A novel approach for pharmacological substantiation of safety signals using plasma concentrations of medication and administrative/healthcare databases: A case study using Danish registries for an FDA warning on lamotrigine.

PHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a warning on the antiseizure drug lamotrigine claiming that it has the potential to increase the risk of arrhythmias and related sudden cardiac death due to a pharmacological sodium channel-blocking effect. We hypothesized that the risk of arrhythmias and related death is due to toxicity. We used the PHARMACOM-EPI framework to investigate the relationship between lamotrigine's plasma concentrations and the risk of death in older patients using real-world data. Danish nationwide administrative and healthcare registers were used as data sources and individuals aged 65 years or older during the period 1996 - 2018 were included in the study. According to the PHARMACOM-EPI framework, plasma concentrations of lamotrigine were predicted at the time of death and patients were categorized into non-toxic and toxic groups based on the therapeutic range of lamotrigine (3-15 mg/L). Over 1 year of treatment, the incidence rate ratio (IRR) of all-cause mortality was calculated between the propensities score matched toxic and non-toxic groups. In total, 7286 individuals were diagnosed with epilepsy and were exposed to lamotrigine, 432 of which had at least one plasma concentration measurement The pharmacometric model by Chavez et al. was used to predict lamotrigine's plasma concentrations considering the lowest absolute percentage error among identified models (14.25 %, 95 % CI: 11.68-16.23). The majority of lamotrigine associated deaths were cardiovascular-related and occurred among individuals with plasma concentrations in the toxic range. The IRR of mortality between the toxic group and non-toxic group was 3.37 [95 % CI: 1.44-8.32] and the cumulative incidence of all-cause mortality exponentially increased in the toxic range. Application of our novel framework PHARMACOM-EPI provided strong evidence to support our hypothesis that the increased risk of all-cause and cardiovascular death was associated with a toxic plasma concentration level of lamotrigine among older lamotrigine users.

Exploring the underlying mechanisms of drug-induced impulse control disorders: a pharmacovigilance-pharmacodynamic study.

INTRODUCTION: Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed. AIM: We aimed to identify targets potentially contributing to pathologic impulsivity. METHOD: We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results. RESULTS: Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P-value = 0.047) and 5-HT1a within antipsychotics (1.92, 0.029). CONCLUSION: Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity.

Weight and body mass index increase in children and adolescents exposed to antipsychotic drugs in non-interventional settings: a meta-analysis and meta-regression.

Antipsychotics increase weight, BMI and waist size, particularly in pediatric patients. Switching antipsychotics is common practice, thus defining the risk for each antipsychotic in real-life settings can be important for clinical guidance. We conducted a meta-analysis on antipsychotic-related changes in body measures in pediatric observational studies. Of 934 publications found on PubMed, we analyzed 38, including nine treatment arms: no treatment, mixed antipsychotic treatment, first-generation antipsychotics, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Changes in weight, BMI, BMI-Z and waist size were meta-analyzed according to the duration of clinical observations: 6, 12, > 12 months. Meta-regressions probed influencing factors. Weight in Kg was increased at 6, 12, > 12 months by olanzapine [+ 10.91, + 10.7, data not available (n/a)], mixed antipsychotic treatment (n/a, + 9.42, + 12.59), quetiapine (+ 5.84, n/a, n/a) and risperidone (+ 4.47, + 6.01, + 9.51) and without treatment (n/a, + 2.3, n/a). BMI was increased at 6, 12, > 12 months by olanzapine (+ 3.47, + 3.42, n/a), clozapine (n/a, + 3, n/a) mixed antipsychotic treatment (+ 3.37, + 2.95, + 3.32), risperidone (+ 2, + 2.13, + 2.16), quetiapine (+ 1.5, + 1.82, n/a), aripiprazole (n/a, + 1.7, + 2.1) and without treatment (n/a, + 0.75, n/a). BMI-Z was increased at 6, 12, > 12 months by olanzapine (+ 0.94, + 0.98, + 0.89), clozapine (n/a, + 0.8, n/a), risperidone (+ 0.62, + 0.61, + 0.48), quetiapine (+ 0.57, + 0.54, n/a), mixed antipsychotic treatment (+ 0.51, + 0.94, + 0.44), without treatment (n/a, + 0.37, n/a) and aripiprazole (no gain, + 0.31, n/a). Waist size in cm was increased at 6, 12 months by risperidone (+ 8.8, + 11.5), mixed antipsychotics treatment (+ 9.1, + 10.2) and quetiapine (+ 6.9, + 9.1). Overall, olanzapine and clozapine displayed maximum risk, followed by risperidone, quetiapine and aripiprazole (more risky at longer terms); ziprasidone was associated with no gains. No time-based trends emerged, suggesting a drug-specific risk magnitude. Meta-regressions evidenced variable roles for persistence in therapy and follow-up length, increased risk for drug-naïve patients, and a ceiling effect determined by higher baseline BMI/BMI-Z values.

Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review.

BACKGROUND: Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained. METHODS: We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association. RESULTS: Of 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4, and hyponatremia, while adrenergic α 1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (adj. odds ratio = 1.21; 95% CI = 1.09-1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68-0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47. CONCLUSIONS: Antipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.

Association between the glyco-metabolic adverse effects of antipsychotic drugs and their chemical and pharmacological profile: a network meta-analysis and regression.

BACKGROUND: Glyco-metabolic deteriorations are the most limiting adverse reactions to antipsychotics in the long term. They have been incompletely investigated and the properties of antipsychotics that determine their magnitude are not clarified.To rank antipsychotics by the magnitude of glyco-metabolic alterations and to associate it to their pharmacological and chemical properties, we conducted a network meta-analysis. METHODS: We searched PubMed, Embase, and Psycinfo on 10 September 2020. We selected studies containing the endpoint-baseline difference or the distinct values of at least one outcome among glucose, HbA1c, insulin, HOMA-IR, triglycerides, total/HDL/LDL cholesterols. Of 2094 articles, 46 were included in network meta-analysis. Study quality was assessed by the RoB 2 and ROBINS-I tools. Mean differences (MD) were obtained by random-effects network meta-analysis; relations between MD and antipsychotic properties were analyzed by linear regressions. Antipsychotic properties investigated were acidic and basic pKa, polar surface area, polarizability, and occupancies of D2, H1, M1, M3, α1A, α2A, 5-HT1A, 5-HT2A, 5-HT2C receptors. RESULTS: We meta-analyzed 46 studies (11 464 patients); on average, studies lasted 15.47 weeks, patients had between 17.68 and 61.06 years of mean age and 61.64% were males. Olanzapine and clozapine associated with greater deteriorations, aripiprazole and ziprasidone with smaller deteriorations. Higher polarizability and 5-HT1A receptor occupancy were associated with smaller deteriorations, H1, M1, and M3 receptor occupancies with larger deteriorations. CONCLUSIONS: Drug rankings may guide antipsychotic switching toward metabolically safer drugs. Mechanistic insights may suggest improvements for combination therapies and drug development. More data are required regarding newer antipsychotics.

The use of biological agents in pregnant women affected by autoimmune disorders: Why we need more research of this neglected area.

Women of childbearing age are largely affected by several autoimmune disorders (the estimates range between 1.5 and 10 per 10,000). The increasing number of effective biological agents has dramatically revolutionized the treatment of these clinical conditions, ameliorating the patient's quality of life. The use of these agents by women during pregnancy is growing to ensure the disease activity control and avoid adverse health outcomes. However, for many newer biological agents, the degree of information concerning their use in pregnancy is often incomplete to perform a conclusive risk assessment on fetal and maternal health given the exclusion of this specific population from pharmacological clinical trials. More recently, the COVID-19 pandemic has confirmed the unacceptable inequities of pharmacological research and medical treatment for pregnant and lactating women, exacerbating the need for filling the gaps of quantitative and qualitative pharmacology data in this sensitive population. ere we summarize (i) what is already known about safety and effectiveness of biological agents in this understudied population (with specific focus on pregnancy-related health outcomes), and what we are going to learn from the on-going studies among pregnant women treated with biological agents; (ii) the methodological and ethical considerations that characterize the pharmacological research in pregnancy, also discussing emerging evidence on the use of therapeutic drug monitoring (TDM) in this clinical setting.

Beta-blocker-associated hypoglycaemia: New insights from a real-world pharmacovigilance study.

