Use and safety profile of antiepileptic drugs in Italy.

OBJECTIVE: To analyse and discuss the use and the safety profile of individual antiepileptic drugs (AEDs) in Italy. METHODS: The AED safety data referred to the period January 1988-June 2005 and were obtained from the database of the Italian Interregional Group of Pharmacovigilance (GIF). This database collects all spontaneous reports of suspected adverse drug reactions (ADRs) from six Italian regions which are the main contributors to the Italian spontaneous reporting system. Individual AED consumption data (defined daily dose/1,000 inhabitants per day) in the GIF area and in the whole of Italy referred to the period January 2003-June 2005 and were derived from drug sales data (Institute for Medical Statistics Health). RESULTS: Phenobarbital was the most frequently used AED in the GIF area (4.26 DDD/1,000 inhabitants per day) followed by carbamazepine (1.97), valproic acid (1.33) and gabapentin (1.10). AED consumption in the whole of Italy showed a similar pattern. Gabapentin was the most frequently used AED among newer AEDs. In the GIF database 37,906 reports (up to June 2005) were present; 666 of them (1.76%) were associated with at least one AED (Anatomical Therapeutic Chemical code N03A). The AED with the highest number of reports was carbamazepine (208 reports) followed by phenobarbital (98), gabapentin (80), phenytoin (56), valproic acid (55), lamotrigine (51), oxcarbazepine (43) and vigabatrin (35). Use and toxicity profile were evaluated only for AEDs associated with at least 30 reports. Skin reactions were the most frequently reported ADRs, followed by haematological, general condition, hepatic, neurological and gastrointestinal adverse reactions. Phenobarbital, lamotrigine, carbamazepine and phenytoin had the highest percentage of skin reactions (69, 67, 60 and 54%, respectively). Many haematological reactions were reported for each AED; the highest percentage was related to valproic acid (25%). Vigabatrin was associated with the highest percentage of reactions related to hearing, vision and other senses (97%). Phenytoin and valproic acid had the highest percentage of hepatic reactions (30 and 20%), whereas gabapentin of nervous system, psychiatric, gastrointestinal and urinary reactions (26, 21, 21 and 14%, respectively) and phenobarbital of musculoskeletal reactions (13%). CONCLUSIONS: In Italy antiepileptic drug therapy appears to be still dominated by traditional drugs. Our analysis showed a different safety profile related to each AED. Some of the drug-adverse reaction associations discussed are not included in the Italian drug leaflets or have not been reported before in the literature.

Channelling of COX-2 inhibitors to patients at higher gastrointestinal risk but not at lower cardiovascular risk: the Cox2 inhibitors and tNSAIDs description of users (CADEUS) study.

PURPOSE: To describe the characteristics of users of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective non-steroidal anti-inflammatory drugs (tNSAIDs) in France. METHODS: Between 1 August 2003 and 31 July 2004, patients who received at least one dispensing of celecoxib, rofecoxib or tNSAIDs were randomly sampled with a 1:1:2 target ratio within the French National Healthcare Insurance database. Patients and prescribers were asked to fill a questionnaire on socio-demographic characteristics, NSAID indication and use and previous medical history. For each respondent, healthcare resources used in the 6 months before inclusion were extracted from the database. Multivariate logistic regression was used to study the determinants of a first COX-2 inhibitor dispensing. RESULTS: Of the 45 217 patients included, 13 065 COX-2 inhibitors and 13 553 tNSAID users had prescriber data. Ninety seven per cent of COX-2 inhibitor prescriptions were for 'rheumatological' indications, whereas 37% of tNSAIDs use was for benign diseases (n = 2643) or analgesia (n = 2318). Among patients with rheumatological indications (n = 4730) and a first COX-2 inhibitor (n = 2427) or tNSAID (n = 2303) dispensing, multivariate analysis of factors associated with COX-2 inhibitors dispensing showed that, compared to new tNSAID users, new COX-2 inhibitor users were older, more often female, on sick leave or unemployed. COX-2 use was also associated with previous gastrointestinal history and previous gastroprotective agent dispensing, but not with previous cardiovascular (CV) history. CONCLUSION: The choice of NSAID depended largely on indication and on previous gastrointestinal history, in line with the recommendations of the French health authorities. Possible knowledge of CV risk associated with COX-2 inhibitors did not influence prescribing.

