Injectable calcium phosphate foams for the delivery of Pitavastatin as osteogenic and angiogenic agent.

Apatitic bone cements have been used as a clinical bone substitutes and drug delivery vehicles for therapeutic agents in orthopedic applications. This has led to their combination with different drugs with known ability to foster bone formation. Recent studies have evaluated Simvastatin for its role in enhanced bone regeneration, but its lipophilicity hampers incorporation and release to and from the bone graft. In this study, injectable calcium phosphate foams (i-CPF) based on α-tricalcium phosphate were loaded for the first time with Pitavastatin. The stability of the drug in different conditions relevant to this study, the effect of the drug on the i-CPFs properties, the release profile, and the in vitro biological performance with regard to mineralization and vascularization were investigated. Pitavastatin did not cause any changes in neither the micro nor the macro structure of the i-CPFs, which retained their biomimetic features. PITA-loaded i-CPFs showed a dose-dependent drug release, with early stage release kinetics clearly affected by the evolving microstructure due to the setting of cement. in vitro studies showed dose-dependent enhancement of mineralization and vascularization. Our findings contribute towards the design of controlled release with low drug dosing bone grafts: i-CPFs loaded with PITA as osteogenic and angiogenic agent.

Combining Multiple Treatment Comparisons with Personalized Patient Preferences: A Randomized Trial of an Interactive Platform for Statin Treatment Selection.

BACKGROUND: Patients and clinicians are often required to make tradeoffs between the relative benefits and harms of multiple treatment options. Combining network meta-analysis results with user preferences can be useful when choosing among several treatment alternatives. OBJECTIVE: Using cholesterol-lowering statin drugs as a case study, we aimed to determine whether an interactive web-based platform that combines network meta-analysis findings with patient preferences had an effect on the decision-making process in a general population sample. METHOD: This was a pilot parallel randomized controlled trial. We used Amazon's Mechanical Turk to recruit adults residing in the United States. A total of 349 participants were randomly allocated to view either the interactive tool (intervention) or a series of bar charts (control). The primary endpoint was decisional conflict, and secondary endpoints included decision self-efficacy, preparation for decision making, and the overall ranking of statins. RESULTS: A total of 258 participants completed the trial and were included in the analysis. On the primary outcome, participants randomized to the interactive tool had significantly lower levels of decisional conflict than those in the control group (difference, -8.53; 95% confidence interval [CI], -12.96 to -4.11 on a 100-point scale; P = 0.001). They also appeared to have higher levels of preparation for decision making (difference, 4.19; 95% CI, -0.24 to 8.63 on a 100-point scale; P = 0.031). No difference was found for decision self-efficacy, although groups were statistically significantly different in how they ranked different statins. CONCLUSION: The findings of our proof-of-concept evaluation suggest that an interactive web-based tool combining published clinical evidence with individual preferences can reduce decisional conflict and better prepare individuals for decision making.

Combination of niacin extended-release and simvastatin results in a less atherogenic lipid profile than atorvastatin monotherapy.

OBJECTIVE: To compare the effects of combination niacin extended-release + simvastatin (NER/S) versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia. PATIENTS AND METHODS: Patients (n = 137) with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4-5 weeks prior to the study) received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks) or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo) A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher's exact test. RESULTS: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B < 80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003). NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022), small LDL (55% versus 45%; P = 0.011), very low-density lipoprotein (VLDL) and total chylomicrons (63% versus 39%; P < 0.001), and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007) and VLDL (9.3% versus 0.1%; P < 0.001), compared with atorvastatin. CONCLUSION: NER/S treatment significantly improved apo A-I levels and the apo B:A-I ratio, significantly lowered the number of atherogenic LDL particles and VLDL and chylomicron particles, and increased the mean size of LDL and VLDL particles, compared with atorvastatin.

