Systematic Data Monitoring and Analysis of Cardiovascular Off-label Prescriptions in Pediatrics: Focus on Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Beta Blockers.

INTRODUCTION: Many efforts have been made to stimulate clinical trials (CTs) in pediatrics but most of the drugs are still authorized only in adults and used off-label in the pediatric population. AIM: To assess how widespread is the off-label prescription in Italy and to identify areas of unmet medical need by applying a model for the systematic collection and analysis of data. METHODS: A study was performed using 2015 data from the Italian Medicines Utilization Monitoring Centre Health Database (OsMed). A study sample of 3,726,583 pediatric patients, was considered. Cardiovascular drugs were selected for this study. Assessment of the off-label use, the analysis of the pharmacovigilance signals, a bibliographic research and the analysis of ongoing CTs were carried out. RESULTS: In 2015, 8,544 pediatric patients received treatment with a cardiovascular drug. Angiotensin converting enzyme inhibitors (ACE-I) followed by beta blockers agents are the most prescribed molecules. Eight molecules were selected and an in-depth analysis conducted. The PhV network showed only one record of adverse reaction as off-label in 2015. The results show several therapeutic areas of use in pediatrics. CONCLUSION: Off-label in pediatrics is largely widespread in Europe and US and our results show it is also present in Italy. Molecules selected are used off-label for therapeutic areas such as oncologic, hematological and rare diseases. Results of pharmacovigilance suggests underreporting. The analysis carried out in this study could be an open track for a systematic monitoring activity and of interest for prescribers, pediatricians and other healthcare professionals during the clinical practice.

Impact of reimbursement limits on patient access to direct-acting antivirals in Italy: analysis of data from national registries.

OBJECTIVE: Hepatitis C virus (HCV) infection is a global epidemic, still highly prevalent in Europe. Given efficacy and safety of HCV therapy by Direct Antiviral Agents (DAA), World Health Organization called for actions to eliminate HCV infection. A limit is represented by access to care, mostly due to the high costs of medicines. In Italy, in 2015, the access to DAA therapy was reimbursed for patients with advanced disease, whereas in 2017 universal access was granted. The aim of this study was to analyse changes in patient recruitment trends treated with DAA with or without limitations to access to therapy. PATIENTS AND METHODS: 165,105 patients treated with DAA in Italy from 2015 to December 2018 were analysed. Daily patient treatment rate was obtained by segmented regression of interrupted time series analysis. RESULTS: 74,199 patients with advanced disease (62% with cirrhosis) had access to the therapy during the time period from 2015 to 2017. Following the extension of reimbursement criteria, 90,906 additional patients were treated (43.2% with F0-F1 and 22.9% with F2), with an absolute reduction of 59.9% of patients with advanced disease (cirrhosis decreased to 18.5%). Segmented regression of interrupted time series analysis of daily patient treatment rate showed a progressive reduction of patients with advanced disease, offset by those with initial disease. Notably, elimination of restrictions to therapy did not change the overall treatment rate. CONCLUSIONS: This study showed that a no-limit reimbursement policy for DAAs prescriptions to HCV infected individuals in Italy widened the types of treated patients, but the process towards elimination of HCV infection was not significantly changed.

Pricing and reimbursement experiences and insights in the European Union and the United States: Lessons learned to approach adaptive payer pathways.

Earlier patient access to beneficial therapeutics that addresses unmet need is one of the main requirements of innovation in global healthcare systems already burdened by unsustainable budgets. "Adaptive pathways" encompass earlier cross-stakeholder engagement, regulatory tools, and iterative evidence generation through the life cycle of the medicinal product. A key enabler of earlier patient access is through more flexible and adaptive payer approaches to pricing and reimbursement that reflect the emerging evidence generated.

The future is now: model-based clinical trial design for Alzheimer's disease.

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry.

BACKGROUND AND AIMS: In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry. METHODS AND RESULTS: From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors. CONCLUSIONS: In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.

Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014.

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review.

