Giampaolo Velo

Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three italian regions.

AbstractObjective: To analyse and compare with one another and with other antibacterial drugs the adverse drug reactions (ADRs) of the different fluoroquinolones currently used in Italy, spontaneously reported from doctors in three northern Italian regions. Methods: The data on fluoroquinolones and other antibacterials were obtained from the spontaneous reporting system database of Emilia Romagna, Lombardy and the Veneto, which are the principal contributors to the Italian spontaneous surveillance system. The fluoroquinolone ADRs with a causality assessment of certain, probable or possible (according to WHO criteria), reported between January 1999 and December 2001, were selected and toxicity profiles of individual drugs were described and compared with one another. The reports were also correlated with sex and age of patients and with regional prescription data to estimate individual fluoroquinolone reporting rate of adverse events. Results: During the study period, 10 011 reports were received by the system (a mean annual reporting rate of approximately 185 per million inhabitants): 1920 referred to systemic antimicrobials, of which 432 (22.5%) involved fluoroquinolones.Pefloxacin was associated with the highest reporting rate (982 reports/daily defined dose/1000 inhabitants/day), followed by moxifloxacin (356), rufloxacin (221) and lomefloxacin (196). The most frequently reported reactions to fluoroquinolones involved the skin, but their percentage (25%) was significantly lower (p < 0.01) than those of other systemic antimicrobials (58.5%), whereas the percentages of reactions involving the central nervous (12.2 vs 3.6%), musculoskeletal (14.7 vs 0.3%) and psychiatric systems (9.3 vs 1.8%) were significantly higher (p < 0.01). We found some significant differences in the safety profiles of individual fluoroquinolones: ciprofloxacin was more frequently associated with skin reactions (p < 0.01), levofloxacin and pefloxacin with musculoskeletal (p < 0.01), and rufloxacin with psychiatric disorders (p < 0.05). Levofloxacin was the fluoroquinolone associated with the highest rate of serious tendon disorders; phototoxic reactions were more frequent with lomefloxacin, and toxic epidermal necrolysis and Stevens-Johnson syndrome were seen only with ciprofloxacin. Conclusions: The differences in the safety profiles should be taken into account when prescribing a fluoroquinolone to individual patients.

Medication errors: prescribing faults and prescription errors

1. Medication errors are common in general practice and in hospitals. Both errors in the act of writing (prescription errors) and prescribing faults due to erroneous medical decisions can result in harm to patients. 2. Any step in the prescribing process can generate errors. Slips, lapses, or mistakes are sources of errors, as in unintended omissions in the transcription of drugs. Faults in dose selection, omitted transcription, and poor handwriting are common. 3. Inadequate knowledge or competence and incomplete information about clinical characteristics and previous treatment of individual patients can result in prescribing faults, including the use of potentially inappropriate medications. 4. An unsafe working environment, complex or undefined procedures, and inadequate communication among health-care personnel, particularly between doctors and nurses, have been identified as important underlying factors that contribute to prescription errors and prescribing faults. 5. Active interventions aimed at reducing prescription errors and prescribing faults are strongly recommended. These should be focused on the education and training of prescribers and the use of on-line aids. The complexity of the prescribing procedure should be reduced by introducing automated systems or uniform prescribing charts, in order to avoid transcription and omission errors. Feedback control systems and immediate review of prescriptions, which can be performed with the assistance of a hospital pharmacist, are also helpful. Audits should be performed periodically.

Copper and zinc body levels in inflammation: An overview of the data obtained from animal and human studies

The development of acute and chronic inflammatory processes induces, in the laboratory animal, a net accumulation of both copper and zinc in many body compartments, the inflammed area included. In rheumatoid arthritis, as well as in animal models, only plasma zinc concentration seems to be significantly correlated with disease severity, while the increase in total plasma copper could be described as an “all or nothing” phenomenon. Moreover, in rheumatoid arthritis, it appears that the disease develops and progresses without being linked to either copper or zinc deficiency conditions.Thus, it seems reasonable to suggest that a rationale for the use of copper and/or zinc in the treatment of inflammatory disorders can only be drawn from the intrinsic pharmacological properties of such trace elements, rather than from the need for their repletion.

