Luciano Caprino

Cisplatin triggers platelet activation.

Clinical observations suggest that anticancer drugs could contribute to the thrombotic complications of malignancy in treated patients. Thrombotic microangiopathy, myocardial infarction, and cerebrovascular thrombotic events have been reported for cisplatin, a drug widely used in the treatment of many solid tumours. The aim of this study is to explore in vitro cisplatin effect on human platelet reactivity in order to define the potentially active role of platelets in the pathogenesis of cisplatin-induced thrombotic complications. Our results demonstrate that cisplatin increases human platelet reactivity (onset of platelet aggregation wave and thromboxane production) to non-aggregating concentrations of the agonists involving arachidonic acid metabolism. Direct or indirect activation of platelet phospholipase A(2) appears to be implicated. This finding contributes to a better understanding of the pathogenesis of thrombotic complications occurring during cisplatin-based chemotherapy.

Cocaine toxic effect on endothelium-dependent vasorelaxation : An in vitro study on rabbit aorta

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

Cost-Analysis of Relapsing-Remitting Multiple Sclerosis in Italy after the Introduction of New Disease-Modifying Agents

Background and objectiveDuring the last decade, several agents have proven to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS), for example interferon-β (IFNβ) and glatiramer acetate. This study aimed to perform a cost-analysis of the treatment of patients with RRMS in Italy after the introduction of these new agents.Study designThis was a retrospective observational study with systematic patient inclusion.Methods and resultsData gathered from 630 patients with confirmed RRMS over a 2-year period were evaluated. Overall, the direct cost over 2 years reached €11 073 100 thousand, corresponding to a per-patient cost of €17 576 (year of costing, 2001). The cost of disease-modifying agents represented approximately 77% of the total expenditure. IFNβ accounted for 94% of the expense of disease-modifying agents, corresponding to a 2-year cost per patient of €20 223. Although glatiramer acetate and immunoglobulins were also associated with a high level of expense, these were prescribed in only 3.8% and 1.1% of patients, respectively. Using regression analyses, IFNβ therapy, disability, number of days spent in hospital per year and the frequency of magnetic resonance imaging procedures were the main predictors of total costs.ConclusionBased on the results of this study, IFNβ treatment considerably modified the management of RRMS and was associated with a rise in cost of treatment per patient.

Dermatan Sulfate versus Unfractionated Heparin for the Prevention of Venous Thromboembolism in Patients Undergoing Surgery for Cancer: A Cost-Effectiveness Analysis

AbstractBackground: In a recent clinical trial, dermatan sulfate was found to be more effective than unfractionated heparin (UFH), but equally well tolerated, for the prevention of deep vein thrombosis (DVT) after major surgery for cancer. Objective: To perform a cost-effectiveness analysis of dermatan sulfate versus UFH in this clinical setting. Design and setting: This was a retrospective economic analysis using data from a randomised clinical trial, and was performed from the hospital perspective. Methods: Clinical event rates were extrapolated from the observed venographic DVT rates, using appropriate assumptions from the scientific literature. The economic effects of switching DVT prophylaxis from UFH to dermatan sulfate and the potential lives saved were assessed by a predictive decision model. Results: The per patient cost, including the burden of residual thromboembolic events and major bleeding complications, was estimated to be 154 euros (EUR) for dermatan sulfate and EUR185 for UFH (1998 values). With reference to a potential target population of 60 000 patients/year undergoing surgery for cancer in Italy, the total prophylaxis-associated cost was EUR9 258 000 for dermatan sulfate and EUR11 096 000 for UFH, whereas the potential deaths from prophylaxis failure were 204 and 392, respectively. This represented a saving of EUR1 838 000 and 188 potential lives per year with the dermatan sulfate option. The final costs and effects were mainly sensitive to variations in the rates of DVT and pulmonary embolism, and to the possible need for 1 extra day of hospitalisation because of the earlier preoperative initiation of dermatan sulfate prophylaxis. Conclusion: dermatan sulfate is more cost effective than UFH for the prevention of postoperative venous thromboembolism in patients with cancer. If the hospital stay needs to be prolonged, then the dermatan sulfate option may involve a small additional cost (EUR47) per potential life saved.

Cost-effectiveness study of imipenem/cilastatin versus meropenem in intra-abdominal infections.

Background: The efficacy of two carbapenems, imipenem/cilastatin (I/C, 1.5 g daily) versus meropenem (3 g daily) in intra-abdominal infections was assessed in a recent multicenter randomized clinical trial. The aim of this article is to perform a cost-effectiveness analysis as in real-world practice according to the findings of this clinical trial. Methods: A decision tree was used to estimate the clinical outcomes and direct costs of treating intra-abdominal infections using the two carbapenems from the perspective of the Italian National Health Service (INHS) or a private insurance company (PIC). Results: In a population of 30,000 patients with intra-abdominal infections in Italy, it was estimated that 97 potential deaths/year could be avoided if these patients were treated with I/C versus meropenem. In addition, from the perspective of INHS, the total costs of treatment were estimated as ITL 106,874 million and 134,042 million for I/C and meropenem, respectively. In favor of the PIC point of view, the total costs were estimated as ITL 110,500 million and 135,899 million for I/C and meropenem, respectively. Conclusion: The treatment of intra-abdominal infections with I/C is shown to be more effective (97 deaths avoided/year) and less costly than with meropenem (with a saving of ITL 27,168 and 25,399 million/year for INHS and PIC, respectively).

β-lactam antibiotic-mediated changes in platelet reactivity and vascular endothelial functions

To evaluate vascular and platelet compatibility of intravenous administration of beta-lactam antibiotics, we assessed the effects of therapeutic concentrations of ceftriaxone, aztreonam, and ceftazidime on platelet reactivity to different agonists (sodium arachidonate, collagen and adenosine diphosphate) and on selected vascular endothelial functions (adenosine diphosphatase activity, prostacyclin production and t-PA release). Ceftriaxone and, to a lesser degree, aztreonam, enhanced platelet reactivity, evaluated as onset of platelet aggregating response, and increased thromboxane production to subthreshold concentrations of arachidonate. There was no modification in platelet reactivity after ceftazidime treatment. Ceftriaxone and ceftazidime, but not aztreonam, inhibited endothelial adenosine diphosphatase activity. Prostacyclin production and t-PA release were inhibited only by ceftriaxone at high concentrations. While it is difficult to establish which marker (platelet or endothelial functions) has more clinical reference in human vascular compatibility, it seems feasible to consider aztreonam the most compatible of the beta-lactams studied.

Una prima valutazione economica dell’impiego di rofecoxib versus FANS convenzionali nell’artrosi

SummaryObjectiveRandomised clinical trials have demonstrated that rofecoxib has a better gastrointestinal tolerability profile than conventional nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis, which results in a reduced utilisation of gastroprotective agents (GPA). The aim of this study was to estimate, from the national healthcare system perspective, the total drug costs in patients switched from NSAIDs plus GPAs to rofecoxib.DesignIn this longitudinal, observational study, drug prescriptions for symptomatic treatment of osteoarthritis were recorded. A decision tree was used to compare the mean daily drug cost of the following therapeutic options for ostheoarthritis: conventional NSAIDs and rofecoxib/conventional NSAIDs.SettingAzienda Unità Sanitaria Locale 110, Ravenna, Italy.Patients56,827 patients affected by osteoarthritis were monitored from January 1997 to December 1999. Of this group, we considered the first 2,935 patients who were examined by 21 General Practitioners in the period July 2000-October 2000, in order to point out changes in GPAs co-prescription after the introduction of rofecoxib in the Italian market.InterventionsAlternative treatments compared were: NSAIDs either alone or combined with GPAs (NSAIDs option), and just after the introduction of rofecoxib, NSAIDs or rofecoxib alone and NSAIDs or rofecoxib combined with GPAs (rofecoxib/NSAIDs option).Main outcome measures and results27,511 out of 56,827 patients (48.4%; IC 95%: 48.0–48.8%) treated with NSAIDs also received a GPA co-medication. In the aforementioned subgroup of 2,935 patients, 1,814 (62%) received multiple prescriptions of NSAIDs or rofecoxib. In this subgroup, rofecoxib was associated with a statistically significant reduction of GPAs utilisation of 58.8% (IC 95%: 30.7–80.1; p = 0.012) compared with what was recorded during treatment with NSAIDs. In fact, the mean daily cost per patient of the NSAIDs option was € 1.66 versus € 1.55 of the rofecoxib/NSAIDs option (6.6% lower).ConclusionsOur preliminary results suggest that the use of rofecoxib is associated with cost savings in terms of total drug costs compared with conventional NSAIDs.

Prostanoid Production in the Presence of Platelet Activation in Hypoxic Cocaine-Treated Rats

To extend our previous in vitro data, we investigated the effects of cocaine on thromboxane A2 (TXA2) and prostacyclin (PGI2) production in vivo in the rat. To obtain the slight platelet activation that our in vitro experiments showed useful to highlight the effect of cocaine, we infused cocaine in rats in the presence of platelet-activating factors (circulation of blood through a perspex vascular device or by infusion of sodium arachidonate) and in various respiratory conditions. Experiments were conducted in rats breathing atmospheric air (normoxic conditions) and in rats breathing an oxygen-poor mixture (hypoxic conditions). In rats under hypoxic conditions cocaine invariably increased TXA2 plasma levels, whereas in normoxic conditions it increased TXA2 only in the presence of platelet-activating factors. Cocaine significantly increased PGI2 plasma levels in arachidonate-treated rats in hypoxic respiratory conditions; in normoxic conditions cocaine left PGI2 levels unchanged. These results support the hypothesis that in cocaine users who have concomitant pathological conditions able to activate platelets, such as atherosclerosis, coronary vasospasm or ischaemia, or both, cocaine may contribute to the onset of thrombotic phenomena by interfering with the prostaglandin system.

An in vitro method for evaluating vascular endothelial ADPase activity.

Some xenobiotics, known to promote the development of thrombotic phenomena, affect vascular endothelium ADPase, a regulatory enzyme that inactivates vaso- and platelet-active adenine nucleotides. This proposed new experimental approach represents an improved method of evaluation of vascular endothelial ADPase activity which is assessed by measuring, at pre-established times, the degradation rate of exogenous ADP incubated with aortic bovine patches. The ADP dosage was performed by using a spectrophotometric enzymatic assay. Statistical analyses showed that the method is capable of highlighting the linearity of the ADPase activity time-course, thus indicating that the slopes of time-degradation curves of ADP are a valid index for this endothelial ectoenzyme activity. Results obtained with ADPase inhibiting or stimulating agent confirm that this in vitro method is an efficient tool for estimating the ability of xenobiotics or drugs to modify the nonthrombogenic properties of vascular endothelium.

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