Solid lipid nanoparticles of cholesteryl butyrate inhibit the proliferation of cancer cells in vitro and in vivo models.

BACKGROUND AND PURPOSE: Solid lipid nanoparticles containing cholesteryl butyrate (cholbut SLN) can be a delivery system for the anti-cancer drug butyrate. These nanoparticles inhibit adhesion of polymorphonuclear and tumour cells to endothelial cells and migration of tumour cells, suggesting that they may act as anti-inflammatory and anti-tumour agents. Here we have evaluated the effects of cholbut SLN on tumour cell growth using in vitro and in vivo models. EXPERIMENTAL APPROACH: Cholbut SLNs were incubated with cultures of four tumour cell lines, and cell growth was analysed by assessing viability, clonogenic capacity and cell cycle. Effects on intracellular signalling was assessed by Western blot analysis of Akt expression. The in vivo anti-tumour activity was measured in two models of PC-3 cell xenografts in SCID/Beige mice. KEY RESULTS: Cholbut SLN inhibited tumour cell line viability, clonogenic activity, Akt phosphorylation and cell cycle progression. In mice injected i.v. with PC3-Luc cells and treated with cholbut SLN, . in vivo optical imaging and histological analysis showed no metastases in the lungs of the treated mice. In another set of mice injected s.c. with PC-3 cells and treated with cholbut SLN when the tumour diameter reached 2 mm, analysis of the tumour dimensions showed that treatment with cholbut SLN substantially delayed tumour growth. CONCLUSION AND IMPLICATIONS: Cholbut SLN were effective in inhibiting tumour growth in vitro and in vivo. These effects may involve, in part, inhibition of Akt phosphorylation, which adds another mechanism to the activity of this multipotent drug.

Innovative formulations for the controlled and site-specific delivery of antiinflammatory drugs.

Pharmaceutical technology has introduced a promising pathway in the future of medicine in particular nanotechnological innovations have provided the opportunity to design and develop efficient drug delivery systems able to target and treat several diseases, including those mediated by inflammation. The engineering of drug delivery systems can be used to target tissues involved in the pathology under treatment, to avoid early drug biological environmental degradation and to modulate drug pharmacokinetics. Glucocorticoids and non-steroidal anti-inflammatory drugs are the most commonly prescribed drug categories worldwide for the treatment of disorders associated with inflammation. Although glucocorticoids can be highly effective in treating inflammation, their systemic application is limited due to the high incidence of serious adverse effects, mainly in long-term treatment. Non-steroidal anti-inflammatory drugs are a heterogeneous group of compounds and most of them have unfavorable pharmacokinetics and pharmacodynamics, leading to adverse effects, such as gastrointestinal disorders. Therefore, the need for drug delivery systems for long term administration of anti-inflammatory drugs with a well-controlled release profile is evident. The aim of this review is to assess innovative colloidal drugs carriers, in particular liposomes and nanoparticles, with special focus on site-specific delivery for particularly problematic tissues such as the gastrointestinal tract, joints and eyes.

Cholesteryl butyrate solid lipid nanoparticles inhibit the adhesion and migration of colon cancer cells.

BACKGROUND AND PURPOSE Cholesteryl butyrate solid lipid nanoparticles (cholbut SLN) provide a delivery system for the anti-cancer drug butyrate. These SLN inhibit the adhesion of polymorphonuclear cells to the endothelium and may act as anti-inflammatory agents. As cancer cell adhesion to endothelium is crucial for metastasis dissemination, here we have evaluated the effect of cholbut SLN on adhesion and migration of cancer cells. EXPERIMENTAL APPROACH Cholbut SLN was incubated with a number of cancer cell lines or human umbilical vein endothelial cells (HUVEC) and adhesion was quantified by a computerized micro-imaging system. Migration was detected by the scratch 'wound-healing' assay and the Boyden chamber invasion assay. Expression of ERK and p38 MAPK was analysed by Western blot. Expression of the mRNA for E-cadherin and claudin-1 was measured by RT-PCR. KEY RESULTS Cholbut SLN inhibited HUVEC adhesiveness to cancer cell lines derived from human colon-rectum, breast, prostate cancers and melanoma. The effect was concentration and time-dependent and exerted on both cancer cells and HUVEC. Moreover, these SLN inhibited migration of cancer cells and substantially down-modulated ERK and p38 phosphorylation. The anti-adhesive effect was additive to that induced by the triggering of B7h, which is another stimulus inhibiting both ERK and p38 phosphorylation, and cell adhesiveness. Furthermore, cholbut SLN induced E-cadherin and inhibited claudin-1 expression in HUVEC. CONCLUSION AND IMPLICATIONS These results suggest that cholbut SLN could act as an anti-metastastic agent and they add a new mechanism to the anti-tumour activity of this multifaceted preparation of butyrate.

