No description available.

Statins, hydroxymethylglutaryl-coenzyme-A reductase inhibitors (HMG-Co-A), are known to reduce plasma cholesterol levels. Interestingly, Simvastatin was previously reported to have a positive effect on the proliferation and odontoblastic differentiation of human dental pulp cells. However, the biocompatibility of Simvastatin has not been studied thoroughly. The purpose of this study was to further compare the effectiveness of different concentrations of Simvastatin on the attachment, proliferation, differentiation, toxicity, mineralization, and flow cytometry of human dental pulp cells (HDPCs) and osteoblasts. HDPCs and osteoblasts were cultured with Simvastatin at various concentrations of 1, 10, 25, 50, 75, 100 μmol/L, and 0 μmol/L was used as a control. The cell attachment was evaluated at 16 hours for HDPCs and 9 hours for osteoblasts. The proliferation rate, differentiation, cytotoxicity, and mineralization were investigated at 7, 14 and 21 days. Cell cycle and apoptosis were assessed at 1 and 3 days. Statistical analysis was performed using ANOVA. P-values ≤0.05 were considered statistically significant. The results showed that 25 μmol/L demonstrated the highest cell attachment efficiency when compared to the control in HDPCs (P<0.05). There was no statistical significance (P>0.05) amongst the groups in the cell attachment efficiency in osteoblasts. All tested concentrations showed a significant decrease in the proliferation rate and mineralization (P<0.001) and an increase in cytotoxicity and cytostasis (P<0.001) in both cell types. ALP levels increased in HDPCs and osteoblasts (P<0.001). DSP and RUNX2 levels decreased in HDPCs (P<0.001). OSC levels were increased in osteoblasts, but RUNX2 was decreased (P<0.001). Cell cycle and apoptosis significantly increased as time increased (P<0.001) in both cell types. In conclusion, the present findings showed that Simvastatin adversely affects the proliferation, cell viability of HDPCs and osteoblasts by inducing apoptosis, which were confirmed by flow cytometry results. There was an increase in the odontogenic and osteogenic markers hinting at early differentiation, which decreased as time increased. / 2025-07-10T00:00:00Z

No description available.

Noroviruses (NoVs) are a cause of nonbacterial acute gastroenteritis affecting all ages. NoV infections result in over 200,000 pediatric deaths in developing countries annually. Vaccine development has been hindered by the lack of cell culture systems and small animal models; thus, vaccine development has relied upon recombinant VP1 capsid proteins, such as virus-like particles (VLPs) and P particles. P particles are a novel vaccine candidate derived from expression of the VP1 protruding (P) domain, while VLPs require expression of the full-length VP1. My studies utilize a gnotobiotic (Gn) pig model of human NoV infection and diarrhea to evaluate the protective efficacy and T cell responses induced by P particles and to compare them with prior NoV infection (NoVPO) and VLPs. Gn pigs received 100 µg of P particles (LoPP) or VLPs, 250 µg P particles (HiPP), or adjuvants only intranasally at post-inoculation day (PID) 0, 10, and 21. Monophosphoryl lipid A and chitosan were used as mucosal adjuvants. At PID 28, a subset of pigs were orally challenged with 10 median infectious doses (ID50) NoV. NoVPO, LoPP, HiPP, and VLPs provided partial protection from diarrhea (83%, 47%, 60%, and 60% protection rates, respectively). Only NoVPO and HiPP provided protection from shedding (49% and 60% protection rates, respectively) and also reduced the number of CD25- regulatory T cells (Tregs) in duodenum following challenge. NoV primary infection induced an overall pro-Treg and low, transient Th1 response. LoPP induced stronger overall T cell responses compared to VLPs, including activated CD4+ T cells and duodenal CD8+IFN-γ+ T cells, suggesting that P particles are more immunogenic than VLPs. I also evaluated the effects of simvastatin, a cholesterol-reducing drug that increases NoV infectivity, on P particle vaccine efficacy. Simvastatin abolished P particle-induced protection and significantly increased diarrhea severity. Simvastatin reduced total numbers of duodenal mononuclear cells, IFN-γ+ T cells pre-challenge, and Tregs post-challenge, indicating that simvastatin impairs development of immune system and immune responses. Findings from these studies elucidate potential mechanisms behind P particle-induced immunity and reveal the negative effects of simvastatin on NoV-induced protective immunity. The knowledge will facilitate the development of effective NoV vaccines. / Ph. D.

