Biological Therapies for Pediatric Atopic Dermatitis - A Review.

Atopic dermatitis (AD) is the most frequent chronic-recurrent inflammatory skin disease in the pediatric age. It has a complex and multifactorial pathogenesis: the two key actors are impaired skin barrier function and immune system dysregulation, which represent the main targets of AD therapy. Monoclonal antibodies have revolutionized the management of moderate-to-severe AD, by selective inhibition of key cytokines in the pathogenetic process. For this reason, there is great interest in exploring AD pathogenetic mechanisms to develop new therapeutic strategies. This review aims to summarize the most recent scientific evidence on available and future biological therapies for the treatment of pediatric AD, emphasizing the molecular mechanisms underlying their action.

Deprescribing Strategies: A Prospective Study on Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are among the most controversially prescribed drugs in polypharmacy. This observational prospective study assessed the PPI prescriptive trend during hospitalization before and after implementation of a prescribing/deprescribing algorithm in a real-life hospital setting and the related clinical-economic benefit at discharge. PPI prescriptive trends were compared between three quarters of 2019 (9 months) and the same period of 2018 by a chi-square test with a Yate's correction. The proportions of treated patients in the two years (1120 discharged patients in 2018 and 1107 in 2019) were compared by the Cochran-Armitage trend test. DDDs (defined daily doses) were compared between 2018 and 2019 by the non-parametric Mann-Whitney test and normalizing DDD/DOT (days of therapy) and DDD/100 bd (bed days) for each patient. Multivariate logistic regression was performed on PPI prescriptions at discharge. The distribution of patients with PPIs at discharge was significantly different in the two years (p = 0.0121). There was a downward trend in the number of PPI prescriptions (29.9%) in the third trimester of 2019 compared to the others of the same year (first trimester: 34.1%, second trimester: 36.0%) and by contrast with the same periods of 2018 (29.4, 36.0, and 34.7%) (p = 0.0124). DDDs/patient did not differ between 2018 and 2019 nor across the three trimesters. However, both DDD/DOT and DDD/100 bd showed a decrease in the third trimester of 2019, with a marked difference for DDD/DOT (p = 0.0107). The reduction in consumption detected in the last phase of 2019 in terms of DDD/DOT was 0.09 with a consequent containment of pharmaceutical spending. The development and implementation of multidisciplinary prescribing/deprescribing protocols in both hospital and community settings could lead to a reduction in the misuse of PPIs, with significant savings in healthcare resources.

Successful Multidisciplinary Management of Aortic Valve Repair in Severe Hemophilia B with Extended Half-Life Recombinant Factor IX Concentrate.

Successful management of surgery in severe coagulation disorders depends on adequate replacement of the deficient factors from intervention until wound healing. Extended half-life (EHL) recombinant factor IX (rFIX) has been increasingly used in hemophilia B (HB) patients. Monitoring of blood levels of EHL rFIX allows to obtain pharmacokinetic (PK) parameters in order to optimize and personalize therapeutic scheme. We describe a case of a young male with severe HB who successfully underwent aortic valve repair. This is the first reported open-heart surgery in a patient with severe HB using EHL rFIX. The success was based on accurate PK evaluation and on meticulous preoperative planning and close cooperation among surgeons, hemophilia specialists, and laboratory team despite the long distance between hemophilia center and surgical clinic.

Alcohol use disorders among adult children of alcoholics (ACOAs): Gene-environment resilience factors.

Both genetic and early environmental factors contribute to the pathogenesis of Alcohol Use Disorder (AUD). Gender and psychopathology symptoms might further moderate this association, resulting in an impairment of both the dopaminergic and serotoninergic pathways that sustain the binge, withdrawal and craving cycle. In a sample of of adult children of alcoholic parents (ACOAs) (n = 107) we compared those with and without an AUD, on socio-demographic variables, adverse childhood experiences, psychopathology symptoms and two polymorphisms associated with an impaired serotoninergic and dopaminergic neurotransmission (5HTTLPR and Taq1A/DRD2). A logistic regression revealed that an early caring environment might lower the risk of developing an AUD. When controlling for the actual psychopathology symptoms, being male and having the genotype associated with an impaired dopaminergic neurotransmission were still associated with AUD. Results were confirmed by an unsupervised approach that showed how the clusters characterised by being male and having the high risk genotypes were still associated with AUD compared to being female without the unfavourable dopamine genotype.Our results point to the need for implementing prevention strategies aimed at creating a caring environment especially in those families with an alcoholic parent. We further suggest that psycho-education as a symptom recognition and avoiding self-medication could improve the outcome in those subjects at higher risk, especially males.

