ASSESSMENT OF SIMULATED SURGICAL DEXTERITY AFTER MODIFIABLE EXTERNAL EXPOSURES AMONG NOVICE VERSUS EXPERIENCED VITREORETINAL SURGEONS.

PURPOSE: To evaluate novice and senior vitreoretinal surgeons after various exposures. Multiple comparisons ranked the importance of these exposures for surgical dexterity based on experience. METHODS: This prospective cohort study included 15 novice and 11 senior vitreoretinal surgeons (<2 and >10 years' practice, respectively). Eyesi-simulator tasks were performed after each exposure. Day 1, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine; day 2, placebo, 0.2 mg/kg propranolol, and 0.6 mg/kg propranolol; day 3, baseline simulation, breathalyzer readings of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentrations; day 4, baseline simulation, push-up sets with 50% and 85% repetitions maximum; and day 5, 3-hour sleep deprivation. Eyesi-generated score (0-700, worst-best), out-of-tolerance tremor (0-100, best-worst), task completion time (minutes), and intraocular pathway (in millimeters) were measured. RESULTS: Novice surgeons performed worse after caffeine (-29.53, 95% confidence interval [CI]: -57.80 to -1.27, P = 0.041) and alcohol (-51.33, 95% CI: -80.49 to -22.16, P = 0.001) consumption. Alcohol caused longer intraocular instrument movement pathways (212.84 mm, 95% CI: 34.03-391.65 mm, P = 0.02) and greater tremor (7.72, 95% CI: 0.74-14.70, P = 0.003) among novices. Sleep deprivation negatively affected novice performance time (2.57 minutes, 95% CI: 1.09-4.05 minutes, P = 0.001) and tremor (8.62, 95% CI: 0.80-16.45, P = 0.03); however, their speed increased after propranolol (-1.43 minutes, 95% CI: -2.71 to -0.15 minutes, P = 0.029). Senior surgeons' scores deteriorated only following alcohol consumption (-47.36, 95% CI: -80.37 to -14.36, P = 0.005). CONCLUSION: Alcohol compromised all participants despite their expertise level. Experience negated the effects of caffeine, propranolol, exercise, and sleep deprivation on surgical skills.

The Hidden Burden of Disease and Treatment Experiences of Patients with Essential Tremor: A Retrospective Claims Data Analysis.

INTRODUCTION: Essential tremor (ET) affects approximately 7 million people in the USA, yet public recognition of the disease and its impact remain low. METHODS: A retrospective observational study examined US claims data from 2015 to 2019 using the Compile database. ET diagnoses were captured using longitudinal data from 2015 to 2019 and for the year 2019, with diagnosis estimates extrapolated to the general US population. Confirmed ET was identified by an ET diagnosis code with at least two relevant prescriptions or by two diagnosis codes for ET and unspecified tremor at least 90 days apart. Comorbidity and treatment use data were extracted, and medication compliance and 2-year treatment persistence were assessed as measures of treatment adherence. RESULTS: A total of 1,336,183 patients with ET diagnoses codes were identified from 2015 through 2019, corresponding to 2,226,971 projected US diagnoses. In 2019, 128,263 patients had a confirmed ET diagnosis, corresponding to 213,772 projected US confirmed diagnoses. Of these, 96% had at least one comorbidity, and 64% received at least one pharmacologic treatment. Propranolol (24%) and primidone (20%) comprised the most common ET prescriptions. Two-year medication discontinuation rates were approximately 40%. CONCLUSION: Our findings revealed that 1 million people were diagnosed and sought treatment for ET in the USA from 2015 to 2019. Projected population estimates of approximately 2 million people diagnosed suggest a further 1 million remain untreated. Our findings highlight the complexity of patient care in ET, complicated by delayed diagnoses, multiple comorbidities, and lack of effective and tolerable therapies that can mitigate treatment adherence limitations.

Prioritization based on risk assessment to study the bioconcentration and biotransformation of pharmaceuticals in glass eels (Anguilla anguilla) from the Adour estuary (Basque Country, France).