Avaliação da qualidade de cápsulas de sinvastatina de farmácias magistrais / Evaluación de la calidad de cápsulas de sinvastatina de farmacias magistrales / Assessment of the quality of simvastatin capsules from compounding pharmacies

OBJETIVO: Validar metodologia por cromatografia líquida de alta eficiência para determinação do teor de sinvastatina em cápsulas manipuladas. MÉTODOS: Foram avaliadas 18 amostras de cápsulas de sinvastatina 40 mg de farmácias magistrais de São Paulo, Guarulhos, São Bernardo do Campo e Campinas, SP, prescritas para pacientes fictícios. As análises basearam-se na Farmacopéia Brasileira e no método da cromatografia, otimizado e validado de acordo com as normas nacionais e internacionais, para os ensaios de identificação, e quantificação em cápsulas manipuladas. RESULTADOS: O peso médio das cápsulas variou de 70 mg a 316 mg; quatro amostras apresentaram variação de peso em desacordo com a especificação. O teor de sinvastatina nas cápsulas estava de acordo com a especificação em 11 amostras; em seis, esse teor variou entre 4 por cento e 87 por cento do valor declarado, descumprindo os requisitos de teor do princípio ativo; a determinação do teor e uniformidade de conteúdo de uma amostra não foram realizadas. No teste de uniformidade de conteúdo, 15 amostras apresentaram valores menores que 85 por cento e com os desvios-padrões relativos maiores que 6 por cento; três farmácias atendiam a especificação desse ensaio. No ensaio de dissolução, oito amostras apresentaram resultados insatisfatórios no primeiro estágio do ensaio e as demais apresentaram resultados inconclusivos. CONCLUSÕES: O método utilizado mostrou boa adequação para aplicação em controle de qualidade, revelando a falta de qualidade de cápsulas de sinvastatina produzidas por algumas farmácias de manipulação.

OBJETIVO: Validar metodología por cromatografía líquida de alta eficiencia para determinación del tenor de sinvastatina en cápsulas manipuladas. MÉTODOS: Fueron evaluadas 18 muestras de cápsulas de sinvastatina 40 mg de farmacias magistrales de Sao Paulo, Guarulhos, Sao Bernardo do Campo y Campinas, Sureste de Brasil, prescriptas para pacientes ficticios. Los análisis se basaron en la Farmacopéia Brasileña y en el método de la cromatografia, optimizado y validado de acuerdo con las normas nacionales e internacionales, para los ensayos de identificación, y cuantificación en cápsulas manipuladas. RESULTADOS: El peso promedio de las cápsulas variaron de 70 a 316 mg; cuatro muestras presentaron variación de peso en desacuerdo con la especificación. El tenor de sinvastatina en las cápsulas estaba de acuerdo con la especificación en 11 muestras; en seis, ese tenor varió entre 4% y 87% del valor declarado incumpliendo los requisitos de tenor del principio activo; la determinación del tenor y uniformidad de contenido de una muestra no fue realizada. En la prueba de uniformidad de contenido, 15 muestras presentaron valores menores que 85% y con los desvíos-patrones relativos mayores que 6%; tres farmacias atendían la especificación del ensayo. En el ensayo de disolución, ocho muestras presentaron resultados insatisfactorios en la primera fase del ensayo, y las demás presentaron resultados inconclusitos. CONCLUSIONES: El método utilizado mostró buena adecuación para aplicación en control de calidad, revelando la falta de calidad de cápsulas de sinvastatina producidas por algunas farmacias de manipulación.

Assessment of the quality of simvastatin capsules from compounding pharmacies.

