Chronic Pharmacological Treatment Research Articles

Isothiocyanate-Corticosteroid Conjugates against asthma: Unity makes strength

Asthma is a major noncommunicable disease, affecting both children and adults, and represents one of the major causes leading to high health care costs due to the need for chronic pharmacological treatments. The standard gold therapy of inflammation in asthmatic patients involves the use of glucocorticoids even if their chronic use is often related to serious adverse effects. Growing evidence suggests the biological relevance of hydrogen sulfide (H2S) in the pathogenesis of airway diseases. Hence, aiming to associate the beneficial effects of steroidal anti-inflammatory drugs (SAIDs) to H2S biological activity, we designed and synthesized novel multi-target molecules by chemically combining a group of glucocorticoids, usually employed in asthma treatment, with an isothiocyanate moiety, well-known for its H2S releasing properties. Firstly, the synthesized compounds have been screened for their H2S-releasing profile using an amperometric approach and for their in vitro effects on the degranulation process, using RBL-2H3 cell line. The physicochemical profile, in terms of solubility, chemical and enzymatic stability of the newly hybrid molecules, has been assessed at different physiological pH values and in esterase-rich medium (bovine serum albumin, BSA). The selected compound 5c, through both its corticosteroid and H2S releasing component, has been evaluated in vivo in experimental model of asthma. The compound 5c inhibited in vivo all asthma features with a significative effect on the restoration of pulmonary structure and reduction of lung inflammation.

Vaccination Confidence among Healthcare Workers: Results from Two Anamnestic Questionnaires Adopted in the COVID-19 and Influenza Campaign.

Following the announcement of the development of COVID-19 vaccines, hesitancy about the safety of vaccinations and their side effects have spread, despite having the approval of international drug agencies. The aim of this study was to test the hypothesis that concern about side effects may have led people to fill out the COVID-19 anamnestic vaccine questionnaire with greater attention compared to the similar instrument used for the influenza vaccination. We analyzed vaccination questionnaires of 218 healthcare workers (HCWs) who underwent both COVID-19 and influenza vaccines in 2020/2021. Outcomes included self-reported allergies, chronic pharmacological treatments, and chronic diseases. We tested the difference in prevalence, analyzed differences using the kappa statistics and concordance correlation, and explored factors associated with differences in reporting. HCWs reported more allergies to substances other than drugs and a higher prevalence of chronic drug intake in the COVID-19 questionnaires than in the influenza ones. Technical staff reported more drug allergies than physicians, and other HCWs reported more outcomes than physicians in the COVID-19 questionnaire. We found that this population of HCWs reported higher conditions during the 2020 COVID-19 vaccination campaign compared to that of the influenza vaccine. The identification of socio-demographic characteristics of the less vaccine-confident HCWs could help in planning targeted interventions to enhance vaccine adherence.

A Cross-Sectional Survey on Medication Management Practices for Noncommunicable Diseases in Europe During the Second Wave of the COVID-19 Pandemic.

Maintaining healthcare for noncommunicable diseases (NCDs) is particularly important during the COVID-19 pandemic; however, diversion of resources to acute care, and physical distancing restrictions markedly affected management of NCDs. We aimed to assess the medication management practices in place for NCDs during the second wave of the COVID-19 pandemic across European countries. In December 2020, the European Network to Advance Best practices & technoLogy on medication adherencE (ENABLE) conducted a cross-sectional, web-based survey in 38 European and one non-European countries. Besides descriptive statistics of responses, nonparametric tests and generalized linear models were used to evaluate the impact on available NCD services of the number of COVID-19 cases and deaths per 100,000 inhabitants, and gross domestic product (GDP) per capita. Fifty-three collaborators from 39 countries completed the survey. In 35 (90%) countries face-to-face primary-care, and out-patient consultations were reduced during the COVID-19 pandemic. The mean ± SD number of available forms of teleconsultation services in the public healthcare system was 3 ± 1.3. Electronic prescriptions were available in 36 (92%) countries. Online ordering and home delivery of prescription medication (avoiding pharmacy visits) were available in 18 (46%) and 26 (67%) countries, respectively. In 20 (51%) countries our respondents were unaware of any national guidelines regarding maintaining medication availability for NCDs, nor advice for patients on how to ensure access to medication and adherence during the pandemic. Our results point to an urgent need for a paradigm shift in NCD-related healthcare services to assure the maintenance of chronic pharmacological treatments during COVID-19 outbreaks, as well as possible future disasters.