The presence of contaminants of emerging concern in the aquatic environment directly impacts water-living organisms and can alter their living functions. These compounds are often metabolized and excreted, but they can also be accumulated and spread through the food chain. The metabolized contaminants can also lead to the formation of new compounds with unknown toxicity and bioaccumulation potential. In this work, we have studied the occurrence, bioconcentration, and biotransformation of CECs in glass eels (Anguilla anguilla) using UHPLC-HRMS. To select the target CECs, we first carried out an environmental risk assessment of the WWTP effluent that releases directly into the Adour estuary (Bayonne, Basque Country, France). The risk quotients of every detected contaminant were calculated and three ecotoxicologically relevant contaminants were chosen to perform the exposure experiment: propranolol, diazepam, and irbesartan. An experiment of 14 days consisting of 7 days of exposure and 7 days of depuration was carried out to measure the bioconcentration of the chosen compounds. The quantitative results of the concentrations in glass eel showed that diazepam and irbesartan reached BCF ≈10 on day 7, but both compounds were eliminated after 7 days of depuration. On the other hand, propranolol's concentration remains constant all along with the experiment, and its presence can be detected even in the non-exposed control group, which might suggest environmental contamination. Two additional suspect screening strategies were used to identify metabolization products of the target compounds and other xenobiotics already present in wild glass eels. Only one metabolite was identified, nordiazepam, a well-known diazepam metabolite, probably due to the low metabolic rate of glass eels at this stage. The xenobiotic screening confirmed the presence of more xenobiotics in wild glass eels, prominent among them, the pharmaceuticals exemestane, primidone, iloprost, and norethandrolone.

Acute effect of propranolol on resting energy expenditure in hyperthyroid patients.

Objective: Hyperthyroidism is a common endocrine disorder which leads to higher resting energy expenditure (REE). Increased activity of brown adipose tissue (BAT) contributes to elevated REE in hyperthyroid patients. For rapid control of hyperthyroid symptoms, the non-selective ß-blocker propranolol is widely used. While, long-term treatment with propranolol reduces REE it is currently unclear whether it can also acutely diminish REE. Design: In the present prospective interventional trial we investigated the effect of propranolol on REE in hyperthyroid patients. Methods: Nineteen patients with overt primary hyperthyroidism were recruited from the endocrine outpatient clinic. REE was measured by indirect calorimetry before and after an acute dose of 80mg propranolol and during a control period, respectively. Additionally, skin temperature was recorded at eleven predefined locations during each study visit, vital signes and heart rate (HR) were measured before and after administration of propranolol. Results: Mean REE decreased slightly after acute administration of 80mg propranolol (p= 0.03) from 1639 ± 307 kcal/24h to 1594 ± 283 kcal/24h. During the control visit REE did not change significantly. HR correlated significantly with the level of free T3 (R2 = 0.38, p=0.029) free T4 (R2 = 0.39, p=0.026). HR decreased 81 ± 12 bpm to 67 ± 7.6 bpm 90 minutes after oral administration of propranolol (p<0.0001). Skin temperature did not change after propranolol intake. Conclusions: In hyperthyroid patients a single dose of propranolol reduced heart rate substantially but REE diminished only marginally probably due to reduced myocardial energy consumption. Our data speak against a relevant contribution of BAT to the higher REE in hyperthyroidism. Clinical trial registration: ClinicalTrials.gov, identifier (NCT03379181).

Possible Extraction of Drugs from Lung Tissue During Broncho-alveolar Lavage Suggest Uncertainty in the Procedure's Utility for Quantitative Assessment of Airway Drug Exposure.

Following inhaled dosing, broncho-alveolar lavage (BAL) is often used for sampling epithelial lining fluid (ELF) to determine drug concentration in the lungs. This study aimed to explore the technique's suitability. Urea is typically used to estimate the dilution factor between the BAL fluid and physiological ELF, since it readily permeates through all fluids in the body. As representatives of permeable small molecule drugs with high, medium and low tissue distribution properties, propranolol, diazepam, indomethacin and AZD4721 were infused intravenously to steady state to ensure equal unbound drug concentrations throughout the body. The results showed that propranolol had higher unbound concentrations in the ELF compared to the plasma whilst this was not the case for the other compounds. Experiments with different BAL volumes and repeated lavaging indicated that the amount of drug extracted is very sensitive to experimental procedure. In addition, the results show that the unbound concentrations in ELF compared to plasma differs dependent on molecule class and tissue distribution properties. Overall data suggests that lavaging can remove drug from lung tissue in addition to ELF and highlights significant uncertainty in the robustness of the procedure for determining ELF drug concentrations.

