Pharmacoutilization and costs of osteoarthritis: changes induced by the introduction of a cyclooxygenase-2 inhibitor into clinical practice.

OBJECTIVE: To establish whether the introduction of a cyclooxygenase-2 inhibitor has led to changes in pharmacoutilization in the treatment of osteoarthritis (OA) in clinical practice. METHODS: Administrative and general practice databases were cross-linked to analyse the use of non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective agents (GPAs) before and after the introduction of rofecoxib. Costs of treatment and costs of hospitalization for gastrointestinal events were also considered. RESULTS: A total of 3090 patients were evaluated. A significant reduction in the use of GPAs in the rofecoxib group was observed, corresponding to reductions of 64 and 59.7% compared to NSAIDs among patients in incident and prevalent cases respectively. The weighted mean daily cost of therapy with rofecoxib in incident cases was 1.88 euro, 7.4% lower than that of NSAIDs (2.03), and in prevalent cases it was 1.87 euro, 28.1% higher than that of NSAIDs (1.46). Although the rate of hospitalization was similar, there was an additional daily cost per patient of 186.6 for patients being treated with NSAIDs and 21.6 euro for those being treated with rofecoxib. CONCLUSIONS: The cyclooxygenase-2 inhibitor rofecoxib determined substantial changes in the pharmacoutilization and costs of OA.

Interferon alpha in the treatment of chronic hepatitis C in children: a meta-analysis [correction of metanalysis].

Children with chronic hepatitis C may be ideal candidates for treatment with interferon alpha (IFNalpha) as they have liver disease at an early stage. However, adverse drug reactions need to be considered. The aim of this study was to conduct a systematic review of literature on interferon therapy of chronic hepatitis C in children, and to perform a meta-analysis of pooled data. A computerized search gave 18 articles on IFNalpha therapy in children with chronic hepatitis C; after exclusion of uncontrolled trials and of trials including patients with comorbidities, data from two studies could be pooled (48 patients). The outcomes assessed were biochemical, defined as normalization of alanine transaminase, and virologic, defined as HCV-RNA loss, both sustained at 24 months after enrollment. Results of the studies were homogenous. Risk difference was 37% (95%CI: 12.9-61) in favour of IFNalpha treated children for sustained biochemical response, and 36.8% (95%CI: 14.3-59.3) in favour of treated children for sustained HCV clearance, respectively. The differences were highly significant (P = 0.007 and P = 0.004, respectively). The histological end-point, as well as side-effects, could not be analysed, due to lack of data. This review identifies the poor methodology of the majority of the published trials. The study provides support for the efficacy of IFNalpha in improving both biochemical and virologic outcomes in chronic hepatitis C in children, but evidence is confined to these surrogate end-points.

Clinical and economic outcomes of pneumonia in children: a longitudinal observational study in an Italian paediatric hospital.

RATIONALE, AIMS AND OBJECTIVES: Antibiotic prescription for acute lower respiratory infections (ALRI) in hospitalized children can have a major impact on cure and costs. We performed a longitudinal study to explore the appropriateness of prescriptions, the predictors of therapeutic patterns, and the main outcomes: readmission, length of stay (LOS) and costs. METHODS: Ninety-nine children who were inpatients of a paediatric hospital receiving antibiotic treatment for community acquired ALRI were consecutively enrolled. To calculate the costs of pneumonia treatment, we collected data on clinical presentation and resources consumption. We used multiple regression analysis to identify predictors of LOS and choice of therapy, and one-way ANOVA to evaluate cost differences among treatment groups. RESULTS: Parenteral antibiotics were administered in 64.6% of cases, whereas 35.4% received oral antibiotic therapy by itself (OAT). Switch therapy (SWT) was performed in 43.4% of cases. The most frequently prescribed antibiotic for parenteral therapy was ceftriaxone (58.3%), and for oral therapy cefprozil (58.1%). The median LOS was 3 days and the cure rate 99% (95%CI: 97-100%). SWT and OAT were significantly associated with a shorter LOS. The clinical variables were not significantly associated with SWT or OAT. The average costs per patient in the management of pneumonia were Euro 1435. SWT or OAT were associated with significant lower costs: Euro 1487 per patient (95%CI: 1395-1580) and Euro 1335 per patient (95%CI: 1233-1437), respectively. CONCLUSIONS: The hospital management of paediatric pneumonia was more influenced by the early discharge policy than by clinical variables without under-cure.

[Evaluation model of the effect of Rofecoxib on the co-prescription of gastroprotective agents observed during the treatment of osteoarthritis]. / Modello valutativo dell'effetto sulla co-prescrizione di gastroprotettori osservato durante il trattamento dell'artrosi con Rofecoxib.