Safety and pharmacokinetics of medical cannabis preparation in a monocentric series of young patients with drug resistant epilepsy.

OBJECTIVES: To evaluate safety and pharmacokinetic parameters (PK) of medical cannabis in add-on for children and young adults with drug-resistant epilepsy. DESIGN, SETTING: Ten patients (4 females, 6 males, age 2.5-23.2 years) were enrolled in a prospective open trial with a galenic preparation (decoction) of Italian cannabis (FM2, ratio THC:CBD = 3:5, range THC 5.2-7.2 %; CBD 8.2-11.1 %). Patients received the first dose in Hospital, progressively augmented by CBD dose titration (from 1 to 4 mg/kg/day). OUTCOME MEASURES: In order to assess safety, blood parameters, heart rates and electrocardiograms (ECGs) were evaluated before the enrollment and during the follow up. The PK study was performed measuring THC and CBD concentrations by UHPLC-MS/MS in plasma samples collected during the first administration and at each follow-up visit. RESULTS: Two out of ten patients stopped the treatment for adverse events (detected in 6/10: gastroenteric, sleep or behavioral disorders) and difficulties in drug supply. We observed minor ECG alterations in two patients and asymptomatic transient reductions of fibrinogen after 6 months of therapy. The PK study during follow-up revealed statistically significant correlations between THC-CBD blood concentrations and: volumes of decoction, FM2 and THC-CBD daily dosages. CONCLUSIONS: The present study, although with some limitations, shows a good safety profile of medical cannabis in children and young patients with drug-resistant epilepsy and encourages the possibility of further studies with oral cannabis-based drugs. The correlations between THC-CBD plasma concentrations and their administered dosages underline the need of a therapeutic drug monitoring for cannabinoids therapy.

Co-Occurring Psychiatric and Substance Use Disorders: Clinical Survey Among a Rural Cohort of Italian Patients.

PURPOSE: Dual diagnosis (DD) is the co-occurrence of both a mental illness and a substance use disorder (SUD). Lots of studies have analysed the integrated clinical approach, which involves both psychiatry and toxicology medical experts. The purpose of this study is to analyse the socio-demographic characteristics and treatment strategies of patients with DD in a rural area of Italy. PATIENTS AND METHODS: Clinical data of 750 patients were collected in 2016 through the analysis of health plan records. RESULTS: The rate of co-occurring disorders is highly variable among people with SUD. In the considered area, patients with DD are 24%, of these only 46.1% have been treated with an integrated clinical program. Moreover, this percentage is further reduced (35.8%) if only patients with heroin use disorder are considered. CONCLUSION: A comprehensive revision of DD treatment is needed, especially for people suffering from heroin use disorder and living in remote areas. Meticulous data analysis from other addiction health services of rural areas could be necessary to identify a science-based clinical intervention.

ß-2 Agonists as Misusing Drugs? Assessment of both Clenbuterol- and Salbutamol-related European Medicines Agency Pharmacovigilance Database Reports.

A recent years' increase in misusing levels of image- and performance- enhancing drugs (IPEDs) has been observed. Out of these drugs, beta-2 agonists have recently emerged for their potential of misuse, especially for slimming and bodybuilding purposes. To this perspective, clenbuterol ('the size zero pill') has been reported as being both popular and widely available from the illegal market. All clenbuterol and salbutamol misuse/abuse/dependence/withdrawal/overdose/off-label spontaneous reports (2006-2016) from the European Medicines Agency (EMA) EudraVigilance (EV) database were collected and analysed by age range, gender, concomitant therapies and source of information. From the EV database, 55 of a total number of 920 'suspect' misuse/abuse/dependence/withdrawal/overdose/off-label ADRs (e.g. 5.97%; corresponding to 25 of 138 individuals) and 1310 of 62,879 ADRs (e.g. 2.08%; corresponding to 474 of 6923 individuals) were, respectively, associated with clenbuterol (typically ingested in combination with a range of anabolic steroids) and salbutamol. Proportional reporting ratio (PRR) value for misuse/abuse ADRs was higher (PRR = 18.38) for clenbuterol in comparison with salbutamol. Clenbuterol misuse/abuse could be a cause for major concern, especially in vulnerable individuals.

