The advent of biosimilars for the treatment of diabetes: current status and future directions.

Biosimilar insulins are likely to enter the market of diabetes therapies as patents for major branded insulin products start to expire in the next few years (on June 2014, the European Medicines Agency authorized the first biosimilar of insulin glargine, Abasria, 100 Units/ml, for the treatment of diabetes mellitus). This would allow providing comparable clinical benefits of the current available insulins at a significantly lower cost, thus increasing the affordability and access of insulin treatment for patients with diabetes. Biosimilars are approved via a stringent regulatory pathway demonstrating quality, safety, and efficacy comparable to the reference product. However, the production complexities of such products raise important considerations for treatment efficacy and patient safety, including naming and product tracking, substitution practices, and pharmacovigilance. Additionally, as practitioners' knowledge regarding the differences about pharmacological, clinical, and regulatory aspects between biosimilars and generic small molecules is often suboptimal, specific education on biosimilar prescribing, dispensing, and administering is critical for ensuring patients' benefit and safety. This article discusses all the issues concerning biosimilar, especially biosimilar insulins.

Effectiveness of risk minimization measures for cabergoline-induced cardiac valve fibrosis in clinical practice in Italy.

On June 2008, the European Medicines Agency (EMA) introduced changes to the Summary of Product Characteristics (SPC) for cabergoline and pergolide, to reduce the risk of cardiac valvulopathy in users of these drugs. To assess the effectiveness of EMA recommendations in Italian clinical practice, we retrospectively reviewed medical charts of patients with degenerative Parkinsonism treated with cabergoline in three large Italian clinics between January 2006 and June 2012. The prevalence and the severity of cardiac valve regurgitation were assessed in patients who stopped cabergoline therapy prior to June 2008 or continued therapy after that date. In addition, the proportion of patients undergoing echocardiographic examination in each cohort was evaluated. A total of 61 patients were available for evaluation. The proportion of patients who underwent a baseline echocardiographic examination increased from 64 % in the period before the 2008 SPC changes to 71 % among those who continued treatment after that date. However, only 18 and 29 % of patients underwent at least two echocardiographic examinations during the pre-SPC and cross-SPC change period, respectively. No severe cardiac valve regurgitation was documented in any of the study patients using cabergoline either prior or after 26th June 2008. Our findings show that the 2008 changes to the SPC resulted in an increase in physicians' awareness of cabergoline-induced valvulopathy risk in Italy. However, only a small percentage of patients underwent serial echocardiography. Further efforts are needed to achieve better compliance with the prescribing guidelines for cabergoline treated patients in clinical practice.

An initial validation of the Italian Mishel Uncertainty Illness Scale (MUIS) for relapsing remitting multiple sclerosis patients.

Multiple sclerosis is a chronic disease, likely to condition patients' daily living and quality of life: given the unpredictability of frequency and severity of the attacks, patients experience a high level of uncertainty. While there have been many analyses whose purpose was to monitor multiple sclerosis (MS) patients' quality of life, the role of uncertainty, that is peculiar to the disease, has not been adequately considered so far. The present study is aimed at filling this gap by validating for Italian MS patients the Mishel's Uncertainty Illness Scale (MUIS). The MUIS has been developed in the USA context in order to assess four aspects of uncertainty: ambiguity, complexity, inconsistency and unpredictability. It has been largely applied in the cancer, cardiac and chronic illness population. Data employed in this study have been collected at two neurological centres in Messina (IRCCS Centro Studi Neurolesi "Bonino Pulejo" and Policlinico di Messina) in the first semester of 2013 and refer to 120 MS patients. The confirmatory factor analysis described in this study validates two of the four dimensions of MUIS, namely ambiguity and inconsistency. The validation, though partial, of the MUIS, allows the use of this instrument in studies investigating quality of life for Italian patients.

Recent advances in the treatment of neurogenic erectile dysfunction.