Review: Copper and inflammation — a possible rationale for the pharmalogical manipulation of inflammatory discorders

Acute and chronic inflammations are characterized, among other features, by changes in the metabolism of copper and by a widespread responsiveness to the therapy with copper-containing molecules.The exact map of inflammation-induced copper movements as well as the role played by the metal in the pathogenesis of inflammatory disorders are, however, far from being clear, and this is especially true in the case of chronic processes.Nevertheless the present knowledge suggests that the ‘copper approach’ may provide a new way for coping with the problem of anti-inflammatory/anti-arthritic therapies. The administration of exogenous copper, and thein vivo manipulation of the endogenous metal levels are proposed as two possible therapeutic strategies, not necessarily mutually exclusive.For a better understanding of the value of such an approach, further research work is needed, especially to attain a more detailed know-how on the involved chemical forms, distribution and functions of copper in both normal as well as inflamed organisms.

Drug-induced anaphylaxis : case/non-case study based on an italian pharmacovigilance database.

AbstractObjective: To identify the number of cases of anaphylaxis reported in association with different classes of drugs and compare it with other reports contained in the same database. Methods: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of ‘anaphylactic shock’ or ‘anaphylactoid reaction’ (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. Results: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines had a significantly lower ROR, thus indicating that anaphylaxis is reported proportionally less than other ADRs. Conclusions: Anaphylaxis is a severe ADR that may also occur with commonly used drugs. It represents 2.7% of all of the ADRs reported in an Italian spontaneous reporting database.

Medication errors: problems and recommendations from a consensus meeting.

Here we discuss 15 recommendations for reducing the risks of medication errors: 1. Provision of sufficient undergraduate learning opportunities to make medical students safe prescribers. 2. Provision of opportunities for students to practise skills that help to reduce errors. 3. Education of students about common types of medication errors and how to avoid them. 4. Education of prescribers in taking accurate drug histories. 5. Assessment in medical schools of prescribing knowledge and skills and demonstration that newly qualified doctors are safe prescribers. 6. European harmonization of prescribing and safety recommendations and regulatory measures, with regular feedback about rational drug use. 7. Comprehensive assessment of elderly patients for declining function. 8. Exploration of low-dose regimens for elderly patients and preparation of special formulations as required. 9. Training for all health-care professionals in drug use, adverse effects, and medication errors in elderly people. 10. More involvement of pharmacists in clinical practice. 11. Introduction of integrated prescription forms and national implementation in individual countries. 12. Development of better monitoring systems for detecting medication errors, based on classification and analysis of spontaneous reports of previous reactions, and for investigating the possible role of medication errors when patients die. 13. Use of IT systems, when available, to provide methods of avoiding medication errors; standardization, proper evaluation, and certification of clinical information systems. 14. Nonjudgmental communication with patients about their concerns and elicitation of symptoms that they perceive to be adverse drug reactions. 15. Avoidance of defensive reactions if patients mention symptoms resulting from medication errors.

Copper metabolism during acute inflammation: studies on liver and serum copper concentrations in normal and inflamed rats

1 The concentration of copper in serum and liver was determined by atomic absorption spectrophotometry in a study performed on normal rats of either sex and in female rats with carrageenan‐induced pleurisy. 2 In the normal animal, total serum copper concentration is significantly higher in female rats, and appears to be higher in mature animals in females. 3 In normal rats of either sex, liver copper concentration undergoes daily variations which are inversely related to the weight of the organ and which leave constant the total amount of metal in the liver. Moreover a day to day non‐cyclic variability of liver copper concentration and liver weight was observed. 4 This first set of data showed that comparison with time control was essential. 5 In the inflamed rat, a significant rise of total serum copper at 22, 48 and 72 h after the induction of inflammation was observed. From 96 h up to 240 h post‐injection no significant differences were evident. 6 Total liver copper content did not change in the inflamed rats. 7 During acute inflammation in the rat, the copper needed for the increased synthesis of caeruloplasmin is supplied without depletion of liver copper stores.

