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Chronic constipation is a common disorder, especially in women. Options available for different subgroups of constipation are limited and in most cases unsatisfactory. The most severe forms of chronic constipation often require the use of laxatives in high doses or the use of invasive therapies. The introduction of a new drug, such as prucalopride, active in promoting intestinal transit, can help to improve the therapy of patients with chronic idiopathic constipation who have not found relief from previous treatment with laxatives. In this review, after a brief discussion of pathophysiology and pharmacotherapy of chronic constipation, we evaluate the pharmacological profile, therapeutic and cost of prucalopride, recently authorized in the EU countries and also available in Italy for the treatment of chronic constipation in women who did not benefit from the use of laxatives

Rheumatoid arthritis (RA) is a chronic, progressive and degenerative illness, which affects about 0.5% of the adult population with significant social costs. In Italy there are approximately 300,000 people with RA, with twice as many women than men. RA causes progressive deformity and disability and is associated with numerous co-morbid conditions that reduce the life expectancy of 5-10 years. The costs of RA have a serious impact on the entire community, especially in terms of disability, hospitalization and medical care. In Italy has been estimated that cost of illness could reach about 1,600 million euros, of which over two thirds are represented by indirect costs. The treatment of RA is evolving and the introduction of biological drugs has resulted in a significant progress in terms of therapeutic possibilities. Etanercept, the only soluble receptor of TNF-alfa currently approved appears to be cost-effective and it is recommended by major guidelines for the treatment of RA. http://dx.doi.org/10.7175/rhc.v3i3.201

HBV infection in Italy is frequently underestimated, raising the risk of important complications, such as cirrhosis and hepatocellular carcinoma, and thus increasing mortality. In infections phases requiring treatment, it’s possible to choose among the currently available drugs: interferons, nucleoside and nucleotide analogues. Entecavir is a nucleoside analogue able to maintain a high genetic barrier, and to reduce the viral load < 300 copies/ml in 67% of HBeAg-positive patients and in 90% of HBeAg-negative patients after 48-weeks treatment, improving also necroinflammatory grade and fibrosis degree. In spite of the high cost of the confection, entecavir induces a saving in health costs because of the decrease in the disease progression. If compared, through pharmacoeconomic models and analysis, to tenofovir, a nucleotide acid considered equivalent in the first-line monotherapy of HBeAg-positive patients and in the long-term treatment of HBeAg-negative patients by the current international and Italian guidelines, it seems favourable in terms of safety and consequently in terms of costs of adverse events spared. However further studies are required: in particular direct comparative studies are still lacking.

Background: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. Methods: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range &lsqb;TiR&rsqb;) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. Results: Baseline results were calculated with 10 000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was &U20AC;50 012 per LY and &U20AC;67 361 per QALY, while, if dialysis costs were not included, the ICER was &U20AC;23 473 per LY and &U20AC;31 616 per QALY. Conclusions: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

Hyperphosphatemia is recognized as a principal mineral disorder in chronic kidney disease (CKD) that leads to the development of secondary hyperparathyroidism. Approximately 70% of patients with end-stage renal disease (ESRD) and dialysis have hyperphosphataemia, which is associated with renal osteodystrophy, metastatic calcification and increased mortality and morbidity. Despite dietary restriction and dialysis, most patients will require a phosphate-binding agent to treat this condition.Lanthanum carbonate is an new, potent, selective, no-resin, non-calcium phosphate binder that retains high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis. Taken with food, it is well tolerated. It is poorly absorbed and does not require functioning kidneys to be removed from the body. There is no evidence from current studies that it accumulates to biologically significant levels in tissues. Lanthanum carbonate has been shown in clinical studies of up to 6 years to be an effective, well-tolerated phosphate binder. Lanthanum carbonate controls hyperphosphataemia without increasing calcium intake above guideline targets and has the potential to reduce pill burden and increase patient compliance compared with other phosphate binders. Reported adverse effects are mainly gastrointestinal, and do not differ from those of calcium carbonate. The new phosphate binders, lanthanum carbonate and sevelamer, have increased the possibilities for serum phosphate control, at the expenses of significant increases in costs. The cost-effectiveness of lanthanum carbonate has been assessed by three different studies. A recent analysis, conducted on the perspective of the UK NHS, shows it is cost-effective to follow current treatment guidelines and treat all patients who are not adequately maintained on calcium carbonate (serum phosphorus above 5.6 mg/dl) with second-line lanthanum carbonate. This is particularly the case for patients with serum phosphorus above 6.6 mg/dl. A retrospective analysis, performed on IHCSI data base (USA), and a prospective study conducted in Spain show that lanthanum carbonate is cost-effective as compared with sevelamer, requiring less number of tablets, a fact that might improve adherence, and that probably explains better results with lower costs.

Despite considerable improvements in the last two decades, chemotherapy-induced nausea and vomiting (CINV) remains a frequent and very bothersome medical problem. It is estimated that about one half to two thirds of all chemotherapy-treated patients experience CINV, the frequency depending on the chemotherapy regimen used and on patient-specific features. The impact of CINV, which may be acute, delayed or even anticipatory in experienced patients, on health-related quality of life (HRQoL) is substantial in all domains. Until recently, effective treatment choices included corticosteroids and first-generation 5-HT3 antagonists, which have been supported by aprepitant, the first clinically available NK1 antagonist, and by palonosetron, considered the first second-generation 5-HT3 antagonist for its high receptor-subtype selectivity and affinity and long plasmatic half-life. In this paper, clinical pharmacology of the latter drug is briefly outlined and recent Italian papers on the epidemiology and HRQoL impact of CINV are reviewed, as well as national pharmacoeconomic evalutations conducted on palonosetron. The role in therapy of palonosteron and its potential for improved clinical, HRQoL and economic outcomes is discussed.

The main aim of this retrospective study was to perform a pharmacoeconomic analysis of long term use of darbepoetin-α (DARB) after switch from erythropoietin-ß (EPO-ß) in treating chronic nephropathy-induced anemia in dialysed patients. Secondary objective was the assessment of the actual EPO-ß-to-DARB dose conversion factor. We extracted data of 78 patients who have been treated with EPO-ß for at least 6 months and then switched to DARB from the database of the dialysis center of the Asti (Piedmont, Italy) hospital. From these, we selected 47 patients (23 males and 24 females) who completed a 120-weeks follow-up treatment with DARB. All patients were treated with a dose adjustment schedule to keep haemoglobin levels in the range 11-12g/dl. Pre-switch EPO-ß administration was thrice a week, while DARB was administered once a week, both via intravenous. Initial DARB dose has been calculated on the basis of the theoretical 200:1 conversion factor. Actual cumulative EPO and DARB consumption was recorded for all patients. Drug costs were valued according to purchasing prices for the Italian National Health System (October 2006). In the 24 pre-switch weeks the average cost (±SD) per patient for EPO-ß was € 2,309.86 (±1,434.78). In the 120 weeks of follow-up the average cost (±SD) per patient for DARB/24 weeks ranged from a minimum of € 1,487.09 (±1,125.51) to a maximum of € 2,125.73 (±1,546.85). The switch of 47 patients to DARB produced an overall net saving for the dialysis centre estimated in 119,540.72 Euro/120 weeks, under the hypothesis that EPO-ß semester costs remain constant: the conversion from EPO-ß to DARB has the potential to maintain long term good haemoglobin control and induces significant savings for the National Health System. However the dosage should be adjusted on an individual basis in order to avoid excessive fluctuation of Hb concentrations. The actual conversion factor resulted on average higher than theoretical factor settling to 240-280:1.