Since the 1970s, clinicians have increasingly become more familiar with hyperprolactinemia (HPRL) as a common adverse effect of antipsychotic medication, which remains the cornerstone of pharmacological treatment for patients with schizophrenia. Although treatment with second-generation antipsychotics (SGAs) as a group is, compared with use of the first-generation antipsychotics, associated with lower prolactin (PRL) plasma levels, the detailed effects on plasma PRL levels for each of these compounds in reports often remain incomplete or inaccurate. Moreover, at this moment, no review has been published about the effect of the newly approved antipsychotics asenapine, iloperidone and lurasidone on PRL levels. The objective of this review is to describe PRL physiology; PRL measurement; diagnosis, causes, consequences and mechanisms of HPRL; incidence figures of (new-onset) HPRL with SGAs and newly approved antipsychotics in adolescent and adult patients; and revisit lingering questions regarding this hormone. A literature search, using the MEDLINE database (1966-December 2013), was conducted to identify relevant publications to report on the state of the art of HPRL and to summarize the available evidence with respect to the propensity of the SGAs and the newly approved antipsychotics to elevate PRL levels. Our review shows that although HPRL usually is defined as a sustained level of PRL above the laboratory upper limit of normal, limit values show some degree of variability in clinical reports, making the interpretation and comparison of data across studies difficult. Moreover, many reports do not provide much or any data detailing the measurement of PRL. Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the potential to cause new-onset HPRL. Considering the PRL-elevating propensity of the newly approved antipsychotics, evidence seems to indicate these agents have a PRL profile comparable to that of clozapine (asenapine and iloperidone), ziprasidone and olanzapine (lurasidone). PRL elevations with antipsychotic medication generally are dose dependant. However, antipsychotics having a high potential for PRL elevation (amisulpride, risperidone and paliperidone) can have a profound impact on PRL levels even at relatively low doses, while PRL levels with antipsychotics having a minimal effect on PRL, in most cases, can remain unchanged (quetiapine) or reduce (aripiprazole) over all dosages. Although tolerance and decreases in PRL values after long-term administration of PRL-elevating antipsychotics can occur, the elevations, in most cases, remain above the upper limit of normal. PRL profiles of antipsychotics in children and adolescents seem to be the same as in adults. The hyperprolactinemic effects of antipsychotic medication are mostly correlated with their affinity for dopamine D2 receptors at the level of the anterior pituitary lactotrophs (and probably other neurotransmitter mechanisms) and their blood-brain barrier penetrating capability. Even though antipsychotics are the most common cause of pharmacologically induced HPRL, recent research has shown that HPRL can be pre-existing in a substantial portion of antipsychotic-naïve patients with first-episode psychosis or at-risk mental state.

Is HCMV vaccine an unmet need? The state of art of vaccine development.

Congenital HCMV infection is the most frequent congenital infection, with an incidence of 0.2- 2.5 percent among all live births. About 11 percent of infected newborns show symptoms at birth, including hepato-splenomegaly, thrombocytopenia, neurologic involvement, hearing impairment and visual deficit. Moreover, 5-25 percent of the asymptomatic congenital HCMV-infected neonates will develop sequelae over months or even years. The relevant social burden, the economic costs of pre-natal screening, post-natal diagnosis, follow-up and possible therapy, although still limited, are the major factors to be considered. Several types of vaccines have been explored in order to develop an effective and safe HCMV vaccine: live attenuated, subunit, vectored, peptide, DNA, and subviral ones, but none are available for use. This review illustrates the different vaccine types studied to date, focusing on the possible vaccination strategy to be implemented once the HCMV vaccine is available, in terms of target population.

Metformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review.

BACKGROUND: Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis. AIM: To review the National Pharmacovigilance Network of the Italian Medicines Agency reporting cases of metformin-associated lactic acidosis. MATERIALS AND METHODS: The National Pharmacovigilance Network of the Italian Medicines Agency, was searched for cases of lactic acidosis that occurred in a 10 years period (from November 2001 to October 2011). Data were analyzed, to identify associated clinical features. A systematic literature research was performed to identify other large case series on metformin associated lactic acidosis. RESULTS: Metformin was the antidiabetic drug most frequently associated with lactic acidosis in the assessed period. Metformin-associated lactic acidosis was the most frequent serious adverse reaction related to metformin reported to the national authority (18.2% of all 650 adverse drug reactions reported). There were 59 cases of metformin-associated lactic acidosis (mortality rate of 25.4%). In most patients (89.8%) there was at least one risk factor for the occurrence of lactic acidosis. The predictors of death were low arterial blood pH and absence of acute renal failure. The systematic research of the literature identified only six case-series with more than 30 patients. CONCLUSIONS: This is the second largest case series ever reported on metformin-associated lactic acidosis. We confirmed that this rare complication of metformin is frequently fatal. Death can be predicted when the patient arrive in the hospital with low pH and, not intuitively, if the patient has no acute kidney injury. Risk minimisation measures taken at national level to prevent this serious complication are described.

Subthreshold depression in older subjects: an unmet therapeutic need.