AIMS: To investigate the statistical association between hypoglycaemia and ß-blocker use and to define what patient and drug characteristics could potentially increase the risk for its occurrence. METHODS: We investigated the relationship between pharmacological parameters of ß-blockers and the occurrence of hypoglycaemia by conducting a case/non case analysis using the Food and Drug Administration Adverse Event Reporting System database. Pharmacological properties that could represent a predictive factor for hypoglycaemia were analysed through a multilinear binary logistic regression (null hypothesis rejected for values of P < .05). We also performed a systematic review of clinical studies on this association. RESULTS: Of 83 954 selected reports, 1465 cases (1.75%) of hypoglycaemia were identified. The association was found statistically significant for nadolol (reporting odds ratio [95% confidence interval]: 6.98 [5.40-9.03]), celiprolol (2.35 [1.35-4.10]), propranolol (2.14 [1.87-2.46]) and bisoprolol (1.42 [1.25-1.61]). Paediatric cases (n = 310) showed a positive association with hypoglycaemia for long half-life drugs (odds ratio [95% confidence interval]: 2.232 [1.398-3.563]) and a negative association for ß1-selectivity (0.644 [0.414-0.999]). Seven papers were included in the systematic review. Because of great heterogeneity in study design and demographics, hypoglycaemia incidence rates varied greatly among studies, occurring in 1.73% of the cases for propranolol treatment (n total participants = 575), 6.6% for atenolol (n = 30) and 10% for carvedilol (n = 20). CONCLUSION: Nadolol appears to be the ß-blocker significantly most associated with hypoglycaemia and children represent the most susceptible sample. Furthermore, long half-life and nonselective ß-blockers seem to increase the risk for its occurrence.

Severe hypoglycemia in children treated with nadolol: A case report and FDA adverse event reporting system (FAERS) database analysis.

OBJECTIVE: We describe a case of severe hypoglycemia in a 14-month-old child as a suspected adverse drug reaction (ADR) to nadolol, and we performed an analysis of the FDA Adverse Event Reporting System (FAERS) database. Although previous reports have identified the risk of severe hypoglycemia in children during treatment with ß-blockers, little is known about hypoglycemia as an ADR in infants treated with nadolol. Moreover, the pharmacodynamic and pharmacokinetic profiles of nadolol in children aged less than 1 year old are still not fully known. MATERIALS AND METHODS: We extracted all ADR reports involving nadolol from the FAERS database; in order to reduce the risk of bias, we only considered cases that exclusively reported nadolol as the suspect drug. We then selected cases of hypoglycemia in the pediatric population and conducted a manual deduplication. RESULTS: Upon FAERS database analysis, a total of 2,674 suspected ADR reports to nadolol were found. Of these, 1,950 (73%) were solely attributed to nadolol, and 63 of them were hypoglycemic events. A total of 47 reports included the relevant pediatric age (74.6%). After deduplication, we identified 25 cases (mean age: 3.65 years old); all of these reports were categorized as serious, and hospitalization was required in 15 cases. CONCLUSION: Hypoglycemia is a reported life-threatening ADR associated with nadolol, especially in infants, in whom this drug should be used with caution.

Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD).

INTRODUCTION: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting up to 5.3% of children and 2.5% of adults depending on the country considered. Current pharmacological treatments for ADHD are based on stimulant or non-stimulant medications, targeting dopaminergic and noradrenergic systems in the frontal cortex and dopaminergic system in the basal ganglia. These drugs are effective and safe for the majority of patients, whereas about 20% of treated patients do not tolerate current therapies or experience insufficient efficacy. The adequate treatment of ADHD is necessary to allow a proper social placement and prevent the acquisition of additional, more severe, comorbidities. AREAS COVERED: We conducted a review of the scientific literature and of unpublished/ongoing clinical trials to summarize the advances made in the last 10 years (2010-2020) for the pharmacological treatment of ADHD. We found many pharmacological mechanisms beyond dopaminergic and noradrenergic ones have been investigated in patients. EXPERT OPINION: Some emerging drugs for ADHD may be promising as add-on treatment especially in children, amantadine to enhance cognitive functions and tipepidine for hyperactivity/impulsivity. Stand-alone emerging treatments for ADHD include viloxazine and dasotraline, which will soon have more clinical data available to support market access requests.

Novel Pharmacotherapies for Recurrent Pericarditis: Current Options in 2020.