Effects of Chronic Pharmacological Treatment on Functional Brain Network Connectivity in Patients with Schizophrenia

Schizophrenia is characterized by the dysfunction of various brain networks. Previous studies suggested that pharmacological treatments for schizophrenia induce functional changes in localized brain regions. However, the effects of antipsychotic treatments on brain networks associated with symptom improvement are still elusive. The elucidation of antipsychotic-induced functional brain changes is essential for the development of biologically informed treatment strategies. Forty-five healthy controls and 44 patients with schizophrenia underwent resting-state fMRI scans at baseline. The patients underwent a second scan after 6 weeks of antipsychotic treatment. At baseline, patients exhibited a significant decrease in functional connectivity of the cingulate gyrus in the default mode network compared to healthy controls, and this decrease was negatively correlated with symptom severity. Clinical improvements were observed after 6 weeks treatment, accompanied by an increase in functional connectivity of the cingulate gyrus in the default mode network and the inferior parietal lobule in the executive control network. The changes in functional connectivity of the inferior parietal lobule were significantly correlated with symptom improvement. These longitudinal neuroimaging findings suggest that schizophrenia might be an outcome of the disruption of the optimal balance of brain networks, and reestablishing this balance through antipsychotic treatment may result in clinical symptom improvement.

T178. MICROPIPETTE-GUIDED DRUG ADMINISTRATION (MDA) METHOD AS A NOVEL PHARMACOLOGICAL TREATMENT METHOD IN MICE: PRECLINICAL VALIDATION USING RISPERIDONE IN THE MATERNAL IMMUNE ACTIVATION MODEL OF NEURODEVELOPMENTAL DISORDERS

BackgroundPharmacological treatments in laboratory rodents remain a cornerstone of preclinical psychopharmacological research and drug development. There are numerous ways how acute or chronic pharmacological treatments can be implemented, with each method having certain advantages and drawbacks. To overcome the main disadvantages of conventional administration routes, we implemented and validated a novel treatment method in mice, which we refer to as the Micropipette-guided drug administration (MDA) method.MethodsThe MDA administration method is based on using sweetened condensed milk solution as vehicle for pharmacological substances, which motivates the animals to consume vehicle and/or drug solutions voluntarily in the presence of the experimenter. First, we measured the corticosterone and pharmacokinetic changes after the administration of a vehicle or drug (Risperidone) solution via traditional oral gavage or by MDA. We then conducted a chronic treatment paradigm in the maternal immune activation model (MIA). Offspring treatment with risperidone started on post-natal day 70 and lasted for a total of 6 weeks, with behavioral testing occurring during the last two weeks of the treatment window.ResultsIn a proof-of-concept study, we show that the pharmacokinetic profiles of the atypical antipsychotic drug, risperidone, are similar when administered via the MDA procedure or via the conventional oral gavage method. Unlike the latter, however, MDA did not induce the stress hormone, corticosterone. Furthermore, we assessed the suitability and validity of the MDA method in a mouse model of maternal immune activation, which is frequently used as a model of immune-mediated neurodevelopmental disorders. Using this model, we found that chronic treatment (> 4 weeks, once per day) with risperidone via MDA led to a dose-dependent mitigation of MIA-induced social interaction deficits and amphetamine hypersensitivity.DiscussionTaken together, the MDA procedure described represents a novel pharmacological administration method for per os treatments in mice, which is easy to implement, cost effective, non-invasive, and less stressful for the animals than conventional oral gavage methods. Moreover, it allows for a more consistent and continual control of the dosages administered to the animals compared to methods involving the dissolution of a substance in the drinking water or contained within the food of the animals.

Preclinical validation of the micropipette-guided drug administration (MDA) method in the maternal immune activation model of neurodevelopmental disorders