Major depression, defined according to DSM IV TR criteria, is less common in older subjects, while other types of depression are two to three times more prevalent. This heterogeneous group of disturbances has received different names: depression not otherwise specified, minor depression, subthreshold or subsyndromal depression. Moreover, each condition has been defined using heterogeneous criteria by different authors. The term of subthreshold depression will be adopted in this position statement. Subthreshold depression has been associated with the same negative consequences of major depression, including reduced well being and quality of life, worsening health status, greater disability, increased morbidity and mortality. Nevertheless, there is a dearth of clinical trials in this area, and therefore older patients with subthreshold depression are either not treated or they are treated with the same non pharmacological and pharmacological therapies used for major depression, despite the lack of supporting scientific evidence. There is an urgent need to reach a consensus concerning the diagnostic criteria for subthreshold depression as well as to perform clinical trials to identify effective and safe therapies in this too long neglected patient group.

Antinociceptive activity of Delta9-tetrahydrocannabinol non-ionic microemulsions.

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of Cannabis sativa L., has been widely studied for its potential pharmaceutical application in the treatment of various diseases and disturbs. This sparingly soluble terpeno-phenolic compound is not easy to handle and to be formulated in pharmaceutical preparations. The aim of this work was to develop a stable aqueous Delta(9)-THC formulation acceptable for different ways of administration, and to evaluate the therapeutic properties of the new Delta(9)-THC based preparation for pain treatment. Due to the thermodynamic stability and advantages of microemulsion based systems, the study was focused on the identification of aqueous microemulsion based systems containing Delta(9)-THC. Oil in water Delta(9)-THC microemulsions were individuated through phase diagrams construction, using the non-ionic surfactant Solutol HS15, being this surfactant acceptable for parenteral administration in human. A selected microemulsion samples containing 0.2 wt% of Delta(9)-THC, stable up to 52 degrees C, was successfully assayed on animal models of pain. Significant antinociceptive activity has been detected by both intraperitoneal and intragastric administration of the new Delta(9)-THC pharmaceutical preparation. The effect has been highlighted in shorter time if compared to a preparation of the same active principle based on previously reported conventional preparation.

1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice.

Neuropathic pain is a devastating neurological disease that seriously affects quality of life in patients. The mechanisms leading to the development and maintenance of neuropathic pain are still poorly understood. However, recent evidence points towards a role of spinal microglia in the modulation of neuronal mechanisms. In this context, cannabinoids are thought to modulate synaptic plasticity as well as glial functions. Here, we have investigated the effect of chronic treatment with a selective agonist of cannabinoid type 2 receptor (CB2), 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3 carboxamide (NESS400), on pain thresholds in the spared nerve injury (SNI) model in the mouse and on the distribution and activation of spinal microglia. Repeated treatment with NESS400 (4 mg/kg) significantly alleviated neuropathic mechanical allodynia and thermal hyperalgesia. In the dorsal horn (L4-L6) of neuropathic mice microglia activation (quantification of the length of microglial processes) and astrocytosis were associated with CB2 receptor over-expression on both cell types. Treatment with NESS400 significantly reduced the number of hypertrophic microglia while leaving microglial cell number unaffected and reduced astrogliosis. Moreover, prolonged administration of NESS400 reduced mRNA expression of pro-inflammatory markers and enhanced anti-inflammatory marker gene expression in dorsal horn extracts. In conclusion, we show that selective CB2 receptor stimulation prevents thermal hyperalgesia, alleviates mechanical allodynia and facilitates the proliferation of anti-inflammatory microglial phenotype in the ipsilateral dorsal horn of the spinal cord in SNI mice.

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats.

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

The need for individualised antipsychotic drug therapy in patients with schizophrenia.

Drug therapy for schizophrenia aims to both reduce symptoms in the acute phase and maintain long-term symptomatic remission during periods of stabilization. Atypical antipsychotic agents are the mainstay of schizophrenia therapy because of their improved tolerability, including a reduced likelihood of extrapyramidal symptoms, compared with conventional antipsychotics. However, responses to antipsychotic therapy are influenced by a wide range of factors, such as age, gender, race, comorbidities, genetics and social and environmental conditions, that make identifying the most appropriate antipsychotic treatment for each individual patients, an ongoing challenge for physicians. Tools that may be useful to assist clinicians in determining appropriate individual therapy include consideration of treatment moderators, which specify for whom or under what conditions a treatment works, treatment mediators, which are mechanisms by which a treatment achieves its effects, and cluster group analyses, which identify subsets of patients with similar characteristics. Further research is required to determine whether cluster groups of patients with schizophrenia can be identified based on treatment moderators and mediators, and whether antipsychotic prescribing based on consideration of these cluster groups leads to improved treatment outcomes.