Neurogenic erectile dysfunction (ED) can be broadly defined as an inability to sustain or maintain a penile erection owing to a neurological impairment, either centrally or peripherally or both. Although significant advances in the pharmacological treatment of ED have occurred in recent years, especially after the introduction of oral selective phosphodiesterase type 5 inhibitor, the treatment of neurological patients with ED may be challenging for prescribers, given poor data available on this topic and the variety of etiologic factors (iatrogenic, endocrine, psychiatric and psychosocial) to consider. At the same time, several, new oral, local and surgical treatments are available and their efficacy and safety depend on the specific cases. This review provides a comprehensive and updated description of current and future ED therapies, including assigned patents, with a special focus on the treatment of neurogenic erectile dysfunction.

Role of melatonin supplementation in neurodegenerative disorders.

Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory and cognitive systems. Despite their different origin, free radicals accumulation and consequent tissue damage are importantly concerned for the majority of them. In recent years, research on melatonin revealed a potent activity of this hormone against oxidative and nitrosative stress-induced damage within the nervous system. Indeed, melatonin turned out to be more effective than other naturally occurring antioxidants, suggesting its beneficial effects in a number of diseases where oxygen radical-mediated tissue damage is involved. With specific reference to the brain, the considerable amount of evidence accumulated from studies on various neurodegeneration models and recent clinical reports support the use of melatonin for the preventive treatment of major neurodegenerative disorders. This review summarizes the literature on the protective effects of melatonin on Alzheimer disease, Parkinson disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Additional studies are required to test the clinical efficacy of melatonin supplementation in such disorders, and to identify the specific therapeutic concentrations needed.

Mood and sleep problems in adolescents and young adults: an econometric analysis.

BACKGROUND: Sleep related problems affect approximately 25-40% of children and adolescents. The acquisition of sleep patterns characterised by later bedtimes, insomnia and excessive daytime sleepiness is related to poorer school performance, daytime drowsiness, physical tiredness and a higher rate of psychiatric illnesses. Many studies have investigated the correlation between sleep and mood in children and adolescents and overall, show a positive association between sleep problems and psychiatric disorders. However, little is known about adolescents' personal perception of their psychological status as it is linked with the occurrence of mood changes and sleep-related problems. AIMS OF THE STUDY: The aim of the study is to explore the impact of variables such as age, gender, education and the perception of their own psychological status (evaluated through suitable questionnaires) on the simultaneous presence of sleep disturbances and affective symptoms in a sample of adolescents. A positive correlation between these two dependent variables signals the need to intervene with proper support programs. METHODS: A recursive bivariate probit model has been employed. This method allows us to take into account two dependent dummy variables and to consider the relationship between the two, presuming that one may also influence the other. The analysis has been carried out on a sample of 2,005 adolescents out of a total of 4,000 who declared their willingness to be telephonically interviewed using a questionnaire in two parts designed to obtain information about the participants sleep habits and affective symptoms. RESULTS: There is a positive correlation between sadness and daytime drowsiness. The estimated joint probability ranging from 5.5% to 9% in girls demonstrates a greater tendency for girls to experience both depression and altered sleep patterns. DISCUSSION AND LIMITATIONS OF THE STUDY: Just as sadness is a key symptom of affective disorders, daytime drowsiness indicates the presence of sleep disorders caused by sleep habits that are likely to evolve into affective symptoms. This assumption is confirmed by the results of this analysis. However, since the interviews were conducted during the years 2003 and 2004, a replication of the analysis would outline whether this evidence is still the same or whether changes in habits and behaviours have intervened to modify substantially this pattern in recent years. As the analysis considers a sample of adolescents living in two southern Italian regions, the study should be replicated in other geographical areas. IMPLICATIONS FOR HEALTH CARE PROVISIONS AND USE: The early detection of affective symptoms in adolescents may presumably lead to a diminished use of antidepressants and an improvement in learning abilities and school results along with strengthening of personal motivations. IMPLICATIONS FOR HEALTH POLICIES: Counselling and educational programs directed towards those adolescents demonstrating poor sleep habits should be planned and implemented to avoid further complications and impact on their mental health.