High energy shock waves and 5-aminolevulinic for sonodynamic therapy: effects in a syngeneic model of colon cancer.

The cytotoxic effect of the natural porphyrin precursor 5-aminolevulinic acid (ALA) exposed to high energy shock waves (HESW) was investigated in vitro on DHD/K12/TRb rat colon cancer cells and in vivo on a syngeneic colon cancer model. In vitro, viable cell growth was determined by trypan blue exclusion assay and cell death was investigated by flow cytometry. ALA (50 µg/ml) and HESW (E1, EFD = 0.22 mJ/mm², 1000 shots or E2, EFD = 0.88 mJ/mm², 500 shots) showed a significant reduction of cancer cell proliferation at day 3 compared to cells exposed to ALA (p < 0.01) or HESW (p < 0.001) alone. An enhancement of necrotic and apoptotic cells was observed after combined treatment at day 1 with ALA and HESW E1 (a 3.1 and 6.4 fold increase vs ALA alone) or E2 (a 3.4 and 5.3 fold increase vs ALA alone). In vivo, apoptosis detection was carried out by TUNEL assay, the pro-apoptotic gene Bad and Bcl-2 mRNA expression was evaluated by quantitative SYBR Green real time RT-PCR and cleavage of poly(ADP-ribose)-polymerase (PARP) was investigated by Western Blotting. An enhancement of apoptosis was observed in tumour tissues after the combined treatment at day 1 with ALA (375 mg/kg i.v.) and HESW (E2) compared to that of ALA exposure alone with improved apoptotic index (a 2.0 fold increase), Bad enhanced mRNA expression (p < 0.01), Bcl-2 decreased mRNA expression (p < 0.05) and increased PARP cleavage. The interaction between HESW and ALA is then effective in inducing apoptosis on a syngeneic colon cancer model.

Oral bioavailability of silymarin phytocomplex formulated as self-emulsifying pellets.

The objective of this study was to develop new solid self-emulsifying pellets to deliver milk thistle extract (silymarin). These pellets were prepared via extrusion/spheronisation procedure, using a self-emulsifying system or SES (Akoline MCM®, Miglyol®, Tween 80®, soy lecithin and propylene glycol), microcrystalline cellulose and lactose monohydrate. To select the most suitable formulations for extrusion and spheronisation, an experimental design of experiences was adopted. The screening amongst formulations (13 different blends) was performed preparing pellets and evaluating extrusion profiles and quality of the spheronised extrudates. The pellets were characterised for size and shape, density, force required to crush them. Although more than one type of pellets demonstrated adequate morphological and technological characteristics, pellets prepared from formulation 7 revealed the best properties and were selected for further biopharmaceutical investigations, including in vitro dissolution and in vivo trials on rats to study serum and lymph levels after oral administration of the pellets. These preliminary technological and pharmacokinetic data demonstrated that extrusion/spheronisation is a viable technology to produce self-emulsifying pellets of good quality and able to improve in vivo oral bioavailability of main components of a phytotherapeutic extract of more than 100 times by enhancing the lymphatic route of absorption.

Cytotoxicity of anticancer drugs incorporated in solid lipid nanoparticles on HT-29 colorectal cancer cell line.

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.

Determination of disodium clodronate in human plasma and urine using gas-chromatography-nitrogen-phosphorous detections: validation and application in pharmacokinetic study.