Pharmacological treatments in laboratory rodents remain a cornerstone of preclinical psychopharmacological research and drug development. There are numerous ways in which acute or chronic pharmacological treatments can be implemented, with each method having certain advantages and drawbacks. Here, we describe and validate a novel treatment method in mice, which we refer to as the micropipette-guided drug administration (MDA) procedure. This administration method is based on a sweetened condensed milk solution as a vehicle for pharmacological substances, which motivates the animals to consume vehicle and/or drug solutions voluntarily in the presence of the experimenter. In a proof-of-concept study, we show that the pharmacokinetic profiles of the atypical antipsychotic drug, risperidone, were similar whether administered via the MDA procedure or via the conventional oral gavage method. Unlike the latter, however, MDA did not induce the stress hormone, corticosterone. Furthermore, we assessed the suitability and validity of the MDA method in a mouse model of maternal immune activation, which is frequently used as a model of immune-mediated neurodevelopmental disorders. Using this model, we found that chronic treatment (>4 weeks, once per day) with risperidone via MDA led to a dose-dependent mitigation of MIA-induced social interaction deficits and amphetamine hypersensitivity. Taken together, the MDA procedure described herein represents a novel pharmacological administration method for per os treatments in mice that is easy to implement, cost effective, non-invasive, and less stressful for the animals than conventional oral gavage methods.

Living with Systematic Lupus Erythematosus: A Profile of Young Female Patients.

The aim is to describe a profile of systemic lupus erythematosus (SLE) patient (socio-demographic data, course of disease, health status, and health care utilization, SLE impact on their life, SLE awareness) and to explore the association of patient’s perspective with clinical indicators. Adult patients diagnosed by SLE were recruited in outpatient clinics (n = 76, 88% female, data collected in 2012–2016, Slovakia). The association of patients’ perspective (SLE status, health complaints during remission, SLE impact, hospitalizations) with clinical activity (European Consensus Lupus Activity Measurement Index—ECLAM) and inflammatory marker (erythrocyte sedimentation rate—ESR) was assessed by t-test for independent variables and one-way ANOVA. Almost 17.9% of patients reported relapse. During remission, they mostly suffered fatigue and pain. Nearly all patients were on chronic pharmacological treatment. Most of the patients assessed SLE impact on their life as restrictive (56.9%) or very restrictive (23.1%). The most frequent source of information was their physician, and 67.2% reported that they have sufficient information about the disease and its treatment. Only the association of SLE status and hospitalization with clinical activity (ECLAM) and inflammatory marker (ESR) were confirmed. With recent improvements in diagnostics and therapy options, the prognosis for patients with SLE has improved. Nevertheless, the impact of this disease on all areas of a patient’s life is extensive.

The Transition from Childhood to Adulthood in Chronic Immune Thrombocytopenia Patients: Clinical Management and the Role of Splenectomy and Thrombopoietin Receptor Agonists in a Single Center Experience

