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.

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.

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.

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.

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.

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.

Gynecomastia possibly induced by rosuvastatin.

Gynecomastia is characterized by benign progressive enlargement of the male breast. A pharmacologic origin is identified in 10-20% of cases. Several case reports have associated this condition to the use of statins. However, to our knowledge, no case of rosuvastatin-induced gynecomastia has been reported in the literature. We describe a 57-year-old man who developed bilateral gynecomastia after 2 months of rosuvastatin therapy. After switching to a different statin, atorvastatin, his symptoms resolved within 1 month. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship between the patient's development of gynecomastia and rosuvastatin therapy. The relatively strong effect of rosuvastatin on inhibiting steroidogenesis might have explained why our patient's gynecomastia occurred only with this agent. Clinicians should be aware of the possibility of adverse endocrine reactions when statins are prescribed, including newer agents such as rosuvastatin.

Rabeprazole and psychiatric symptoms.

OBJECTIVE: To report the case of a patient who developed marked anxiety associated with episodes of panic attacks after starting rabeprazole therapy. CASE SUMMARY: An otherwise healthy 55-year-old woman was prescribed rabeprazole 20 mg/day administered in the morning for persistent symptoms of dyspepsia. Ten days later, she presented with a 7 day history of marked anxiety associated with panic attacks, night terror (pavor nocturnus), episodic mental confusion, and attention deficit. Within 2 days of discontinuing rabeprazole, the patient recovered completely from the neuropsychiatric manifestations. Subsequent esomeprazole therapy did not cause psychiatric symptoms. DISCUSSION: Rabeprazole-induced hypergastrinemia may have played a role in this neuropsychiatric adverse reaction. Several lines of evidence have indicated that gastrin-releasing peptide, whose release is mediated by proton pump inhibitor (PPI)-induced secretion of gastrin, is involved in regulating aspects of behavior that might be altered in disorders such as anxiety, depression, and dementia. The fact that rabeprazole has the highest capacity of inducing gastrin increase compared with other PPIs might explain why our patient's panic symptoms disappeared after switching to esomeprazole. Based on the Naranjo probability scale, rabeprazole was the probable cause of the adverse reaction. CONCLUSIONS: Specific studies are needed to investigate the potential role of PPI-induced hypergastrinemia in neuropsychiatric adverse reactions.

Adverse reactions induced by NSAIDs and antibacterials: analysis of spontaneous reports from the Sicilian regional database.

OBJECTIVES: To (i) evaluate the suspected adverse drug reactions (ADRs) related to NSAIDs and antibacterials that were reported to Sicilian local health officers by healthcare professionals; and (ii) to detect new or serious potential signals of alarm related to these two widely used drug categories. METHODS: We selected all the spontaneous reports of ADRs sent between January 1998 and June 2004 and analysed those attributed to NSAIDs and systemic antibacterials, applying proportional reporting ratio (PRR) methodology. PRRs >2, chi(2) >4 and >3 ADRs were regarded as signals. RESULTS: During the period considered, 1585 reports of ADRs were received overall (42.6% serious), with an annual reporting rate of approximately 49.1 reports per million inhabitants on average; 351 referred to systemic antibacterials, and 179 to NSAIDs. There were 174 (49.6%) reports of serious ADRs associated with antimicrobials and 108 (60.3%) associated with NSAIDs. Disproportionality was observed, in particular for anaphylactic shock induced by ceftriaxone (all reports were associated with off-label use of the drug), photosensitivity reaction induced by lomefloxacin (administered in the summer), hepatitis induced by nimesulide (three cases leading to liver transplantation) and vasculitis induced by nimesulide. CONCLUSION: Our analysis highlighted several signals of alarm deserving further investigation or measures to influence prescribing. This study underlines the value of a regional centre in identifying local factors (such as prescribing patterns) that may increase the prevalence of serious ADRs.

Short-term memory loss associated with rosuvastatin.

Memory loss and cognitive impairment have been reported in the literature in association with several 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), but we found no published case reports associated with rosuvastatin. To our knowledge, this is the first reported case of rosuvastatin-related short-term memory loss. A 53-year-old Caucasian man with hypercholesterolemia experienced memory loss after being treated with rosuvastatin 10 mg/day. He had no other concomitant conditions or drug therapies. After discontinuation of rosuvastatin, the neuropsychiatric adverse reaction resolved gradually, suggesting a probable drug association. During the following year, the patient remained free from neuropsychiatric disturbances. Clinicians should be aware of possible adverse cognitive reactions during statin therapy, including rosuvastatin.

Venlafaxine-induced urinary incontinence resolved after switching to sertraline.

The authors report a case of urinary incontinence (UI) that occurred in a woman after administration of venlafaxine. UI resolved after discontinuation of the drug and did not reappear after switching to sertraline therapy. A 56-year-old white woman with a diagnosis of reactive depression developed severe UI after a 30 days' treatment with venlafaxine 75 mg/day. Symptoms resolved without consequence 48 hours after discontinuation of venlafaxine. The patient was then treated with sertraline without experiencing any incontinence episodes. Urinary incontinence is an important medical condition with clinical and social implications. Further studies need to be carried out to clarify the pharmacologic differences between dual and selective 5-HT and norepinephrine reuptake inhibitors on lower urinary tract function.

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.

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.