OBJECTIVE: To validate a method for determining the simvastatin content of compounded capsules, using high performance liquid chromatography. METHODS: Eighteen samples of simvastatin 40 mg capsules from compounding pharmacies in the cities of São Paulo, Guarulhos, São Bernardo do Campo and Campinas, Southeastern Brazil, prescribed for fictitious patients were assessed. The analyses were based on the Brazilian Pharmacopoeia and on the high performance liquid chromatography method, optimized and validated in accordance with national and international standards for identification and quantification tests on compounded capsules. RESULTS: The mean weight of the capsules ranged from 70 mg to 316 mg; four samples presented weight variation outside of the specification. The simvastatin content in the capsules was within the specification in 11 samples. In six, the content ranged from 4% to 87% of the declared quantity, thereby not complying with the content requirements for the active agent. For one sample, no content or uniformity determinations were performed. In the content uniformity test, 15 samples presented indices of less than 85%, with relative standard deviations greater than 6%. Three pharmacies had met the specification in this test. In the dissolution test, eight samples presented unsatisfactory results in the first stage of the test, while the remainder presented inconclusive results. CONCLUSIONS: The method used was shown to be suitable for application to quality control, and it revealed the poor quality of the simvastatin capsules produced by some compounding pharmacies.

Comparison of simvastatin tablets from the US and international markets obtained via the Internet.

BACKGROUND: Convenient access to prescription drugs produced outside the US has been facilitated by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The Food and Drug Administration has issued warnings to potential buyers that the safety of drugs purchased through the Internet cannot be guaranteed and may present consumers with a health risk from substandard products. OBJECTIVE: To determine whether generic simvastatin tablets and capsules obtained via the Internet from international markets are equivalent to the US innovator product regarding major aspects of pharmaceutical quality. METHODS: Twenty simvastatin tablets and capsules were obtained for pharmaceutical analysis: 19 generic samples from international Internet pharmacy Web sites and the US innovator product. Tablet samples were tested according to US Pharmacopeial (USP) guidelines where applicable, using high-performance liquid chromatography, disintegration, dissolution, weight variation, hardness, and assessment of physical characteristics. These tests are often used to detect formulation defects of drug products during the manufacturing process. RESULTS: Several international samples analyzed were not comparable to the US product in one or more aspects of quality assurance testing, and significant variability was found among foreign-made tablets themselves. Five samples failed to meet USP standards for dissolution and 2 for content uniformity. Among all samples, variability was observed in hardness, weight, and physical characterization. CONCLUSIONS: Results suggest that manufacturing standards for the international generic drug products compared with the US innovator product are not equivalent with regard to quality attributes. These findings have implications for safety and effectiveness that should be considered by clinicians to potentially safeguard patients who choose to purchase foreign-manufactured drugs via the Internet.

"Insight" into drug quality: comparison of simvastatin tablets from the US and Canada obtained via the Internet.

BACKGROUND: Recently, there has been much debate in the US concerning drug importation from Canadian Internet pharmacies. The Food and Drug Administration and US drug manufacturers assert that drugs obtained from international markets via the Internet present a health risk to consumers from substandard products. The public's perception is that drugs from Canada are as safe as those from the US. OBJECTIVE: To determine whether simvastatin tablets obtained via the Internet from Canadian generic manufacturers are comparable in blend uniformity, a major attribute of tablet quality, with the US innovator product. METHODS: Generic simvastatin tablets from 4 Canadian Internet pharmacy Web sites and the US innovator product were obtained for pharmaceutical analysis. Tablet samples were analyzed using near-infrared spectroscopic imaging techniques, which are designed to detect formulation defects of drug products during the manufacturing process. Digital images were created, revealing the tablets' internal structures. RESULTS: The blend uniformity of the active pharmaceutical ingredient in the tablet samples from Canada was determined and compared with that of the US innovator product. Results indicated that there is little significant difference in blend uniformity among US innovator and Canadian generic tablets. CONCLUSIONS: Results of this study suggest comparable quality assurance manufacturing standards for the US innovator product and the Canadian generic drug products tested. These findings have clinical, legal, and economic implications that should be addressed by policy makers to safeguard consumers who choose to purchase Canadian-manufactured drugs via the Internet.

More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin, pravastatin, or simvastatin therapy.

BACKGROUND: Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). METHODS AND RESULTS: A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). CONCLUSIONS: Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS.