Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

Aim  

The aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence.     

Antibacterial macrolides: a drug class with a complex pharmacological profile.

Macrolides are widely used antibacterial agents. Although generally well tolerated, they have a number of important additional pharmacological effects, which can sometimes result in significant adverse reactions. This review focuses on three of these side effects: the prokinetic action associated with stimulation of motilin receptors, the proarrhythmic effect due to prolongation of the QT interval of the electrocardiogram and the potential for drug interactions due to inhibition of drug metabolising enzymes. For macrolides that have obtained marketing authorisation in Italy, United Kingdom or United States of America, we also considered whether these actions are properly reported in the approved summaries of the product characteristics and tried to provide strategies to identify patients at risk of significant side effects when macrolides are administered.     

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system

Aim

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).

Methods

We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.

Results

DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).

Conclusions

The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.     

Sensitivity of Ph1+ CFU-GM to human recombinant interferon α and γ alone and in combination

Summary The in vitro effect of human recombinant interferon (IFN) alone and in combination were studied on granulomonocytic colony forming units (CFU-GM) from the peripheral blood of 10 Ph1+ chronic myeloid leukemia (CML) patients and from the marrow of 5 normal or non-leukemic subjects. - and -IFN alone determined a slight inhibition on colony growth with a preferential effect on pure macrophagic colonies. At maximum concentration (10⁴ U/ml) leukemic colony inhibition was 46±34% for IFN and 43±19% for IFN. Culture growth with + IFN in combination were significantly inhibited (up to 96±4%) with a concentration-related effect. Similar results were obtained with normal CFU-GM. The synergism that was found in vitro is probably relevant for the in vivo therapeutic effects of these compounds in CML and suggest that the combination is worth testing in vivo.This work was supported by CNR, Oncology Finalized Project, contract n. 8701169.44. and n. 8600603.44. and by AIRC     

Autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma: comparison of different parameters in predicting the kinetics of haematological recovery

We analysed the kinetics of haematological recovery after autologous bone marrow transplantation (ABMT) in 31 patients with non-Hodgkin's lymphoma, of whom 14 had received chemotherapy and 17 had received no chemotherapy before marrow harvesting. The time for recovery of polymorph (PMN) and platelet numbers was assessed in relation to patient's sex, age, the numbers of mononuclear cells (MNC) and of granulocyte-macrophage colony-forming cells (CFU-GM) reinfused, the therapy before harvesting and the conditioning regimens. The results showed that the most important factor influencing the speed of haematological recovery was therapy before marrow collection; recovery was faster in patients not treated before harvesting than in those treated. The mean day for PMN recovery to 0.5 x 10(9)/l was 14.6 vs 21.8 (p less than 0.001); the mean day for platelet recovery to 50 x 10(9)/l was 16.5 vs 44.4 (p less than 0.00002). The other parameters assessed did not correlate with the kinetics of haemopoietic recovery. We conclude that NHL patients who undergo ABMT without chemotherapy prior to marrow harvest have rapid haematological recovery, which suggests that better timing of the harvest could be of value in the management of NHL patients for whom 'reinforcement' with ABMT is scheduled.     

Pattern of NSAID use in the Italian general population: a questionnaire-based survey

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medicines in the developed countries. The most important adverse reactions involve the upper gastrointestinal tract and can be life threatening. A detailed knowledge of the pattern of use of NSAIDs may help doctors in advising their patients about appropriateness and safety of use. Aim The aim of the present survey was to evaluate the prevalence and pattern of NSAID use in the general population, as well as the main characteristics of NSAID users. Methods Between March and September 2002, a self-administered questionnaire was submitted to a random sample, stratified by gender and age, representative of the Italian adult population (n=3,250). The questionnaire was divided into three parts regarding: (1) sociodemographic information, (2) symptoms/illnesses and (3) any drug taken during the previous week and the corresponding purpose. A statistical analysis (logistic regression) was performed. Results Of the 2,738 subjects who filled in the questionnaire, 65% took at least one drug in the previous week and, among them, 35% used NSAIDs (top drug class; n=633). Of the NSAID users, 20% were 65 years of age and 18% were chronic users (daily or frequent use for more than 6 months). NSAID use was significantly higher in women, both for overall and chronic use. The older age groups showed an increasing risk of chronic NSAID use. Among NSAIDs, nimesulide was the most used compound (35%) followed by acetylsalicylic acid (14%) and ibuprofen (11%). The main reasons for NSAID use, as reported by subjects, were: headache (25%), osteoarticular pain (19%), unspecified pain (15%) and osteoarthrosis (9%). More than 50% of all the NSAIDs were prescribed by physicians (general practitioner, specialist, hospital physician), whereas about 44% were taken as self-treatment or following the advice of a pharmacist, relative/friend, etc. Conclusions Our study confirms that NSAIDs are widely used in the Italian general population and that, in most cases, they are used in accordance with their approved indications. However, their large and often chronic use in the elderly, as well as the high frequency of self-treatment, recommends a higher awareness by all physicians.     

Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus

BACKGROUND: The growing list of non-antiarrhythmic drugs associated with QT prolongation and the relevant regulatory interventions have generated concern for two reasons. First, QT prolongation is sometimes viewed as an intrinsic effect of a whole therapeutic class (for example, antihistamines), whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. Second, drug-induced Torsades de Pointes are still considered idiosyncratic, totally unpredictable adverse drug reactions, whereas a number of risk factors for their occurrence is now recognised. OBJECTIVES: In order to increase awareness among prescribing physicians that many non-antiarrhythmic drugs can affect cardiac repolarisation, we would like to propose a comprehensive and updated list of QT-prolonging drugs that should be a starting point to maintain a "consensus list" to be periodically updated. METHODS: The drug list was generated by performing a Medline search, by using published lists as starting points to retrieve the relevant references quoted in each article and by considering the International Registry for Drug-induced Arrhythmias maintained by the Georgetown University and mainly based on the FDA approved labelling. RESULTS: The drug list presented in this paper: (1) includes virtually all non-antiarrhythmic drugs with QT-prolonging potential, (2) organises the available information on each drug at different levels of clinical relevance and (3) is as up-to-date as possible in order to provide a fast track for the clinical pharmacologist to retrieve the original publications. CONCLUSIONS: This list should be considered as a starting point to call for consensus on: (1) the criteria used to generate the list, (2) possible ways to implement the use of this list as a quick reference for clinicians, for instance by providing a "proarrhythmic score" for each drug, and (3) inclusion/exclusion of a given agent into the list on the basis of evidence that may not be available to us.     

Excipients in medicinal products used in gastroenterology as a possible cause of side effects

Although most adverse drug reactions are caused by the active substances, excipients may sometimes affect the safety profile of a medicinal product. The aim of this review is twofold: (1) To identify the excipients most frequently contained in oral medicinal products marketed in Italy for gastrointestinal indications, and to evaluate the main safety concerns, considering both intrinsic toxicity and patient-related risk factors. (2) To analyze possible differences with medicinal products marketed in the United Kingdom and USA in terms of excipients and relevant warnings reported in the label. We identified excipients with potential impact on safety profile and calculated frequency of use of each identified excipient in 98 selected medicinal products. We discussed possible safety concerns in clinical practice. We also analyzed US and UK Summary of Products Characteristics (SmPC) of oral gastrointestinal products by searching in appropriate collections of regulatory agencies. Eleven excipients with a safety impact were identified (sucrose, saccharin, aspartame, sorbitol, mannitol, lactose, ethanol, propylene glycol, parabens, menthol and silica) and no substantial differences were found between drugs marketed in the three countries concerning excipient content. Warnings were more detailed in the SmPC of UK or USA products rather than Italian products. Information about pharmaceutical excipients with known effects is important in clinical practice, but the frequent lack of details in the related section of the SmPCs makes it difficult for health professionals to provide relevant advice. The availability of alternative products of the same therapeutic class, but lacking specific excipient(s) should be considered in selected patients.     

Gastro-intestinal problems and concomitant medication in NSAID users: additional findings from a questionnaire-based survey in Italy

Background In a previous questionnaire-based survey, we found extensive use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects with risk factors for serious gastrointestinal complications. Aim This study focused on the use of NSAIDs in subjects who reported either (a) pre-existing disorders which would have required caution in using NSAIDs (e.g. dyspepsia/heartburn or peptic ulcer) or (b) co-medication with drugs having a high risk of interacting with NSAIDs. Methods Between March and September 2002, 65 general practitioners (GPs) submitted a validated self-administered questionnaire on health status and drug use to 3,250 subjects (age ≥18 years, stratified by sex and age). The questionnaire was divided into three parts: (1) sociodemographic information, (2) symptoms/illnesses (in the previous 6 months) and (3) drugs taken during the previous week. Results Of the 2,738 subjects who filled in the questionnaire (84% of responders), 633 (23%) used NSAIDs and, among them, 114 (18%) were chronic users. Among the subjects reporting dyspepsia/heartburn or ulcer (n=909 of 2,738), 24% were occasional NSAID users and 6% chronic users. Of the chronic NSAID users reporting gastrointestinal symptoms, 35% also used a drug for acid-related disorders, but only 14% used daily a proton pump inhibitor (PPI). One hundred six subjects used concomitantly more than one NSAID. Eighteen percent of the subjects using corticosteroids also reported NSAID use; similar proportions were seen in subjects using selective serotonin reuptake inhibitor (SSRI) antidepressants or calcium channel blockers, whereas 6% of the subjects with oral anticoagulants used NSAIDs. Conclusions Our study shows that NSAIDs are frequently used in patients with upper gastrointestinal complaints or in combination with potentially interacting medications. Adverse effects and untoward drug interactions should be monitored in patients treated with NSAIDs in order to minimise their occurrence.