Recent advances have shown impressive results by anti-interleukin 1 (IL-1) agents in refractory idiopathic recurrent pericarditis. PURPOSE OF REVIEW: We critically discuss the current state of the art of therapy of relapsing pericarditis, with a focus on new pharmacological approaches and on specific clinical settings such as pregnancy, pediatric patients, and secondary forms of relapsing pericarditis. RECENT FINDINGS: Antagonism of the IL-1 is highly effective in idiopathic recurrent pericarditis with autoinflammatory features. Currently, available anti-IL-1 agents are anakinra and canakinumab. Rilonacept is another IL-1 antagonist, currently studied in the phase-3 clinical trial RHAPSODY. Available data suggest similar efficacy and safety profiles of these three agents, although only anakinra has been tested in randomized clinical trials. These agents have slightly different pharmacological properties, being canakinumab a specific IL-1ß antagonist while anakinra and rilonacept are unselective IL-1α and IL-1ß blockers. To date, there is no evidence that specificity against IL-1ß affects safety and efficacy in patients with relapsing pericarditis, although it has been proposed that unspecific blockage might be useful in severe disease. Anakinra is the first anti-IL-1 agent with well-documented efficacy and safety in adult and pediatric patients with idiopathic relapsing pericarditis. Other anti-IL-1 agents are currently under study. Future research should clarify the optimal duration of therapy and tapering schedule of treatment with these agents. Moreover, biomarkers would be required to understand which patients will benefit from early administration of IL-1 blockers due to refractoriness to conventional therapy and which others will suffer from recurrences during the tapering of these agents. Lastly, future studies should focus on the subjects with the autoimmune or the pauci-inflammatory phenotype of idiopathic refractory pericarditis.

Adverse Drug Reactions Related to Mood and Emotion in Pediatric Patients Treated for Attention Deficit/Hyperactivity Disorder: A Comparative Analysis of the US Food and Drug Administration Adverse Event Reporting System Database.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) can be comorbid with frequent anxiety and mood disorders, as well as emotional symptoms (anxiety, irritability, mood lability). These may also be triggered by drugs and appear as adverse drug reactions (ADRs). METHODS: We mined data from the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database, focused on methylphenidate, atomoxetine, amphetamine, lisdexamfetamine, and their derivatives. We collected reports of ADRs connected with mood or emotional symptoms in pediatric patients, excluding drug abuse/accidents. Reporting odds ratios (RORs) were calculated and compared between drug classes and children/adolescents. RESULTS: We collected 6176 ADRs of interest of which 59% occurred in children. Atomoxetine accounted for 50.7% of reports, methylphenidate for 32.5%, lisdexamfetamine for 14.2%, and amphetamine for 2.6%. Irritability, anxiety, obsessive thoughts, depressed mood, and euphoria scored significant RORs for all drugs, overall with an increasing risk from methylphenidate to atomoxetine, lisdexamfetamine, and amphetamine. Apathy regarded mostly atomoxetine, and crying regarded all drugs except methylphenidate. Several age-based differences were found. Notably, affect lability hit only adolescents. All drugs scored significant self-injury RORs, except lisdexamfetamine in adolescents, with an increasing risk from methylphenidate to lisdexamfetamine, atomoxetine, and amphetamine. For suicidality, all drugs had significant RORs in children, and methylphenidate was better than atomoxetine and lisdexamfetamine. In adolescents, only methylphenidate and atomoxetine scored significant RORs. CONCLUSIONS: We conclude that real-world data from the US Food and Drug Administration Adverse Event Reporting System are consistent with previous evidence from meta-analyses. They support a hierarchy of drug safety for several ADRs (except self-injury/suicidality) with methylphenidate as safest, followed by atomoxetine, lisdexamfetamine, and amphetamine last. Self-injury and suicidality RORs were overall higher in children.

Central nervous system-active drug abused and overdose in children: a worldwide exploratory study using the WHO pharmacovigilance database.