Postthalamic stroke dystonic choreoathetosis responsive to tetrabenazine.

OBJECTIVE: To describe the case of a woman with poststroke choreoathetosis whose symptoms improved after treatment with tetrabenazine. CASE SUMMARY: A 48-year-old left-handed woman developed progressive involuntary dystonic choreoathetoid movements of her arm following a cerebrovascular event. Involuntary abnormal movements (IAMs) were treated with haloperidol, but they worsened 6 months later, also involving her mouth, tongue, and perioral area. Because of the suspected occurrence of drug-induced tardive dyskinesia, treatment was switched to tetrabenazine (titration up to 100 mg/daily), with rapid remission of the involuntary abnormal movements (Abnormal Involuntary Movement Scale score switching from 20 to 1). One month later, following discontinuation of tetrabenazine, the dystonic choreoathetoid movements rapidly reappeared. Subsequent rechallenge with tetrabenazine caused remission of her symptoms. DISCUSSION: Poststroke IAMs are rare, and lesions involving the basal ganglia and/or thalamus seem to be particularly implicated in such disorders. The exact pathogenic mechanism has not been clarified; however, it has been postulated that a central dopaminergic overactivity might play an important role in the IAM occurrence. Thus, antipsychotics are the main treatment option, but they are often associated with therapeutic failure or adverse effects, including extrapyramidal symptoms and metabolic complications. Interestingly, when our patient was treated with tetrabenazine for haloperidol-induced tardive dyskinesia, she demonstrated substantial improvement in the dystonic choreoathetoid movements of her left upper limb. CONCLUSIONS: The improved response of this case to tetrabenazine monotherapy suggests that tetrabenazine may be a pharmacologic alternative for patients with poststroke choreoathetosis that is intolerant or unresponsive to antipsychotic agents. Further studies are needed to better define the risk versus benefit profile of tetrabenazine.

Neurogenic ejaculatory disorders: focus on current and future treatments.

Ejaculation is a complex and still poorly understood neurological mechanism, at both spinal and cerebral levels as it is closely associated with orgasm. Physiologically, ejaculation is defined as the expulsion of seminal fluid from the urethral meatus and consists of two phases, namely emission and expulsion. Ejaculation is mediated by a spinal control center, referred to as a spinal pattern generator that coordinates sympathetic, parasympathetic and motor (somatic) outflows, integrating the latter with the inputs from the supraspinal sites in brainstem, hypothalamus and preoptic area. Premature ejaculation (PE) is the most common sexual dysfunction among young men, and it has been considered mostly psychogenic in origin, although it can be associated to diverse urological and neurological diseases. On the contrary, retrograde ejaculation and anejaculation are predominantly related to organic causes, particularly to neurogenic ones. Since ejaculation is mostly a spinal reflex, it is comprehensible that ejaculatory disorders are more frequent in spinal cord injury than in other neurological disorders. Over the past decades, research has focused on PE, and evidence from clinical studies showed a beneficial effect of antidepressants for the treatment of men with PE. Other ejaculatory disorders, especially painful ejaculation, have been less investigated and the proper therapy is still controversial. Aim of this review is to provide a comprehensive description of both currently available treatments and most promising future therapies, including assigned patents, for the neurogenic ejaculatory disorders.

Current and future therapies of erectile dysfunction in neurological disorders.

Erection is a neurovascular event characterized by the tumescence of the cavernous bodies that relies upon integration of neural and humoral mechanisms requiring the participation of autonomic and somatic nerves and the integration of numerous spinal and supraspinal sites. Erectile dysfunction (ED) is a highly prevalent problem increasing with age, as well as the major men's sexual concern. Significant advances in the pharmacological treatment of ED have occurred in recent years, most notably after the introduction of sildenafil, the first oral selective phosphodiesterase type 5 inhibitor. Nevertheless, many other oral, local and surgical treatments are available and their efficacy and safety depend on the specific cases. This review provides a comprehensive description of both currently available neurogenic ED treatments and most promising future therapies, including assigned patents.

