Safety and compliance of long-term low-dose ondansetron in alcohol use disorder treatment.

BACKGROUND: The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies. Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker). The liver safety of AD04 has never been evaluated in subjects with AUD. The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD. METHODS: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling. ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24. Adverse cardiac events, general well-being, and study completion were also assessed. RESULTS: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin. While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04. Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment. CONCLUSIONS: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort. Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

Sensitization to Gibberellin-Regulated Protein (Peamaclein) Among Italian Cypress Pollen–Sensitized Patients

Background: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen–hypersensitive patients.Objective: We investigated monosensitization to peamaclein among Italian cypress pollen–allergic patients.Patients: A total of 835 cypress pollen–hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7.Results: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein–allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP.Conclusion: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein (AU)

Antecedentes: La proteína del melocotón regulada por giberelina (peamacleina) ha sido descrita recientemente con alérgeno alimentarioen los pacientes con alergia al polen de ciprés.Objetivo: Determinar la presencia de monosensibilización a peamacleina en los pacientes italianos con alergia al polen de ciprés.Pacientes: Se estudiaron 835 pacientes italianos con alergia al polen de ciprés, provenientes de 28 centros hospitalarios. En todos ellosse realizó historia clínica dirigida a detectar alergia alimentaria así como prick test con extractos comerciales de melocotón que conteníanpeamacleína. En los pacientes sensibilizados a melocotón se determinó IgE específica a Pru p 3 y aquellos con resultado negativo seclasificaron como potencialmente monosensibilizados a peamacleina. Se realizó determinación de IgE específica a Pru p 7 medianteimmunoblot e ImmunoCAP con Pru p 7.Resultados: El prick test con melocotón fue positivo en 163 pacientes (19,5%), pero 127 de estos pacientes fueron excluidos por estarsensibilizados a Pru p 3. 24 pacientes (14,7%), que correspondían al 2,8% de la población global, fueron considerados como potencialmentemonosensibilizados a peamacleína. La distribución de estos pacientes no seguía ningún patrón geográfico. 17/24 (70,8%) tenían historiade alergia alimentaria, en la mayoría de los casos a melocotón (n=15). Los pacientes también referían síntomas con otros alimentoscomo otras frutas rosáceas, cítricos, higo, melón, frutos secos y kiwi. Solo 3/18 pacientes presentaban en el immunoblot una banda dealrededor de 7 kDa; otros 4 pacientes reconocían una banda de 50-60 kDa. 10/18 presentaron positividad en el ImmunoCAP a Pru p 7.Conclusión: En Italia, la alergia o sensibilización a peamacleina es baja. La mayor parte de los pacientes reaccionan con el melocotón,aunque otras frutas rosáceas y cítricos también desencadenan síntomas

Evaluation of two commercial peach extracts for skin prick testing in the diagnosis of hypersensitivity to lipid transfer protein. A multicenter study.

Summary: The clinical usefulness of two commercial peach extracts for SPT (by Lofarma SpA and ALK-Abellò, respectively) was compared in a multicenter study carried out in Italy. Peach allergic patients were tested with the two extracts in parallel and underwent the detection of IgE specific for all three peach allergens currently available (Pru p1, Pru p3, and Pru p4, respectively). The two extracts were almost identical in terms of sensitivity and specificity, being able to detect virtually all patients sensitized to stable peach allergens (lipid transfer protein (LTP) and, presumably, peamaclein) but scoring negative in patients exclusively sensitive to labile allergens (either PR-10 and/or profilin). Thus, the two extracts represent an excellent tool to carry out a preliminary component-resolved diagnosis of peach allergy at the first patient visit.

Sensitization to Gibberellin-Regulated Protein (Peamaclein) Among Italian Cypress Pollen-Sensitized Patients.

BACKGROUND AND OBJECTIVES: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen-hypersensitive patients. Objective: We investigated monosensitization to peamaclein among Italian cypress pollen-allergic patients. MATERIAL AND METHODS: A total of 835 cypress pollen-hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7. RESULTS: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein-allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP. CONCLUSION: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein.

Severe asthma in adolescents and adults: a national, multicenter registry in real life.

Summary: The number of patients with uncontrolled asthma is growing especially in young people. Although current therapies improve the disease management, the heterogeneity of clinical outcomes results in patients whose asthma is refractory to standard therapies. To understand not responsive phenotypes, we instituted a web-registry aimed to collect real life data of adolescent and adult patients. One-hundred and five Italian medical Centers are part of the network. Participants above 14 years and affected by severe asthma will be included in the study. Demographic and clinical data will be collected for 5 years on a dedicated electronic database. For the first time in Italy, our study will provide information on epidemiological, clinical and therapeutic aspects related to the natural course of the disease, filling the gap between adolescents and adults.