Introduction. Children diagnosed with Immune thrombocytopenia (ITP) will develop a chronic disease (plt < 100 x 109/L lasting >12 months since the onset) in 20-30% of cases. The transition from ITP started in childhood to adulthood has been scarcely studied and no specific studies have been publishedAims.To present the results of a single center retrospective survey on ITP pts diagnosed in childhood who were sent in an adult setting to continue the managementMethods. Charts of ITP pts diagnosed in childhood (1-17 yrs) in our Pediatric Dept who developed a chronic disease, need at least one line of therapy and were sent to our adult ITP office from Jan 2013 to Feb 2018, were retrospectively reviewed. Demographic and clinical data were collected and outcome was assessed based on established guidelinesResults. Our Pediatric Dept accounts for a mean of 37 newly ITP diagnosis/year in children aged 1-17 yrs, with 32.8% of pts developing a chronic disease. During the selected observation time, 60 pts was expected to become > 18 yrs old with a chronic ITP. Overall 28 pts (14 female) pts were sent to our Adult ITP office at pediatrician's discretion (46.6% of expected). Table 1 summarizes demographic and clinical characteristics of pts. Median age at ITP diagnosis was 9.5 yrs (12 moths to 17 yrs). Median age of pts coming to the adult ITP office was 21 yrs (18 to 37 yrs) and the reason they were sent for was the need to continue a pharmacological treatment in 8 cases (eltrombopag-Elt-), bleeding in 3 cases, pregnancy in 4 cases, plt count < 50 x 109/L in 13 cases. The median n of lines of treatment already received in childhood was 1 (1 to 4). 16 pts have received only steroid since diagnosis (on demand treatment for bleedings), 8 pts were treated with thrombopoietin receptor agonists (TPO-RA) and 1 also with rituximab. One patient, 8 yrs old, was splenectomized because of grade 3 multiple bleedings, with complete response (CR). He was sent to adult ITP office at 37 yrs when ITP relapsed, with grade 3 bleeding. Overall the median follow up from diagnosis, after the transition to adult ITP office is 18 yrs (4-39 yrs), the median n of lines at data cut-off was 2.5 (1-5) and the overall outcome is summarized in Fig 1. 11 patients were treated with TPO-RA (8 pts received Elt since childhood, 2 pts started Elt and 1 Rom in adulthood), ORR was 81.8% (CR=7). Since the transition 4 patients switched the TPO-RA because response to the first TPO-RA was suboptimal or minor side effect (headache) was reported or limited compliance was suspected. Splenectomy was offered to all patients treated with TPO-RA to avoid chronic pharmacological treatment, and to other selected patients with a low plt count and a history of bleeding. 8/11 patients accepted splenectomy. Median time since diagnosis to splenectomy was 8 yrs (1 to 18 yrs) and in all pts a stable CR (plt > 100 x 109/L) was achieved, with a median follow up after surgery of 36.5 months (10-48 months). Surgery was performed also in the previous splenectomized pt (29 yrs later) because an accessory spleen was detected, and a CR was achieved (follow up 40 months). 2 patients stopped TPO-RA on a personal decision, refused splenectomy or other treatments: their plt count is < 30 x 109/L without bleeding. 15 pts were on active follow up without therapy (median plt count 58 x 109/L) and without any bleeding. One patient is waiting for splenectomy, taking prednison. The 4 pregnant patients were treated with steroids and IVIG, had natural labour without adverse events and their babies had a normal plt count. After pregnancy one pt was treated with Elt for 1 year, then she refused treatment and splenectomy. All 4 women returned to a number of plts similar to pre-gestational count. In 1 pt a MYH9 related-disorder was confirm at 21 yrs.Overall a CR was achieved during TPO-RA treatment in 9/11 pts and 9/28 (32%) achieved a stable CR after splenectomyConclusions. The transition from childhood to adulthood in chronic ITP pts leads clinicians to challenges related to growing age, especially in female pts approaching the fertility and pregnancy specific needs. However only a minority of children with ITP developed a chronic disease which required a prolonged treatment. TPO-RA seems to be effective and well tolerated but chronic administration has limited compliance. Splenectomy, even if performed in adulthood after many yrs since diagnosis, allows to achieve a stable CR sparing young adults from chronic pharmacological treatment. DisclosuresGambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

Long-Term Therapy with Corticosteroids in Nasal Polyposis: A Bone Metabolism Assessment.

Chronic rhinosinusitis associated with nasal polyposis (RSCwNP) affects 4% of the general population. As chronic condition, it requires chronic pharmacological treatment, whereas the surgical approach becomes necessary in obstructive and/or complicated cases. Intranasal and systemic corticosteroids (CS) represent the "Gold Standard" treatment for RSCwNP. The present study aimed to evaluate the side effects of prednisone in a group of patients with RSCwNP treated with long-term CS. In particular, attention was focused on bone disorders (osteopenia and osteoporosis) and prospective fracture risk increase. Forty patients (26 females, mean age 55.70 ± 14.03years) affected by RSCwNP have been enrolled. Control group included 40 healthy subjects (17 females, mean age 56.37 ± 13.03years). Nasal endoscopy, skin prick tests, nasal cytology, and bone densitometry were evaluated in all subjects. The likelihood of impaired bone metabolism (osteopenia or osteoporosis) was superimposable in both groups. Within RSCwNP group, no parameter was statistically significant in predicting a metabolism alteration.

Autonomic imbalance in cardiac surgery: A potential determinant of the failure in remote ischemic preconditioning

Remote ischemic preconditioning (RIPC) is a cardioprotective strategy against myocardial damage by ischemia-reperfusion. Many in-vivo and ex-vivo animal researches have demonstrated that RIPC decreases significantly the ischemia-reperfusion myocardial damage, by up to 58% in isolated rat heart. Cardiac artery bypass graft surgery (CABG) is a clinical model of myocardial ischemia-reperfusion and a clinical potential application to RIPC. However, although RIPC has shown successful results in experimental studies, clinical trials on CABG have failed to demonstrate a benefit of RIPC in humans. Strikingly, the main proposed factors associated with this translational failure also impair the balance of the autonomic nervous system (ANS), which has shown to play a key role in RIPC cardioprotection in animal models. Comorbidities, chronic pharmacological treatment and anesthesic drugs - common conditions in CABG patients - cause an ANS imbalance through parasympathetic activity decrement. On the other hand, ANS and specially the parasympathetic branch are essentials to get cardioprotection by RIPC in animal models. Consequently, we propose that ANS imbalance in CABG patients would explain the failure of RIPC clinical trials. Whether our hypothesis is true, many patients could be benefited by RIPC: a cheap, simple and virtually broad-available cardioprotective maneuver. In this paper we discuss the evidence that support this hypothesis and its clinical implications.