Nimesulide and renal impairment.

OBJECTIVES: To analyse from spontaneous reporting data the renal adverse reactions associated with the use of nimesulide. METHODS: Case reports were obtained from a Northern Italian Regional database (Veneto Pharmacovigilance System), containing all the spontaneous reports filed between 1988 and 1997. The Veneto Region is the principal contributor to the Italian spontaneous reporting system, with an annual report rate of approximately 17 per 100,000 inhabitants. The clinical records of hospitalized patients were also analysed. RESULTS: Of the 120 reports associated with oral nimesulide, 11 referred to suspected renal adverse reactions. The drug was taken by ten patients for a short period. All the patients discontinued the therapy and hospitalization was required in six cases. Other risk factors were identified in six cases. DISCUSSION: Together with the new insights into the possible consequences of renal cyclooxygenase-2 (COX-2) inhibition, the reported cases should draw the attention of doctors and patients to the importance of recognizing any possible signs of renal impairment during nimesulide therapy, although only extensive epidemiological data can define the real impact of its renal toxicity.

A copper-complex reduced gastric damage caused by acetylsalicylic acid and ethanol.

We investigated the effect of oral administration of CuNSN, a bis(2-benzimidazolyl) thioether (see structure 1) on gastric lesions induced in rats by acetylsalicylic acid (ASA) or ethanol. The involvement of endogenous eicosanoids and nitric oxide in protection by CuNSN was evaluated with indomethacin and NG-nitro-L-arginine (L-NNA), inhibitors of prostaglandin and NO synthesis respectively. L-arginine and its enantiomer D-arginine were also used. Pretreatment with graded doses of CuNSN inhibited ASA- and ethanol-induced mucosal injury. CuNSN increased PGE2 output in rat ex vivo gastric mucosal pieces after administration of 100 mg/kg of ASA. Pretreatment with indomethacin only partially counteracted the protective activity of CuNSN against ethanol-induced damage. L-NNA did not attenuate the protection by CuNSN, which was reduced but not prevented by indomethacin, suggesting that prostanoids contribute to the CuNSN protective effect, together with some mechanism(s) other than NO synthesis.

Effects of copper and zinc on proteoglycan metabolism in articular cartilage.

Co-Cultures of porcine articular cartilage and synovium or synovial conditioned medium were used as an in vitro model to mimic inflammatory events at the cartilage/synovial junction in degenerative joint disease. This model provides a useful tool to assess the anti-inflammatory and antiarthritic properties of pharmacological agents. In this study the effects of copper and zinc on (i) PG synthesis by cartilage and (ii) synovial-induced PG depletion have been investigated. Copper sulphate at a concentration of 0.01 mM did not stimulate PG synthesis significantly in cultured cartilage explants but completely abrogated the inhibitory effects of synovial tissue in co-culture experiments. This finding was supported by the histological demonstration of copper-dependent reversal of the PG depletion in cartilage exposed to synovial conditioned medium. Zinc sulphate at 0.01 mM had no effect on PG synthesis and was unable to protect cartilage against synovialinduced PG depletion. These results reveal possible mechanisms by which copper exerts its anti-inflammatory and anti-arthritic actions.

Gastric eicosanoid synthesis in normal subjects and alcoholics after ethanol stimulation.

This work studied the effect of different ethanol concentrations on the eicosanoid accumulation in human gastric incubates of healthy volunteers and chronic alcoholics, determining the in vitro eicosanoid release both in the basal condition and after different ethanol concentrations. The basal release of PGE2 and LTC4 in alcoholics is higher than in healthy volunteers. Various alcohol concentrations cause an increase in LTC4 and PGE2 in healthy volunteers; we observed no LTC4 increase in alcoholics and although PGE2 levels increased after 20% ethanol, they remained constant at higher ethanol concentrations.

Eicosanoid and gastroprotection by copper derivatives and NDGA.