Design and evaluation of a semantic approach for the homogeneous identification of events in eight patient databases: a contribution to the European EU-ADR project.

The overall objective of the EU-ADR project is the design, development, and validation of a computerised system that exploits data from electronic health records and biomedical databases for the early detection of adverse drug reactions. Eight different databases, containing health records of more than 30 million European citizens, are involved in the project. Unique queries cannot be performed across different databases because of their heterogeneity: Medical record and Claims databases, four different terminologies for coding diagnoses, and two languages for the information described in free text. The aim of our study was to provide database owners with a common basis for the construction of their queries. Using the UMLS, we provided a list of medical concepts, with their corresponding terms and codes in the four terminologies, which should be considered to retrieve the relevant information for the events of interest from the databases.

Nicolau syndrome following etanercept administration.

Nicolau syndrome (NS), or embolia cutis medicamentosa, is a well-known but rare adverse effect of a still largely unidentified pathogenesis, observed primarily after the intramuscular administration of various drugs. NS is characterized by immediate excruciating pain, early pallor and erythema and oedema at the injection site, followed by cutaneous, subcutaneous and even muscular aseptic necrosis in a livedoid pattern. It is a potentially serious reaction that is little influenced by which drug is injected. A case is reported of NS following a subcutaneous self-injection of etanercept for psoriasis and psoriatic arthritis. This case is remarkable because NS developed after subcutaneous and not after intramuscular drug administration, and because no cases of NS following the injection of tumour necrosis factor alpha inhibitors have been reported in the literature or in the World Health Organization adverse drug reactions database. Although not directly linked to the drug, the occurrence of NS has to be considered in patients receiving biological agents.

Construction of a telephone interview to assess the relationship between mood and sleep in adolescence.

Telephone interviews have been used extensively as a tool to explore and assess sleep disorders and psychopathological conditions. The aim of this study was to set up and validate a telephone interview aimed at assessing the correlation between mood and sleep variables in adolescents. The study included 16-18 years subjects. A total of approximately 4,000 calls were made; 529 adolescents were finally enrolled. The questionnaire was divided into two parts: the first one focused on affective variables, the second one explored sleep variables. A factorial analysis was carried out to explore the structure of the questionnaire according to two factors: the first, which we labeled "affective factor", and the second, "quality of sleep". A positive correlation was found regarding the feeling of wellbeing on awakening. A negative correlation was found between feeling of wellbeing on awakening and daytime drowsiness. In adolescence, increased daytime sleepiness seemed to correlate with worsening mood.

Hemorrhagic cystitis induced by an herbal mixture.

A healthy 33-year-old woman consumed a slimming product containing a mixture of herbal remedies without seeking medical advice. Two months later, the patient had hemorrhagic cystitis and discontinued the herbal product. Symptoms spontaneously remitted in a few days. Four months later, she took the same herbal remedy and the hemorrhagic cystitis reappeared. She then consulted her general practitioner. A urine culture test was negative, and the patient was advised to discontinue the herb intake. Again, the cystitis resolved within a week. The product involved contains a mixture of herbs, some of which have been associated with adverse effects that might account for the symptoms reported in this case.

Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor?

PURPOSE: Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. METHODS: Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. RESULTS: An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. CONCLUSIONS: A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and new issues in drug safety arise.

A semantic approach for the homogeneous identification of events in eight patient databases: a contribution to the European eu-ADR project.