Codeine Precipitating Serotonin Syndrome in a Patient in Therapy with Antidepressant and Triptan.

The serotonin syndrome is a serioius medical condition due due to an intensive stimulation of setonin receptors. It is a rare, but severe, consequence of interaction between serotomimetic agents. This is a report of a 70-year-old woman steadily in therapy with venlafaxine and rizatriptan for migraine and major depressive syndrome. She was admitted to neurology unit for decreased light reflex with miotic pupils, global hyperreflexia, tremor, anxiety, ataxia and incoordination. The patient was diagnosed as a probable case of serotonin syndrome due to a pharmacological interaction between venlafaxine and rizatriptan trigged by opioid intake. In this paper, the development of syntomatology, the clinical examination and the possible pharmacokinetics explanation were carefully discussed and analysed.

Report on the International Workshop on Drug Prevention and Treatment in Rural Settings Organized by United Nation Office on Drugs and Crime (UNODC) and World Health Organization (WHO).

Very little evidence has been reported in literature regarding the misuse of substances in rural areas. Despite the common perception of rural communities as a protective and risk-mitigating environment, the scientific literature demonstrated the existence of many risk factors in rural communities. The Drug Prevention and Health Branch (DHB) of the United Nations Office on Drugs and Crime (UNODC), and the World Health Organization (WHO), in June 2016, organized a meeting of experts in treatment and prevention of SUDs in rural settings. The content presented during the meeting and the related discussion have provided materials for the preparation of an outline document, which is the basis to create a technical tool on SUDs prevention and treatment in rural settings. The UNODC framework for interventions in rural settings is a technical tool aimed to assist policy makers and managers at the national level. This paper is a report on UNODC/WHO efforts to improve the clinical conditions of people affected by SUDs and living in rural areas. The purpose of this article is to draw attention on a severe clinical and social problem in a reality forgotten by everyone.

Perceived parental care during childhood, ACTH, cortisol and nicotine dependence in the adult.

Studies evidenced the relationship between adverse childhood experiences (ACEs) and tobacco smoking in adulthood. An appropriate parenting style has been found to be associated with children's less frequent tobacco consumption. Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity could represent the potential link between ACEs, mood disorders and smoking susceptibility. We studied a sample of 50 male smokers, affected by nicotine dependence and 50 controls who never smoked. Self-reported retrospective perception of neglect (Child Experience of Care and Abuse: CECA-Q questionnaire), age of smoking onset, number of cigarette/day, psychiatric symptoms (Symptoms Check List 90 scale: SCL 90) and basal level of ACTH and cortisol have been evaluated. Total SCL-90 scores, CECA-Q values and cortisol plasma level were significantly higher among smokers. Cortisol and ACTH values showed a significant direct correlation with CECA-Q and SCL90 total score and an inverse significant correlation with the age of smoking. Cortisol and ACTH did not correlate with the number of cigarette smoked. Once controlled for SCL90 and CECA-Q with multiple regression measures, the association between smoking and hormone levels reversed, suggesting that increased cortisol and ACTH basal levels were attributable to preexisting conditions such as early-life exposure to emotional neglect, psychological problems and a predisposition to addictive behavior.

Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients.

PURPOSE: Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens. METHODS: Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR). RESULTS: Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions. CONCLUSIONS: Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.

Determination of deferasirox plasma concentrations: do gender, physical and genetic differences affect chelation efficacy?