We investigated the effect of oral administration of graded doses of: nordihydroguaiaretic acid (NDGA), CuNSN, a bis(2-benzimidazolyl)thioether and CuCl2 on ethanol-induced gastric damage in the rat and the role of leukotrienes and prostaglandins in attenuating this damage. In the experiments we determined ex-vivo eicosanoid release in the rat gastric mucosa pretreated with the above-mentioned compounds. The results indicate that the gastric lesion is accompanied by an increase in mucosa-synthesize LTC4, while PGE2 formation remains unchanged. Pretreatment with NDGA, CuNSN and CuCl2, protects the gastric mucosa from damages and reduces the increase in LTC4 mucosal formation. CuNSN and CuCl2 increase the PGE2 release, while NDGA has no effect on this pathway. These results suggest that one of the possible mechanisms of the NDGA protective effect is related to the inhibition of LTC4 formation, while the PGE2 increase in synthesis together with the leukotriene inhibition could contribute to the protective effect of CuNSN and CuCl2.

Antimicrobial drug utilisation in hospitals in Italy and other European countries.

Antibiotic prescribing patterns in hospitals are analysed in this review of three drug utilisation studies conducted in six European countries, with special emphasis to the third-generation cephalosporins. A great variability in the use of antimicrobial drugs is evident, both between countries and between hospitals in the same country. This variability is found also between patients with the same infectious disease. The possible reasons for these differences are discussed and a strategy to modify the hospital drugs prescribing is suggested.

Synthesis of prostaglandin E2 in rat liver.

We have investigated whether rat liver microsomes can release prostaglandins and determined the 'optimal conditions' for the in vitro synthesis of PGE2. We also studied the effect of the oral administration of indomethacin, piroxicam and ibuprofen on PGE2 release ex vivo. The drugs were administered to animals at high doses for one or three consecutive days and the animals were killed 24 h after the first or the third administration. The increased PGE2 synthesis observed for indomethacin and piroxicam (animals treated for three consecutive days) could be explained by the depression of cytochrome P-450 observed in the same animals. Cytochrome P-450 could modulate the activity of eicosanoids derived from cyclooxygenase. Moreover the different inhibition of PG synthesis exhibited by these drugs could lead to a different rise in concentration of arachidonic acid in microsome membranes and contribute to an increased PGE2 synthesis.

Blood copper and zinc changes in runners after a marathon.

This study reports plasma and total blood cell (TBC) Cu and Zn levels of 16 runners before and after a marathon race. All the pre-race plasma values were in the normal range, while the TBC Cu level was 29.3% (P < 0.01) lower and the TBC Zn level was 29.5% (P < 0.01) higher than mean values of the control group. The run induced a significant decrease in TBC Cu concentration during the days following the race and a light increase in plasma Cu values. It caused a significant increase in TBC Zn concentration at the end of the race (followed by a decrease 24 hours later) without plasma Zn variations. These data show that intense physical exercise could modify trace-element metabolism.

Copper and zinc status in rheumatoid arthritis: studies of plasma, erythrocytes, and urine, and their relationship to disease activity markers and pharmacological treatment.

We studied the status of copper and zinc in rheumatoid arthritis (RA). The aims of the work were to ascertain whether or not RA is associated with copper and/or zinc deficiency, to establish the relationship between these trace metals and the main biohumoral and clinical indices of the disease, and to examine the effect on copper and zinc of the drugs normally used by RA patients. Metal levels were measured by atomic absorption spectroscopy in the plasma, whole blood cells and 24 hr urine of 120 RA patients; 70 patients suffering from primary osteoarthritis were used as the control group. In the plasma of RA patients copper and ceruloplasmin levels were found to be significantly increased whereas zinc levels were significantly decreased. No major variations were observed in the blood cell and 24 hr urine copper and zinc levels. Plasma copper was significantly correlated with some of the biohumoral markers of RA, but did not correlate with any of the clinical indices of the disease. Plasma zinc was significantly correlated with numerous of the biohumoral as well as clinical markers of RA. With the exception of an increased urinary excretion of copper in D-penicillamine treated RA patients, drug therapy did not influence the copper status in RA. Conversely, plasma zinc was found to be lower in RA patients taking NSAIDs and/or steroids. These results suggest the following conclusions: i) RA patients do not seem to be deficient in either copper or zinc; ii) plasma copper appears to be a poor index of RA severity; iii) plasma zinc could have some practical value in defining the overall severity of the disease.

Anti-ulcer activity of carbenoxolone and ISF 3401 on PGE2 release in rat gastric mucosa.

