Epidemiological and Psychopharmacological Study About Off-Label Treatment in Child and Adolescent Psychiatric Emergencies: A Tertiary/Single Center Experience.

OBJECTIVE: The study used an epidemiological and pharmacological description of child and adolescent psychiatric emergencies (CAPEs), during which psychotropic medications are frequently administered as off-label therapies. METHODS: We retrospectively describe CAPE in 190 patients (mean age, 14.7 years) referring in the emergency department of a single tertiary center, from June 2016 to June 2018, focusing on off-label administration rate, most of all in emergency setting. RESULTS: An intrinsic fragility was observed in this population, where 28.4% of patients present a history of self-harm, 24.7% a concomitant neurodevelopmental disorder, and 17.3% a history of substance abuse. Psychomotor agitation was the most frequent referral reason, and it represents an unspecified clinical presentation of several conditions, while self-harm showed a stronger association with depressive disorders (55.2%).Globally, 811 medications were administered both as baseline therapy (67.8% of off-label rate) and/or in the emergency setting, where the off-label rate raised to 78.3%. Benzodiazepines had the highest rate of off-label use (98.2% as baseline therapy, 92.9% in acute context). Nevertheless, in 83.5% cases of acute administrations, a singular oral benzodiazepine (mostly lorazepam) guaranteed psychomotor agitation resolution, with a lower rate of adverse effects in contrast with atypical antipsychotics. CONCLUSIONS: Off-label drug use in CAPEs is a recurrent clinical practice. An international agreement about off-label drugs is crucial to obtain standard long-term pharmacoepidemiological, safety, and efficacy data. Pharmacological pediatric trials and international guidelines are also required to regulate pharmacological treatments of CAPEs, most of all in emergency settings.

Propranolol 0.1% eye micro-drops in newborns with retinopathy of prematurity: a pilot clinical trial.

BACKGROUND: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. This study evaluated safety and efficacy of propranolol eye micro-drops in preterm newborns with ROP. METHODS: A multicenter open-label trial, planned according to the Simon optimal two-stage design, was performed to analyze safety and efficacy of propranolol micro-drops in newborns with stage 2 ROP. To this end, hemodynamic and respiratory parameters were monitored, and blood samples were collected weekly, for 3 wk. Propranolol plasma levels were also monitored. The progression of the disease was evaluated with serial ophthalmologic examinations. RESULTS: Twenty-three newborns were enrolled. Since the fourth of the first 19 newborns enrolled in the first stage of the study showed a progression to stage 2 or 3 with plus, the second stage was prematurely discontinued. Even though the objective to complete the second stage was not achieved, the percentage of ROP progression (26%) was similar to that obtained previously with oral propranolol administration. However, no adverse effects were observed and propranolol plasma levels were significantly lower than those measured after oral administration. CONCLUSION: Propranolol 0.1% eye micro-drops are well tolerated, but not sufficiently effective. Further studies are required to identify the optimal dose and administration schedule.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits.

BACKGROUND: Oral propranolol, a nonselective ß-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. METHODS: Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 µl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. RESULTS: The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. CONCLUSION: Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity.

Repurposing drugs for the management of COVID-19.

Introduction: The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 represents a serious health issue worldwide, with more than 61 million cases and more than 1.4 million deaths since the beginning of the epidemic near the end of 2019. The scientific community strongly responded to this emergency situation with massive research efforts, mostly focused on diagnosis and clinical investigation of therapeutic solutions. In this scenario, drug repurposing played a crucial role in accelerating advanced clinical testing and shortening the time to access the regulatory review.Areas covered: This review covers the main and most successful drug repurposing approaches from a design, clinical, and regulatory standpoint. Available patents on repurposed drugs are also discussed.Expert opinion: Drug repurposing proved highly successful in response to the current pandemic, with remdesivir becoming the first specific antiviral drug approved for the treatment of COVID-19. In parallel, a number of drugs such as corticosteroids and low molecular weight heparin (LMWH) are used to treat hospitalized COVID-19 patients, while clinical testing of additional therapeutic options is ongoing. It is reasonably expected that these research efforts will deliver optimized and specific therapeutic tools that will increase the preparedness of health systems to possible future epidemics.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Characterization of serious adverse drug reactions as cause of emergency department visit in children: a 5-years active pharmacovigilance study.

BACKGROUND: To describe frequency, preventability and seriousness of adverse drug reactions (ADRs) in children as cause of emergency department (ED) admission and to evaluate the association between specific factors and the reporting of ADRs. METHODS: A retrospective analysis based on reports of suspected ADRs collected between January 1st, 2012 and December 31st, 2016 in the ED of Meyer Children's Hospital (Italy). Demographics, clinical status, suspected drugs, ADR description, and its degree of seriousness were collected. Logistic regression was used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of potential predictors of ADR seriousness. RESULTS: Within 5 years, we observed 834 ADRs (1100 drug-ADR pairs), of whom 239 were serious; of them, 224 led to hospitalization. Patients were mostly treated with one drug. Among patients treated with more than one drug, 78 ADRs presented a potential interaction. The most frequently reported ADRs involved gastrointestinal system. The most frequently reported medication class was antinfectives. Risk of serious ADR was significantly lower in children and infants compared to adolescents (ROR 0.41 [95% CI: 0.27-0.61] and 0.47 [0.32-0.71], respectively), and it was significantly increased in subjects exposed to more than one drug (ROR 1.87 [1.33-2.62] and 3.01 [2.07-4.37] for subjects exposed to 2 and 3 or more drugs, respectively). Gender, interactions and off-label drug use did not influence the risk of serious ADRs. CONCLUSION: Active surveillance in pharmacovigilance might represent the best strategy to estimate and characterize the clinical burden of ADRs in children.