Adverse drug reactions related to the use of NSAIDs with a focus on nimesulide: results of spontaneous reporting from a Northern Italian area.

AbstractObjective: To analyse and compare the adverse drug reactions (ADRs) associated with the use of nimesulide with those associated with diclofenac, ketoprofen, and piroxicam, reported spontaneously in a northern Italian area (Veneto and Trentino). Methods: Data were obtained from the spontaneous reporting system database of Veneto-Trentino, the principal contributor to the Italian spontaneous surveillance system. All case reports that occurred in association with all formulations of the nonsteroidal anti-inflammatory drugs (NSAIDs) under investigation during the period from January 1988 to December 2000, were analysed in detail.Sales data from June 1996 to May 1999 and prescription data, from 1997 to 2000 from the Veneto region were utilised to select the most widely used NSAIDs to be included in the study. The prescription data were also used to look at the drug use in relation to age. Results: During the study period, 10 608 reports describing 16 571 adverse reactions were entered into the surveillance system. We found 207 case reports for nimesulide, 187 for diclofenac, 174 for ketoprofen, and 137 for piroxicam. Analysis of sales and prescription data revealed that in the Veneto region nimesulide was the most widely prescribed drug followed at a long distance by diclofenac, piroxicam and ketoprofen.No age-related difference in the use of the four drugs was found. Analysis of the case reports revealed significantly different toxicity profiles for the four drugs. In particular, nimesulide was associated with fewer and less severe gastrointestinal (GI) ADRs compared with the other NSAIDs. Nimesulide was associated with about half the number of GI reactions (10.4%) than the other three NSAIDs (21.2% for diclofenac, 21.7% for ketoprofen, 18.6% for piroxicam). Two previously unreported reactions were also found for piroxicam and ketoprofen. Conclusions: Nimesulide is the most frequently used NSAID in Italy. Spontaneous reporting data suggest that nimesulide has the most favourable GI tolerability profile of the NSAIDs investigated, with few reports of severe GI reactions. A few reports of hepatic and renal impairment associated with nimesulide suggest caution in patients at risk. Age-related reporting analysis suggests a higher toxicity for diclofenac and piroxicam in the elderly compared with nimesulide and ketoprofen.This analysis of the Veneto-Trentino database on spontaneous reporting confirms that NSAIDs differ in their tolerability profile, and this fact should be taken into account in the choice of drugs in relation to patient characteristics.

Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy.

AbstractBackground: The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level. Objective: The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors (‘statins’) and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors (‘coxibs’) and increase in cardiovascular risk. Methods: The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day. Results: ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000–4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically. Conclusion: Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor’s and patient’s awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs.

Copper and zinc status in rats with acute inflammation: focus on the inflamed area.

Status of copper and zinc in plasma, blood cells, liver and hind paws (sectioned at the tibio-tarsal joint) were evaluated in rats with carrageenan-induced paw-oedema; moreover, concentrations of copper and zinc in the supernatant and cell fractions obtained from exudates pooled from rats with carrageenan-induced pleurisy were also determined.The evaluation of copper and zinc status in the blood and in the liver of rats with carrageenan-induced paw oedema, showed that only minor variations differentiated this experimental pathology from the previously studied carrageenan-induced pleurisy in rat.In inflammatory exudates withdrawn from pleural cavity, copper concentrations were found to be higher than the basal values measured in the whole paw, whereas zinc concentrations were found to be dramatically lower.Thus the induction of the carrageenan paw-oedema determined an increase in copper and a decrease in zinc concentrations in the inflamed paw; however, in the inflamed paw, the total amounts of both copper and zinc were found to be significantly increased.