Der Hedgehog Signaltransduktionsweg (HhP) ist in der Embryologie und für die Tumor-entstehung bedeutsam und kann durch den spezifischen Antagonisten Cyclopamin (Cyc) inhibiert werden. Simvastatin (Sim) kann die für den HhP essentielle Cholesterolsynthese blockieren. Die therapeutische Unterdrückung des HhP in Kopf-Hals-Plattenepithel-karzinomen (HNSCC) zu untersuchen erschien nach verschiedenen Literaturhinweisen lohnend. In den Experimenten, deren Ergebnisse bereits in Artikeln publiziert wurden, konnten antineoplastische Effekte von Cyc bzw. Sim allein und in Kombination mit den Leitlinientherapeutika Cisplatin (Cis) oder Docetaxel (DTX) an der epithelialen Zelllinie KB, den Kopf-Hals-Zelllinien FaDu und HN-5, sowie an primären HNSCC ex vivo nachgewiesen werden. Biopsien von 49 HNSCC wurden im FLAVINO-Assay mit Cyc bzw. Sim in steigenden Konzentrationen allein und kombiniert mit Cis oder DTX untersucht. In die Auswertung konnten gemäß den Einschlusskriterien (histopathologisch bestätigtes HNSCC und suffiziente Koloniebildung im FLAVINO-Assay) 18 HNSCC einbezogen werden. Bei den Voruntersuchungen führten sowohl Cyc als auch Sim zu einer signifikanten Zeit- und Dosis-abhängigen Reduktion der Lebensfähigkeit von KB, FaDu und HN-5. Ebenso unterdrückten sowohl Cyc als auch Sim die Koloniebildung epithelialer Zellen im FLAVINO-Assay hochsignifikant. Auch tolerierbare Cis- und DTX-Konzentrationen zeigten eine signifikante Wachstumshemmung. In der Analyse des Interaktionsmodus wurde in den untersuchten Kombinationen (Sim+Cis, Sim+DTX, Cyc+Cis und Cyc+DTX) in allen Fällen Additivität als prädominanter Interaktionstyp ermittelt. Die Ergebnisse dieser Arbeit weisen den HhP als potentielles Target in HNSCC aus. Potentere und human besser verträgliche HhP-Blocker sollten unsere Ergebnisse bestätigen und in klinischen Studien getestet werden. Auch die Wirksamkeit von Sim auf HNSCC sollte in prospektiven klinischen Studien weiter analysiert und bestätigt werden. Möglicherweise vermag Sim bzw. die HhP-Blockade zukünftig einen Beitrag zur Therapie von HNSCC im Rahmen multimodaler Therapiekonzepte zu leisten.