Recent epidemiological studies have reported an increase in central nervous system (CNS)-active drug abuse rates in paediatric settings, raising several public health concerns. No study to date has explored this issue worldwide. We performed an extensive analysis of drugs abuse/overdose reported for children in the last decade by using the largest pharmacovigilance database, i.e. the VigiBase, collecting adverse drug reaction reports that involved at least one suspect drug belonging to the Anatomical Therapeutic Chemical code "Nervous System" through the Standardised Medical Dictionary for Drug Regulatory Affairs Queries for Drug abuse. 8.682 reports matched our criteria. An increase in reporting activity was observed, starting from 2014; an intentional overdose was reported more frequently than an accidental one, with a difference between age groups. We retrieved 997 reports with death outcome. These referred more to adolescents (n = 538) than subjects of any other paediatric age group. Paracetamol and opioid analgesics were the most common suspect drugs in deaths across all age groups due to hypoxic-ischaemic encephalopathy, brain death, and cardio-respiratory arrest.Conclusion: The number of reports associated with drug abuse and overdose is increasing (for opioid and paracetamol-containing products) and a considerable number of adverse drug reactions are serious. Data on the patterns of use of such medicines from each country may help in implementing strategies of risk-minimisation and renewing healthcare recommendations worldwide. An increased clinical awareness of drug abuse and overdose is warranted, while continuing to provide effective treatments. What is Known: • The large increase in paediatric prescriptions for CNS-active drugs in the last 20 years has recently raised public health concerns about drug abuse and overdose. • No study to date has examined this issue in paediatric patients worldwide. What is New: • The number of paediatric reports associated with CNS drug abuse and intentional overdose is increasing, including those with fatal outcome; over 4 years; more than 35% of the reports was entered from European countries. • Opioid and paracetamol were most frequently suspected for ADRs with fatal outcome across all age groups, due to hypoxic-ischaemic encephalopathy and cardio-respiratory arrest, suggesting the need to implement strategies of risk-minimisation.

Severe acquired brain injury aetiologies, early clinical factors, and rehabilitation outcomes: a retrospective study on pediatric patients in rehabilitation.

Objective: Studies on pediatric severe acquired brain injury (sABI) outcomes focused mostly on single etiologies, not clarifying the independent role of clinical factors, and scantly explored inter-dependence between variables. We assessed associations of clinical factors at admission with essential outcomes, controlling for inter-dependence and sABI etiology. Methods: We reviewed the clinical records of 280 patients with traumatic and 292 with non-traumatic sABI, discharged from intensive care to pediatric neurological rehabilitation. We analyzed the distribution of clinical factors based on sABI etiology; conducted a factor analysis of variables; built multivariate models evaluating the associations of variables with death, persistent vegetative states, duration of coma, GOS outcome, length of stay. Results: We described the study sample. Factor analysis of inter-dependence between GCS, time before rehabilitation, dysautonomia, device use, produced the indicators "injury severity" and "neurological dysfunction", independent from sABI etiology, age, sex, and admittance GOS. Multivariate analyzes showed that: coma duration, GOS outcome, and length of stay, which may depend on rehabilitation courses, were directly associated with injury severity, neurological dysfunction, and patients' age; death and persistent vegetative states were also associated with etiology. Conclusion: Future studies should analyze larger cohorts and investigate mechanisms linking specific etiologies and patients' age with outcomes.

An update on the assessment and management of metabolic syndrome, a growing medical emergency in paediatric populations.

In the last decades the increasing rate of obesity in children and adolescents worldwide has led to the onset in paediatric age of metabolic syndrome, a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA's Adverse Event Reporting System database.

Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings.

PURPOSE: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. METHODS: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. RESULTS: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9%) but lower intra-patient (34.2%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1%, while the intra-patient variability was much lower (29.3%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). CONCLUSION: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.

Enalapril Associated with Furosemide Induced Acute Kidney Injury in an Infant with Heart Failure. A Case Report, a Revision of the Literature and a Pharmacovigilance Database Analysis.

The use of angiotensin converting enzyme (ACE) inhibitors in combination with diuretics is a common strategy used for the treatment of patients affected by heart failure. An infant affected by initial congestive cardiac failure, after starting the treatment with enalapril in association with furosemide, developed acute kidney injury (AKI). No underlying renal disease or renal artery stenosis was found. He recovered from kidney injury after the therapy was suspended, thus suggesting that the drug combination is responsible for the onset of the adverse reaction. The present case report, the appraisal of the current knowledge on the onset of AKI and the analysis of available pharmacovigilance databases indicate that particular caution should be exercised when infants affected by heart failure are treated with the enalapril and furosemide combination therapy. Moreover, we strongly suggest an up-to-date revision of the ACE-inhibitor dosing guidelines in pediatric patients to define unambiguously the safe upper limits of this class of drugs.