The overall objective of the eu-ADR project is the design, development, and validation of a computerised system that exploits data from electronic health records and biomedical databases for the early detection of adverse drug reactions. Eight different databases, containing health records of more than 30 million European citizens, are involved in the project. Unique queries cannot be performed across different databases because of their heterogeneity: Medical record and Claims databases, four different terminologies for coding diagnoses, and two languages for the information described in free text. The aim of our study was to provide database owners with a common basis for the construction of their queries. Using the UMLS, we provided a list of medical concepts, with their corresponding terms and codes in the four terminologies, which should be considered to retrieve the relevant information for the events of interest from the databases.

A case of topiramate-induced epistaxis.

The current case describes epistaxis in a patient treated with a daily regimen of topiramate 100mg for migraine. The patient had not a past medical history of nosebleeds and laboratory parameters were within normal ranges. She was then advised to withdraw topiramate, and the epistaxis resolved within 12 hours after its discontinuation. Since then, the patient never complained other blood clotting disorders. The potential antiplatelet activity of topiramate is discussed.

Drug safety information through the internet: the experience of an Italian website.

BACKGROUND: The Internet may play a crucial role in the prompt provision of updated drug safety information. Nevertheless, limited knowledge of the English language among healthcare professionals or suboptimal search skills constitute barriers to widespread and appropriate use of the Internet for this purpose in Italy. In order to provide accurate information on drug safety and to promote the reporting of adverse drug reactions, in 1999 the clinical section of the Italian Society of Pharmacology created the website www.farmacovigilanza.org, financially supported by a non-profit foundation. The website promptly and independently provides news published in the international literature on drug safety, translated into Italian. The site also contains specific sections dedicated to adverse reactions to herbal products and cosmetic preparations. OBJECTIVES: The aim of this paper was to describe the number and characteristics of users and the most intensively visited sections of the website. Furthermore, in September 2006, 300 registered users who had accessed a registered users area aimed specifically at health professionals more than 20 times in the preceding 12 months received a ten-item multiple choice questionnaire via e-mail, to assess satisfaction with the accuracy and promptness of information provided, text comprehension and other information sources for drug-related issues. We hereby describe the results of the survey, after careful analysis of the questionnaires. RESULTS: Up until July 2007, the site had over 600 000 direct accesses and 9760 healthcare professionals registered to use the site. A total of 108 responses to the e-mailed questionnaire were received (response rate = 36%), of which 103 were analysed; five were excluded due to missing information. Overall, the majority of responders judged the information on the site as objective and understandable. More than 85% of participants declared that the site has influenced their opinion and attitudes toward the safety of medicines. In particular, responders said that they pay more attention to drug interactions and to the safety profile of newly marketed drugs, and spend more time on communicating the risks of drugs used by their patients. Specifically, responders stated that they pay more attention to drug interactions (87.7%), newly marketed drugs (68.5%), herbal remedies (56.2%), drugs in patients at increased risk (42.5%), drugs in pregnant women (42.5%) and cosmetics (13.7%). CONCLUSIONS: The website www.farmacovigilanza.org appears to be an effective tool that provides users of the site with independent, relevant and reliable safety information. It was found to influence (and possibly improve) the quality of prescribing of a large proportion of the general practitioners who responded to our questionnaire, and our results indicate a high appreciation of the information found on the website. Moreover, the survey disclosed that there is a substantial need for such information in the national language by healthcare professionals. We think that our approach can serve as a model for similar initiatives in countries elsewhere in the world.

Amoxicillin and amoxicillin plus clavulanate: a safety review.

Despite the considerable number of newer antibacterials made available over the past decades, amoxicillin, alone or in combination with clavulanic acid, still accounts among the most widely used antibacterial agents. Although they are often considered 'twin drugs', they are different both in terms of antibacterial activities and of safety profile. It is well documented that the clavulanate component may cause adverse reactions by itself, thus exposing patients to further, and sometimes undue, risks. Although amoxicillin/clavulanate should be considered as an alternative agent only for the treatment of resistant bacteria, evidence shows that it is often used also when a narrow-spectrum antibiotic would have been just as effective. This prescription habit may have serious consequences in terms of patients' safety, as well as in terms of the development of bacterial resistance.