OBJECTIVE: This study was conducted to define an evaluation model to estimate changes in the co-prescription of gastroprotective agents (GPAs) induced by rofecoxib in the treatment of osteoarthritis (OA). METHODS: On the basis of a cross-linking information, which were stored in different administrative and clinical databases, a multivariate regression analysis was used to develop the model. Data were collected by 30 general practitioners of the Local Health Unit of Ravenna (middle-north of Italy). RESULTS: The study population consisted of 2,944 patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and 487 treated with rofecoxib. Patients treated with rofecoxib generally presented a higher number of gastrointestinal damage risk factors and also a lower level of GPAs co-prescription compared to those treated with NSAIDs. Including in the model variables such as type of anti-inflammatory treatment (NSAIDs or rofecoxib), gender, age by class, previous hospital admissions due to gastrointestinal complications, number of different NSAIDs used, and prescription of corticosteroids, the regression equation and its coefficients were identified. A non-linear relationship between the percentage of patients treated with rofecoxib and the relative reduction of GPAs co-prescription was found. It has been estimated the basis of the registered percentage of patients treated with rofecoxib (17,6%) adjusting for gastrointestinal damage risk factors, and on a 63% (CI95%: 55%-70%) relative reduction of GPA use with rofecoxib with respect to NSAIDs was estimated. CONCLUSIONS: Based on data collected in the clinical practice after the introduction of rofecoxib, a model evaluating the relationship between the frequency of its use in the OA population and the expected reduction of GPAs, has been developed.

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.

Beta-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.

Dermatan sulfate versus unfractionated heparin for the prevention of venous thromboembolism in patients undergoing surgery for cancer. A cost-effectiveness analysis.

BACKGROUND: 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.

[Drugs for the treatment of benign prostatic hypertrophy]. / Farmaci per il trattamento dell'ipertrofia prostatica benigna.

Benign Prostatic Hyperplasia (BPH) usually occurs in males 45-50 old and progressively involves 75% of the male population over 75 years of age. The clinical manifestations of BPH are related primarily to bladder outlet obstructions resulting from enlargement (mechanical component) of the prostate gland, and from extrinsic and intrinsic sympathetic activation of alpha-adrenoceptors (dynamic component) present in the prostatic muscle tissue, prostatic urethra, bladder base and neck. Several drugs have been employed in the last decades: LHRH analogs (Leuprorelin and Goserelin) which can reduce the testicular production of androgens with reduction in prostate size; Serenoa repens for its anti-androgenic and anti-estrogenic activities; Finasteride (5-alpha-reductase inhibitor) which blocks the conversion of testosterone into the more active dihydrotestosterone. Finally, the alpha 1 blocking agents (Terazosin, Doxazosin, Tamsulosin) that improve urinary symptoms by acting on dynamic component. Clinical improvements derive from their antagonist action on alpha 1 adrenergic receptors which mediate contraction of the prostate gland, proximal urethra, bladder base and neck, with the consequent reduction of urethral pressure, bladder outlet resistance, and increase of urinary flow. Due to its pharmacodynamic and pharmacokinetic properties, as well as the clinical results obtained, Terazosin, alpha 1 blocker, appears to be particularly useful in the treatment of patients with mild- to moderate symptomatic BPH.

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.

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).

Effects of sodium selenite on vascular smooth muscle reactivity.

The effects of sodium selenite (Na(2)SeO(3)) on the vascular smooth muscle reactivity of rabbit aorta were studied. In isolated rabbit aorta, Na(2)SeO(3) inhibited contractile response to phenylephrine and developed a lasting contracture in the vascular tissue. Relaxation in phenylephrine-precontracted aortic rings induced by sodium nitroprusside and 8-bromo-guanosine 3':5'-cyclic-monophosphate was also inhibited. Preliminary data obtained with ascorbic acid suggested a partial involvement of an oxidative mechanism. Excluding the possibility that Se damages actin or modifies its distribution (immunohistochemical evaluation), results indicate that Se alters vascular smooth muscle reactivity by inhibiting both its contracting and relaxing properties. Calcium-dependent mechanisms appear to be primarily involved and an interference with calcium re-uptake by sarcoplasmic reticulum as a possible site of Se vascular action could be hypothesized.

Potential health effects of gasoline and its constituents: A review of current literature (1990-1997) on toxicological data.