<p>Interindividualne razlike u sastavu i aktivnosti crevne mikroflore mogu uticati na metabolizam lekova kao i na njihov konačan terapijski odgovor. Simvastatin je lek iz grupe statina i karakteri&scaron;e ga izuzetno mala rastvorljivost u vodi, mala bioraspoloživost (&lt;5%) i velike interindividualne razlike u terapijskom odgovoru čiji uzroci nisu u potpunosti obja&scaron;njeni. Poslednjih godina velika pažnja se posvećuje ispitivanjima žučnih kiselina u razvoju novih farmaceutskih formulacija zbog svoje uloge u solubilizaciji i modifikaciji prodora lekova kroz biolo&scaron;ke membrane. Zbog svega navedenog, u fokusu na&scaron;eg istraživanja su bile potencijalne interakcije između simvastatina, probiotskih bakterija i žučnih kiselina o kojima se vrlo malo zna, a od izuzetne su važnosti, zbog mogućeg uticaja na farmakokinetske i farmakodinamske osobine simvastatina, pa samim tim i na konačan terapijski odgovor kod pacijenta.Cilj istraživanja je bio da se ispita prodor i metabolizam simvastatina u probiotskim bakterijama kao i uticaj različitih žučnih kiselina na transport ovog leka u bakterijske ćelije. Takođe, cilj je bio da se ispita uticaj soli žučnih kiselina na distribucioni koeficijent simvastatina, kao i interakcije žučnih kiselina sa simvastatinom na nivou transportnih proteina probiotskih bakterija kako bi se objasnila priroda očekivanih interakcija.Identifikacija i kvantifikacija uzoraka vr&scaron;ena je metodom tečne hromatografije sa masenom spektrometrijom (LC-MS/MS). Kori&scaron;ćenjem programskih paketa VolSurf+ i Molinspiration, za identifikovane metabolite su izračunati molekulski deskriptori koji opisuju fizičko-hemijske i farmakokinetske osobine molekula. Određivanje distribucionog koeficijenta vr&scaron;eno je Shake-flask metodom. Interakcije žučnih kiselina sa simvastatinom na nivou transportnih proteina probiotskih bakterija ispitane su doking studijama pomoću SwissDock programa. Prilikom dvadesetčetvoročasovne inkubacije sa probiotskim bakterijama uočen je statistički značajan pad koncentracije simvastatina u ekstracelularnom sadržaju. Ukupan sadržaj simvastatina, kao zbir ekstracelulamog i intracelularnog sadržaja, je tokom čitavog ispitivanog perioda bio statistički značajno niži u odnosu na kontrolnu grupu bez probiotika navodeći na zaključak da se deo simvastatina tokom vremena metabolisao pod dejstvom enzima ispitivanih bakterija. Detektovano je i identifikovano 8 metaboličkih produkata simvastatina. Na osnovu izračunatih vrednosti molekulskih deskriptora, očekuje se da će metabolit M-452, koji predstavlja hidroksilovani produkt simvastatinske kiseline, pokazati najbolje rezultate u pogledu fizičko-hemijskih osobina i bioraspoloživosti u biolo&scaron;kom sistemu. Žučne kiseline nisu dovele do statistički značajne modifikacije transporta simvastatina u/iz probiotskih bakterija. Ipak, u nekim vremenskim tačkama primećena je ne&scaron;to veća koncentracija leka u ekstracelulamom prostoru u grupama sa žučnim kiselinama. Ove razlike se mogu delimično objasniti rezultatima određivanja distribucionog koeficijenta koji su pokazali da ispitivane žučne kiseline dovode do statistički značajnog smanjenja distribucionog koeficijenta simvastatina usled povećanja rastvorljivosti u vodenoj fazi. Rezultatima doking studija procenjeno je da ispitivane žučne kiseline imaju veći afinitet prema čak 80% multidrug transportera ispitivanih bakterija u odnosu na simvastatin &scaron;to govori o mogućnosti ostvarivanja interakcija žučnih kiselina sa ovim lekom na nivou transportnih proteina probiotskih bakterija. Na osnovu dobijenih rezultata možemo zaključiti da probiotske bakterije imaju ogroman uticaj na sudbinu simvastatina u biolo&scaron;kom sistemu. Uzimajući u obzir činjenicu da probiotske bakterije ulaze u sastav normalne crevne flore i da svaki organizam poseduje specifičan bakterijski sastav, trebalo bi posvetiti vi&scaron;e pažnje ispitivanju njegovog uticaja na farmakokinetiku lekova. Neophodna su dalja in vivo ispitivanja kako bi se utvrdila potencijalna farmakolo&scaron;ka aktivnost identifikovanih metabolita simvastatina nastalih pod dejstvom enzimske aktivnosti probiotskih bakterija. Povećanje rastvorljivosti simvastatina pomoću žučnih kiselina otvara mogućnost za dalja istraživanja u cilju razvoja novih farmaceutskih formulacija sa pobolj&scaron;anom bioraspoloživosti i farmakokinetskim osobinama.