The use of Gammarus pulex as a model organism for ecotoxicological assessment of ibuprofen and propranolol at environmental relevant concentrations.

The aim of this study is to assess the toxicity of ibuprofen (IBU) and propranolol (PRO) drugs usingGammarus pulex as a model organism. Firstly, the 96 h LC50 values of IBU and PRO were determined and then three sublethal concentrations of the drugs were exposed to G. pulex. The activities of superoxide dismutase (SOD), catalase (CAT) and acetylcholinesterase (AChE) were evaluated. SOD activity decreased in G. pulex exposed to IBU and PRO compared to control. In all groups exposed to IBU, CAT activity increased at different concentrations at 24 and 96 h. In the groups exposed to different PRO concentrations, CAT activities increased after 24 h compared to the control group (p < 0.05). AChE activities increased in all application groups exposed to IBU for 96 hours (p < 0.05). In conclusion, exposure to IBU and PRO resulted in increased oxidative damage. PRO has been found to cause neurotoxicity.

Safety assessment of propranolol for infantile hemangioma: a study in an Asian population.

OBJECTIVE: To evaluate the safety of initiating and maintaining propranolol therapy for infantile hemangioma (IH) and the safety of different doses. METHODS: The retrospective analysis included 336 consecutive cases of infants with IH treated between January 2016 and October 2017. The patients were assessed in the hospital at the initiation of the therapy and later in outpatient settings during the therapy. The monitoring included blood pressure (BP), heart rate (HR), blood glucose, hepatic and renal function, myocardial enzymes and serum lipids. Cardiac examinations in the outpatient follow-up included electrocardiography, ultrasound echocardiography, height, weight and head circumference. RESULTS: Propranolol decreased BP and HR at the initiation of treatment. The incidences of sinus bradycardia and hypoglycemia increased with the time of administration. Mean height, weight and head circumference were not affected during the treatment. The incidence of PR prolongation was 0%-5.7%. The effect of propranolol on the cardiovascular system, metabolism and physical development was not affected by its dose. CONCLUSION: Oral propranolol is a safe treatment for IH. Serious side effects were not observed. Attention should be paid to the side effects during clinical treatment.

Solid-phase microextraction for assessment of plasma protein binding, a complement to rapid equilibrium dialysis.

Aim: Determination of plasma protein binding (PPB) is considered vital for better understanding of pharmacokinetic and pharmacodynamic activities of drugs due to the role of free concentration in pharmacological response. Methodology & results: Solid-phase microextraction (SPME) was investigated for measurement of PPB from biological matrices and compared with a gold standard approach (rapid equilibrium dialysis [RED]). Discussion & conclusion: SPME-derived values of PPB correlated well with literature values, and those determined by RED. Respectively, average protein binding across three concentrations by RED and SPME was 33.1 and 31.7% for metoprolol, 89.0 and 86.6% for propranolol and 99.2 and 99.0% for diclofenac. This study generates some evidence for SPME as an alternative platform for the determination of PPB.

A comprehensive aquatic risk assessment of the beta-blocker propranolol, based on the results of over 600 research papers.