We reviewed toxicological studies, both experimental and epidemiological, that appeared in international literature in the period 1990-1997 and included both leaded and unleaded gasolines as well as their components and additives. The aim of this overview was to select, arrange, and present references of scientific papers published during the period under consideration and to summarize the data in order to give a comprehensive picture of the results of toxicological studies performed in laboratory animals (including carcinogenic, teratogenic, or embryotoxic activity), mutagenicity and genotoxic aspects in mammalian and bacterial systems, and epidemiological results obtained in humans in relation to gasoline exposure. This paper draws attention to the inherent difficulties in assessing with precision any potential adverse effects on health, that is, the risk of possible damage to man and his environment from gasoline. The difficulty of risk assessment still exists despite the fact that the studies examined are definitely more technically valid than those of earlier years. The uncertainty in overall risk determination from gasoline exposure also derives from the conflicting results of different studies, from the lack of a correct scientific approach in some studies, from the variable characteristics of the different gasoline mixtures, and from the difficulties of correctly handling potentially confounding variables related to lifestyle (e.g., cigarette smoking, drug use) or to preexisting pathological conditions. In this respect, this paper highlights the need for accurately assessing the conclusive explanations reported in scientific papers so as to avoid the spread of inaccurate or misleading information on gasoline toxicity in nonscientific papers and in mass-media messages.

Toxicological effects of beryllium on platelets and vascular endothelium.

Although ample research has described the toxic effects of the metal beryllium on the respiratory apparatus, less is known about its effects on the vascular apparatus, including pulmonary blood vessels. We investigated the in vitro effects of beryllium on endothelial vascular adenosine diphosphatase activity and prostacyclin production in bovine aortic endothelium, and on nitric oxide release in isolated rabbit arteries. Rabbit and human platelet responsiveness was also evaluated. Beryllium inhibited vascular endothelial adenosine diphosphatase activity, prostacyclin production, and nitric oxide release, thus inducing functional alterations in vascular endothelial cells. It also induced platelet hyperreactivity to arachidonic acid, as shown by a lowering of the threshold of aggregating concentration and by concurrently increasing thromboxane production. In contrast, beryllium left the response to aggregating and nonaggregating concentrations of ADP and collagen unchanged. These findings show that beryllium may impair some vascular endothelial functions and alter the interaction between platelet and endothelial mediators.

Modulation of ADPase and t-PA release by radiographic contrast media in bovine aortic endothelium.

Vascular endothelial injuries induced by intravascular administration of radiographic contrast agents may be clinically relevant to the development of thrombosis and platelet activation. In this connection, we investigated the in vitro effects induced by iodamide, iopamidol, and ioxaglate on vascular endothelial ADPase activity and tissue plasminogen activator (t-PA) release in bovine aortic endothelium, in order to extend knowledge required to evaluate endothelial compatibility of radiographic contrast media. Undiluted and Tris-diluted contrast agent formulations were employed, and mannitol and sucrose hyperosmolar solutions were used as comparison. Results demonstrated that the high-osmolar ionic contrast agent iodamide, and to a lesser extent, the low-osmolar nonionic agent iopamidol, stimulated endothelial ADPase activity of the aortic endothelium; the low-osmolar ionic agent ioxaglate left endothelial ADPase activity unchanged. Furthermore, the diluted formulations of iodamide and iopamidol, as well as high-osmolar mannitol and sucrose solutions, were devoid of activity in ADPase. This suggests that the endothelial ADPase stimulation induced by both radiographic contrast media was a hyperosmolar-independent pharmacodynamic activity. Iopamidol and ioxaglate reduced endogenous t-PA release from bovine aortic endothelium only in undiluted formulation, while iodamide showed this inhibiting action in both diluted and undiluted formulations. No effect was observed when using mannitol solutions at different osmolarity values. Our in vitro findings agree with published data on the different thrombotic tendency attributed to the contrast agents used, suggesting endothelial enzymatic activities (ADPase and t-PA release) as suitable tools for evaluating endothelial vessel wall compatibility with radiographic contrast media.

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.

The co-operative action of hyaluronidase and urokinase on the isoproterenol-induced myocardial infarction in rats.

The effects of the intravenous administration of hyaluronidase (HY; 2,500 IU/kg) and urokinase (UK; 20,000 and 40,000 IU/kg), alone or in combination, on the isoproterenol (ISP) induced myocardial infarction (MI) in rats, were studied. The severity of infarction was determined by measuring the levels of serum enzymes (CPK, GOT, LDH) and by evaluating the extent of the injured areas and the incidence of mortality. Plasma thromboxane B2 (TXB2) levels were also determined. All the treatments reduced the infarction area and the enzyme levels (increased by ISP) to a varying degree. However, a definite potentiating activity was obtained when HY was combined with the highest dose of UK. This combination was also capable of reducing the mortality rate. Finally, both HY and UK or the combined preparation brought the plasma TXB2 levels back to normal. These findings suggest the possibility of complementary activities of HY and UK in the treatment of experimental MI.