RItA: The Italian severe/uncontrolled asthma registry.

BACKGROUND: The Italian severe/uncontrolled asthma (SUA) web-based registry encompasses demographic, clinical, functional, and inflammatory data; it aims to raise SUA awareness, identifying specific phenotypes and promoting optimal care. METHODS: Four hundred and ninety three adult patients from 27 Italian centers (recruited in 2011-2014) were analyzed. RESULTS: Mean age was 53.8 years. SUA patients were more frequently female (60.6%), with allergic asthma (83.1%). About 30% showed late onset of asthma diagnosis/symptoms (>40 years); the mean age for asthma symptoms onset was 30.2 years and for asthma diagnosis 34.4 years. 97.1% used ICS (dose 2000 BDP), 93.6% LABA in association with ICS, 53.3% LTRAs, 64.1% anti-IgE, 10.7% theophylline, and 16.0% oral corticosteroids. Mean FEV1 % pred of 75.1%, median values of 300/mm3 of blood eosinophil count, 323 kU/L of serum total IgE, and 24 ppb of FENO were shown. Most common comorbidities were allergic rhinitis (62.4%), gastroesophageal reflux (42.1%), sinusitis (37.9%), nasal polyposis (30.2%), and allergic conjunctivitis (30.2%). 55.7% of SUA patients had exacerbations in the last 12 months, 9.7% emergency department visits, and 7.3% hospitalizations. Factors associated with exacerbation risk were obesity (OR, 95% CI 2.46, 1.11-5.41), psychic disorders (2.87, 0.89-9.30-borderline), nasal polyps (1.86, 0.88-3.89-borderline), partial/poor asthma treatment adherence (2.54, 0.97-6.67-borderline), and anti-IgE use in a protective way (0.26, 0.12-0.53). Comparisons to severe asthma multicenter studies and available registries showed data consistency across European and American populations. CONCLUSIONS: An international effort in the implementation of SUA patients' registries could help to better understand the clinical features and to manage severe asthma, representing a non-negligible socioeconomic burden for health services.

In vitro and in silico characterisation of Tacrolimus released under biorelevant conditions.

This work aims to better understand the in vivo behaviour of modified release (MR) formulations (Envarsus® tablets and Advagraf® capsules) using in vitro properties of tacrolimus and in silico simulations. The in silico concentration profiles of tacrolimus released from the MR formulations were predicted after building a three compartments PK model with GastroPlus™, and using the experimentally determined in vitro physico-chemical properties as input parameters. In vitro-in vivo correlations (IVIVC) were obtained after deconvolution of in vivo data from a clinical trial. The IVIVC showed that the in vitro dissolution was faster than the in vivo deconvoluted dissolution for Advagraf®, while the in vitro dissolution was slightly slower than the in vivo deconvoluted dissolution for Envarsus®. Population PK simulation showed that variability in the simulation was lower for Envarsus® compared to Advagraf®. The in silico predicted preferential absorption sites were the proximal and distal tract for Advagraf® and Envarsus®, respectively. The integration of experimental in vitro solubility, permeability and biorelevant dissolution data allowed to generate in silico tacrolimus concentrations for two different MR formulations. This permitted to compare the two formulations in a single PK profile, in a simulated population PK study and with respect to their absorption sites.

Near fatal asthma: treatment and prevention.

Near-fatal asthma (NFA) is described as acute asthma associated with a respiratory arrest or arterial carbon dioxide tension greater than 50 mmHg, with or without altered consciousness, requiring mechanical ventilation. Risk factors for near fatal asthma have not been fully elucidated. In 80-85% of all fatal events, a phenotype, characterized by eosinophilic inflammation associated with gradual deterioration occurring in patients with severe and poorly controlled asthma, has been identified. Regarding to the management, acute severe asthma remains a significant clinical problem, which needs to be identified to facilitate early and appropriate therapeutic interventions. The assessment relies on clinical signs, but additional information might be obtained from chest radiography or blood gas analysis. No investigation should delay the initiation of appropriate therapy. The goals of therapy are the maintenance of oxygenation, relief of airflow obstruction, reduction of airways edema and mucus plugging (with Increased use of medications such as beta-agonists via metered dose inhalers and nebulizers, oral and/or intravenous (other than by inhalation) corticosteroids and oral or intravenous theophylline) whereas supporting ventilation as clinically indicated. Of course, the emergency physician needs to consider the wide range of potential complications, as attention to these problems when managing severe acute asthma might significantly improve outcome. An understanding of the available agents and potential pitfalls in the management of NFA is mandatory for the emergency physician.

An in vitro-in vivo correlation study for nifedipine immediate release capsules administered with water, alcoholic and non-alcoholic beverages: Impact of in vitro dissolution media and hydrodynamics.