T181. ABNORMAL FRONTAL AND PARIETAL SYNAPTIC GAIN RESPONSES IN FIRST EPISODE SCHIZOPHRENIA DURING A P300 TARGET DETECTION TASK

BackgroundThe “dysconnection hypothesis” proposes that schizophrenia is best understood in terms of aberrant brain functional integration and synaptic neuromodulation, which may underlie illness psychopathology and cognitive decline. Impairments in the P300 potential are well documented in schizophrenia and progressive over the years with the illness. We used Dynamic Causal Modeling (DCM) to investigate intrinsic (self-) connectivity in a frontoparietal cortical hierarchy during a P300 task; that is, how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors.MethodsThirty-one patients with schizophrenia (16 first episode and 15 chronic patients) and 31 healthy controls underwent EEG recordings during an auditory oddball paradigm to elicit the P300 response. We studied 16 frontoparietal models (primary auditory, superior parietal, and superior frontal sources) and identified an optimal model of neural coupling, explaining illness ‘diagnosis’ and ‘chronicity’ effects, as well as their interactions with ‘task condition’.ResultsThe winning model included changes in connectivity in all 3 hierarchical levels. Compared to healthy controls, all patients (chronic and first episode) showed decreased self-inhibition – i.e., increased cortical excitability – in right superior parietal gyrus across task conditions. On the other hand, first episode patients – but not chronic – showed in the left frontal and parietal source a reversal of the normal synaptic gain changes in response to targets, relative to standard tones.DiscussionWe confirmed that both subjects with chronic and first episode schizophrenia show a context-independent loss of parietal synaptic gain control. Importantly, in the highest levels of the hierarchy, first episode patients showed a specific abnormal gain modulation pattern in response to task-relevant stimuli not present in those chronically treated. Abnormal synaptic gain is plausibly caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells, and may be independent of illness advance and chronic pharmacological treatment.

Low-dose statin treatment increases prostate cancer aggressiveness.

Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.

Migraines in Women: Current Evidence for Management of Episodic and Chronic Migraines.

Migraine headache is a disabling brain disorder that affects millions of women in the United States. Many migraine sufferers are undertreated. Both inadequate treatment and overuse of abortive migraine medication can contribute to progression from episodic to chronic migraine disorders. A significant number of migraine headaches or severity of episodic migraine headaches warrants treatment with prophylactic medications for prevention. This clinical update reviews the pathophysiology and diagnosis of migraine headaches in women, discusses the efficacy of abortive and chronic pharmacologic treatment, and examines strategies to prevent progression from episodic migraine to chronic migraine. A discussion of treatment during pregnancy and lactation is included.

Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention

Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and – more recently – inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations.To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.

Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy.

Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1α; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk.

Pain in Intellectually Disabled Children: Towards Evidence-Based Pharmacotherapy?

This critical opinion article deals with the challenges of finding the most effective pharmacotherapeutic options for the management of pain in intellectually disabled children and provides recommendations for clinical practice and research. Intellectual disability can be caused by a wide variety of underlying diseases and may be associated with congenital anomalies such as cardiac defects, small-bowel obstructions or limb abnormalities as well as with comorbidities such as scoliosis, gastro-esophageal reflux disease, spasticity, and epilepsy. These conditions themselves or any necessary surgical interventions are sources of pain. Epilepsy often requires chronic pharmacological treatment with antiepileptic drugs. These antiepileptic drugs can potentially cause drug–drug interactions with analgesic drugs. It is unfortunate that children with intellectual disabilities often cannot communicate pain to caregivers. Although these children are at high risk of experiencing pain, researchers nevertheless often have to exclude them from trials on pain management because of ethical considerations. We therefore make a plea for prescribers, researchers, patient organizations, pharmaceutical companies, and policy makers to study evidence-based, safe and effective pharmacotherapy in these children through properly designed studies. In the meantime, parents and clinicians must resort to validated pain assessment tools such as the revised FLACC scale.