A comprehensive aquatic environmental risk assessment (ERA) of the human pharmaceutical propranolol was conducted, based on all available scientific literature. Over 200 papers provided information on environmental concentrations (77 of which provided river concentrations) and 98 dealt with potential environmental effects. The median concentration of propranolol in rivers was 7.1 ng/L (range of median values of individual studies 0.07 to 89 ng/L), and the highest individual value was 590 ng/L. Sixty-eight EC50 values for 35 species were available. The lowest EC50 value was 0.084 mg/L. A species sensitivity distribution (SSD) provided an HC50 value of 6.64 mg/L and an HC5 value of 0.22 mg/L. Thus, there was a difference of nearly 6 orders of magnitude between the median river concentration and the HC50 value, and over 4 orders of magnitude between the median river concentration and the HC5 value. Even if an assessment factor of 100 was applied to the HC5 value, to provide considerable protection to all species, the safety margin is over 100-fold. However, nearly half of all papers reporting effects of propranolol did not provide an EC50 value. Some reported that very low concentrations of propranolol caused effects. The lowest concentration reported to cause an effect - in fact, a range of biochemical and physiological effects on mussels - was 0.3 ng/L. In none of these 'low concentration' papers was a sigmoidal concentration-response relationship obtained. Although inclusion of data from these papers in the ERA cause a change in the conclusion reached, we are sceptical of the repeatability of these 'low concentration' results. We conclude that concentrations of propranolol present currently in rivers throughout the world do not constitute a risk to aquatic organisms. We discuss the need to improve the quality of ecotoxicology research so that more robust ERAs acceptable to all stakeholders can be completed.

News on infantile haemangioma. Part 2: therapy and evaluation.

Infantile haemangioma (IH) is the most frequently occurring tumour of childhood. While benign, in more than half of the cases, less or more severe sequelae can be observed. In Part 1 of this review, we discussed the clinical course and pathomechanism of IHs. In Part 2 of this state-of-the-art review, we will discuss the current management of IH and focus on the working mechanism of ß-blockers in IHs. Furthermore, we will discuss options for the evaluation of patients and their families (quality of life and family burden), as well as for the evaluation of IHs by healthcare providers, such as assessments of activity and severity. This review will update the reader on the working mechanism of propranolol in IHs and offer an oversight of tools (questionnaires and scoring systems) that can be used in clinical practice or for research.

A novel, injury-free rodent model of vulnerability for assessment of acute and preventive therapies reveals temporal contributions of CGRP-receptor activation in migraine-like pain.

AIM: Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. METHODS: A "two-hit" hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone, a transient receptor potential ankyrin 1 (TRPA1) activator, in uninjured female and male C57BL/6 mice. Priming (i.e. the first hit) was induced by three consecutive daily episodes of restraint stress; repeated umbellulone was also evaluated for potential priming effects. Sixteen days after the first restraint stress, mice received inhalational umbellulone (i.e. the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1B/D agonist), as well as olcegepant, an experimental calcitonin gene related peptide (CGRP) receptor antagonist and nor-Binaltorphimine (nor-BNI), an experimental long-acting kappa opioid receptor (KOR) antagonist, were investigated for their efficacy to block priming and prevent or reverse umbellulone-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia was determined by responses to periorbital or hindpaw probing with von Frey filaments. RESULTS: Repeated restraint stress, but not umbellulone exposure, produced transient cutaneous allodynia that resolved within 16 d. Restraint stress produced long-lasting priming that persisted beyond 16 d, as demonstrated by reinstatement of cutaneous allodynia following inhalational umbellulone challenge. Pretreatment with propranolol or nor-BNI prior to restraint stress prevented both transient cutaneous allodynia and priming, demonstrated by a lack of umbellulone-induced cutaneous allodynia. Following establishment of restraint stress priming, olcegepant, but not propranolol or nor-BNI, prevented umbellulone-induced cutaneous allodynia. When administered 1 h after umbellulone, sumatriptan, but not olcegepant, reversed umbellulone-induced cutaneous allodynia in restraint stress-primed rats. CONCLUSION: We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. Restraint stress priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as "latent sensitization". The development of latent sensitization could be prevented by blockade of stress pathways with propranolol or with a kappa opioid receptor antagonist. Following establishment of latent sensitization, subthreshold stimulation with umbellulone reinstated cutaneous allodynia, likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in restraint stress-primed animals, sumatriptan reversed umbellulone-induced cutaneous allodynia, supporting peripheral sites of action, while propranolol and nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with latent sensitization when given prior to, but not after, umbellulone challenge, suggesting time-dependent contributions of calcitonin gene-related peptide receptor signaling in promoting migraine-like pain in this model. Activation of the calcitonin gene-related peptide receptor participates in initiating, but has a more limited role in maintaining, pain responses, supporting the efficacy of small molecule calcitonin gene-related peptide antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-calcitonin gene-related peptide receptor-mediated nociceptive mechanisms. Kappa opioid receptor antagonists may represent a novel preventive therapy for stress-related migraine.