The impact of hydrodynamics and media composition on nifedipine dissolution profile from IR (immediate release) soft capsules was investigated using dissolution apparatus USP1, USP2, USP3 and USP4 (United State Pharmacopoeia). Media composition was varied in terms of pH and content, to mimic the dosage form intake with water or non-alcoholic beverages (orange juice) and alcoholic beverages (orange juice/ethanol mixture (47% v/v)). Through construction of in vitro-in vivo correlations (IVIVC) with corresponding in vivo data from the literature, it was possible to evaluate the in vitro conditions that are likely to simulate the in vivo formulation behaviour. Both linear and nonlinear correlations were obtained depending on experimental set-ups. Testing of 20mg nifedipine capsules in FaSSGFst (Fasted State Simulated Gastric Fluid pH 1.6; water administration) produced IVIVC with the USP3 (after time scaling) and USP4 apparatus. IVIVC were obtained for USP2, USP3 and USP4 in FaSSGFoj (Fasted State Simulated Gastric Fluid pH 3.4; orange juice administration). Linear and nonlinear correlations were obtained with the USP1, USP2 and USP3 apparatus when testing the capsules in FaSSGFoj/EtOH (orange juice/ethanol administration). This study highlighted that selection of physiologically relevant dissolution set-ups is critical for predicting the in vivo impact of formulations co-administration with water, non-alcoholic and alcoholic beverages.

Design of pharmaceutical products to meet future patient needs requires modification of current development paradigms and business models.

Drugs represent the most common intervention strategy for managing acute and chronic medical conditions. In light of demographic change and the increasing age of patients, the classic model of drug research and development by the pharmaceutical industry and drug prescription by physicians is reaching its limits. Different stakeholders, e.g. industry, regulatory authorities, health insurance systems, physicians etc., have at least partially differing interests regarding the process of healthcare provision. The primary responsibility for the correct handling of medication and adherence to treatment schedules lies with the recipient of a drug-based therapy, i.e. the patient. It is thus necessary to interactively involve elderly patients, as well as the other stakeholders, in the development of medication and medication application devices, and in clinical trials. This approach will provide the basis for developing a strategy that better meets patients' needs, thus resulting in improved adherence to treatment schedules and better therapeutic outcomes.

Clinical relevance is associated with allergen-specific wheal size in skin prick testing.

BACKGROUND: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. OBJECTIVE: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. METHODS: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. RESULTS: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. CONCLUSION: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.

[Work-related diseases and the fitness to work in construction industry]. / Malattie lavoro-correlate e giudizio di idoneità lavorativa in edilizia.

The construction industry is characterized by a high number of fatal and nonfatal injuries and even higher prevalence of work-related diseases. The aim of this work is to analyze the results of a research project that has among its objectives the study of the prevalence of work-related diseases and the fitness to work in construction industry. In the period 2003-2011 were evaluated 2069 construction workers, from 218 companies (average age 37.9 years, mean seniority 21.1 years, 17.1 in the construction industry). The prevalence of work-related diseases was 14.06%, in the first place the noise-induced hearing loss, followed by musculoskeletal disorders and entrapment neuropathies. The 24.7% of fitness to work was influenced by the presence of limitations, the 0.6% of the population was not suitable for the specific task. The prevalence of work-related diseases in construction industry is high, with a peak among the elderly, but also significant occurrence among young people. It is important the percentage of the population with health problems that limit the fitness to work.

The ARGA study with Italian general practitioners: prescriptions for allergic rhinitis and adherence to ARIA guidelines.

BACKGROUND: General practitioners (GPs) are the healthcare professionals to whom patients with rhinitis firstly refer for their symptoms. OBJECTIVE: In the present study, we assessed drug prescriptions for allergic rhinitis (AR) and evaluated prescriptive adherence to ARIA treatment guidelines. METHODS: Data on 1379 AR patients were collected by 107 Italian GPs. Adherence to ARIA guidelines was evaluated according to AR severity classification. RESULTS: AR was diagnosed by GPs as mild intermittent for 46.2% of patients, mild persistent for 26.6%, moderate-severe intermittent for 20.2%, and moderate-severe persistent for 7%; 43.7% of AR patients had concomitant asthma. The most frequently prescribed therapeutic groups were antihistamines (anti-H, 76%) and nasal corticosteroids (NCS, 46%). Anti-H were significantly used more often to treat AR alone than AR + asthma (85 vs. 68%, p < 0.001), whereas NCS were used more often to treat AR + asthma than AR alone (50 vs. 42%, p = 0.01). Among patients with only mild intermittent AR, 39% were prescribed combined therapy. Among patients with moderate-severe persistent AR, 30% of those with AR alone and 18% of those with AR + asthma were prescribed monotherapy based on anti-H. GPs were more compliant with ARIA guidelines while treating AR alone (57%) than AR + asthma (46%) patients. The adherence increased according to the severity grade and was satisfactory for moderate-severe persistent AR (89% for AR alone and 95% for AR + asthma). CONCLUSIONS: Adherence to ARIA guidelines is satisfactory only for treatment of more severe patients, thus GPs often tend to treat patients independently from ARIA guidelines. Since prescription data only provide limited information to judge prescribing quality, some deviation from the gold standard are to be expected.

[Energy expenditure in construction industry]. / Il dispendio energetico in edilizia.

The aim of this study is to show the results obtained from measuring energy expenditure (EE) during work, through portable devices, in a group of male construction workers. After defining cardio-respiratory parameters in laboratory, authors applied to all subjects an heart rate monitor for measuring the heart rate (HR) and, at the same time, a calorimeter for measuring energy expenditure (EE). To analyse data obtained, authors calculate the Relative Aerobic Strain (RAS), both for the measurements of EE and for HR detected. Results confirm that in many of the typical activities of construction industry, in particular in those characterised by an higher component of manual engagement compared to foreman, workloads are exceeding limits of the probable threshold fatigue (33% of RAS), both for energy expenditure than for HR measured.

[Prevalence of contact dermatitis as occupational diseases in a group of construction workers followed up by the 'Territorial Joint Committee of Bergamo' between 2003-2011]. / Prevalenza delle dermatiti da contatto occupazionali in una coorte di lavoratori edili seguiti presso il Comitato Paritetico Territoriale di Bergamo nel periodo 2003-2011.

UNLABELLED: Occupational contact dermatitis is the most represented skin disease within the broad spectrum of occupational dermatoses, that also include skin cancers, skin infections and "scleroderma like disease." The scientific literature has long noted an increase in dermatological disease in the construction industry. MATERIALS AND METHODS: retrospective evaluation (2003-2011), in a group of construction workers followed by the 'Territorial Joint Committee of Bergamo', of the prevalence of allergic and irritant contact dermatitis. DISCUSSION AND CONCLUSIONS: The following report confirms the literature data and reaffirms the need for a careful medical surveillance, as a result of a strict cooperation between the different professionals involved (company physicians, dermatologists/allergists, family physicians).

[The skin cancer in the construction industry]. / La neoplasia cutanea nel settore edile.

UNLABELLED: The risk factors for the development of cutaneous neoplasms are well-known (skin type, ultraviolet rays, familiar occurrence, etc.) and the exposure to ultraviolet light is probably the most important one. Construction workers, due to the characteristics of the work performed (outdoor work), are exposed to UV rays for most of their workday, often in association with the exposure to chemicals (PAHs, solvents) with a role in promoting skin carcinogenesis. The construction industry is therefore a true "test" for the prevention of skin cancer. MATERIALS AND METHODS: description of skin cancer in the construction workers subject to medical surveillance at the "Territorial Joint Committee of Bergamo" (8 basal cell cancers, 1 squamous cell carcinomas and 4 melanomas). PURPOSE: review of the medical literature data, evaluation of the exposure to multiple risk factors, prevention proposals in a professional field where the "culture of tanning" is still widespread.

[Role of ECG screening and cardiologic examinations in occupational health prevention program for construction workers; results of study in the Province of Bergamo]. / Utilità dell'elettrocardiogramma e degli approfondimenti cardiologici nella sorveglianza sanitaria di una popolazione di operatori edili della Provincia di Bergamo.

Aim of this study was to estimate prevalence of resting electrocardiogram (ECG) abnormalities in men with high physical work demand, like construction workers and the prevalence of secondary related cardiovascular examinations. Several guidelines for cardiovascular risk management recommend an ECG in patients with cardiovascular risk but there are no clear indications about the frequency of resting ECG during evaluation for fitness for work. The results of our study confirm the presence of age-related ECG abnormalities with a similar stratified prevalence distribution in all age-classes. Our fundings intend to contribute to further discussion in occupational health policies and periodical medical evaluations.

[Occupational injuries and lifestyle in construction working population workers: which interaction?]. / Fenomeno infortunistico e stili di vita di una popolazione di lavoratori edili: quale correlazione?

Many factors of organizational, technical, social and human are involved in determining occupational injury. The purpose of this study was to evaluate how the characteristics of the human factor can influence the accident phenomenon. From records of the construction firms involved in the project "Protection of health on construction sites" promoted by CPT Bergamo and Occupational Medicine of Bergamo Hospital were extracted data on lifestyle of workers involved in occupational injuries in the period 2007-2011. The indicators of lifestyles used were the smoking status, alcohol consumption and drugs, body mass index (BMI), physical activity.