OBJECTIVES: Bioavailability of deferasirox (DFX) is significantly affected by the timing of administration relative to times and to composition of meals. Its elimination half-life is also highly variable - in some patients as a result of gene polymorphisms. Understanding whether deferasirox plasma levels are related to specific characteristics of patients could help physicians to devise a drug regimen tailored the individual patient. METHODS: We analyzed deferasirox plasma concentrations (CDFX ) in 80 patients with transfusion-dependent anemias, such as thalassemia, by a high performance liquid chromatography (HPLC) assay. We used a multivariate linear regression model to find significant associations between CDFX and clinical/demographical characteristics of patients. All patients were genotyped for UGT1A1. RESULTS: Fifty-six patients were female, 24 were male, the great majority (88%) affected by ß-thalassemia, and 15 were children and adolescents. No statistical correlation was detectable between CDFX and DFX dose (P = 0.6). Age, time from last drug intake to blood sampling, and ferritin levels in the 6 months before study initiation were significantly and inversely associated with CDFX in univariate analysis. In the multivariate analysis, the only two factors independently and inversely associated with CDFX levels were time from last drug intake to blood sampling and ferritin levels (P = 0.006). A significant inverse correlation (P = 0.03) was observed between CDFX and UGT1A1*28 gene polymorphism, but only in patients with levels of lean body mass (LBM) below the median (P for interaction = 0.05). CONCLUSIONS: The results could indicate that a higher plasma DFX concentration could be associated with greater chelation efficacy. As a correlation between dose and CDFX was not demonstrated, it seems useful to monitor the concentrations to optimize and determine the most appropriate dose for each patient. Interesting results emerged from the analysis of genetic and physical characteristics of patients: LBM was a borderline significant effect modifier of the relationship between UGT1A1 polymorphisms and CDFX . Individual patient-tailored dosing of DFX should help to improve iron chelation efficacy and to reduce dose-dependent drug toxicity.

Uncommon serum creatine phosphokinase and lactic dehydrogenase increase during diosmin therapy: two case reports.

INTRODUCTION: Short-term administration of diosmin is usually considered safe, with only minor side effects (stomach and abdominal pain, diarrhea, dermatological disorders, and headache) occasionally observed. Within a 4-year period, a general practitioner noticed 17 cases of mild, diosmin-induced side effects, two of which showed particular interest. CASES PRESENTATION: Case 1: A 55-year-old Caucasian woman presented with chronic leg venous insufficiency. She was prescribed diosmin 450 mg twice a day. After 5 days of therapy, she developed pain in the legs (myalgia), and diosmin therapy was suspended. She made a spontaneous attempt of drug rechallenge and her leg pain reappeared. Thus, she underwent blood analysis, which showed elevation of creatine phosphokinase levels. Creatine phosphokinase values normalized only after prolonged discontinuation of the therapy. Case 2: A 79-year-old Caucasian man, who was diagnosed with acute hemorrhoidal syndrome. After 21 days of continuous diosmin treatment, increased levels of serum lactic dehydrogenase were detected. In both cases a comprehensive analysis of all possible causes for enzyme elevation was made. CONCLUSIONS: A feasible hypothesis to explain these rare effects could be that exaggerated adrenergic activity occurred on microcirculation, leading to an excessive peripheral vasoconstriction and subsequent ischemic damage. An individual predisposition is strongly suggested. A concurrence of events was probably responsible for the elevation of nonspecific tissue necrosis markers. Physicians and patients must be aware of these rare, but possible, adverse drug reactions.

An unexpected Streptococcus pneumoniae strain.

This clinical driven report describes the unexpected detection of a multidrug resistant (MDR) Streptococcus pneumoniae strain. Italy is usually considered a country characterized by a low prevalence of MDR S. pneumoniae. We describe the occurrence of bacterial meningitis sustained by a MDR S. pneumoniae strain in Italy. The first-line treatment was started with ceftriaxone and dexamethasone, but after the identification of such a resistant strain a second-line regimen was needed. The new regimen was chosen on both susceptibility and pharmacokinetic criteria. Linezolid and levofloxacin were started and a dramatic improvement was observed. A more sensitive anamnesis revealed some elements known to be associated to a MDR S. pneumoniae occurrence (immunesuppression, former antibiotic therapy). So this case should pinpoint our attention on risk factors of MDR for a careful choice of antibiotic therapy in serious pneumococcal infections.