after discontinuation of drug use. Author Affiliation: (a) Motherisk Program, Division of Clinical Pharmacology & Toxicology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Canada Article History: Received 14 November 2008; Revised 24 March 2009; Accepted 1 April 2009

Vitamin B6 is often prescribed for the treatment of nausea and vomiting of pregnancy (NVP), at much higher doses than initially recommended. Large doses of vitamin B6 have been associated with cases of neuropathy. We set out to assess whether higher than standard doses of vitamin B6 during the first trimester of pregnancy were associated with a risk of maternal adverse events, major malformations, miscarriages or low birth weight. This was a prospective comparative observational study. The study group included women who were exposed to >50 mg/day of vitamin B6 during the first trimester; the control group included pregnant women with a non-teratogen exposure. A total of 192 pregnancies were followed-up. The mean dose of B6 used in the study group was 132.3 mg/day (median 110 mg/day, range 50 – 510 mg/day), for a mean period of 9 ± 4.2 weeks. In this group (n = 96), there were 91 live births, one major malformation and the mean birth weight was 3,542 ± 512 g. There were no statistical differences in the study endpoints between the vitamin B6 and the control groups. Within the limits of our sample size, higher than standard doses of vitamin B6 do not appear to be associated with an increased risk for major malformations. [ABSTRACT FROM AUTHOR]

Question: One of my patients has been diagnosed with breast cancer and started treatment with trastuzumab. She has recently discovered that she is pregnant and wishes to continue the pregnancy. What are the consequences of trastuzumab treatment during pregnancy and can she continue her pregnancy?Answer: Human data regarding the safety of trastuzumab during pregnancy are scarce. Only 3 case reports could be located in the published literature. Anhydramnios was observed in a case where the exposure to trastuzumab occurred during the second trimester, which reversed after discontinuation of the drug without any apparent consequences to the baby. Evidence is insufficient to provide any recommendations, but in light of the case reports, pregnancies exposed to trastuzumab during the second trimester should be closely followed with particular attention to amniotic fluid volume. [ABSTRACT FROM AUTHOR]

QUESTION:One of my patients who was taking sibutramine to lose weight found out that she had unexpectedly conceived. The medication was stopped as soon as she found out, about 5 weeks into the pregnancy. Is the baby at risk? Should the pregnancy be aborted?ANSWER:No data to date suggest that involuntary exposure to sibutramine during pregnancy carries major risk of congenital malformations. Nevertheless, this medication should be avoided whenever possible during pregnancy, as there is little information on its effects. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine abuse has been gathering momentum as a serious public health problem. Evidence of chronic use, particularly during pregnancy, is hard to obtain.Methamphetamine accumulates in hair and can be detected several months after exposure. Drugs that cross the placenta can be detected in hair of newborns.Methods: We developed a hair immunoassay for methamphetamine at Motherisk laboratory in Toronto. The aim of the study was to find evidence of methamphetamine exposure during pregnancy using hair measurements of the drug.Results: Out of 1124 positive methamphetamine results, we identified 8 mother-child pairs who had methamphetamine positive hair. None of the pairs identified included mothers with negative results, but there were 2 (25%) of the neonates who had a negative methamphetamine result although the mother was positive. Mean methamphetamine values were 1.8 ng/mg of hair in the mothers and 1.08 ng/mg in the neonates. There was a trend towards correlation between maternal and fetal levels.Conclusion: To our knowledge, this is the first report that shows transplacental passage of methamphetamine, with accumulation in the fetal hair. We believe this provides the basis for studies to define pharmacokinetics of this drug in the mother-child couple.We have also shown that hair measurement of methamphetamine in neonates is a useful screening method to detect intra-uterus exposure. As fetal hair grows in the last trimester of pregnancy, a positive result may indicate maternal addiction.Clinical Pharmacology & Therapeutics (2005) 79, P18–P18; doi: 10.1016/j.clpt.2005.12.063 [ABSTRACT FROM AUTHOR]