</p> / <p>Interindividual differences in the composition and activity of the gut microflora may affect the metabolism of drugs as well as their final therapeutic response. Simvastatin is drug from the group of statins and has extremely low water solubility, low bioavailability (&lt;5%) and high interindividual differences in therapeutic response whose causes are not fully understood. In recent years, great attention has been paid to studies of bile acids in the development of new pharmaceutical formulations because of their role in the drug solubilization and modification of drug transport through biological membranes. Accordingly, interactions between simvastatin, probiotic bacteria and bile acids were the focus of our research due to great importance and potential influence on the pharmacokinetic and pharmacodynamic properties of simvastatin, and therefore the final therapeutic response in the patients. The aim of the study was to investigate the simvastatin transport and metabolism in probiotic bacteria as well as the effect of various bile acids on drug transport into the bacterial cell. Additonally, the aim was to investigate the influence of bile salts on the distribution coefficient of simvastatin, and the interactions of bile acids with simvastatin at the level of probiotic transport proteins in order to elucidate the nature of expected interactions. Identification and quantification of samples were performed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Molecular descriptors that describe the physico-chemical and pharmacokinetic properties of identified metabolites were calculated using the software packages VolSurf+ and Molinspiration. Determination of the distribution coefficient was performed using Shake-flask method. Interaction of bile acids with simvastatin at the level of bacterial transport proteins were studied using docking studies with SwissDock program. During the twenty-four hours of incubation with probiotic bacteria, simvastatin concentrations in the extracellular contet showed a statistically significant decrease. The total amount of simvastatin, as the sum of the extracellular and intracellular amount, during the whole study period, was significantly lower in comparison with control group without probiotics, suggesting that the part of simvastatin was metabolized by the enzymatic activity of studied bacteria. Accordingly, eight metabolic products of simvastatin were detected and identified. Based on the calculated values of molecular descriptors, it is expected that the metabolite M-452, which is the hydroxylated product of simvastatin acid, will show the best results in terms of physico-chemical properties and bioavailability in biological system. Bile acids did not show a significant influence on simvastatin transport into probiotic bacteria. However, in some time points, slightly higher drug concentrations in the extracellular medium in groups with bile acids were observed. These differences can be partly explained by the results of the determination of the distribution coefficients which showed that investigated bile acids lead to a statistically significant decrease in simvastatin distribution coefficient due to increased solubility in the aqueous phase. The results of docking studies estimated that studied bile acids have stronger affinities for the 80% of bacterial multidrug transporters compared to simvastatin indicating the possibility of achieving the interactions of bile acids with simvastatin at the level of transport proteins of probiotic bacteria. Based on the obtained results it could be concluded that probiotic bacteria have great influence on the fate of simvastatin in a biological system. Taking into account the fact that probiotic bacteria are the normal part of gut microflora and that each individual has specific bacterial fingerprint, more attention should be paid on studying its influence on drug pharmakocinetics. Further in vivo studies are required in order to determine potential pharmacological activity of identified simvastatin metabolites. Increased water solubility of simvastatin with bile acids may open the possibility for further investigations with the aim of development of new pharmaceutical formulation with improved bioavailability and pharmacokinetic properties.</p>

Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is used for the treatment of hyperlipidemia. Simvastatin has recently been studied for its potential use in cancer therapy. In-vitro studies have shown that simvastatin displays anticancer activity, but at concentrations unlikely to be achieved in patients being receiving typical antihyperlipidemic treatment doses. Thus, several clinical trials were conducted to study the tolerability of high dose statins in cancer patients. The maximum tolerated dose of simvastatin was determined to be 15 mg/kg/day, 25-fold higher than a typical dose. However, it is not known if simvastatin plasma concentrations can reach those found to be effective in-vitro. In this context, we initiated a clinical study to determine the pharmacokinetics of high dose simvastatin in patients with chronic lymphocytic leukemia. For this purpose, an LC-MS/MS method was developed and validated for the quantitation of simvastatin and its acid form in plasma and peripheral blood mononuclear cells obtained from CLL patients. Results show that simvastatin concentrations were dose proportional relative to the antihyperlipidemic doses, but lower than those required for in-vitro cytotoxicity against cancer cells. These findings demonstrate that the in-vitro effective concentrations of simvastatin are not achievable clinically, which might explain the limited effectiveness of high dose simvastatin in this study and in previous clinical trials. In view of these data, the use of simvastatin as a sole therapy in cancer treatment was not encouraging and led us to examine the use in combination with other anticancer drugs. After screening several chemotherapeutic agents in combination with simvastatin, we showed that tipifarnib (a farnesyltransferase inhibitor) interacts synergistically in several leukemia cell lines. Mechanistically we showed that simvastatin augments the cytotoxicity of tipifarnib by disrupting the localization of RAS in the cell membrane and by subsequent deactivation of the ERK pathway. Consistent with this observation, drug treatment led to the induction of apoptosis through the caspase cascade activation and the cleaved PARP upregulation. Notably, this synergistic effect was observed at clinically achievable concentrations of simvastatin and tipifarnib. Thus, the effectiveness of this combination should be explored further in future clinical studies.

Intimal hyperplasia (IH) is characteristic of a cell population increase within the innermost layer of the arterial wall. It is hypothesized that extracellular matrix vascular remodeling secondary vascular injury is dependent upon the Th17 subset of the CD4+ lymphocytes. Male C57BL/6J and FVB/NJ murine strains underwent complete left common carotid artery ligation for periods of 14 and 28 days. A therapeutic simvastatin model was carried out in the FVB/NJ strain and involved a daily subcutaneous injection regimen of 40 mg/kg/mouse beginning 72 hours prior to and daily following a 14 day carotid ligation period. Histological and RT-PCR analysis was carried out with harvested carotid artery samples. The FVB/NJ 14 day and 28 day histological stains of the left common carotid artery following ligation injury developed evident structured and disassembled intimal hyperplasia, respectively. A gene array demonstrated dramatic expression of immune and cytokine transcription markers particularly in the FVB/NJ strain at both ligation time points. IL-17 and IL-6 transcriptional gene expression was upregulated greater than 20-fold in the FVB/NJ 28 day injury model. IL-17 transcription was significantly expressed by a change of 50.06 ± 0.19 (p = 0.004) in this strain at 28 days versus the control. Lastly, the simvastatin treatment model was found to exacerbate the immune response to ligation injury. These results revealed that the immune system elicits a role in the vascular remodeling that potentiates intimal hyperplasia.

A ezetimiba e a sinvastatina são fármacos hipolipidêmicos. A ezetimiba pertence à nova classe das 2 - azetidinona, inibidores e bloqueadores do colesterol intestinal. A sinvastatina pertence à classe dos inibidores competitivos da hidroxi-3-metilglutarilcoenzima A redutase (HMG-CoA), que é a última etapa regulada na síntese do colesterol. O objetivo do trabalho foi desenvolver e validar métodos por cromatografia liquida de alta eficiência (HPLC) e eletroforese capilar (CE), rápidos, seletivos e confiáveis para determinação dos hipolipidêmicos em formulações farmacêuticas. A separação cromatográfica foi realizada usando coluna Nano separation technologies (NST) Cianopropril (CN) (150 mmx 4,6 mm, com partícula 3,5 &#181;m), e eluição isocrático usando água purificada: acetonitrila (48:52, v/v); vazão 0,8 mL/min e volume de injeção de 20 &#181;L. A temperatura da coluna foi de 35 ºC e a detecção foi realizada com detector na região do UV em 238 nm. O método por cromatografia eletrocinética micelar (MEKC) foi desenvolvido utilizando capilar de sílica fundida 30 cm (comprimento efetivo) x 50 &#181;m d.i. e eletrólito constituído de tetraborato de sódio (TBS) 20 mmol L-1: dodecil sulfato de sódio (SDS) 30 mmol L-1, pH 9,0 ajustado com 10% ácido fosfórico: acetonitrila 12% v/v. O tempo de injeção foi de 3 segundos com pressão hidrodinâmica de 20 mbar, voltagem aplicada de 30 kV e detecção no UV em 238 nm. Os métodos analíticos foram validados de acordo com os requerimentos vigentes da ANVISA, ICH e Farmacopéia Americana. Portanto, os métodos propostos demonstraram ser lineares, precisos, exatos e adequados para quantificação simultânea da ezetimiba e sinvastatina em formas farmacêuticas sólidas. / Ezetimibe and simvastatin are hipolipidemic drugs. Ezetimibe belongs to a new class of 2 - azetidione, inhibitors and blockers of intestinal chrolesterol. Simvastatin belongs a class of competitive inhibitors of 3-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, which is the last regulated step in the cholesterol synthesis. The aim of this project was to develop and validate fast, selective and reliable chromatographic and electrophoretic methods, to determine hypolipidemic drugs in pharmaceutical formulations. The chromatographic separation was carried out on a Nano separation technologies (NST) Cyanpropyl (CN) (150 mm x 4,6 mm, 3,5 &#181;m), isocratic elution using purified water: acetonitrila (48:52 v/v), the flow rate was 0,8 mL/min and the injection volume was 20 &#181;L. The column temperature was kept at 35 ºC and detection wavelength was set at 238 mn. The micellar electrokinetic chromatographic method was developed using a fused silica capillary column 30 cm (effective length) x 50 &#181;m i.d, the electrolyte was constituted of 20 mmol L-1 tetraborate buffer solution: 30 mmol L-1 sodium dodecyl sulphate (SDS), pH 9.0 adjusted with 10% phosphoric acid: 12 % v/v acetonitrile. The injection time was 3 s at 20 mbar, the applied voltage was 30 kV and detection was set at 238 nm. The both methods were developed and validated according to ANVISA, ICH and US Pharmacopeia guidelines. Therefore, the proposed methods proved to be linear, precise, accurate and suitable for simultaneous quantitation of ezetimibe and simvastatin in solid pharmaceutical formulations.

Em estudos prévios, mostramos que uma nanoemulsão lipídica (LDE) é reconhecida e se liga aos receptores de LDL após sua injeção na corrente sanguínea. Como tais receptores estão superexpressos em células com altas taxas de proliferação, como ocorre no câncer e na aterosclerose, a LDE pode ser utilizada como veículo para direcionar fármacos a essas células, diminuindo sua toxicidade e aumentando sua eficácia terapêutica. Anteriormente, reportamos que o tratamento com um derivado do paclitaxel, o oleato de paclitaxel, associado à LDE (PTX-LDE), reduziu em 60% a área lesionada de aortas de coelhos submetidos à dieta aterogênica, comparados a animais não tratados. No presente trabalho, avaliamos o efeito da associação de sinvastatina, medicamento hipolipemiante, e PTX-LDE, sobre a aterosclerose induzida por dieta em coelhos. Trinta e seis coelhos machos da raça Nova Zelândia foram submetidos à dieta enriquecida com 1% de colesterol durante oito semanas. A partir da quinta semana, os animais foram divididos em quatro grupos, de acordo com o tratamento: controle (solução salina EV), sinvastatina (2mg/kg/dia, VO), paclitaxel (PTX-LDE, 4mg/Kg/semana, EV), ou combinação de sinvastatina (2mg/Kg/dia, VO) com paclitaxel (PTX-LDE, 4mg/Kg/semana, EV). Após oito semanas, os animais foram sacrificados para análise das aortas. Em comparação aos controles, a área lesionada das aortas foi em torno de 60% menor, tanto no grupo paclitaxel, quanto no grupo da combinação, e em torno de 40% menor no grupo sinvastatina (p<0,05). A razão entre as camadas íntima/média foi menor nos grupos tratados, em relação ao grupo controle (controles, 0,35±0,22, sinvastatina, 0,10±0,07, paclitaxel, 0,06±0,16 e combinação, 0,09±0,05, p<0,0001). Os grupos combinação e sinvastatina apresentaram um aumento da porcentagem de colágeno nas lesões (combinação, 20% e sinvastatina, 22%), em comparação aos controles (11%) e ao grupo paclitaxel (12%), (p<0,0001). Houve uma diminuição da porcentagem de macrófagos na lesão em todos os grupos tratados (paclitaxel, 11%, sinvastatina, 8% e combinação, 5%), comparados ao grupo controle (30%), (p<0,0001). O grupo paclitaxel apresentou menor porcentagem de células musculares lisas na lesão (20%) em relação aos controles (33%), (p<0,0001), já na combinação, houve aumento dessa porcentagem (44%), (p<0,0001). A combinação com sinvastatina não aumentou a eficácia do tratamento com PTX-LDE na redução da área de lesões ateroscleróticas, porém, os efeitos adicionais sobre o perfil lipídico e na composição das lesões, observadas com o uso da combinação, são achados importantes, que sugerem benefícios no sentido de aumentar a estabilidade das placas ateroscleróticas, o que nos abre um caminho de pesquisa muito promissor. / In previous studies we have shown that a lipid nanoemulsion (LDE) is recognized and binds to LDL receptors after injection into the bloodstream. As those receptors are upregulated in cells with higher proliferation rates, as occurs in cancer and atherosclerosis, LDE can be used as a vehicle to direct drugs to those cells, diminishing toxicity and increasing therapeutic efficacy. Previously, we reported that treatment with antiproliferative agent paclitaxel derivative, paclitaxel oleate, associated with LDE (PTX-LDE), reduced by 60% the injured area of the aorta of rabbits subjected to atherogenic diet compared to untreated animals. In the current study we aim to test the effect of a combination of lipid-lowering drug simvastatin with PTX-LDE on diet-induced atherosclerosis in rabbits. Thirty-six male New Zealand rabbits were fed a 1% cholesterol diet for 8 weeks. Starting from week 5, animals were divided into four groups, according to the following treatments: controls (I.V. saline solution injections), simvastatin P.O. (2mg/kg/day), paclitaxel (PTX-LDE I.V. injections, 4mg/Kg/week), or paclitaxel-simvastatin combination (PTX-LDE I.V., 4mg/Kg/week + simvastatin P.O., 2mg/Kg/day). After 8 weeks, the animals were sacrificed for aorta evaluation. Compared to controls, the injured area was reduced by 60% in both paclitaxel and combination groups, and by 40% in simvastatin group (p<0,05). The intima/media ratio was reduced in treated groups, compared to control group (controls, 0,35±0,22, simvastatin, 0,10±0,07, paclitaxel, 0,06±0,16 and combination, 0,09±0,05, p<0,0001). Simvastatin and combination groups showed increased collagen content within the lesions (simvastatin, 22% and combination 20%), compared to controls (11%) and to paclitaxel group (12%), (p <0.0001). Macrophage content within the lesions was reduced in all treated groups (paclitaxel, 11%, simvastatin, 8% e combination, 5%), compared to controls (30%), (p <0.0001). The percentage of smooth muscle cells in the lesions was diminished in paclitaxel group (20%) compared to control group (33%), while the combination group showed increased percentage (44%) of smooth muscle cells in the lesions (p<0,0001). The combination of simvastatin did not improve the efficacy of the treatment with PTXLDE in reducing the area of atherosclerotic lesions, but the additional effects on lipid profile and lesion composition observed with the use of the combination are important findings that suggest benefits in order to enhance the stability of atherosclerotic plaques, which may lead us to a very promising research path.