Hypercholesterinämie und andere Risikofaktoren tragen zur Entstehung von Atherosklerose bei. Ein entscheidendes Merkmal der Pathogenese ist eine gestörte Endothelfunktion. Hierbei kommt es zu einer reduzierten Bioverfügbarkeit von NO (Stickstoffmonoxid), welches vasodilatativ und atheroprotektiv wirkt. NO kann jedoch auch abhängig vom vaskulären Milieu proatherogen wirken. Es ist Produkt verschiedener NO-Synthasen (NOS). Die potenten Cholesterinsenker Simvastatin und Ezetimib haben vermutlich zusätzliche pleiotrope Effekte auf die Endothelfunktion, deren Untersuchung Gegenstand der vorliegenden Arbeit ist. Hierzu wurden an LDL-R-KO Mäusen - neben Bestimmung der Plasmacholesterinspiegel und atherosklerotischer Plaqueläsionen - Messungen von NO und eNOS, korrelativen Parametern der endothelialen Funktion, durchgeführt. Endovaskuläre Messungen von NO zeigten erhöhte NO-Werte in direkter Nähe atherosklerotischer Plaques. Diese sind am ehesten als Korrelat einer erhöhten iNOS-Aktivität in den Läsionen anzusehen. Im Sinne der mehrdimensionalen Funktion von NO ist hier von einer proatherogenen Wirkung des NO auszugehen. Messungen der ubiquitären, im Blut zirkulierenden NO-Mengen dagegen zeigten eine signifikant erhöhte NO-Bioverfügbarkeit in mit Simvastatin behandelten Tieren. Dies belegt die bereits in der Literatur beschriebene Pleiotropie von Statinen, NO kommt hier eine atheroprotektive Bedeutung zu. Die rein quantitative Bestimmung der eNOS-Expression zeigte zum Zeitpunkt der Untersuchung keine signifikanten Unterschiede in allen Versuchsgruppen. Hierbei sind jedoch keine Rückschlüsse auf die Enzymaktivität oder die Genexpression in anderen Zielgeweben möglich. Simvastatin und Ezetimib wirken sowohl in Mono- als auch in Kombinationstherapie über ihre cholesterinsenkende Wirkung hinaus atheroprotektiv. Die Untersuchungen zeigen, dass bei der Betrachtung der Endothelfunktion die verschiedenen NO-Produktionsquellen sowie der Funktionszustand des NO von entscheidender Bedeutung sind. / Hypercholesterolemia and other risk factors are associated with the development of atherosclerosis. Endothelial dysfunction is one important step in the pathogenic process leading to a decreased nitric oxide (NO) bioavailability. NO provides vasodilatation and atheroprotection but depending on the vascular situation it can also have a proatherogenic effect. NO is produced by different isoforms of NO synthases (NOS). The lipid lowering therapy with Simvastatin and Ezetimibe supposably has additional pleiotropic effects on the endothelial integrity. For the current study plasma cholesterol levels and lesion areas of atherosclerotic plaques were measured in LDL receptor knockout mice. To assess the endothelial function we investigated bioavailability of NO and expression of eNOS. We found increased levels of endovascular NO close to atherosclerotic plaques, suggesting that here NO is produced by highly active iNOS in plaque lesions. According to NO’s multidimensional functions we assume that NO here has proatherogenic effects. For overall circulating NO we found increased levels in mice treated with Simvastatin, indicating the known pleiotropic effects of statins and the atheroprotective role of NO. The expression of eNOS did not show any difference at the point of our studies. However we cannot proof the enzymes’ activity or expression in other tissues. Lipid lowering therapy with Simvastatin, Ezetimibe, or both has an additional atheroprotective effect. Regarding the endothelial function the results show that we need to focus on different sources of NO production as well as the specific function of NO itself.

Simvastatin is a cholesterol-lowering drug designed to lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins also inhibit the production of coenzyme Q (CoQ), which shares the same biosynthetic pathway. CoQ is an essential part of the mitochondrial electron transport chain (ETC) and has antioxidant properties. In addition, statins have been shown to effect the expression of antioxidant enzymes and heat shock proteins. Aerobic exercise has also been shown to have an effect on the aforementioned proteins. Statins and aerobicexercise are often co-prescribed by physicians even though the interaction of statins and exercise in heart and skeletal muscle has not been adequately explored. Purpose: To determine the interaction of simvastatin and exercise on CoQ, catalase (CAT), glutathione peroxidase (GPx), Manganese superoxide dismutase (Mn SOD), and heat shock protein 70 (HSP70) in cardiac muscle tissue and the expression of CoQ in the plantaris. Methods: Female 4-mo-old Sprague-Dawley rats were randomly assigned to four treatment groups (N = 15-18/group): sedentary (SED), sedentary treated with simvastatin (SED+SIM), exercise trained (EX), and exercise trained treated with simvastatin (EX+SIM). Rats assigned to simvastatin treated groups received 10 mg simvastatin (Zocor®)/kg body/eight/day for four weeks. Rats assigned to exercise groups were exercised on a treadmill five days/week for four weeks at about 70% VO2max for a duration that was gradually increased to 60 minutes/day. Twenty-four hours after the last session, the animals were euthanized and the heart and both plantaris muscles were removed. Some hearts were perfused for 20 minutes to rinse away blood and others were subjected to an ischemia-reperfusion (I-R) protocol. Left ventricles of IR hearts and the left plantaris were homogenized in ddH2O and lipids were extracted and analyzed for CoQ by high performance liquid chromatography. CAT, GPx, and Mn SOD activity was measured polarographically and HSP70 expression was determined by western blotting of the supernatant of homogenate from the left ventricular tissue of rinsed hearts. Results: A simvastatin main effect was observed on CoQ expression of cardiac and skeletal muscle, and CAT activity of cardiac muscle tissue. Expression of CoQ was decreased while CAT activity was increased following statin treatment. An exercise main effect was observed on CoQ and HSP70 expression of cardiac muscle tissue. Exercise decreased CoQ expression, but increased HSP70 expression in the heart. An interaction effect was observed on both HSP70 expression and Mn SOD activity of cardiac tissue. With respect to HSP70, treatment with simvastatin slightly attenuated an exercise induced increase in HSP70 expression. With respect to Mn SOD, treatment with simvastatin or exercise decreased activity while a combined treatment restored Mn SOD activity to a level similar to that of animals who received no treatment. Conclusion: Treatment with simvastatin or exercise alone results in alterations in the expression of CoQ and HSP70 and activity of CAT, GPx, and Mn SOD. With co-administration, simvastatin and aerobic exercise interact in such a way that maintains one's antioxidant defenses despite impairment the body's ability to synthesize CoQ.

Background. The published reports of the effectiveness of simvastatin in treatment of hypercholesterolemia were mostly conducted in western populations, and only few studies in Asian or domestic populations have ever been reported. By regulations from Bureau of National Health Insurance, the effective dosage of lipid lowering agents should be started from lower dose, such as 20 mg of simvastatin per day. Whether this dosage of simvastatin is effective for treatment of patients with hypercholesterolemia and the efficacy and safety of such dosage are the objects of this study. Materials and Methods. After the approval of IRB in a medical center located at north Taiwan, a randomized 12-week study was conducted to evaluate the efficacy and safety of 20mg/day simvastatin treatment on hypercholesterolemia. By randomization 65 patients, followed up at cardiovascular outpatient department under the diagnosis of primary hypercholesterolemia, were enrolled into a 4-week washout period, and finally 49 intent-to-treat patients entered a 12-week treatment with 20mg simvastatin per day, given through oral routine in the evening. Demographic and laboratory data were obtained before and after treatment. The primary efficacy measure was the changes from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the most commonly reported adverse experiences. Results. The per-protocol analyses included 39 hypercholesterolemic patients whom completed 12 weeks of therapy. Total cholesterol and LDL cholesterol at the end of the study period showed significant reductions by 22.5¢H (p<0.001) and 29.8¢H(p<0.001), respectively. Triglyceride also showed a significant reduction by 31.8% (p=0.006), whereas total alkaline phosphatase and calcium showed a weak and insignificant change over the study period. The female group had significantly greater reduction in triglyceride than that in the male group, and the non-smoking group also had significantly greater reduction in triglyceride than that in smoking group after 12-week treatment. There were 17 studied cases (34.7%) had minor transient but clinical insignificant increases in serum aspartate aminotransferase and alanine aminotransferase, and 7 cases (14.3%) experienced symptom of painful muscle, of whom 3 cases (6.1%) dropped out this study. Conclusion. Our results, although obtained from a small scale of hypercholesterolemic patients, suggest a probable positive efficacy and good tolerability with only few minor side effects of simvastatin on blood lipids.