Chronic Pain Pharmacological Treatment in Patients with Depressive Disorders

Background and Objective: Frequently patients with chronic pain show depressive disorders. The co-morbidity of pain and depressive disorders has a negative impact on the patient’s outcome, with an increase of the costs relating to health expenses, a reduction of productivity and a reduction of a probable remission of depressive symptoms. Following the evidences till now examined and reported, the study group elaborated recommendations for the pain and depressive disorder treatment. Databases and Data Treatment: We searched all potentially relevant publications in Medline database from 1990 to 2014. A quality assessment was conducted categorizing following a power of evidence criteria. Results: Forty-six relevant publications were identified: 34 randomized and controlled studies (RCT), 11 metaanalyses or reviews of literature and 1 observational open-label. Conclusions: In a condition of co-morbidity of chronic pain and depressive disorder there is poor evidence for the tricyclic antidepressant efficacy. Among the inhibitors of the serotonin-noradrenalin reuptake, duloxetine proved to be efficient in the short-long term treatment of the pain and depressive disorder states. There is poor evidence for the inhibitor use of serotonin re-uptake in the co-morbidity states of arthritis pain and depressive disorder, against their higher efficacy in the irritable bowel syndrome

Interventional therapy of tachyarrhythmias in the pediatric population

Over the past decades, interventional therapy of tachyarrhythmias in children without structural heart disease has evolved as an alternative to chronic pharmacological treatment. Catheter ablation in children over 5 years with symptomatic tachycardia using radiofrequency- or cryoenergy is nowadays performed with high success and low complication rates at experienced centers. The use of modern technologies such as non-fluoroscopic 3-dimensional mapping has further increased efficacy and safety of catheter ablation, and has led to a significant reduction of fluoroscopy time and dose.Arrhythmia substrates treated most frequently by catheter ablation in children include accessory pathways (WPW syndrome) leading to atrioventricular reentrant tachycardia (AVRT) and dual AV nodal pathways causing atrioventricular nodal reentrant tachycardia (AVNRT). Success rates of catheter ablation for these substrates during long-term follow up are over 90 %. Less common forms of tachycardias in children, such as focal atrial tachycardia, ventricular outflow tachycardias or idiopathic left ventricular tachycardia, are also amenable to catheter ablation with good long-term results. In asymptomatic children with preexcitation on the surface ECG (accessory pathway with the risk of rapid antegrade conduction during atrial fibrillation) the indication for catheter ablation of the accessory pathway for the prevention of sudden cardiac death should already be evaluated during childhood.

Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.

FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation 1,2. Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis 3,4. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes.

Serum uric acid and impaired cognitive function in a cohort of healthy young elderly: data from the Brisighella Study.

Contrasting evidence shows a possible association between serum uric acid (SUA) and cognitive function in elderly subjects. We aimed at evaluating the impact of circulating SUA levels on cognitive function in a cohort of pharmacologically untreated young elderly subjects. For this study, we selected 288 healthy young elderly participants from the historical cohort of the Brisighella Heart Study (M: 108, F: 180; mean age: 69 ± 6 years old). Exclusion criteria were limitation of activities of daily living, depression, chronic pharmacological treatment, patients in secondary prevention for cardiovascular disease, known neurodegenerative disorders, confirmed diabetes or gout, and ultrasonic evaluated carotid atherosclerosis. Cognitive functions were assessed by scholarship-adjusted mini-mental state examination (MMSE). A stepwise multiple regression analysis was carried out including a large set of clinical and laboratory parameters, carotid intima-media thickness, and the Beck Depression scale score. The analysis was then repeated by gender. In the multiple regression analysis, the only factors associated with the MMSE score were: age (B = -0.058, 95% CI -0.108, -0.009, p = 0.022), LDL-C (B = -0.639, 95% CI -0.912, -0.411, p = 0.034) and SUA (B = -0.527, 95% CI -0.709, -0.344, p = 0.022). Repeating the analysis by low or high SUA level (based on the gender specific SUA distribution 50th percentile), it appears that in subjects with a low SUA, cognitive decline is only associated with age, while in those with high SUA it is associated with LDL-C (OR 1.18, 95% CI 1.07-1.33, p = 0.019) and SBP (OR 1.02, 95% CI 1.001-1.048, p = 0.039). Our data demonstrate a positive association between circulating levels of uric acid and cognitive dysfunction in a sample of pharmacologically untreated young elderly subjects.