The effects of suppressing the biological stress systems on social threat-assessment following acute stress.

RATIONALE: Stress is associated with increased sensitivity to threat. Previous investigations examining how stress affects threat processing have largely focused on biomarker responses associated with either the sympathetic-nervous-system (SNS) or the hypothalamus-pituitary-adrenal (HPA) axis. OBJECTIVES: We pharmacologically suppressed activations of SNS, HPA, or both, prior to stress and investigated how each stress system modulates social threat assessment. METHODS: One hundred sixty-one healthy men and women were randomized in a between-subject design, to one of four pharmacological or placebo conditions: dexamethasone-placebo, placebo-propranolol, dexamethasone-propranolol, or placebo-placebo. Participants provided threat assessments for angry and neutral human faces on a baseline day, and immediately after stress induction on a testing day. RESULTS: With both systems responding normally to stress (placebo-placebo), threat assessment was higher for neutral faces compared with angry. Compared with placebo, SNS suppression resulted in increased threat assessment for angry faces. HPA suppression resulted in decreased threat assessment for neutral and angry faces. When both systems were suppressed, there was an increase in threat assessment for angry faces, and no difference from placebo for neutral. CONCLUSION: Our findings demonstrated that when intact, the biological stress systems adaptively support organisms during stress by focusing attention towards specific stimuli that are relevant to the threat. Dysregulations of the stress systems result in important system specific consequences on threat evaluation, such that suppression of either stress system alone resulted in reduced threat assessment for contextually relevant threatening stimuli, whereas when both systems were suppressed, individuals appear indiscriminately attentive to all potential threats in the environment, resulting in increased threat processing of both contextually relevant and irrelevant stimuli. Given that stress-related psychopathologies have been associated with dysregulations of the stress systems and biased responses to social threat, a systematic understanding of the mechanisms that underlie how stress systems modulate social threat assessment is needed, and can provide important insights into the cognitive processes that are involved in the development and maintenance of stress-related psychopathologies.

Association of Weight-Adjusted Caffeine and ß-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery.

Importance: Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. Objectives: To establish weight-adjusted cutoffs for caffeine and ß-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. Design, Settings, and Participants: This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). Interventions: Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. Main Outcomes and Measures: An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. Results: Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, -53.0; 95% CI, -99.3 to -6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, -12.0; 95% CI, -21.2 to -2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, -51.0; 95% CI, -77.6 to -24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, -16.0; 95% CI, -31.8 to -0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). Conclusions and Relevance: The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.

Assessment of Oral Propranolol Administration for Infantile Hemangioma in Oral and Maxillofacial Region Aided by Ultrasonography.

BACKGROUND: Propranolol has become the first-line therapy for the treatment of complicated infantile hemangioma. However, there are still many queries regarding the hemangioma volume in relation to drug's dose and duration. OBJECTIVE: The aim of this study was to evaluate the therapeutic effect of oral propranolol for treating infantile hemangiomas in the oral and maxillofacial region aided by gray scale ultrasonography (GSU). MATERIALS AND METHODS: Twelve patients with infantile hemangioma, age ranged between 2 and 11 months, have been treated with oral propranolol for 6 months' period. They received a dose of 1 mg/kg per body weight per day, increased after 1 week to 2 mg/ kg per body weight per day maintenance for 24 weeks. The changes in tumor sizes were evaluated by ultrasonography (GSU) using 4-points scale system: excellent, good, fair, poor) RESULTS:: All infants less than 6 months of age showed more hemangiomas regression in size in comparison with of those aged >6 months (P value 0.042) as a rapid response. After the 24 week; 5 patients had excellent results, 4 patients had good results, 2 patients had fair results, and only 1 patient had poor results. None of the treated infants showed rebound phenomena after cessation of treatment. CONCLUSION: Oral propranolol at dose of 2 mg/kg/day in 2 divided doses for 24 weeks aided by GSU is shown to be a safe and effective treatment of infantile hemangioma during the proliferative phase.

Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity.

Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression. Overexpression of CYP3A4 resulted in increased HEK293 proliferation, while exposure to four compounds with reported metabolically induced cytotoxicity in liver-derived cells overexpressing CYP3A4 resulted in no increase in cytotoxicity. Our results indicate that overexpression of a single CYP450 isoform in hepatic cell lines may not be a reliable method to discriminate which enzymes are responsible for metabolic induced cytotoxicity.

Efectividad del propranolol en el tratamiento de malformaciones vasculares cutáneas / Effectiveness of propranolol in treatment of cutaneous vascular malformations

Se realizó un estudio cuasi-experimental de series temporales para evaluar la efectividad del propranolol en el tratamiento de malformaciones vasculares cutáneas en 48 pacientes que asistieron a la consulta del Servicio de Dermatología del Hospital Central Universitario Dr. Antonio María Pineda durante el período febrero-julio 2018. Los resultados muestran que existen diferencias estadísticamente significativas (p <0.05; p0,0001) antes y después del primer mes de tratamiento con propranolol, las cuales se mantiene hasta los seis meses, con respecto al tamaño, color, consistencia y temperatura. Se espera que los resultados sirvan para proponer el uso de propranolol como una opción terapéutica no invasiva en el tratamiento de las malformaciones vasculares cutáneas(AU)

A quasi-experimental study of time series was carried out to evaluate the effectiveness of propranolol in the treatment of cutaneous vascular malformations in 48 patients attending the Dermatology Service of the Hospital Central Universitario Dr. Antonio Maria Pineda during the period February - July 2018. The results show that there are statistically significant differences (p <0.05; p0,0001) before and after treatment with propranolol starting one month post-treatment which are kept until six months, related to size, color, consistency and temperature of lesions. We hope that these results will encourage the use of propranolol as a non-invasive therapeutic option in the treatment of cutaneous vascular malformations(AU)

Environmental risk assessment of propranolol in the groundwater bodies of Europe.

A growing concern for contamination due to pharmaceutical compounds in groundwater is expanding globally. The ß-blocker propranolol is a ß-adrenoceptors antagonist commonly detected in European groundwater bodies. The effect of propranolol on stygobiotic species (obligate groundwater dweller species) is compelling in the framework of environmental risk assessment (ERA) of groundwater ecosystems. In fact, in Europe, ERA procedures for pharmaceuticals in groundwater are based on data obtained with surrogate surface water species. The use of surrogates has aroused some concern in the scientific arena since the first ERA guideline for groundwater was issued. We performed an ecotoxicological and a behavioural experiment with the stygobiotic crustacean species Diacyclops belgicus (Copepopda) to estimate a realistic value of the Predicted No Effect Concentration (PNEC) of propranolol for groundwater ecosystems and we compared this value with the PNEC estimated based on EU ERA procedures. The results of this study showed that i) presently, propranolol does not pose a risk to groundwater bodies in Europe at the concentrations shown in this study and ii) the PNEC of propranolol estimated through the EU ERA procedures is very conservative and allows to adequately protect these delicate ecosystems and their dwelling fauna. The methodological approach and the results of this study represent a first contribution to the improvement of ERA of groundwater ecosystems.

Safety assessment during initiation and maintenance of propranolol therapy for infantile hemangiomas.