Severe forms of vascular malformations (VM) can highly impact patients' quality of life and lead to life-threatening organ dysfunction. Numerous VM are caused by somatic activating mutations in the PI3K/AKT/mTOR signalling pathway. Alpelisib, a PIK3CA inhibitor was recently FDA-approved for paediatric PIK3CA-related overgrowth syndrome (PROS). However, an empiric and fixed dose of 50 mg was selected, irrespective of weight, in the absence of any pharmacokinetic (PK) data. We aim to report novel alpelisib PK data in children to support dosing decisions. Nine patients with severe VM (PROS: n = 4, other VM: n = 5) were included. Mean age was 10.5 years (SD = 5.2 years), and mean weight was 43 kg (SD = 24 kg). AUC on the fixed dose of 50 mg/day was highly variable (mean = 7035 ng*h/mL, SD = 4057, CV = 58%). AUC was correlated with weight. As short- and long-term adverse effects to alpelisib in children are unknown, a dosing based on PK data is urgently needed., (© 2025 British Pharmacological Society.)

Aims: Chagas disease (ChD) affects approximately 7 million people in Latin America, with benznidazole being the most commonly used treatment., Methods: Data from a retrospective cohort study in Argentina, covering January 1980 to July 2019, was reanalysed to identify and characterize benznidazole-related adverse drug reactions (ADRs)., Results: The study included 518 patients: 449 children and 69 adults (median age in children: 4 years; adults: 25 years; age ranges: 1 month-17.75 years and 18-59 years, respectively). The median benznidazole doses received were 6.6 mg/kg/day for at least 60 days in children and 5.6 mg/kg/day for a median of 31 days in adults. Overall, 29.34% (152/518) of patients developed benznidazole-related ADRs, with an incidence of 25.83% (116/449) in children and 52.17% (36/69) in adults (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.19-0.54, P < .001). The incidence rate was 177 cases per 1000 person-years (95% CI = 145-214) in children and 537 per 1000 person-years (95% CI = 360-771) in adults. There were 240 ADRs identified, primarily mild to moderate. Severe ADRs occurred in 1.11% (5/449) of children and 1.45% (1/69) of adults. The skin was the most affected system. A total of 10.23% (53/518) of patients discontinued treatment. More adults than children discontinued treatment (OR = 3.36, 95% CI = 1.7-6.4, P < .001)., Conclusions: Although 29.34% of patients experienced ADRs, most were mild to moderate, indicating a manageable safety profile for benznidazole. While optimized dosing schedules and new drugs are needed, avoiding benznidazole solely due to safety concerns is not justified., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations., (© 2024 Wiley Periodicals LLC.)

Aims: Shiga toxin-producing Escherichia coli-haemolytic uraemic syndrome (STEC-HUS) is considered a toxaemic disorder in which early intervention with neutralizing antibodies may have therapeutic benefits. INM004, composed of F (ab') 2 fragments from equine immunoglobulins, neutralizes Stx1/Stx2, potentially preventing the onset of HUS., Methods: A single-centre, randomized, phase 1, single-blind, placebo-controlled clinical trial to evaluate INM004 safety, tolerance and pharmacokinetics (PK) in healthy adult volunteers, was conducted; in stage I, eight subjects were divided in two cohorts (n = 4) to receive a single INM004 dose of 2 or 4 mg kg -1 , or placebo (INM004:placebo ratio of 3:1). In stage II, six subjects received three INM004 doses of 4 mg kg -1 repeated every 24 h, or placebo (INM004:placebo ratio of 5:1)., Results: Eight subjects (57.1%) experienced mild treatment-emergent adverse events (TEAEs); most frequent were rhinitis, headache and flushing, resolved within 24 h without changes in treatment or additional intervention. No serious AEs were reported. Peak concentrations of INM004 occurred within 2 h after infusion, with median C max values of 45.1 and 77.7 μg mL -1 for 2 and 4 mg kg -1 , respectively. The serum concentration of INM004 declined in a biphasic manner (t 1/2 range 30.7-52.9 h). Systemic exposures increased with each subsequent dose in a dose-proportional manner, exhibiting accumulation. Geometric median C max and AUC values were 149 and 10 300 μg h mL -1 , respectively, in the repeated dose regimen. Additionally, samples from subjects that received INM004 at 2 mg kg -1 showed neutralizing capacity against Stx1 and Stx2 in in vitro assays., Conclusions: The results obtained in this first-in-human study support progression into the phase 2 trial in children with HUS., (© 2024 British Pharmacological Society.)

Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: Prazosin is an antihypertensive medication which can be used to help with post-traumatic stress disorder (PTSD) symptoms. Little data is currently available on its safety in pregnancy. The aim of this study was to assess the fetal and pregnancy safety associated with prazosin exposures in early pregnancy., Methods: Subjects were 11 patients who took prazosin during pregnancy and were counselled at the FRAME clinic in London Health Sciences Centre (Ontario, Canada) between 1 January 2000 and 31 December 2021. Data on their other exposures and pregnancy outcomes were collected from medical records and through telephone questionnaires., Results: It was found that 6/11 (54.5%) subjects did not report any adverse outcomes and experienced uneventful pregnancies. There were two miscarriages. Birthweights were within the normal range for the remaining nine pregnancies. Adverse events reported were consistent with background population expectation, including: one postpartum haemorrhage, one case of preeclampsia, one preterm birth, two NICU admissions, and two caesarean sections., Conclusions: For these 11 subjects, pregnancy outcomes after exposure to prazosin were consistent with typical outcomes from unexposed pregnancies. More data are needed to conclude that prazosin is safe for use in pregnant subjects. However, the lack of adverse effects above baseline is reassuring to future patients who may be unintentionally exposed to prazosin while pregnant. Therefore, this study contributes valuable data towards monitoring safety of prazosin in pregnancy., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: There is a major need for information on pharmacokinetics (PK) of benznidazole (BNZ) in children with Chagas disease (CD). We conducted a multicentre population PK, safety and efficacy study in children, infants and neonates with CD treated with BNZ (formulated in 100 mg tablets or 12.5 mg dispersible tablets, developed by the pharmaceutical company LAFEPE, in a collaboration with DNDi)., Methods: 81 children 0-12 years old were enrolled at 5 pediatric centers in Argentina. Diagnosis of T. cruzi infection was confirmed by direct microscopic examination, or at least two positive conventional serological tests. Subject enrolment was stratified by age: newborns to 2 years (minimum of 10 newborns) and >2-12 years. BNZ 7.5 mg/kg/d was administered in two daily doses for 60 days. Five blood samples per child were obtained at random times within pre-defined time windows at Day 0 at 2-5 h post-dose; during steady state, one sample at Day 7 and at Day 30; and two samples at 12-24 h after final BNZ dose at Day 60. The primary efficacy endpoint was parasitological clearance by qualitative PCR at the end of treatment., Results: Forty-one (51%) patients were under 2 years of age (including 14 newborns <1 month of age). Median age at enrolment was 22 months (mean: 43.2; interquartile range (IQR) 7-72 months). The median measured BNZ Cmax was 8.32 mg/L (IQR 5.95-11.8; range 1.79-19.38). Median observed BNZ Cmin (trough) concentration was 2 mg/L (IQR 1.25-3.77; range 0.14-7.08). Overall median simulated Css was 6.3 mg/L (IQR 4.7-8.5 mg/L). CL/F increased quickly during the first month of postnatal life and reached adult levels after approximately 10 years of age. Negative qPCR was observed at the end of treatment in all 76 patients who completed the treatment. Five patients discontinued treatment (3 due to AEs and 2 due to lack of compliance)., Conclusion: We observed lower BNZ plasma concentrations in infants and children than those previously reported in adults treated with comparable mg/kg doses. Despite these lower concentrations, pediatric treatment was well tolerated and universally effective, with a high response rate and infrequent, mild AEs., Trial Registration: Registered in clinicaltrials.gov #NCT01549236., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Altcheh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Parasite persistence after acute infection with Trypanosoma cruzi is an important factor in the development of Chagas disease (CD) cardiomyopathy. Few studies have investigated the clinical effectiveness of CD treatment through the evaluation of cardiological events by long term follow-up of treated children. Cardiological evaluation in children is challenging since features that would be diagnosed as abnormal in an adult's ECG may be normal, age-related findings in a pediatric ECG trace. The objective was to evaluate cardiac involvement in patients with Chagas disease with a minimum follow-up of 6 years post-treatment., Methodology: A descriptive study of a cohort of pediatric patients with CD treated with benznidazole (Bz) or nifurtimox (Nf) was conducted. Children (N = 234) with at least 6 years post CD treatment followed at the Parasitology and Chagas Service, Buenos Aires Children's Hospital (Argentina) were enrolled. By convenience sampling, children who attended a clinical visit between August 2015 and November 2019 were also invited to participate for additional cardiovascular studies like 24-hour Holter monitoring and speckle-tracking 2D echocardiogram (STE). Benznidazole was prescribed in 171 patients and nifurtimox in 63 patients. Baseline parasitemia data was available for 168/234 patients. During the follow-up period, alterations in routine ECG were observed in 11/234 (4.7%, 95% CI [2-7.4%]) patients. In only four patients, with complete right bundle branch block (cRBBB) and left anterior fascicular block (LAFB), ECG alterations were considered probably related to CD. During follow-up, 129/130 (99%) treated patients achieved persistent negative parasitemia by qPCR. Also decrease in T.cruzi antibodies titers was observed in all patients and negative seroconversion occurred in 123/234 (52%) patients., Conclusions: A low incidence of cardiological lesions related to CD was observed in patients treated early for pediatric CD. This suggests a protective effect of parasiticidal treatment on the development of cardiological lesions and highlights the importance of early treatment of infected children., Trial Registration: ClinicalTrials.gov NCT04090489., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 González et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, drug-induced severe adverse reaction that usually occurs 3-6 weeks after initial exposure to certain drugs. It affects mainly adults and children to a lesser extent. Clinical features include fever, facial oedema, generalized skin rash, lymphadenopathy, haematological abnormalities and internal organ involvement. The objective was to investigate the clinical and laboratory features of patients with DRESS in our centre., Methods: We retrospectively describe and analyse 19 cases of DRESS whose diagnosis was based on the RegiSCAR criteria (≥6 points) that occurred from January 2009 to December 2019., Results: Patient age ranged from 4 to 76 years (4 children/15 adults); 10 were female (52.3%). The most common culprit drugs were antibiotics (74%) and anticonvulsants (21%). The most common comorbidities were epilepsy (26%) and hypertension (26%). All patients developed cutaneous manifestations and of those, 58% presented facial oedema. Liver function tests, urea/creatinine and troponin elevation were present in 74, 32 and 42%, respectively. The median time to develop the skin rash after the drug exposure was 3.7 weeks (interquartile range 2.4-4.2 wk). Eosinophilia (≥0.7 × 10 9 /L) was present in 95% of the patients and peaked around 10 days after the skin manifestations. Leucocytosis and reactive lymphocytes were reported in 84% and 26% of all patients respectively. Treatment with systemic steroids was reported in 16 patients. The mean recovery time was 2 weeks (interquartile range 2-3.5 wk) and mortality was 5%., Conclusion: DRESS is a serious condition with significant morbidity and mortality, which requires more research for a better understanding., (© 2022 British Pharmacological Society.)