We present a specific method for the determination of disodium clodronate in human plasma and urine using a gas-chromatographic system with nitrogen phosphorus detector (NPD). The compound was extracted from plasma and urine samples by an anion-exchange resin and derivatizated with bistrimethylsilyltrifluoroacetamide (BSTFA). Sodium bromobisphosphonate was used as internal standard. The calibration curves were linear in both plasma and urine, with a regression coefficient r > 0.9975 in plasma and r > 0.9977 in urine. The limit of quantitation was 0.3 microg/ml in plasma and 0.5 microg/ml in urine. The method was validated by intra-day assays at three concentration levels. During the study we carried out inter-day assays to confirm the feasibility of the method. The precision in plasma at 0.5, 15, and 45 microg/ml was 12.4, 0.2, and 6.5% (n = 40), respectively; in urine at 0.8, 8, and 40 microg/ml it was 8.6, 6.4, and 9.3% (n = 40), respectively. The method was accurate and reproducible, and was successfully applied to determine the pharmacokinetic parameters of clodronate in healthy volunteers after intravenous infusion and intramuscular injection of 200 mg of the compound. The Cmax after intravenous infusion and intramuscular injection was 16.1 and 12.8 microg/ml, respectively. AUC(0-48 h) after infusion administration and intramuscular injection was 44.2 +/- 18.0 and 47.5 +/- 12.4 h microg/ml, respectively. The elimination half-life in both administrations was 6.31 +/- 2.7 h.

Long-term analgesic effect of clodronate in rodents.

Several studies have shown that treatment with bisphosphonates can reduce the pain associated with different painful diseases. In a previous study we demonstrated that in mice two bisphosponates, clodronate and pamidronate, had an antinociceptive effect under acute conditions not related to bone processes, after in vein (iv) or intracerebroventricular (icv) injection. The present study tested the time-dependent antinociceptive action of clodronate and pamidronate in comparison with that of acetylsalicylic acid (ASA) and morphine after iv and icv injection using the tail-flick test in acute and chronic treatment. The effects of clodronate on other measures of animal behaviour were also evaluated. In the tail-flick test, administration of clodronate iv produced an antinociceptive effect that was greater than that of ASA and statistically significant up to 16 h; pamidronate iv showed a significant antinociceptive effect for only 6 h. Clodronate and pamidronate icv showed an increase in tail-flick latency time that was significant and lasted for 16 and 6 h, respectively, while morphine produced an antinociceptive effect for 24 h. In the test we found significant differences between male and female mice in the latency time values but not in the length of the analgesic effect. In the chronic treatment paradigm, clodronate produced a significant increase of the tail-flick latency after the first injection. The analgesic effect increased up to 50% after 5 days of treatment. Significant analgesic effects were still present after 3, 7, and 14 days from the end of treatment. Clodronate did not produce any significant behavioural effects in the Rota-rod test, pentobarbital-induced sleeping time, and locomotor activity cage. These data indicate that clodronate presents a central and peripheral prolonged antinociceptive effect, without any behavioural side effects.

Dexibuprofen (S+-isomer ibuprofen) reduces gastric damage and improves analgesic and antiinflammatory effects in rodents.

UNLABELLED: We determined the analgesic and antiinflammatory actions and the related acute mucosal gastric damage from the active S(+)-isomer ibuprofen (dexibuprofen), in comparison with those of the standard racemic formulation of ibuprofen in rodents. The antinociception was evaluated by hot-plate and tail-flick methods after IV and oral (PO) administration in mice and after PO administration in rats. S(+)-Ibuprofen was at least twice more potent than the ibuprofen racemic formulation. The antiinflammatory action of the test compound, assessed with the abdominal constriction test in mice (IV and PO) and with hind paw edema in rats (IV and PO), was found to be significantly more potent than that of ibuprofen after IV treatment in mice and PO administration in rats. Moreover, the test compound caused significantly less mucosal gastric damage than the racemic formulation administered at identical doses (50 mg/kg PO in rats). In conclusion, the S(+)-ibuprofen isomer was found to be more potent than the racemic formulation in analgesic and antiinflammatory tests and presented fewer gastric toxic effects. On the basis of the results of this work, we suggest that the administration of chemical entities, such as R(-)-ibuprofen, should be avoided if they are not essential for the anticipated therapeutic activity. IMPLICATIONS: Ibuprofen is a nonsteroidal antiinflammatory drug often prescribed as a racemic formulation. We studied the analgesic and antiinflammatory effects of the active S(+)-isomer. The S(+)-ibuprofen was found to be more potent than the racemic formulation and produced less acute gastric damage.

Simultaneous HPLC determination of 5-fluorouracil and its metabolites in plasma of cancer patients.