Psoriatic arthritis is an inflammatory and possibly destructive form of arthritis; left untreated, psoriatic arthritis can be a progressively disabling disease. The arthritic manifestations often include debilitating disease of the hands and feet, as well as painful inflammation of the tendon insertions and arthritis of the spine. The most common treatments prescribed for the psoriatic arthritis are nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, corticosteroids and disease-modifying antirheumatic drugs (DMARDs). Due to a recently suggested role of the tumour necrosis factor (TNFα) in the pathogenesis of psoriatic arthritis, new therapies specifically blocking TNFα have been investigated. Aim of the present study is to compare cost/effectiveness (CEA) and cost/utility (CUA) ratios of anti-TNF medications currently available on the Italian market: etanercept, infliximab and adalimumab. The evaluation was conducted through the development of a single Markov model. Clinical data were obtained from three Phase III trials attesting the clinical efficacy of the biological therapies. Both cost/effectiveness and cost/utility analysis were implemented through the deterministic evaluation and the probabilistic evaluation, in order to assess the convenience for the Italian National Healthcare Service. Adalimumab appears to be cost effective for the treatment of psoriatic arthritis, especially considering the incremental cost/effectiveness ratio (ICER) and the incremental cost/utility ratio (ICUR); the results suggest that ICER and ICUR values of adalimumab over etanercept is definitely lower than the maximum acceptable willingness-to-pay value. Moreover, compared with infliximab, adalimumab is less costly and more effective.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its medical and economical burden represents a serious matter in Europe and Usa, due to its high mortality rates and drug costs. Lung cancer is responsible for about 30% of cancer death in men and women; in Europe only about 8 per cent of people with lung cancer survive for 5 years. At present combination chemotherapy based on cisplatin or carboplatin associated with paclitaxel, vinorelbine or gemcitabine is the state of the art for the treatment in patients with stage IIIb or IV NSCLC. Aim of this study was to compare the cost-effectiveness of paclitaxel/carboplatin (PCb), gemcitabine/cisplatin (GC) and vinorelbine/cisplatin (VC) in the perspective of the Italian National Health Service. Therefore we perfomed a semi-Markov decision model mainly based on clinical results from the Italian Lung Cancer Project. The model included differential direct medical costs registered for two years from starting chemotherapy, using tariffs valid for 2005. Benefits was measured by years of life saved (YOLs). The model also allowed to estimate only costs accrued over the period of time, performing a cost-minimisation analysis. According to cost-effectiveness analysis, VC is dominated because it’s more costly and less effective than GC. On the contrary, combination chemotherapy with GC is more inexpensive but less effective than paclitaxel/carboplatin (PCb): in this case we compared the incremental cost-effectiveness ratio (ICER) with a maximum acceptable willingness-to-pay (WTP) value. In the base scenario the ICER of PCb over GC treatment is 52,326 euro/ YOLs, which is definitely lower than the maximum acceptable WTP value. Sensitivity analyses confirmed the robustness of the results from cost-effectiveness analysis in the base scenario.

Darbepoetin (DARB), a human erythropoietin with improved pharmacological parameters (longer half life and a dose-response relationship independent from the route of administration) is a new treatment option for chronic nephropathy-induced anemia that in many Italian dialysis centers is substituting older erythropoietins, mainly due to greater ease of use. At current prices and at the theoretical and recommended 200:1 dose conversion factor, DARB pharmaceutical cost ranges from –9% to +17% of EPO cost. In this monocentric study, real drug consumption and related actual costs of a pre-switch semester with EPO were analysed and compared to the first two post-switch semesters with DARB therapy. Furthermore, erythropoetic response was recorded and related to drug exposition levels, in order to establish a real life EPO:DARB dose conversion factor. In this experience, the conversion factor was estimated in at least 250-280:1, depending on the method adopted for the estimation. The initial dose, chosen on the basis of the recommended conversion factor, induced an excessive erythropoietic response, which was generally followed by a dose reduction and successive titration to target desired Hb levels, generating the spiraliform dose-response curve associated with delayed feed-back mechanisms. The pharmacoeconomical analysis, conducted in the perspective of the public health service, indicated that the choice of substituting DARB for EPO in the treatment of chronic kidney failure-associated anemia is univocally convenient, the former being less costly and more effective.

Significant advances in the management of hypercholesterolemia have been made possible by the development of statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. More recently, statins have demonstrated benefit in primary and secondary prevention of cardiovascular disease also in patients without hypercholesterolemia. Therefore statins help to reduce the impact of cardiovascular disease on morbility, mortality and social costs. Statins inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Prescribing statins as first line therapy in management of hypercholesterolemia as a part of a more comprehensive prevention program of cardiovascular disease is widely recommended by international guidelines (e.g. National Cholesterol Education Program - NCEP - Adult Treatment Panel - ATP- III reports). Currently in Italy there are five available statins: atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin; each of them presents some differences in physical and chemical characteristics (solubility), pharmacokinetics (absorption, proteic binding, metabolism and excretion) and pharmacodinamics (pleiotropic effects). Compared to other statins, fluvastatin extended-release (RP) 80 mg provides an equal efficacy in lowering total cholesterol and low-density lipoprotein cholesterol (LDL-C), with an important action on triglyceride (TG) levels and superior increases in HDL-C levels, reducing the incidence of major adverse cardiac events (MACE). Aim of this study is to outline an updated therapeutic and pharmacoeconomic profile of fluvastatin, particularly regarding extended-release (RP) 80 mg formulation.

Pharyngotonsillitis (FT) and acute otitis media (OMA) are among the most frequent infectious diseases of the childhood and exact a heavy toll on the Italian national health service (INHS), families and society as a whole. In case of established or suspected bacterial origin, current treatment guidelines for FT recommend 5-10 days of oral antibiotics, chosen among available penicillins, cephalosporins, or macrolides. More controversial appears the systematical use of an antibiotic for OMAs, but prevalent expert opinion suggests use of the same agents. In this paper, an economical appraisal of five of the most prescribed oral antibiotics for these indications in Italy (cefaclor, amoxicyllin, amoxicyllin/clavulanate, clarithromycin and azithromycin) is provided. The evaluation was conducted through the development and implementation of two distinct models, constructed to reflect national treatment patterns of these infections. Clinical and economical data were obtained from several sources: literature review, including published meta-analyses, consultation of an expert panel and, most importantly, from the results of a specific questionnaire-based survey completed by 136 pediatricians, based throughout Italy. The models were run to conduct both cost-effectiveness and cost-minimization analyses, that consistently indicated cefaclor and amoxicyllin to be substantially equivalent in terms of total costs to the INHS and the Italian society, but significantly more convenient than amoxicyllin/clavulanate, claritrhomycin or azithromycin. Extensive probabilistic sensitivity analyses confirmed the robustness of this conclusion.