Building a virtual archive using brain architecture and Web 3D to deliver neuropsychopharmacology content over the Internet.

The vast amount of heterogeneous data generated in various fields of neurosciences such as neuropsychopharmacology can hardly be classified using traditional databases. We present here the concept of a virtual archive, spatially referenced over a simplified 3D brain map and accessible over the Internet. A simple prototype (available at http://aquatics.crs4.it/neuropsydat3d) has been realized using current Web-based virtual reality standards and technologies. It illustrates how primary literature or summary information can easily be retrieved through hyperlinks mapped onto a 3D schema while navigating through neuroanatomy. Furthermore, 3D navigation and visualization techniques are used to enhance the representation of brain's neurotransmitters, pathways and the involvement of specific brain areas in any particular physiological or behavioral functions. The system proposed shows how the use of a schematic spatial organization of data, widely exploited in other fields (e.g. Geographical Information Systems) can be extremely useful to develop efficient tools for research and teaching in neurosciences.

Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients.

BACKGROUND: Recognition by the DSM-IV of rapid cyclicity as a course specifier has raised the question of the stability and long-term outcome of rapid-cycling (RC) patients. Data on this topic is sparse and often inconsistent. To our knowledge, these are the first personally followed patients over the long term, dealing directly with the issue of the duration of the RC course. METHODS: We examined the evolution of the course of 109 RC patients (68 women and 41 men) followed for a minimum of 2 years and up to 36 years, beginning with the index episode when the RC course was diagnosed by the authors (A.K., G.P.M., P.G., L.P., D.R.). Patients were included in the study if they met criteria for RC as defined by>or=4 affective episodes per year (Dunner and Fieve, 1974). The follow-up period varied from 2-5 years for 25 patients, 6-10 years for 24 patients, 11-15 years for 24 patients, 16-20 years for 19 patients, 21-25 years for 13 patients, 30-36 years for four patients. RESULTS: In 13 patients (12%), RC emerged spontaneously and in 96 patients (88%), it was associated with antidepressant and other treatments. In 19 women (28% of all women) RC course started in perimenopausal age (45-54 years). The mean duration of RC during the follow-up period was 7.86 years (range 1-32) and its total duration (including RC course prior to the follow-up period) was 11 years (range 1-40). The total duration of the affective disorder, from the first episode to the end of the follow-up, was 21.78 years (range 1-70). At the end of the follow-up, 36 patients (33%) had complete remission for at least the past year, 44 (40%) stayed rapid cycling with severe episodes (six of this group committed suicide), while 15 (14%) were rapid cycling but with attenuated episodes. The other 14 patients (13%) became long cyclers, eight with severe episodes and six with milder ones. The main distinguishing features between those who remitted from and those who persisted in the RC course were: (1). the initial cycle pattern: patients with Depression-Hypomania(mania)-Free interval cycles (53 patients) had a worse outcome: 26.4% remitted and 52.8% persisted in the RC course through to the end of the follow up period. The Mania/Hypomania-Depression-Free interval cycles (22 patients) had a significantly better outcome, with 50% remitted and 27.2% persisting RC; and (2). the occurrence of the switch process from depression to hypomania/mania and the occurrence of agitated depressions made the prognosis worse. Continuous treatment was more effective against mania/hypomania than against depression, yet in all persisting RC cases the mania/hypomania remitted only partially. LIMITATIONS: These data derive from clinics known for their expertise in mood disorders, and they may have attracted and retained patients with a more severe course. Treatment was uncontrolled and consisted more of lithium than divalproex, lamotrigene and olanzapine, recently shown to be beneficial in subgroups of patients with rapid-cycling. CONCLUSIONS: Our findings suggest that rapid cyclicity, spontaneous or induced, once established, becomes for many years a stable rhythm in a substantial proportion of patients, linked to endogenous and environmental factors. The suggestion is made to consider as rapid-cyclers, at least for research purposes, those patients who have had a rapid cycling course for at least 2 years, borrowing the duration criterion currently employed for other chronic disorders such as Dysthymia and Cyclothymia. That our patients had poorer prognosis than some other cohorts in the literature is probably due to the shorter duration of "rapid-cycling" at entry in the latter cohorts. A true understanding of the nature of rapid-cycling will require a rigorous definition of not only duration, but also pole-switching and course patterns at entry into study.

Hymenoptera sting anaphylactic reactions in the Mediterranean population of Albania.