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 x 250 mm ODS1 (5 micro m) not end-capped column, operating at room temperature. Elution was performed under isocratic conditions, employing a 1.5 mM K(3)PO(4) mobile phase (pH 5). 5-Bromo-5,6-dihydro-uracil was used as internal standard. The limits of quantitation were 0.5 micro g/mL for 5-fluorouracil, 1 micro g/mL for 5-fluoro-5,6-dihydro-uracil, 3 micro g/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/m(2)) by intravenous administration, followed by an i.v. bolus of 5-Fu (400 mg/m(2)). 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.

Transmucosal transport of tobramycin incorporated in solid lipid nanoparticles (SLN) after duodenal administration to rats. Part II--tissue distribution.

Tobramycin-loaded solid lipid nanoparticles (SLN) were prepared and administered by duodenal and intravenous (i.v.) routes to rats and the tissue distributions were determined successively at fixed times (30 min, 4 h and 24 h) and compared to those of the tobramycin solution after i.v. administration. The tissue distribution between tobramycin-loaded SLN administered duodenally and i.v. was different. A marked difference between tobramycin-loaded SLN administered duodenally and tobramycin solution administered i.v. was also evidenced. In particular, the amounts of tobramycin in the kidneys after tobramycin-loaded SLN administration either duodenally or i.v. were lower than after administration of i.v. solution. Tobramycin-loaded SLN were able to pass across the blood-brain barrier in rats to a greater extent after i.v. injection than after duodenal administration.

Analgesic effect of bisphosphonates in mice.

Bisphosphonates are analogues of inorganic pyrophosphate and are inhibitors of bone resorption. Many derivatives have been developed for the treatment of enhanced bone resorption; several reports reveal that treatment with bisphosphonates is able to reduce the pain associated with different painful diseases. This study tested the antinociceptive action of four bisphosphonates, clodronate, alendronate, pamidronate and etidronate, in comparison with that of morphine and acetylsalicylic acid using two algesimetric tests in mice, tail-flick and writhing tests. In the tail-flick test, after intravenous (i.v.) injection, a dose-dependent antinociception was present after pamidronate, clodronate and acetylsalicylic acid whereas etidronate and alendronate produced an analgesic effect only with the highest dose tested. We also studied the central effect of clodronate and pamidronate and, after intracerebroventricular injection, both bisphosphonates showed a dose-dependent antinociceptive effect. In the writhing test clodronate and pamidronate showed a statistically significant antinociceptive action after i.v. and intramuscular administration. To verify if clodronate and pamidronate could modulate the peripheral opioid receptors we evaluated the gastrointestinal transit time in mice, but we did not find any effect on the gastrointestinal motility. These data indicate that clodronate and pamidronate present a central and peripheral antinociceptive effect; however, the main mechanism cannot be determined from the present data. We discuss the possible pharmacological hypothesis to interpret the present results. The findings suggest a pharmacological role of the bisphosphonates in the modulation of antinociception even in acute conditions not related to accelerated osteolytic and inflammatory response, with a possible clinical application to control pain.

Transmucosal transport of tobramycin incorporated in SLN after duodenal administration to rats. Part I--a pharmacokinetic study.

Tobramycin-loaded solid lipid nanospheres (SLN) were prepared and administered to rats into the duodenum; their behaviour was compared to that of tobramycin-loaded SLN administered intravenously (i.v.). A tobramycin control solution was also administered to rats. Tobramycin in solution is not absorbed by the gastrointestinal route, while tobramycin incorporated in the SLN is absorbed. A high concentration of tobramycin is still present in plasma 24 hours after the duodenal administration of tobramycin-loaded SLN. Tobramycin-loaded SLN administered i.v. showed a prolonged circulation time compared to the i.v. administered tobramycin solution. The AUC of tobramycin in SLN administered duodenally is higher than those of tobramycin in SLN and in solution administered i.v.

Biodistribution of stealth and non-stealth solid lipid nanospheres after intravenous administration to rats.

Drug-free stealth and non-stealth solid lipid nanospheres (SLNs) were administered intravenously to rats to evaluate their tissue distribution and their transport across the blood-brain barrier. Two types of experiments were performed using unlabelled and labelled SLNs. Rats were administered labelled non-stealth or stealth nanospheres (NSSLNs and SSLNs) and their tissue distribution was monitored for 60 min. In another experiment, rats were injected with unlabelled NSSLNs or SSLNs and the cerebrospinal fluid (CSF) was analysed using transmission electron microscopy (TEM) to confirm the presence of the SLNs. Some differences were found in the biodistribution between labelled NSSLNs and SSLNs. In particular, the radioactivity in the liver and the lung was much lower for SSLNs than for NSSLNs, confirming a difference in their uptake. Both types of SLNs were detected in the brain. TEM analysis showed both types of SLNs in rat CSF.

Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats.

Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin were prepared as drug delivery systems. The pharmacokinetics and tissue distribution of doxorubicin in these SLN were studied after i.v. administration to conscious rats and were compared to the commercial solution of doxorubicin. The same dose of each formulation (6 mg kg(-1)of body weight) of doxorubicin was injected in the rat jugular vein. Blood samples were collected after 1, 15, 30, 45, 60 min and 2, 3, 6, 12, and 24 h after the injection. Rats were sacrificed after intervals of 30 min, 4 h, and 24 h and samples of liver, spleen, heart, lung, kidney, and brain were collected. In all samples, the concentration of doxorubicin and of the metabolite, doxorubicinol, were determined. Doxorubicin and doxorubicinol were still present in the blood 24 h after injection of stealth and non-stealth SLN, while they were not detectable after the injection of the commercial solution. The results confirmed the prolonged circulation time of the SLN compared to the doxorubicin solution. In all rat tissues, except the brain, the amount of doxorubicin was always lower after the injection of the two types of SLN than after the injection of the commercial solution. In particular, SLN significantly decreased the heart concentration of doxorubicin.

Plasma erythropoietin concentrations in patients receiving intensive platinum or nonplatinum chemotherapy.

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.

Determination of Ibuprofen in human plasma by high-performance liquid chromatography: validation and application in pharmacokinetic study.

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.

Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN).

The pharmacokinetics of doxorubicin incorporated as ion-pair into solid lipid nanospheres (SLN) was compared with that of the commercial solution of the drug. Male albino rats (Wistar-derived strain) were treated i.v. with equivalent doses (6 mg kg(-1)) of two different doxorubicin formulations: an aqueous dispersion of SLN carrying doxorubicin and a commercial doxorubicin solution (Adriablastina). These formulations were injected, under general anaesthesia, through a cannula into the jugular vein and blood samples were collected at 1, 15, 30, 45, 60, 120 and 180 min after administration. After 180 min rats were killed and samples of liver, heart, lung, kidney, spleen and brain were collected. Blood and tissue samples were analysed by a spectrofluorimetric method. The anthracycline concentration in the blood was markedly higher at each point times with the SLN than with the commercial solution. The drug concentration was also higher in the lung, spleen and brain. SLN-treated rats showed a lower doxorubicin concentration in liver, heart and kidney. The results showed that SLN increased the area under the curve (0-180 min) of doxorubicin compared to conventional doxorubicin solution and led to a different body distribution profile.

Economic impact of resistance in the community.

Antimicrobial resistance is assumed to be an important health problem and an economic burden to society. However, the relationship between the emergence of in vitro microbiological resistance and its clinical and socioeconomic consequences has not yet been satisfactorily determined for either nosocomial or community-acquired infection. In the case of both nosocomial and community-acquired infection, previous exhaustive reviews of published and unpublished reports concluded that mortality, likelihood of hospitalization, and length of hospital stay were usually at least twice as great for patients infected with drug-resistant strains as for those infected with drug-susceptible strains of the same bacteria. However, evaluation of the economic impact of resistance is still problematic and the adverse economic and health effects of drug-resistant bacterial infections can only be roughly quantified. Decision analysis models, such as decision trees, can aid evaluation of the impact of resistance on health and economic outcomes from the perspective of a given decision maker. A model of cost analysis should be based on a knowledge of the incremental consumption of resources specifically dependent on the dynamics of antimicrobial resistance in a given clinical setting (e.g. home care or hospital care). In general, we can assume that the increased rate of isolation of resistant strains from community-acquired infections correlates positively with an increase in morbidity, mortality, risk of hospitalization and the need for additional days in hospital and for more expensive and powerful antibiotics. We implemented and simulated a general decision-tree model to analyse the influence of antibiotic resistance on the economic outcomes of community-acquired lower respiratory tract infections, from the perspective of both society and the health-care local organization (HCLO). This model allows simulation of the impact of different degrees of resistance on the direct costs of an antibiotic therapy as well as on the cost-effectiveness of antibiotics with different degrees of resistance.