BACKGROUND: Propranolol is an effective method of treatment for infantile hemangiomas (IH). A recent concern is a shift of the therapy into outpatient settings. OBJECTIVES: The aim of the study was to evaluate the safety of initiating and maintaining propranolol therapy for IH. MATERIAL AND METHODS: The study involved 55 consecutive children with IH being treated with propranolol. The patients were assessed in the hospital at the initiation of the therapy and later in outpatient settings during and after the therapy. Each time, the following monitoring methods were used: physical examination, cardiac ultrasound (ECHO), electrocardiography (ECG), blood pressure (BP), heart rate (HR), and biochemical parameters: blood count, blood glucose, aspartate transaminase (AST), alanine transaminase (ALT), and ionogram. The therapeutic dose of propranolol was 2.0 mg/kg/day divided into 2 doses. RESULTS: Four children were excluded during the qualification or the initiation of propranolol; a total of 51 patients were subject to the final analysis. All the children presented clinical improvement. There was a significant reduction in the mean HR values only at the initiation of propranolol. There were no changes in HR during the course of the therapy. Blood pressure values were within normal limits. Both systolic and diastolic values decreased in the first 3 months. Bradycardia and hypotension were observed sporadically, and they were asymptomatic. Electrocardiography did not show significant deviations. The pathological findings of the ECHO scans were not a contraindication to continuing the therapy. There were no changes in biochemical parameters. Apart from 1 symptomatic case of hypoglycemia, other low glucose episodes were asymptomatic and sporadic. The observed adverse effects were mild and the propranolol dose had to be adjusted in only 6 cases. CONCLUSIONS: Propranolol is effective, safe and well-tolerated by children with IH. The positive results of the safety assessment support the strategy of initiating propranolol in outpatient settings. Future studies are needed to assess the benefits of the therapy in ambulatory conditions.

The role of freshwater copepods in the environmental risk assessment of caffeine and propranolol mixtures in the surface water bodies of Spain.

In this study we aimed at assessing: (i) the environmental risk posed by mixtures of caffeine and propranolol to the freshwater ecosystems of Spain; (ii) the sensitivity of freshwater copepod species to the two compounds; (iii) if the toxicity of caffeine and propranolol to freshwater copepods contributes to the environmental risk posed by the two compounds in the freshwater bodies of Spain. The environmental risk was computed as the ratio of MECs (i.e. the measured environmental concentrations) to PNECs (i.e. the respective predicted no-effect concentrations). The effects of caffeine and propranolol on the freshwater cyclopoid Diacyclops crassicaudis crassicaudis were tested both individually and in binary mixtures. Propranolol posed an environmental risk in some but not in all the surface water ecosystems of Spain investigated in this study, while caffeine posed an environmental risk to all the investigated freshwater bodies, both as single compound and in the mixture with propranolol. Propranolol was the most toxic compound to D. crassicaudis crassicaudis, while caffeine was non-toxic to this species. The CA model predicted the toxicity of the propranolol and caffeine mixture for this species. D. crassicaudis crassicaudis was much less sensitive than several other aquatic species to both compounds. The sensitivity of D. crassicaudis crassicaudis does not increase the environmental risk posed by the two compounds in the freshwater bodies of Spain, however, further testing is recommended since the effect of toxicants on freshwater copepods can be more pronounced under multiple stressors and temperature increasing due to climate change.

Clinical and economic impact of surgery for treating infantile hemangiomas in the era of propranolol: overview of single-center experience from La Paz Hospital, Madrid.

Propranolol has changed the management of infantile hemangiomas (IHs). We summarize the evolution of surgical treatment for IH at La Paz Children's Hospital (Madrid) in the era of propranolol, with a focus on hepatic IHs.Retrospectively, we compared surgical treatment of IHs in children referred during the periods 2004-2009 and 2009-2014. Hepatic IH mortality rates before and after the introduction of propranolol therapy were evaluated specifically.The majority of hemangiomas needing surgical excision were located on the head/face/scalp of female patients. Since the introduction of propranolol therapy, surgery for IH has decreased from about 60 to 6 procedures/year at our institution and no transplants for hepatic IH have been registered.Conclusions: Surgical procedures for IH have decreased by about 90% at our institution since the introduction of propranolol treatment and hepatic IH have not needed liver transplantation. Referrals for surgery for IH are generally the consequence of absent or delayed propranolol treatment. Given the significant reduction in the number of surgical procedures, propranolol can be considered as having a strong economic and social impact. What is Known: • The use of oral propranolol solution is currently considered as the treatment of choice in the management of infantile hemangiomas. • Propranolol treatment achieves better outcomes and less side effects than systemic corticosteroids. What is New: • Social and financial impact of the significant reduction in the number of reconstructive surgical procedures and liver transplants due to the use of propranolol in tertiary health institutions remains to be analyzed.