The hospitalised patients in a cardiological hospital (Lille, France) over an 18-month period were subjected to a prospective high-intensity adverse drug reaction (ADR) monitoring in order to assess the additional financial resource utilisation associated with ADRs and analyse the distribution of excess of cost according to ADR nature and therapeutic classes. Over 18 months, among the 16,916 hospitalised patients, 371 verified ADRs detected by self-report stimulated by a special unit of nurses and pharmacologists occurred in 336 patients with an overall ADR rate of 2.2%. This rate increased with age. The most common reactions were cutaneous events (24%), cardiovascular events (21%), metabolic disorders (12%), coagulation disorders (10%) and nervous system impairment (10%). The most common drug classes involved were cardiovascular agents (36%), contrast media (20%), drugs affecting blood clotting (13%) and anti-infectives (14%). Increased ADR-induced costs result especially from prolongation of length of stay and cost increase was evaluated at Euro 4150 per ADR. Among the 371 ADRs, 134 ADRs, which were significantly more severe, induced a prolongation of length of stay. Renal insufficiency and cardiovascular events were significantly over-represented in this sub-group. The most common ADR-inducing drugs associated with a prolongation of length of stay are cardiovascular agents and drugs affecting blood clotting. In contrast, cutaneous ADRs were significantly over-represented in the group of ADRs without prolongation of length of stay. The severity and substantial costs of ADRs in hospital justify investments to prevent these events. Nevertheless, only a portion of ADRs induces cost increases, suggesting that prevention efforts should focus on this limited category of ADRs.

Background and purpose: Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t-PA) during the acute phase of cerebral ischaemia. Experimental approach: The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t-PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg·kg ) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion. Key results: Depletion of circulating neutrophils significantly reduced t-PA-induced ICH (vinblastine, 4.6 Ϯ 1.0; mAbRP3, 5.2 Ϯ 1.0 vs. saline, 10.8 Ϯ 2.7 haemorrhages; P < 0.05). This depletion was associated with a decrease in cerebral infiltration by neutrophils and a decrease of endothelium-dependent, vascular dysfunction in isolated MCA, induced by the ischaemia/ reperfusion and t-PA treatment. Brain infarct volume was significantly decreased after vinblastine treatment (159 Ϯ 13 mm 3 vs. 243 Ϯ 16 mm 3 with saline; P < 0.01) but not after depletion with mAbRP3 (221 Ϯ 22 mm 3 ). Conclusions and implications:Our results showed that pharmacological depletion of PMNs prevented t-PA-induced ICH, in parallel with a decrease in cerebral infiltration by PMNs and a decreased endothelial dysfunction in cerebral blood vessels.

Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N-DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.

Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1-100 microM) do not alter the action potential parameters even at a concentration as high as 100 microM. The stimulation rate is without effect on repolarization. On the contrary, sparfloxacin (1-100 microM) lengthens concentration-dependently the duration of action potential, this effect being significant from the concentration of 10 microM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 microM. Under low stimulation rate, the sparfloxacin-induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 microM and in four other fibers at the concentration of 100 microM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.

Background and Purpose-In a model of mechanical focal ischemia, we investigated the involvement of thrombolysis products (TLP) in recombinant tissue plasminogen activator (rtPA)-induced intracerebral complications and the effects on infarct volume and postischemic endothelial function. Methods-Hemorrhage incidence and severity were evaluated by histomorphometric analysis in male spontaneously hypertensive rats (SHR) subjected to 60-minute intraluminal middle cerebral artery (MCA) occlusion and receiving intravenously 5 hours later either saline, rtPA (3, 10, or 30 mg/kg), or rtPA (10 mg/kg) associated with TLP (rtPAϩTLP). In addition, MCA reactivity was assessed in rtPA-or rtPAϩTLP-treated SHR versus control Wistar-Kyoto rats or SHR. Results-No hemorrhage was observed visually in SHR receiving saline. In contrast, rtPA administration induced hemorrhagic complications in infarcted areas in a dose-independent manner. Administration of rtPAϩTLP solution, containing a high concentration of plasmin, did not affect hemorrhage incidence but significantly increased hemorrhage severity (8.8Ϯ2.3 petechiae versus 3.0Ϯ1.0 petechiae in rtPA group; PϽ0.001). This increased severity was associated with a significant increase of both infarct volume (182Ϯ10 versus 144Ϯ15 mm 3 in rtPA group; PϽ0.01) and postischemic impairment of MCA endothelium-dependent relaxation (9Ϯ0.5% versus 13Ϯ1% in rtPA group; PϽ0.05). Key Words: hemorrhage Ⅲ ischemia, focal Ⅲ plasmin Ⅲ thrombolysis Ⅲ tissue plasminogen activator T hrombolytic therapy with recombinant tissue plasminogen activator (rtPA) has demonstrated improvement in clinical outcome in acute ischemic stroke. 1,2 However, the threat of intracerebral hemorrhage (ICH) is an important barrier to widespread administration of thrombolytic agents. While many factors, such as elevated blood pressure, diabetes, age, and rtPA administration time, contribute to the occurrence of ICH, the underlying mechanisms remain elusive. [3][4][5] ICH are preferentially located in the infarct area, suggesting a role of ischemia per se. 6,7 In response to ischemic and inflammatory stimuli, vascular modifications may also be involved in ICH pathophysiology. 8 In particular, endothelium-dependent relaxation, a marker of ischemia-induced impairment of cerebral vasculature, 9,10 is worsened in vitro by the application of rtPA. 11 It remains unknown whether rtPA directly induces ICH or if the interaction between rtPA and thrombus, via the resulting thrombolysis products (TLP), is involved. Existence of rtPA-induced ICH in thromboembolic models has been well established, 7,12-15 whereas it remains more uncertain in mechanical models of ischemia. 6,16 The difference between the 2 models suggests that thrombus may contribute to the occurrence of ICH. To test this hypothesis, we compared the effects of rtPA or rtPA-induced TLP in a model of mechanical middle cerebral artery (MCA) occlusion on ICH incidence and severity. We also studied infarct volume and MCA endothelial function to investigate the mechanism of ICH occur...