Current international guidelines for the management of immuno-compromised patients with febrile neutropenia recommend a systemic antimicrobial therapy if fever hasn’t receded after three days of antibiotic treatment. Amphotericin B remains the gold standard because of its broad spectrum fungicidal action and minimal resistance development risk. Nonetheless, therapeutic use of the standard formulation, Amphotericin B deoxycholate, is limited by its toxicity, especially on the kidneys. To counteract this, amphotericin B has been encapsulated in liposomes, a process which reduces its toxicity and allows higher doses to be given. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (L-AmB). These lipid formulations differ in pharmacodynamics and pharmacokinetics, and can’t therefore be considered interchangeable. Besides, they are more expensive than Amphotericin B deoxycholate. Aim of the study is to perform a cost/effectiveness analysis (CEA) comparing L-AmB (3mg/kg/die or 5mg/kg/ die) and ABLC (5mg/kg/die) as first-line antimicrobial empirical treatments in immuno-compromised patients with febrile neutropenia resistant to broad spectrum antibiotics. Secondly, we present a cost-minimization analysis (CMA) of the considered alternatives, assuming the same efficacy for all treatments. At the end we value the principal cost items from the point of view of the Italian Health Service, with a particular focus on the economic burden caused by adverse reactions.

Despite the fact that an effective vaccine against hepatitis B virus (HBV) has been available for over 30 years, the worldwide prevalence of this infection is still very high. Until recently, there were only two effective therapeutic options for chronic hepatitis B (CHB), interferon and lamivudine, but both are considered suboptimal therapies, for different reasons. Adefovir dipivoxil (ADV) is the oral prodrug of adefovir, an acyclic nucleotide analogue that demonstrated virological and clinical effectiveness against HBV in experimental and real world settings. In this paper the main pharmacological and clinical evidence of ADV in CHB is reviewed. Health care economics data on the direct costs of CHB in different countries are presented and potential economical consequences of its introduction in Italy are discussed.

Current practice guidelines for the treatment of COPD recommend the use of combined inhaled corticosteroids and long-acting bronchodilators in severe and very severe patients (GOLD stages III and IV). OBJECTIVES: To analyze the economical and clinical impact of this recommendation, the affordability of its widespread application, as well as the relative pharmacoeconomical performance of the available options for severe and very severe COPD in Italy. METHODS: Published data on the Italian COPD population were fitted in a disease progression model based on a Markov chain representing severity stages and death. Alternative therapeutic options (salmeterol/ fluticasone - SF, formoterol/budesonide - FB, salmeterol alone - S, fluticasone alone - F and control - C) were represented as competing arms in a decision tree. Efficacy data from international trials were expressed in terms of risk reduction. Clinical parameters used were number of exacerbations and symptom-free days. Direct and indirect costs were considered and valued according to present prices and tarifs. The analyses were conducted from National Health System, societal and patient perspectives with time horizons of 1,5, and 10 years, and lifelong. RESULTS: The yearly total direct costs of treating COPD patients in Italy is estimated in approximately 7 billion Euro, with a mean cost/patient/year around 2,400 Euro. Mean survival of the cohort is 11,5 years. The C and F strategies are dominated (i.e. are associated with worse outcomes and higher costs) by all alternatives. S/F and F/B are the most effective strategies, with a slight clinical superiority of the latter, but are also marginally more expensive than S. Incremental cost/effectiveness of S/F vs. S is 679,55 Euro/avoided exacerbation and 3,31Euro/gained symptom-free day. CONCLUSIONS: The recommended use of combined inhaled corticosteroids and long-acting bronchodilators for severe and very severe COPD patients, as compared with current practice, has the potential of improving clinical outcomes without increasing health care costs.

Type 2 diabetes mellitus (DM) and peripheral arterial disease (PAD) are two very relevant cardiovascular (CV) risk factors, which can often be found concurrently in the same patient. The DAVID trial, a double-blind, randomized, aspirin(ASA)-controlled study, has demonstrated that the use of picotamide, a thromboxane A2 synthase and receptor dual inhibitor, is associated with lesser CV morbidity and mortality in this type of patients in comparison to ASA, considered the standard antiplatelet agent. In order to estimate clinical and economic impacts of picotamide in the Italian health care setting, we developed a pharmacoeconomic model based on clinical data from DAVID and national economic parameters and demographics. The base case scenario, which reflects current prices and reimbursement policy (i.e. ASA fully paid for, picotamide out-of-pocket for patients) yielded an incremental cost/effectiveness ratio (ICER) of about 8,500 euro/year of life (YOL) saved, which falls below conventionally adopted willingness to pay thresholds. This cost, however, is totally born by the patient, while the savings on health care expenditures for avoided events (and less ASA) benefit the national health service (NHS). These results may help the physician in explaining the consequences of this choice to his/her patients, facilitating a fully-informed choice. The availability of a theoretical model allowed to explore some alternative scenarios, that indicate that the ICER can be further lowered and the economical burden better distributed through policy changes. In conclusion, the pharmacoeconomic model indicated that picotamide is likely to be a cost/effective option for CV mortality and morbidity prevention in patients with concurrent type 2 DM and PAD and that the level of adoption of this strategy will depend on willingness to pay and policy priorities of the NHS and patients themselves.

Dialysis-associated hyperphosphatemia has been treated with chelating calcium salts, in particular with calcium carbonate. A new option for the management of this problem is represented by sevelamer, a chelating agent which contains no calcium and no metals. Sevelamer and calcium carbonate are more or less equally effective and tolerated. The prolonged use of sevelamer instead of calcium carbonate, nevertheless, reduces calcemia and C-reactive protein levels, with a consequent reduction in myocardial infarction, angina pectoris and other peripheral vasculopathies. The limit to the wide-spread use of sevelamer is in its very high acquisition cost, as compared to the alternative. In this article, a semi-markovian pharmacoeconomical model for the comparison of clinical and economical outcomes of sevelamer and calcium carbonate is presented. The analysis is conducted in the perspective of the Italian health system (SSN). Clinical data are derived from published studies and integrated with expert panel estimates, cost data are relative to the Italian setting. The incremental cost-effectiveness analysis indicated that sevelamer is more costly, but also more costeffective: a one month gain in survival costs the SSN additional 2710 Euro, a value inferior to the conventionally accepted willingness-to-pay of industrialised countries. The majority of this excess cost is derived from the gain in survival, and consequent increase in dialysis costs. Thus, the choice of using sevelamer instead of calcium carbonate is even more justified from an ethical point of view. Sensibility analyses confirmed the robustness of the basic scenario results.

Solid lipid nanoparticles (SLN) carrying cholesteryl butyrate (chol-but), doxorubicin and paclitaxel had previously been developed, and the antiproliferative effect of SLN formulations versus conventional drug formulations was here evaluated on HT-29 cells. The 50% inhibitory concentration (IC(50) values were interpolated from growth curves obtained by trypan blue exclusion assay. In vitro cytotoxicity of SLN carrying chol-but (IC(50 72 h) 0.3 +/- 0.03 mM vs >0.6 mM) and doxorubicin (IC(50 72 h) 81.87 +/- 4.11 vs 126.57 +/- 0.72 nM) was higher than that of conventional drug formulations. Intracellular doxorubicin was double after 24 h exposure to loaded SLN versus the conventional drug formulation, at the highest concentration evaluated by flow cytometry. In vitro cytotoxicities of paclitaxel-loaded SLN and conventional drug formulation (IC(50 72 h) 37.36 +/- 6.41 vs 33.43 +/-1.17 nM) were similar. Moreover, the combination of low concentrations of chol-but SLN (0.1-0.2 mM) and doxorubicin (1.72 nM) or paclitaxel (1.17 nM) exerted a greater-than-additive antiproliferative effect at 24 h exposure, while the combination of Na-but and doxorubicin or paclitaxel did not. These preliminary in vitro results suggest that SLN could be proposed as alternative drug delivery system.

The incidence of nosocomial infections from Gram-positive pathogens has been increasing in the last two decades, alongside the development of antibiotic resistance in many bacteria. Glycopeptidic drugs are the most widely used options for these patients, but some bacterial strains with low sensibility to vancomycin and teicoplanin are starting to emerge, warranting careful monitoring and control of nosocomial and also community- acquired infections. This paper outlines a clinical, therapeutic and economic profile of linezolid, the first drug of the only new antibiotic class developed in the last thirty years. In clinical trials, linezolid has demonstrated very promising efficacy and safety in the treatment of antibiotic-resistant infections, in particular those caused by methicillin-resistant staphylococci (MRSA), obtaining greater or equal clinical and microbiological success rates than the standard options. Linezolid, as most newer drugs, has higher acquisition costs than the alternatives, but also bears interesting features that may modify the formation of infection treatment costs. In particluar, linezolid is very well absorbed after oral administration, allowing the planning of sequential iv/os strategies that have the potential to reduce health care costs and to improve the quality of life of the patients by shortening the length of hospitalization. Economic evaluations have demonstrated that this advantage is not merely theoretical, but that it can be achieved in real practice. In particular, linezolid has been shown to be more cost-effective than teicoplanin and vancomycin in the treatment of hospitalized, MRSA-related nosocomial pneumonia and severe infections.

Uncontrolled epilepsy has a significant negative impact on patient’s quality of life, on his emotional well-being and his social functioning. Seizure places an undue economic burden on the patient and community. The increased costs are direct and indirect (e.g.,inpatient care and loss of earnings associated with time lost from work). Levetiracetam is a new antiepileptic drug used as adjuntive therapy in the treatment of refractory epilepsy. Its nonconventional mechanism of action is not completely understood, but preclinical studies suggest that its antiepileptic action.may depend on a reversible, saturable and stereoselective binding site in CNS membranes. In this paper, we review the main clinical and economic data available in the scientific literature. Levetiracetam has a favourable pharmacokinetic profile characterised by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamic effect that permits twice-daily dosing. Several placebo-controlled clinical trials have demonstrated that its efficacy has enabled many patients who were refractory to treatment with other antiepileptic drugs to achieve long-term seizure freedom; furthermore in levetiracetam trials the frequency of adverse events is low and withdrawal rates are comparable with those of placebo. A cost/effectiveness analysis compared direct medical costs of levetiracetam add-on therapy with maintenance of standard therapy alone within the UK National Health Service. A 1-year dose escalation decision model was set up in refractory patients who failed to respond to two or more other currently available therapies, with seizure freedom selected as the measure of effectiveness. Available pharmacoeconomic data show that the incremental cost of treating patients with levetiracetam is low when compared with the benefits of seizure freedom, at least in the UK. Furthermore, current studies suggest that this antiepileptic drug has a potential as first-line treatment for many types of epilepsy and in many different patient populations.

Losartan is an angiotensin II receptor antagonist (ARB) that has been proven effective and well tolerated in the treatment of hypertension and in the reduction of global cardiovascular risk, but is more expensive than many alternatives. The present paper resumes its main pharmacological and clinical features, as a basis for analyzing its economical value. Despite the universally accepted relevance of good blood pressure control, hypertension is still undertreated and poorly controlled. Among the main reasons for this, poor adherence to therapeutic regimens plays a relevant role. Losartan and ARBs have been shown to be associated with compliance rates superior to those observed with any other antihypertensive drug class, due to an adverse events incidence similar to placebo and scarcity of relevant pharmacological interactions, and can therefor improve the cost-effectiveness of hypertension treatment. Several trials have indicated that losartan determines clinical benefits that go beyond its haemodynamic effect, such as renal protection, reduced incidence of stroke and cognitive improvement. The addition of losartan to conventional hypertensive therapy in diabetic patients with nephropathy has been estimated to induce net health cost savings in different settings, a relevant result, as very few medical interventions have demonstrated such a potential. To understand the real economical value of losartan, its drug acquisition costs have to be balanced against the benefits deriving from antihypertensive effectiveness, high compliance and non-haemodynamic target organ protection.

Invasive aspergillosis (IA) is a common and life-threatening infectious complication of immune system depression. Amphotericin B deoxycholate (AMB-d) has been considered standard therapy for IA for over 40 years, despite the fact that success rates rarely exceed 40% and adverse effects are quite common. At present two more recent pharmacological agents are available for the treatment of IA: liposomal amphotericin B (L-AMB) and voriconazole (VOR). In this article, we present a pharmaco-economical study comparing the relative costeffectiveness of 5 alternative strategies in the treatment of invasive aspergillosis, analysed from the point of view of the Italian hospital: administration of L-AMB as first line therapy, followed by no rescue treatment in case of failure (L-AMB I°); administration of L-AMB as first line therapy, followed by VOR in case of failure (LAMB I° + VOR rescue); AMB-d as first line, followed by L-AMB in case of failure (L-AMB rescue); AMB-d as first line, followed by other antifungals as needed (AMB-d I°) and VOR as first line, followed by rescue treatments in case of failure (VOR I°). The cost-effectiveness analysis was conducted using decision tree modelling techniques: efficacy data were obtained from published clinical trials; costs parameters were fitted on the Italian setting. The results indicate that two strategies, L-AMB rescue and VOR I°, are dominated, i.e. induce higher costs and lower success rates than the alternatives. The three remaining strategies are neither dominated nor dominate the others, but are associated with different clinical and economical outcomes: AMB-d I° has the lowest total cost, but also the highest cost-effectiveness ratio and the lowest overall efficacy; L-AMB I° has the best cost-effectiveness, but requires the willingness to pay 2,100 euro for each additional success; L-AMB I° + VOR rescue is the most effective treatment, but this choice is associated with incremental costs of 17,200 euro for each additional success, compared with L-AMB I°. In conclusion, our analysis indicates that for clinical, economical and ethical reasons the best option in the treatment of IA is the administration of L-AMB as first line therapy, thus limiting the use of VOR to the rescue of the patients not cured by this approach.