Made available in DSpace on 2014-06-11T19:27:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-07-07Bitstream added on 2014-06-13T19:47:52Z : No. of bitstreams: 1 castro_mjd_me_sjc.pdf: 292516 bytes, checksum: 4537a19f3141bee87f8f83796feffbe9 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Devido ao aumento na taxa de óbitos relacionados à aterosclerose e AVC a sinvastatina tornou-se o medicamento eleito pelo SUS, por sua eficácia no combate às altas taxas de colesterol plasmático e diabete melitos. Enfermidades estas, decorrentes tanto de histórico familiar de hipercolesterolemia, quanto devido a hábitos de vida sedentária e de alimentação desregrada, que vem acometendo adultos jovens e mulheres em idade fértil; que já fazem uso de um ou mais medicamentos. Associado às vezes a uma gravidez não planejada, afetando também o feto. Inúmeros trabalhos têm sido feitos com o intuito de conhecer melhor sobre a atuação desse fármaco utilizado durante o período gestacional, tanto que, diversos medicamentos em princípio são contra indicados, principalmente nos primeiros três meses. Entretanto a sinvastatina, embora controversa a sua contra indicação, é o fármaco de escolha nos postos de saúde e essas jóvens mulheres grávidas estão fazendo uso dos mesmos. O objetivo desse trabalho foi o de fornecer maior embasamento a essa contra indicação. Foram utilizadas 24 ratas em período gestacional, onde desde o primeiro dia da prenhez confirmada as mesmas receberam por gavagem o fármaco manipulado pela farmácia de manipulação “A Especialista”. Os animais foram divididos em 4 grupos: as ratas controle, que receberam óleo de amêndoas doce e as ratas que receberam 10, 20 e 40 mg/kg de sinvastatina diariamente. Os resultados foram plotados em planilhas do Excel e submetidos aos testes estatísticos não paramétricos e serviram para corroborar a contra indicação do fármaco pois houve aumento significativo do número de reabsorções fetais nos cornos uterinos comprometendo a prenhez, reduzindo o número de fetos gerados nas ratas que receberam 40 mg/kg, além de diminuir o peso e comprimento dos fetos em geral / Simvastatin is currently the medicine chosen actually due to hight atherosclerosis death index and its effectiveness in combating high rates of plasma cholesterol and diabetes mellitus. Diseases caused both by family histories of hypercholesterolemia as well, due to sedentary lifestyles and eating disorders, which are affecting young adults and women of childbearing age who, due to this family history, had used one or more drugs which interact intensifying their effect, .associated some times to, an unplanned pregnancy, and drug interaction, affecting both. Several studies have been done in order to learn and get better foundation about the actions of these drugs during pregnancy, so that several medications, in principle, are contraindicated. However simvastatin, controversial contraindication, is the choosen drug in health care, and those pregnant women with a family history of hypercholesterolemia are making use of them. Therefore, the purpose of this study is to confirm this contraindication. The sample consisted of 24 female rats with confirmed pregnancy from day one. The entire sample received by gavage the drug - manipulated by the Specialist pharmacy. The animals were divided into four groups: 1. control (SC), where the rats received sweet almond oil and three other groups (S10, S20 and S40) where the rats received simvastatin 10, 20 and 40 mg / kg daily, respectively. The results were plotted in an excel spreadsheet and submitted to a nonparametric statistical test. They served to confirm our initial goal confirming the simvastatin contraindication drug due to uterin reabsortion increased number reducing little rats number, wheight and size. Thus compromising pregnancy

Despite the great success of hip implant surgeries, wear particle-induced implant aseptic loosening still limits the implant longevity. Simvastatin, an FDA-approved cholesterol lowering statin, is a promising drug candidate for the treatment of implant aseptic loosening due to its anti-inflammatory properties as well as its ability to stimulate bone growth and inhibit bone resorption. In addition, alginate microspheres have been used extensively in drug delivery applications because of alginate properties, including biocompatibility and gelation in mild conditions. However, the hydrophobicity of simvastatin, as well as the large alginate microsphere pore size leading to the leakage of low molecular weight drugs are limiting factors for their use as a delivery system for simvastatin. Therefore, the objectives of this thesis were twofold: 1. To complex simvastatin with 2-hydroxypropyl-β-cyclodextrin (HP-βCD) in order to increase its solubility; and 2. To increase simvastatin encapsulation efficiency in alginate microspheres by coating the microspheres with chitosan, adding dextran sulfate in the alginate solution, and optimizing the gelation conditions used for the synthesis of the microspheres (e.g., volume of gelation medium, curing time, and addition of simvastatin in the gelation medium). Results showed that simvastatin complexation with HP-βCD increased with HP-βCD to simvastatin molar ratio, to a maximum of 97.6% at the molar ratio of 10. Results also showed that chitosan coating of the alginate microspheres increased simvastatin encapsulation efficiency (up to 10.6%), which was further improved (up to 14.0%) when adding 2.0% (w/v) dextran sulfate to the alginate solution. This increase was likely due to electrostatic interactions between dextran sulfate and chitosan in addition to alginate, resulting in a denser coating. Finally, the addition of simvastatin in the gelation medium was shown to also increase simvastatin encapsulation (up to 22.4%), likely because of a decrease in the diffusion of simvastatin out of the microspheres. Overall, this work completed the initial steps for the development of an alginate-based drug delivery system for simvastatin with the long-term goal of providing a local delivery of simvastatin to modulate implant aseptic loosening.