We aimed to evaluate the effect of a combination of natural products on parameters related to inflammation, endothelial dysfunction, and oxidative stress in a cohort of familial Mediterranean fever (FMF) patients with Serum Amyloid A amyloidosis, in a non-randomized, 24-week open-label interventional study. Morinda citrifolia (anti-atherosclerotic-AAL), omega-3 (anti-inflammatory-AIC), and extract with Alaskan blueberry (antioxidant-AOL) were given to patients with FMF-related biopsy-proven AA amyloidosis. Patients were >18 years and had proteinuria (>3500 mg/day) but a normal estimated glomerular filtration rate (eGFR). Arterial flow-mediated dilatation (FMD), carotid intima media thickness (CIMT), and serum biomarkers asymmetric dimethylarginine (ADMA), high sensitivity C-reactive protein (hs-CRP), pentraxin (PTX3), malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GSH-Px) were studied at baseline and after 24 weeks of treatment. A total of 67 FMF-related amyloidosis patients (52 male (77.6%); median age 36 years (range 21−66)) were enrolled. At the end of a 24-week treatment period with AAL, AIC, and AOL combination therapy, ADMA, MDA, PTX3, hsCRP, cholesterol, and proteinuria were significantly decreased compared to baseline, while CuZn-SOD, GSH-Px, and FMD levels were significantly increased. Changes in inflammatory markers PTX3, and hsCRP were negatively correlated with FMD change, and positively correlated with decreases in proteinuria, ADMA, MDA, cholesterol, and CIMT. Treatment with AAL, AIC and AOL combination for 24 weeks were significantly associated with reduction in inflammatory markers, improved endothelial functions, and oxidative state. Efficient control of these three mechanisms can have long term cardiovascular and renal benefits for patients with AA amyloidosis.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long-term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin-1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence-based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF., (© 2021 British Pharmacological Society.)