[Editorial in Italian]

Oxatomide is an antiallergic drug with a double mechanism of action: it possesses antagonistic activity on the H1 histaminergic receptor and it inhibits the production and release of flogistic and allergic mediators by effector cells, presumably acting as a selective calcium channel blocker on these cellular types. The efficacy and safety of oxatomide have been evaluated in many studies conducted on patients affected by different clinical conditions, demonstrating remarkable flexibility. It proved to be safe and effective also in extreme ages, i.e. children under 3 months of age and elderly over 80 years. Approved indications include rhinitis, asthma, conjunctivitis, urticaria, atopic and allergic dermatitis and food allergy and intolerance. In direct comparisons, oxatomide consistently proved superior than placebo and equally or more effective than other consolidated antiallergics. The drug tolerability is good, its main side effects are drowsiness and weight gain, usually transient. Cardiac and hepatic safety data are very reassuring, as is the case for drug interaction potential. Form an economical point of view, the drug acquisition cost is acceptable, being among the lowest in its class, at equally effective doses. Overall, the efficacy in several clinical conditions, the good tolerability in most patients and the reasonable purchase cost suggest that oxatomide is characterized by excellent risk-to-benefit and cost-to-benefit ratios in the treatment of allergic pathologies.

The term inflammatory bowel diseases (IBD) refers to two distinct clinical entities: Crohn.s disease and ulcerative cholitis, two chronic and non-specific disorders of unknown origin. Although quite uncommon and usually not life-threatening, IBDs have a strong economical impact, as they tend to affect patients in high productivity ages and require long and demanding therapies, medical and sometimes surgical. The pharmacological approaches to IBD treatment include aminosalicylates, corticosteroids and immunosuppressive agents. Aminosalicylic acids are the most widely used agents for maintaining remission and for the cure of mild-tomoderate forms of IBDs. This paper outlines the main pharmacological and clinical properties of one of these drugs, mesalamine (mesalazine). Mesalamine is the active moiety of sulfasalazine, an effective but not always tolerated agent. Mesalamine is available in several pharmaceutical forms, to be administered either by the oral or by the rectal route. As the therapeutic action of aminosalicylates is ascribed to their topical action on the inflamed intestine, while the adverse effects are believed to be caused by the systemically adsorbed (mainly in the first tract of the small bowel) fraction, slow-release formulations are usually preferred. From an economical point of view, mesalamine appears to have a moderate acquisition cost, widely offset by the savings induced on direct sanitary and, most importantly, indirect costs of IBDs. In particular, the availability of a generic drug with advanced colon-delivery technology provides the physician with the opportunity to treat patients with the best available technology at a reasonable price.

Fluoxetine has been the first antidepressive agent of the class of selective serotonine reuptake inhibitors (SSRI) to be introduced in therapy, back in 1987. The availability of SSRIs has meant a great advance in the treatment of major depression and other neuro-psychiatric pathologies. In this paper we review the scientific and clinical research on fluoxetine that has been published in the last six years, as the prior work has been extensively examined in a review conducted on the tenth anniversary of its introduction on the market. The review focuses on cost minimization strategies that can be conducted following the introduction of low cost generic fluoxetine.

Moxifloxacin is a new fluorquinolone antibiotic, recently introduced among the treatment options for upper and lower airways infections. It possesses a wide antibiotic spectrum, covering the major pathogens involved in the genesis of community acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and acute bacterial sinusitis (ABS). It acts in a concentration-dependent manner by inhibition of bacterial DNAgirase and topoisomerase IV, has a long biological half-life (about 12 hours), good oral bioavailability, excellent tissue diffusion and a better safety profile than other quinolones, because of the lack of phototoxicity and the scarsity of clinically significant drug interactions. The clinical results of moxifloxacin in CAP, AECB and ABS have been compared with those of available alternative antibiotics in several multicentric, double-blind studies, and the new fluorquinolone resulted at least as effective as the comparators, with similar tolerability profiles. These studies demonstrated a high correlation among the eradication of the pathogen and the clinical recovery of the patients. The pharmacodynamics, pharmacokinetics and clinical results of moxifloxacin render it one of the most attractive options for the empirical treatment of upper and lower airways infections, more so since its pharmacoeconomic profile appears to be very convenient. In fact, the low dosing frequency (once daily), the possibility of oral administration, the quick onset of the therapeutic action, the high clinical and microbiological success rate even with low duration cycles (5 days) and the good safety profile make the cost/efficacy ratio of moxifloxacin in the treatment of common airways infections very advantageous in comparison to those of all available treatment alternatives.

Parecoxib sodium is the first selective COX- 2 inhibitor to be available for parenteral administration. This pharmaceutical feature, alongside its favorable efficacy and safety profile, makes the new drug particularly suitable for simple and effective management of post-surgical pain. The first part of the present article describes the most important pharmacological characteristics of parecoxib and reviews the main efficacy and safety studies that were performed on patients presenting with post-surgical pain. Starting from these clinical data, the second part outlines the pharmacoeconomical profile of the drug in the Italian setting, focusing on the comparison with parenteral ketorolac, the most widely prescribed treatment for post-surgical pain in Italy. The available scientific evidence suggests that the introduction of parecoxib in the arsenal of available options for the management of this kind of patients in Italy may have a positive clinical and economical impact, despite of the higher drug acquisition price. In particular, the better tolerability shown by parecoxib in the comparison with non-selective NSAIDs would permit a reduction in the costs for the prevention and the cure of drugrelated adverse events and reduce the need for patient monitoring. Furthermore, the improved safety and the longer duration of the analgesic action could allow the management of more minor surgery patients in daysurgery units, with great economical advantages for the hospital and the health system and improved quality of life for the patients.