Physiologically-based pharmacokinetic (PBPK) modelling is traditionally employed to predict drug concentration-time profiles in plasma and tissues using information from physiology/biology, in vitro experiments and in silico predictions. Model-based analysis of population pharmacokinetic (PK) data is rarely performed in such a mechanistic framework, as empirical compartmental models are mainly utilised for this purpose. However, the combination of traditional PBPK methodologies with parameter estimation techniques and non-linear mixed effects modelling is an approach with progressively increasing impact due to the significant advantages it offers. Therefore, the general aim of this thesis is to illustrate, explore and thus further facilitate the application of physiologically-based pharmacokinetic models in the context of population data analysis. In order to pursue this aim, this work firstly particularly focuses on the population pharmacokinetics of simvastatin (SV) and its active metabolite, simvastatin acid (SVA). The complex simvastatin pharmacokinetics and their clinical significance, due to the association with simvastatin-induced myopathy, provide an excellent case to illustrate the advantages of a mechanistically sound population model. In the current work, both conventional and physiologically-based population models were developed using clinical PK data for SV and SVA. Specifically, the developed model-based approaches successfully quantified the impact of demographics, genetic polymorphisms and drug-drug interactions (DDIs) on the SV/SVA pharmacokinetics. Therefore, they can be of significant application either in the clinic or during drug development in order to assess myopathy and DDI risk. Secondly, in this work the following advantages offered by integrated population PBPK modelling were clearly illustrated through specific applications: 1) prediction of drug concentrations at the tissue level, 2) ability to extrapolate outside the studied population and/or conditions and 3) ability to guide the design (sample size) of prospective clinical studies. Finally, in the current work, further methodological aspects related to the application of this integrated population PBPK modelling approach were explored. Of specific focus was the parameter estimation process aided by prior distributions and the derivation of the latter from different in vitro/in silico sources. In addition, specific methodology is illustrated in this work that allows the incorporation of stochastic population variability in the structural parameters of such models without neglecting the underlying physiological constraints.

Dentistry has come a long way from its humble beginnings. Like all other healthcare specialties, dentistry has evolved through the years. The understanding of physiology of dental health and disease has evolved allowing us to treat dental diseases much more efficiently. However not all dental problems are fully understood. Diseases that affect the bone and soft tissue around teeth and dental implants, also known as “periodontal” and peri-implant” diseases respectively, have proven to be among the least understood and challenging dental diseases to treat. Recent advancements in microbiology and immunology have revealed that periodontal and peri implant disease have a plethora of interactions between the invading bacteria, the defensive human cells, and signaling micro molecules that control inflammation. Those interactions have opened up a new frontier for researchers in dentistry, microbiology, immunology, pharmacology and dental materials to understand these interactions and explore possible new treatments. Simvastatin is a commonly prescribed drug used to control blood cholesterol. Recent research has revealed that simvastatin also possesses potent anti-inflammatory properties, and research has shown that topical application simvastatin is effective at controlling inflammation around teeth with periodontitis. However it has not yet been tested around dental implants with peri-implant disease. Thus the purpose of the current study is to investigate the effect of topical simvastatin on implants with peri-implant inflammation

Targeting the mutant BRAF and immunotherapy are new approaches to the treatment of metastatic malignant melanoma that has significantly improved survival but is associated with significant toxicity and cost. Potent and specific BRAF inhibitors like vemurafenib and dabrafenib are superior to chemotherapy in treatment of BRAF mutant melanomas which represent nearly 50% of all melanomas. A less toxic approach to treatment of malignant melanoma is hence appealing. Delta-tocotrienol (DT3), an unsaturated vitamin E isoform, and simvastatin, an HMG-CoA reductase inhibitor have been shown to have anti-neoplastic properties. We studied the effects of these chemicals in both BRAF-mutated SK-MEL-28 and BRAF-wild type SK-MEL-2 melanoma cells. MTS assays were used to analyze cytotoxicity. SK-MEL-28 and SK-MEL-2 cells were cultured in MEM media containing 10% serum and plated in 96-well culture plates for 48 hours then treated with DT3 (0-80 µM), simvastatin (0-10 µM), or a combination and dosed again at 72 hours. SK-MEL-28 and SK-MEL-2 cells were grown in 60 mm plates and treated with DT3 at concentrations of 30 µM, simvastatin at concentrations of 10 µM and combination of DT3 and simvastatin at concentrations of 10 µM and 2 µM. Cell were lysed with RIPPA buffer with protease and phosphatase inhibitor after 6 hours of treatment. Protein concentration of cell lysates was measured spectrophotometrically (GLO Max Multi+, Promega), using a BCA protein assay kit. The samples were run in SDS PAGE and blotted onto nitrocellulose membranes. Membranes were incubated with antibodies against Hsp 70 (Enzo Life Sciences, Farmingdale, NY), Hsp 90 (Santa Cruz, Dallas, TX), pS6 and pERK (Cell Signaling, Danvers, MA) and pAKT. Using MTS assay, we found that DT3 (IC50 75.2 μM) and simvastatin (IC50 8.3μM) have cytotoxic effects on melanoma cell line SK-MEL-2, but not on the SK-MEL-28 cells DT3 and simvastatin at the concentrations studied (10-80 μM DT3) and (0.625- 10 μM simvastatin). Further studies determined that simvastatin decreased expression of pS6, pERK on SK-MEL-2 and not DT3. However, these effects are different in SK-MEL-28 cells where there is only decrease in expression of pS6; treated SK-MEL-2 cells also show over-expression of Hsp70 suggestive of a rescue effect leading to lesser cytotoxic activity. The selective cytotoxicity observed in wild type BRAF melanoma cell lines by DT3 and simvastatin warrants further research into the potential therapeutic use of these drugs. A differential cytotoxicity is shown by DT3 and simvastatin in malignant melanoma cells with selective more potency in wild type BRAF melanoma compared to mutant BRAF melanoma cells. Further studies will be undertaken to dissect the mechanistic basis of this differential response.

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.

Common biodegradable polyesters such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) are used as drug delivery vehicles for tissue regenerative applications. However, they are typically bioinert, with drug loading limitations. Polymerizing the active agent or precursor into its respective biodegradable polymer would control drug loading via molar ratios of drug to initiator used for synthesis. Simvastatin was chosen due to its favorable anti-inflammatory, angiogenic, and osteogenic properties. In addition, its lactone ring lends itself to ring-opening polymerization and, consequently, the synthesis of poly(simvastatin) with controlled simvastatin release. Simvastatin was first polymerized with a 5kDa methyl-terminated poly(ethylene glycol) (mPEG) initiator and catalyzed via stannous octoate to form poly(simvastatin)-block-poly(ethylene glycol). Molecular weights ranged from 9.5kDa, with a polydispersity index (PDI) of 1.1 at 150 °C, to 75kDa with a PDI of 6.9 at 250 °C. First-order propagation rates were seen. Infrared spectroscopy showed carboxylic and methyl ether stretches unique to simvastatin and mPEG in the copolymer, respectively. Slow degradation was seen in neutral and alkaline conditions, with simvastatin, simvastatin-incorporated macromolecules, and mPEG identified as degradation products. Alternatively, triazabicyclodecene (TBD) was used to mediate simvastatin polymerization. A lower temperature of 150°C led to successful polymerization using 5kDa mPEG, compared to at least 200 °C via stannous octoate. TBD was also successful for reactions using 2 or 0.55kDa mPEG. The biodegradability of poly(simvastatin)-block-poly(ethylene glycol) via TBD improved, losing twice more mass in phosphate-buffered saline, pH 7.4, than the copolymer synthesized via stannous octoate. Release rates of three different copolymers synthesized demonstrated tunable simvastatin release. To further modulate degradation, poly(simvastatin)-block-poly(ethylene glycol) was blended with 5, 2, or 0.55kDa mPEG-initiated PLA copolymers. The blends showed a compressive elastic modulus ranging from 26 to 44MPa, within the magnitude of trabecular bone (approximately 50MPa). Tunability in mass loss and release was also seen due to varied ratios of incorporated PLA copolymers. Lastly, copolymer degradation byproducts inhibited HMG-CoA reductase and showed possible enhancement of osteoblastic activity in vitro. A pilot study using a rodent calvarial onlay model showed tolerability of the polymers and potential for long-term evaluations of bioactivity. Poly(simvastatin) may be useful in regenerative applications.