BACKGROUND: Relatively few studies have examined the relation of different hymenoptera sting reactions. OBJECTIVE: To investigate the relation of anaphylactic reactions against stings of different hymenoptera subspecies in the Mediterranean population of Albania. MATERIALS AND METHODS: A retrospective study was conducted using the clinic files of 111 patients who were diagnosed for hymenoptera sting reactions from 1987 to 1996. Antigens used consisted of purified hymenoptera venom (bee, wasp, and paperwasp). The patients were diagnosed by intracutaneous tests in concentrations of 0.001 microgram/ml, 0.01 microgram/ml, 0.1 microgram/ml, and 1 microgram/ml. RESULTS: The median age of the patients was 27 years. 57% of stings occurred between 20 to 40 years of age. The majority of anaphylactic reactions were recorded during the months of June to October, 81% of the patients were admitted to the hospital due to Mueller grade II to III reactions. In 26% of all cases, crossreactions (bee-wasp 16%, bee-wasp-paperwasp 7%, wasp-paperwasp 2%, bee-paperwasp 1%) were found. Of all anaphylactic reactions, 64% were attributed to bees, 24% to wasps, 8% to both bees and wasps, and 2% to paperwasps. CONCLUSIONS: In contrast to industrialized countries such as the United States or Western Europe where urban populations predominate, reactions to bee venom were more prevalent in the present study population.

Clinical implications of dopamine research in schizophrenia.

One of the most stimulating problems posed by second generation antipsychotics is the question of whether their ability to act on the negative, as well as the positive, symptoms of schizophrenia relies on the same neurochemical mechanisms as those responsible for their lack of extrapyramidal symptoms (EPS). Amisulpride is a substituted benzamide antipsychotic, which is known to be efficacious against both the positive and the negative symptoms of schizophrenia and to have a lower propensity to induce EPS than conventional antipsychotics. Amisulpride preferentially blocks the D2 and D3 subtypes of dopamine receptors, both presynaptically in the frontal cortex, enhancing dopaminergic transmission, and postsynaptically in subcortical areas such as the nucleus accumbens, so reducing dopaminergic transmission. Given that dopaminergic under-activity in the frontal cortex is thought to produce negative symptoms, and over-activity in the limbic system to produce positive symptoms, it is proposed that these are the mechanisms by which amisulpride produces its atypical profile.

The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia.

In this paper the historical and scientific background that led to the use of substituted benzamides in two apparently unrelated clinical conditions namely dysthymic disorder and schizophrenia will be reviewed, in order to understand if a common mechanism of action may support this dual therapeutic indication. The dopaminergic antidepressant action of substituted benzamides such as sulpiride, has been proposed, since the late 1970s, by several authors and extensively explored in preclinical experiments by our group. In Italy the first marketing authorization obtained for the new substituted benzamide amisulpride, was with the sole indication of dysthymia and therefore a solid clinical experience exists in the use of substituted benzamides in mild forms of depression, with more than 1 000 000 patients being treated in the last 7 years. The proposed mechanism of action of substituted benzamides implies a selective modulation of the dopaminergic system in the mesocorticolimbic area, important for cognitive processing of internal and external cues, related to survival. The selective antagonism of dopamine D2-D3 receptors has been evoked to explain, in small to moderate doses (ie 50-100 mg day(-1)), the antidepressant effect and, in moderate to medium doses (100-400 mg day(-1)), the reported efficacy on negative symptoms of schizophrenia. Thus, substituted benzamides could represent the first class of atypical antipsychotics successfully employed for both depressive states and schizophrenia. Interestingly, recent evidence in the literature suggests that depressive episodes belonging to the bipolar spectrum are among "alternative indications" of other atypical antipsychotics such as olanzapine and risperidone.

The role of limbic and cortical regions in schizophrenia: focus on dopamine.

Dopamine is implicated in the pathogenesis of both the positive and the negative symptoms of schizophrenia. Clinical efficacy of antipsychotic drugs, without the production of side-effects, may be achieved by a dose-response separation of pharmacological function, regional (i.e., anatomical) selectivity of action, or by the selective targeting of neuroreceptors. The atypical antipsychotics have many different ways of acting on receptors in the brain, but they have in common a decreased likelihood of producing extrapyramidal side-effects. Patients respond well to them by showing improvements of both positive and negative symptoms. The preclinical profile of amisulpride shows specificity for D2/D3 dopamine receptors and selective activity in the limbic system. There is evidence that amisulpride is effective in treating both the negative and positive symptoms of schizophrenia, and that it has a low propensity to induce motor side-effects. Therefore, both positive and negative symptoms can be treated, without inducing these side-effects, by selectively targeting dopamine receptors.