Doxofylline is a methyl-xanthine with bronchodilator activity which clinical efficacy in the treatment of asthma and COPD is equivalent to theophylline. Clinical trials prooved that while doxofylline is as effective as theophylline in the treatment of asthma, it is associated with lesser side effects. For our pharmacoeconomical evaluation, we employed the data of an international multi-centric study that compared the efficacy and tolerability of 12 weeks of treatment with either theophylline 250 mg tid, or doxofylline 400 mg tid, or placebo. The efficacy was evaluated with pulmonary function tests and by recording the number of asthma attacks and beta-2 agonist puffs: doxofylline 1200 mg/day and theophylline 750 mg/day resulted equally effective, but the former resulted better tolerated, as the adverse effects were lesser in number and severity. We performed a cost/effectiveness analysis in order to compare the two treatments, considering the perspective of the Italian health system (SSN) and of the Italian society. For the purposes of this analysis, the efficacy indices we considered were two: one simple, consisting in the number of avoided asthma attacks (AAA), and a more complex one, i.e. UATD (Utility Adjusted Therapy Days). For the construction of this index, we extracted the survival curve of the patients remaining in therapy; this curve showed that the cumulative number of therapy days is significantly greater in the doxofylline group, although the percentage of dropouts is similar at the end of the three months: this is due to the fact that the drop-outs in the theophylline group occur earlier after treatment start. The number of therapy days was then weighed for an utility index inversely proportional to the main daily number of avoided asthma attacks, thus obtaining the UATDs. The results of the cost/effectiveness analyses showed that doxofylline dominates theophylline treatment in asthma, as it is less expensive and more effective (in terms of AAAs and UATDs) for both considered decision-makers, i.e. Italian SSN and society. The consistency of these results was further confirmed by oneway sensitivity analyses.

Alprazolam is a triazolo analog of the 1,4 benzodiazepine class, widely used to treat patients with anxiety disorder, panic attacks and anxiety comorbidity with depressive disorder. Following oral administration, alprazolam is readily absorbed with peack plasma levels in 2 hours; extensive hepatic metabolism occurs and about 80% of the oral dose is excreted by kidney. The main metabolic route is hydroxylation catalyzed by cytochrome P450 3A: alpha-hydroxy alprazolam is partially active. Alprazolam possesses anxiolytic properties similar to other benzodiazepines; however, the triazolo ring confers to alprazolam a peculiar antidepressant and antipanic activity. Anxiety disorder, panic attacks with or without agoraphobia, and mixed anxiety-depressive disorder represent an heavy economic burden to National Health System (NHS) and to society. In the present work the clinical pharmacology and the therapeutic profile of alprazolam are reviewed and analysed under the pharmacoeconomic perspectives of the italian patients, General Practitioners, NHS and society.

In this study we mean to outline a brief pharmacoeconomic review of fluvoxamine, considering only its antidepressant use. Essential objective is to highlight all the variables of cost effectiveness, tolerance and safety that can lead some types of differential costs. This study analyses the epidemiology and the economic burden of depression and a pharmacoeconomic profile of fluvoxamine, with its characteristics of effectiveness, tolerance, safety and handiness. The pharmacoeconomic evaluation is conducted according to the cost minimization analysis (CMA), considering fluvoxamine, Selective Serotonine Reuptake Inhibitors (SSRI) and antidepressant tricycic as native treatments. Fluvoxamine differs from the others SSRI far the purchase cost and it’s more convenient than the antidepressant tricycic treatment, especially for long term therapy. Economic benefits can be distributed in a balanced way between the Italian national healthcare system (NACS), the society and the patients.

Aims Platinum chemotherapy has been shown to have potent antineoplastic activity against various tumours, especially testicular, bladder, ovarian, head and neck cancers. This activity is accompanied by side-effects of nephrotoxicity and cumulative myelosuppression, the latter frequently presenting as severe anaemia. Cisplatin and carboplatin nephrotoxicity might lower erythropoietin (Epo) secretion and, by this mechanism, contribute to the anaemia that follows therapy with this chemotherapeutic agent. The aim of the present work is to study the plasma immunoerythropoietin and haemoglobin levels of cancer patients treated with platinum or 5-fluorouracil-based chemotherapy. Methods Plasma was obtained from 25 patients who were about to receive chemotherapy for advanced malignancy: 15 treated with cisplatin or carboplatin and 10 with nonplatinum drugs. Blood was collected on the first day (before drug administration) and around day 15 of every chemotherapy course. Complete blood count, creatinine and immunoreactive Epo levels were also measured in 22 healthy volunteers. Results An increase in Epo levels occurred following every course of 5-FU or platinum based chemotherapy in patients with steady concentrations of creatinine and decreased levels of haemoglobin (Hb). In particular, we observed an increase after about 15 days of the chemotherapy treatment and the Epo levels declined toward normal just before the following course. This phenomenon was evident in every course. Conclusions Our results suggest that chemotherapy administration, using the current standards of hydration and forced diuresis, slightly lowered Hb levels but did not depress Epo production, both in 5-FU and in platinum treated subjects.

A specific method for the simultaneous determination of S-(+)Ibuprofen and R-(-)Ibuprofen enantiomers in human plasma is described. Adopting a high-performance liquid chromatographic (HPLC) system with spectrofluorometer detector, the compounds were extracted from plasma in alcohol medium and were separated on C18 column, using a solution of acetonitrile-water-acetic acid-triethylamine as mobile phase. The limit of quantitation was 0.1 microg/mL for both compounds. The method was validated by intra-day assays at three concentration levels and was used in a kinetic study in healthy volunteers. During the study we carried out inter-day assays to confirm the feasibility of the method.

Standard treatment for inflammatory bowel diseases (IBD) necessitates frequent intake of anti-inflammatory and/or immunosuppressive drugs, leading to significant adverse events. To evaluate the role solid lipid nanoparticles (SLN) play as drug delivery system in enhancing anti-inflammatory activity for drugs such as dexamethasone and butyrate in a human inflammatory bowel diseases whole-blood model. ELISA assay and the peripheral blood mononuclear cell (PBMC) cytokine mRNA expression levels were evaluated by quantitative SYBR Green real-time RT-PCR to determine the IL-1beta, TNF-alpha, IFN-gamma and IL-10 secretion in inflammatory bowel diseases patients' PBMC culture supernatants. There was a significant decrease in IL-1beta (p

The structure of both carrier and anticancer drug affects the intracellular fate of a transported drug. The study investigated in vitro intracellular accumulation and cytotoxic activity of doxorubicin-loaded solid lipid nanoparticles (SLN), doxorubicin in pegylated liposomes (Caelyx®) and free doxorubicin. Intracellular doxorubicin levels and cytotoxic activity were determined by high performance liquid chromatography with fluorescence detection, and by the trypan blue dye exclusion assay, respectively. Doxorubicin-loaded SLN inhibited cell growth more strongly than either free or liposomal doxorubicin, in human colorectal adenocarcinoma, HT-29, retinoblastoma Y79, and glioblastoma U373 cell lines. The IC50 values for doxorubicin-loaded SLN were significantly lower after 24 h exposure than those for free doxorubicin in all cell lines; after 48 h exposure they were lower than those for liposomal doxorubicin in HT-29 and Y79 cells. The enhanced cytotoxic activity of doxorubicin-loaded SLN was associated with increased drug incorporation in cells: intracellular doxorubicin levels were significantly enhanced after exposure to drug-loaded SLN versus either free or liposomal drug. Rate of intracellular accumulation and cytotoxic activity also differed among different cell lines; in particular, cells of epithelial origin were found to be more sensitive to doxorubicin-loaded SLN. In conclusion, the greater sensitivity of HT-29, Y79, and U373 cells to doxorubicin-loaded SLN than to the other drug formulations may be due to the capability of the delivery system to enhance drug action, through a marked uptake and accumulation of SLN within the cell.

Sulodexide is a highly purified glycosaminoglycan approved for leg ulcers treatment. It contains two principal components: heparan sulfate, a fast-moving heparin fraction, (80%) and dermatan sulfate (20%). Sulodexide is available as an oral agent and as an injectable preparation. Its pharmacological action is obtained by dose-dependent coagulation factors inhibition: dermatan sulfate upgrades the physiological action of a selective thrombin inhibitor, heparin cofactor II, and heparan sulfate depresses activated factor X, via an increase of antithrombin III action. The antithrombotic action is enhanced by platelet aggregation inhibition and by the activation of the fibrinolytic system. This paper summarizes the results of some of the main trials that evaluated sulodexide in the treatment of peripheral occlusive arterial disease and venous leg ulcers; a trial on prevention of recurrent deep venous thrombosis with sulodexide is also reviewed. We analyzed data about the clinical and economical impact of chronic venous insufficiency with a particular attention to the cost of medication, hospitalization and management of leg ulcers. The hypothetical savings correlated to the reduction of leg ulcers incidence and healing time attainable with sulodexide have been estimated. A comparison between the different acquisition costs of the drugs frequently used to treat leg ulcers is also provided. Finally we reviewed some quality of life trials in which the psychological and sociological influence of the disease and its treatments on the patient are assessed.

Tramadol is one of the preferred weak opioid agonists in the management of chronic pain, due to a good efficacy and safety profile, to a particularly low interference with cardiovascular and respiratory functions and a low dependence and abuse potential. The successful use of tramadol, nevertheless, is often limited by low patient compliance, a consequence of gastrointestinal side effects (mainly nausea and vomiting) and frequent dosing regimens, among other reasons. In this paper, clinical studies conducted on slow-release formulations of tramadol and other strategies for compliance improvement in various pain conditions are reviewed. From the examined literature, it appears that the strategy with the best compliance is the use of slow release (SR) formulations, which simplify dosing regimens and tend to have a somewhat better tolerability, and a slow dose escalation, which improves tolerability. The advantages of SR formulations have to be weighed against the superior acquisition cost and the slower onset of analgesia. A frame for the evaluation of the clinical and economical advantages and disadvantages of SR versus immediate release formulations of tramadol is also proposed.

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.

Tramadol is an effective central analgesic with a dual mechanism of action: antagonism on mu-opioid receptors and inhibition of serotonin and norepinephrine reuptake. In this paper a pharmacological, clinical and economical profile of its use in pain management is provided. Tramadol has proven effective in the treatment of moderate and severe pain associated with acute and chronic conditions of different ethiology, at oral or parenteral doses of about 50-100 mg every 4-6 hours. The maximal daily dose should not exceed 400 mg, less in case of liver or kidney dysfunction. Tramadol has low potential for physical or psychological dependence; the minimal likelihood of provoking typical opioid adverse events represents an advantage over other morphine-like agents. From a pharmacoeconomical point of view, tramadol prescription appears to be efficient: the comparisons conducted in the management of post-surgical pain have shown tramadol to be more convenient than the studied alternatives. Overall, tramadol appears to be a safe and effective drug for the management of pain and it is one of the most relevant week opioids to be used in the second step of the pain management latter proposed by the WHO. The recent introduction of generic tramadol permits to choose among more products and allows to obtain savings on the cost of managing acute and chronic painful conditions.

Orphan drugs definition should be related to prevalence criteria. In Europe the prevalence criterion is 5/10.000. These drugs are called “orphans” because the pharmaceutical industry has little interest under normal market conditions in developing and marketing products intended for only a small number of patients. For this reason governments have emphasized the need for economic incentives to encourage drug companies to develop and market orphan drugs. Aim of this study is the analysis of the contributing factors involved in the price definition of orphan drugs in Italy, focusing on the case of DepoCyte®, a new orphan drug recently approved by the European Medicines Agency. DepoCyte® is a slow-release formulation of cytarabine designed for intrathecal administration in the treatment of neoplastic meningitis due to metastatic cancers. It maintains cytotoxic concentrations of free cytarabine in the cerebrospinal fluid for more than 14 days following a single injection. In two randomized clinical trials DepoCyte® was compared to standard formulation of cytarabine, showing a better time to neurologic progression and survival trend in favor of DepoCyte®, associated with an improved mean change about quality of life in Karnofsky performance score. The innovative technology and the efficacy of DepoCyte® allow to frame some interesting pharmacoeconomical consequences: the results of the present work showed that DepoCyte® is more expensive but also more effective than standard formulation, and the new formulation-correlated improvement in the patients’ quality of life seems to justify the difference between the costs of the two alternatives.

Cardiovascular disease (CVD) remains one of the leading causes of mortality and morbidity worldwide. Since several pharmacological approaches are available for the reduction of incidence and severity of cardiovascular events and health resources in modern managed care systems are limited, the evaluation of the clinical and economical consequences of any treatment is very valuable for decison-makers and physicians. In this article we present a flexible pharmacoeconomic model that permits the calculation of the marginal costeffectiveness of cardiovascular prevention with ramipril, a drug of the class of ACE-inhibitors. The clinical data used for the modelization are derived from the HOPE (Heart Outcomes Prevention Evaluation) study, a landmark cardiovascular prevention study that showed how the benefits of ACE-inhibition with ramipril go beyond the effects on blood pressure, while Italian epidemiological, demographic and economical data make the results appliable to the Italian population. The model, structured as a decision tree comparing the alternatives “to treat” or “not to treat” with Markow chains at the terminal nodes, calculates the marginal cost-effectiveness of the preventive treatment in terms of cost/year of live saved. The model is characterized by high flexibility, as it allows health decision-makers to set epidemiological and economical data in order to reflect the local population at high risk for developing cardiovascular diseas. The model was tested on a high risk population, formed by all acute myocardial infarction survivors in Italy, and indicated that life-long treatment of this patients would yield significant clinical benefits, with a cost/ effectiveness of 3,932 euro/year of life saved. This value is well below the standards that are considered acceptable, and offsprings from the partial offset of pharmaceutical costs caused by the reduction in the expenses for diagnosis and treatment of the cardiovascular events avoided with the preventive therapy.

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

5-Fluorouracil (5-Fu) is a commonly used anticancer agent for treatment of solid tumours. Certain studies have reported conflicting results between individual plasma concentration levels and toxicity or therapeutic effects. For this reasons some authors proposed to evaluate the plasma levels of 5-Fu metabolites 5-fluorouridine, 5-fluoro-2′-deoxyuridine and 5-fluoro-5,6-dihydro-uracil. The aim of the present work is to develop and validate a new HPLC method simultaneously determining 5-fluorouracil and its three metabolites, to be used to study the plasma levels, therapeutic effects and toxicity in cancer patients. The analytes were separated on a 4.6 × 250 mm ODS1 (5 µm) not end-capped column, operating at room temperature. Elution was performed under isocratic conditions, employing a 1.5 mM K3PO4 mobile phase (pH 5). 5-Bromo-5,6-dihydro-uracil was used as internal standard. The limits of quantitation were 0.5 µg/mL for 5-fluorouracil, 1 µg/mL for 5-fluoro-5,6-dihydro-uracil, 3 µg/mL for 5-fluoro-2′-deoxyuridine and 5-fluorouridine; the stability, recovery, linearity, accuracy and specificity of the compounds were evaluated according to the criteria widely accepted. Using this method we measured plasma samples of 18 cancer patients treated with folinic acid (100 mg/m2) by intravenous administration, followed by an i.v. bolus of 5-Fu (400 mg/m2). The concentration levels of 5-fluorouracil and for 5-fluoro-5,6-dihydro-uracil were detectable in all the subjects while 5-fluorouridine and 5-fluoro-2′-deoxyuridine were present only in eight patients. Copyright © 2002 John Wiley & Sons, Ltd.

Pregnancy-related hypertension, intrauterine growth retardation, post-maturity and unfavorable local conditions are among the most frequent indications for labor induction. There are two competing strategies for the induction of labor in term pregnancies: formal induction with artificial rupture of the membranes and/or intravenous oxytocin on one side, and cervical ripening and induction with exogenous prostaglandins on the other. The use of prostaglandins in obstetrics relies on two pharmacological properties: the capacity of inducing the biochemical changes in the connective tissue of the cervix that lead to its maturation and the stimulation of the uterine smooth musculature. While the latter property is shared with oxytocin, the former offers great clinical advantages, in particular in those women that present an indication for labor induction but whose cervix, normally assessed with the use of the Bishop score, does not show “ripeness”, i.e. does not permit vaginal delivery. Since the acquisition cost of the prostaglandins is quite high, but the clinical benefit appears evident, several studies have analyzed the overall economical impact of their use, both as pre-induction cervical ripening agents and as induction drugs. When compared to a strategy of expectant management in term pregnancies without cervical ripeness, exogenous prostaglandin administration has proven to be more cost-effective and better accepted by the patients. Prostaglandins have also proven to be more cost-effective than oxytocin and/or amniotomy in women with an indication to labor induction and unripe cervix, due to the reduced number of induction failures and cesarean sections required with this strategy. The economical analyses that have compared oxytocin and prostaglandins in women with ripe cervices deliver more ambiguous data, but it appears that their cost-effectiveness is comparable. Furthermore, none of the reviewed studies has considered intangible costs, but it is a wide-spread opinion that induction with prostaglandins results in a more “natural” and less painful labor.

• Conclusions To assess the economic and clinical impact of the use of peginterferon α-2a (40KD) versus LAM for the treatment of HBeAg-negative CHB and versus IFN for the treatment of HBeAg-positive CHB disease in Italy. • Objective Chronic Hepatitis B (CHB) is caused by chronic infection with Hepatitis B Virus (HBV) and represents a major global health problem. Traditional CHB treatments are lamivudine (LAM) and interferon α-2a (IFN). Peginterferon α-2a (PEG) has been recently approved for the treatment of CHB disease.

The pharmacokinetics of ibuprofen enantiomers were investigated in a crossover study in which seven healthy male volunteers received single oral doses of 800 mg racemic ibuprofen as a soluble granular formulation (sachet) containing L-arginine (designated trade name: Spedifen), 400 mg (-)R-ibuprofen arginine or 400 mg (+)S-ibuprofen arginine. Plasma levels of both enantiomers were monitored up to 480 minutes after drug intake using an enantioselective analytical method (HPLC with ultraviolet detection) with a quantitation limit of 0.25 mg/l. Substantial inter-subject variability in the evaluated pharmacokinetic parameters was observed in the present study. After (+)S-ibuprofen arginine, the following mean pharmacokinetic parameters +/-SD were calculated for (+)S-ibuprofen: tmax 28.6 +/- 28.4 min; Cmax 36.2 +/- 7.7 mg/l; AUC 86.4 +/- 14.9 mg.h/l; t1/2 105.2 +/- 20.4 min. After (-)R-ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S-ibuprofen and (-)R-ibuprofen, respectively: tmax 90.0 +/- 17.3 and 50.5 +/- 20.5 min; Cmax 9.7 +/- 3.0 and 35.3 +/- 5.0 mg/l; AUC 47.0 +/- 17.2 and 104.7 +/- 27.7 mg.h/l; t1/2 148.1 +/- 63.6 and 97.7 +/- 23.3 min. After racemic ibuprofen arginine, the following mean pharmacokinetic parameters were calculated for (+)S- and (-)R-ibuprofen, respectively: tmax 30.7 +/- 29.1 and 22.9 +/- 29.8 min; Cmax 29.9 +/- 5.6 and 25.6 +/- 4.4 mg/l; AUC 105.1 +/- 23.0 and 65.3 +/- 15.0 mg.h/l; t1/2 136.6 +/- 20.7 and 128.6 +/- 45.0 min. Tmax values of S(+)- and (-)R-ibuprofen after a single dose of 400 mg of each enantiomer did not differ significantly from the corresponding parameters obtained after a single dose of 800 mg of racemic ibuprofen arginine, indicating that the absorption rate of (-)R- and (+)S-ibuprofen is not different when the two enantiomers are administered alone or as a racemic compound. An average of 49.3 +/- 9.0% of a dose of the (-)R-ibuprofen arginine was bioinverted into its antipode during the study period (480 minutes post-dosing). The percent bioinversion during the first 30 minutes after (-)R-ibuprofen arginine intake averaged 8.1 +/- 3.9%. The mean AUC of (+)S-ibuprofen calculated after 800 mg racemic ibuprofen arginine (105.1 +/- 23.0 mg.h/l) was lower than the mean AUC value obtained by summing the AUCs of (+)S-ibuprofen after administration of 400 mg (+)S-ibuprofen arginine and 400 mg (-)R-ibuprofen arginine (133.4 +/- 26.6 mg.h/l). In conclusion, the administration of Spedifen resulted in very rapid absorption of the (+)S-isomer (eutomer) with tmax values much lower than those observed for this isomer when conventional oral solid formulations such as capsules or tablets of racemic ibuprofen are administered. This characteristic is particularly favourable in those conditions in which a very rapid analgesic effect is required.