We have investigated the ability of carbenoxolone and ISF 3041, a new carbenoxolone derivative, to protect the rat gastric and intestinal mucosa against lesions induced by acetylsalicyclic acid (ASA) and indomethacin. Moreover, we determined the capacity of the rat gastric mucosa to release PGE2 both in vitro and ex vivo, in the presence or absence of carbenoxolone or its analogs. These compounds are effective against lesions induced by ASA and intestinal damage induced by indomethacin. The amount of PGE2 obtained from incubated rat gastric mucosal pieces by in vitro and ex vivo indicate that carbenoxolone and ISF 3401 cause a concentration related increase of PGE2 with exception of the highest concentration. Increased prostaglandin content of gastric mucosa can partly explain the gastric and intestinal protection of these compounds and additional mechanisms could be involved in this action.

Oral zinc as initial therapy in Wilson's disease: two years of continuous treatment in a 10-year-old child.

Two years of continuous therapy promoted a significant overall amelioration in a 10-year-old boy affected by an hepatic form of Wilson's disease in which zinc sulphate was the sole therapy. In particular, liver function returned to normal and hepatic histology also improved. The parameters characterizing copper metabolism were kept under good control, and a decrease in copper concentration was found in both erythrocytes and liver. The copper balance study performed during the 25th month of treatment showed that oral zinc was still efficiently inhibiting the intestinal absorption of copper. No side effects have been reported so far.

Copper supplementation in the rat: preliminary observations on the clinical, hematological and histopathological profile.

Complete toxicological examinations in female rats fed an "anti-inflammatory" 200 ppm copper-containing diet for 30 and 58 days were performed. Copper was found to accumulate in liver, kidneys and paws; however, at the hematological, clinical chemical and histopathological levels, this treatment did not seem able to induce any toxic accumulation phenomenon in the examined rats.

Anti-inflammatory activity of monomethoxypolyethylene glycol superoxide dismutase on adjuvant arthritis in rats.

In previous studies we observed an enhanced anti-inflammatory activity of MPEG-SOD derivatives in acute inflammation in rat. To assess the activity in chronic inflammation we tested the compound with longer half-life (MPEG-SOD 18) in complete adjuvant arthritis in rat. According to the prophylactic schedule of treatment (i.m. administration at alternative days of 10 mg/kg from day 3 to day 21), the MPEG-SOD derivative reduced arthritic lesions in a significant way (P less than 0.01 at 14th, 21st, 28th day). Indomethacin, administered i.m. daily at the dose of 1.5 mg/kg according to the same schedule, significantly inhibited adjuvant arthritis each time it was considered (% of inhibition are 66.5% at 14th day, 58.3% at 21st day and 50.8% at 28th day). Native SOD and inactivated enzyme, administered from day 3 to day 21 did not show any anti-inflammatory properties. According to the therapeutic schedule of treatment (from day 14 to day 28), neither MPEG-SOD nor native SOD showed antiarthritic activity.

Indomethacin induced hepatic alterations in mono-oxygenase system and faecal Clostridium perfringens enterotoxin in the rat.

The administration of indomethacin to rats, at the dose of 10 mg/kg once daily for three days, caused a loss of microsomal cytochrome P-450 and cytochrome b5 in the liver, and a fall in drug-metabolizing enzyme activities (i.e. aminopyrine N-demethylase, NADP cyt. c. reductase). Indomethacin also induced intestinal lesions and a significant increase in Clostridium perfringens enterotoxin levels in the feces at 24 hours after both the second and third day of treatment. The above findings suggest that the development of intestinal lesion and the accompanying release of Clostridium perfringens enterotoxin, as well as hepatic enzyme alterations in the rat, result from indomethacin administration. Some of the data in this paper were presented at the Meeting of British Pharmacological Society in Ireland, July 6th-8th, 1988.

Nongastrointestinal adverse reactions to NSAID.

The use of nonsteroidal antiinflammatory drugs (NSAID) has been associated with numerous adverse reactions other than gastrointestinal (GI) damage, the most widely recognized and extensively studied of the deleterious effects of these agents. Those of particular importance include inhibition of blood clotting, impairment of renal and hepatic function, dermatologic and respiratory intolerance reactions, such hematologic disorders as agranulocytosis and aplastic anemia, and untoward effects on pregnancy; in addition, the use of aspirin or salicylates in children has been associated with the occurrence of Reye's syndrome. NSAID inhibition of prostaglandin biosynthesis, the mechanism responsible for GI adverse reactions, is known or suspected to play a role in many of the non-GI adverse reactions. However, the precise mechanisms underlying most of these effects have not been fully elucidated.