Método modificado para la síntesis de hidrocloruro de amantadina / A modified method for synthesis of amantadine hydrochloride

Introducción: El hidrocloruro de amantadina (I) es conocido como un medicamento antiviral utilizado para prevenir y tratar las infecciones por influenza A. También se utiliza para aliviar los síntomas de la enfermedad de Parkinson en el período inicial. Se han informado varios métodos para la preparación de (I). Estos procedimientos comienzan con adamantano (II) en cuatro o tres pasos de reacción, para producir hidrocloruro de amantadina con rendimientos globales que van del 45 por ciento al 58 por ciento. Objetivo: Mejorar el método para la síntesis de hidrocloruro de amantadina, que puede introducirse a escala industrial. Métodos: La optimización paso a paso para reducir el uso de reactivos, disolventes, así como las condiciones de cada paso, se seleccionaron para ser menos agresivas y más amigables con el medio ambiente. Resultados: Todos los factores relacionados con el rendimiento de la reacción para sintetizar los compuestos intermedios y finales se seleccionaron para obtener el mayor rendimiento de cada etapa. Finalmente, se estableció un procedimiento de dos pasos para la síntesis de (I) a partir de (II), a través de N- (1-adamantil) formamida (III), con un rendimiento global mejorado del 78 por ciento y una pureza del 99,2 por ciento. Se confirmó la estructura del producto por 1H-NMR, 13C-NMR, IR y MS. La síntesis de N- (1-adamantil) formamida (VI) a partir de (II) también se logró con éxito en un solo paso. Este método evita el uso de bromo líquido o ácido sulfúrico gaseoso como reactivos. La conversión posterior de (VI) a (I) se llevó a cabo bajo condiciones de reacción, más suaves sin usar solventes peligrosos. Conclusiones: Se logró la síntesis mejorada del clorhidrato de amantadina (I). Este resultado puede utilizarse en una producción industrialmente conveniente. Las materias primas y reactivos utilizados en esta investigación son baratas y están disponibles. El tiempo total de preparación se redujo significativamente, con ahorro de energía y mano de obra(AU)

Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45 percent to 58 percent. Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale. Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly. Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl) formamide (III) with improving overall yield of 78 percent and a purity of 99.2 percent was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl) formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents. Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor(AU)

The efficacy of saxagliptin in T2DM patients with non-alcoholic fatty liver disease: preliminary data

SUMMARY OBJECTIVE To investigate the clinical efficacy and the possible mechanisms of saxagliptin in the treatment of type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD). METHODS A total of 95 T2DM and NAFLD patients were randomly divided into group A (saxagliptin group), group B (glimepiride group), and group C (glimepiride combined with polyene phosphatidylcholine group). RESULTS After intervention treatment for 24 w, body mass index (BMI), waist-to-hip ratio (WHR), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), and quantitative detection of liver steatosis of study subjects were observed, the action of liver steatosis in subjects of groups A and C were significantly different from those of group B; however, there were no differences between groups A and C. The FINS, HOMA-IR, and IL-6 of subjects in group A was lower than those in groups B and C; however, there were no significant differences between the latter two groups. CONCLUSION For T2DM combined with NAFLD patients, the saxagliptin treatment could not only effectively control blood glucose but also attenuate insulin resistance and inflammatory injury of the liver to improve fatty liver further.

RESUMO OBJETIVO Investigar a eficácia clínica e os possíveis mecanismos da saxagliptina no tratamento do diabetes mellitus tipo 2 (DM2) associado à doença hepática gordurosa não alcoólica (DHGNA). MÉTODOS Um total de 95 DM2 combinados com pacientes com DHGNA foram aleatoriamente divididos em grupo A (grupo saxagliptina), grupo B (grupo glimepirida) e grupo C (glimepirida combinado com grupo fosfatidilcolina polienizada). RESULTADOS Após a intervenção tratamento por 24 w, índice de massa corporal (IMC), relação cintura-quadril (RCQ), hemoglobina glicada (HbA1c), glicemia de jejum (FPG), insulina de jejum (Fins), avaliação do modelo homeostático de insulina resistência (Homa-IR), interleucina-6 (IL-6), triglicérides (TG), colesterol total (CT), alanina aminotransferase (ALT), aspartato aminotransferase (AST), γ-glutamiltransferase (γ-GT) e detecção de esteatose hepática dos sujeitos do estudo foram observados. Ação de esteatose hepática de indivíduos nos grupos A e C foram significativamente diferentes do grupo B; no entanto, não houve diferenças entre os grupos A e C. Os grupos Fins, Homa-IR e IL-6 dos participantes do grupo A foram menores que os dos grupos B e C; no entanto, não houve diferenças significativas entre os dois últimos grupos. CONCLUSÃO Para o DM2 combinado com pacientes com DHGNA, o tratamento com saxagliptina pode não apenas controlar efetivamente a glicemia, mas também atenuar a resistência à insulina e a lesão inflamatória do fígado para melhorar ainda mais o fígado gorduroso.

Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin

ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.

Adamantylidene-substituted alkylphosphocholine TCAN26 is more active against Sporothrix schenckii than miltefosine

Sporotrichosis is the most frequent subcutaneous mycosis in the world and its increasing incidence has led to the search for new therapeutic options for its treatment. In this study, we demonstrated that three structural analogues of miltefosine (TCAN26, TC19, and TC70) showed inhibitory activity against Sporothrix schenckii sensu stricto and that TCAN26 was more active in vitro than miltefosine against several isolates. Scanning electron microscopy showed that S. schenckii exposure to TCAN26 resulted in cells that were slightly more elongated than untreated cells. Transmission electron microscopy showed that TCAN26 treatment induced loss of the regular cytoplasmic electron-density and altered the cell envelope (disruption of the cell membrane and cell wall, and increased cell wall thickness). Additionally, TCAN26 concentrations required to kill S. schenckii cells were lower than concentrations that were cytotoxic in mammalian cells, and TCAN26 was more selective than miltefosine. Thus, the adamantylidene-substituted alkylphosphocholine TCAN26 is a promising molecule for the development of novel antifungal compounds, although further investigations are required to elucidate the mode of action of TCAN26 in S. schenckii cells.

Seguridad y eficacia de vildagliptina en el tratamiento de pacientes adultos mayores con diagnóstico de diabetes mellitus tipo 2, con riesgo de hipoglicemia y limitantes para uso de insulina (con alto grado de dependencia), sin control metabólico adecuado (según HBA1C) a pesar de tratamiento con metformina a dosis máxima y glibenclamida / Safety and efficacy of vildagliptin in the treatment of elderly patients with a diagnosis of type 2 diabetes mellitus, with risk of hypoglycemia and limitations of insulin use (with a high degree of dependence), without adequate metabolic control

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) ha recibido la solicitud de evaluar el uso de vildagliptina para su uso en pacientes adultos mayores con diagnóstico de diabetes mellitus tipo 2, con riesgo de hipoglicemia y limitantes para uso de insulina (con alto grado de dependencia), sin control metabólico adecuado (según HBA1c) a pesar de tratamiento con metformina a dosis máxima y Glibenclamida dentro del sistema de EsSalud, indicación actualmente no contemplada en el petitorio de medicamentos. Generalidades: La diabetes mellitus tipo 2 (DM-2), forma que representa el 90-95% de los casos de diabetes. Es una enfermedad metabólica crónica que se caracteriza por la pérdida paulatina de la capacidad de secretar insulina a nivel de las células beta del páncreas así como por el aumento progresivo de la resistencia a la insulina, lo cual hace que los pacientes mantengan y eventualmente sufran las consecuencias de mantener niveles elevados de glucosa en su sangre. Como tal la DM-2 constituye una seria amenaza para la salud pública tanto a nivel mundial como en el Perú donde se prevé que pronto se convertirá uno de los principales contribuyentes a la carga de enfermedad en el país. Su incidencia en el Perú se encuentra en aumento. Tecnología Sanitaria de Interés: Los Inhibidores de DPP-4: Los inhibidores de DPP-4 son hipoglicemiantes orales que actúan como inhibidores reversibles de las enzima DPP-4 (dipeptidil peptidasa 4, EC 3.4.14.5), una enzima que está implicada en la inactivación de las hormonas incretinas GLP-1 (péptido similar al glucagón 1) y GIP (polipéptido insulinotrópico dependiente de la glucosa), ambas a su vez implicadas en la regulación fisiológica de la homeostasis de la glucosa. Descubiertos hace ya más de una década, a la fecha en el mercado internacional se disponen de más de ocho diferentes inhibidores de DPP-4. METODOLOGÍA: Estrategia de Búsqueda: El protocolo de esta revisión sistemática fue preparado y revisado con el equipo técnico de IETSI. Las siguientes fuentes han sido revisadas y consultadas: Medline/Pubmed, Embase, Scopus, Web of Science, Trip Database, The Cochrane Library, The National Institute for Health and Care Excellence (NICE) del Reino Unido, The National Guideline Clearinghouse (NCG) de los Estados Unidos, The International Diabetes Federation (IFD). RESULTADOS: uego de revisar un total de 837 documentos resultados de nuestra búsqueda bibliográfica, logramos filtrar 61 estudios relevantes para nuestra pregunta PICO de interés (Tabla 1), de los cuales sólo 8 fueron finalmente seleccionados para nuestro análisis toda vez que constituían estudios relevantes que resumían la mejor evidencia disponible (5 ensayos clínicos, 1 meta-análisis y una guía clínica) sobre la eficacia y seguridad atribuible al uso de un inhibidor de DPP-4 en regímenes de terapia doble (combinado con metformina) o triple (combinado con metformina y una sulfonilurea) comparados con metformina más una sulfonilurea en el manejo de pacientes con diagnóstico de diabetes mellitus de tipo 2. CONCLUSIONES: A la fecha no se puede recomendar el uso de inhibidores de DPP-4 como una alternativa tan o más eficaz y segura a la terapia combinada con metformina y una sulfonilurea, ya sea en regímenes de terapia doble (como reemplazo de la sulfonilurea) o triple (como un tercer hipoglicemiante oral adicional a este esquema de tratamiento) en el manejo de pacientes con diabetes mellitus tipo 2 con mal control metabólico no tributarios de manejo con insulina. La evidencia disponible sugiere que el uso de inhibidores de DDP-4 en un régimen doble (metformina más un inhibidor de DPP-4) si bien es una alternativa de tratamiento que se asocia con un riesgo igual o menor de eventos adversos que la terapia combinada con metformina y una sulfonilurea, no ofrece mayor beneficio en términos de eficacia; mientras que por el contrario, en el caso de la terapia triple (metformina más una sulfonilurea y un inhibidor de DPP-4) si bien sí constituye una alternativa de tratamiento más eficaz que la terapia combinada con metformina y una sulfonilurea se asocia con un mayor riesgo de eventos adversos asociados al tratamiento, y en particular con un mayor riesgo de eventos hipoglicémicos. Asimismo a la fecha, poco se sabe con respecto la seguridad del uso de inhibidores de DPP-4 al largo plazo, en cualquier régimen de tratamiento, desconociéndose en particular cuál puede ser impacto en el riesgo cardiovascular de los pacientes al largo plazo. En consecuencia, no podemos recomendar el uso de ningún inhibidor de DPP-4 en regímenes de terapia dual o triple, en el tratamiento de pacientes adulto mayores de 60 años con diagnóstico de DM-2, con riesgo de hipoglicemia y limitantes para uso de insulina (con alto grado de dependencia*), sin control metabólico adecuado (según HbAl c) con metformina a dosis máxima y Glibenclamida por cuanto no se disponen de evidencias suficientes para sobrepesar los beneficios con respecto a los riesgos al largo plazo que su uso pueda tener.

Effectiveness, safety and tolerability of vildagliptin and vildagliptin+metformin in real-world setting in the Philippines--Results from the GUARD study

INTRODUCTION: GUARD (vildaGliptin clinical Use in reAl woRlD) was  a  multinational,  prospective,  observational  study that assessed the effectiveness,safety  and  tolerability of vildagliptin and vildagliptin+metformin in patients with type 2 diabetes mellitus (T2DM) under real-world conditions across four  geographical  regions  (Asia,  the  Middle  East,  Central  America and Africa). The current paper discusses the results of patients with T2DM enrolled in the Philippines.METHODS: Patients  with  T2DM  who  were  prescribed vildagliptin or vildagliptin+metformin combination therapy were enrolled and followed as per routine clinical practice for 24 ± six weeks. Primary endpoint was the change in HbA1c from  baseline  to  study  end  (week  24±6).  Key  secondary endpoints included proportion of patients reaching target HbA1c ?7.0%, incidence of hypoglycemic events, adverse events (AEs) and serious AEs (SAEs).RESULTS: A total of 1,117 patients were included in the final analysis, 280 on vildagliptin (of these, eight patients received additional oral antidiabetes medications) and 837 on vildagliptin+metformin. At baseline, the mean (±SD) age of the enrolled population was 54.1±11.5 years, BMI 26.3±4.7 kg/m2, HbA1c 8.0±1.2% and T2DM duration 2.3±4.0 years.At  study  end,  significant  mean  (±SE)  reductions  in  HbA1c of -1.2±0.1% (pCONCLUSION: Vildagliptin  and  vildagliptin+metformin significantly  reduced  HbA1c  with  good  weight  control and low incidence of hypoglycemia in patients with T2DM under real-world conditions in Philippines

Therapeutic effect of saxagliptin in rat models of nonalcoholic fatty liver and type 2 diabetes / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism.</p><p><b>METHODS</b>Rats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting.</p><p><b>RESULTS</b>Compared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin.</p><p><b>CONCLUSION</b>Saxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.</p>

Therapeutic effect of vildagliptin and insulin aspart injection in elderly patients with type 2 diabetes / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the therapeutic effect and safety of vildagliptin combined with insulin aspart injection in elderly patients with type 2 diabetes.</p><p><b>METHODS</b>Sixty-six elderly patients with type 2 diabetes who had poor blood glucose control with insulin aspart injection were divided into two groups to have additional Vildagliptin (50 mg, twice daily, n=36, observation group) or Acarbose (50 mg, three times a day, n=30, control group). Blood glucose (including FBG and 2hPG), HbA1C, fasting c-peptide, postprandial c-peptide, BMI and GFR were observed after 12 weeks.</p><p><b>RESULTS</b>In the observation group, FBG, 2hPG and HbA1C decreased significantly (P<0.05), fasting and postprandial c-peptide increased (P<0.05), and BMI and GFR showed no obvious changes (P>0.05). In the control group, 2hPG and HbA1C were significant lowered (P<0.05) but FBG, fasting and postprandial c-peptide, BMI or GFR showed no changes (P>0.05). Compared with those in the control group, FBG in the observation group showed a significant reduction (P<0.05), but no significant differences were found in 2hPG, HbA1C, BMI or GFR (P>0.05). No hypoglycemia occurred in the two groups during the treatment.</p><p><b>CONCLUSION</b>Vildagliptin with insulin aapart injection has equivalent effect with Acarbose combined with insulin aspart injection in decreasing 2hPG and HbA1C without increasing the body weight or the risk to hypoglycemia or causing lowered GFR. Vildagliptin has better effect in decreasing FBG and improving the function of the islet cells.</p>

A comparative study of the effect of vildagliptin and glimepiride on glucose variability in type 2 diabetic patients with inadequate glycemic control on metformin

BACKGROUND: Vildagliptin is believed to improve glucose variability by restoring the physiologic pattern of insulin secretion and improving beta and alpha cells' sensitivity to glucose but with less increase in insulin secretion compared to sulfonylureas resulting in similar glucose levels but with less risk of hypoglycemia.OBJECTIVE: To compare the effect of vildagliptin and glimepiride on glucose variability among Type 2 diabetic patients not controlled on metformin alone.METHODS: This investigation is a prospective, interventional, open-labeled, active control, parallel assignment, efficacy study that included patients with inadequate glycemic control on monotherapy with metformin, randomly assigned either to vildagliptin or glimeparide. For one month, one group took vildagliptin 50mg/tablet one tablet twice a day while the other group took glimepiride 1 mg/tablet one tablet once a day. Subjects were asked to monitor their capillary blood glucose at seven points throughout the day for 35 days.RESULTS: A total of 18 patients were recruited for the study and randomly assigned to either of the two treatment arms. However, only 16 patients completed the study. The vildagliptin and glimepiride groups had comparable blood sugars at baseline and at the end of the study although the glimepiride group showed a steeper decline in the blood sugar levels. Subjects in both groups showed a downward trend in the blood glucose values from day one to the 35th day with comparable mean glucose values between treatments and across combinations of day and treatment. Likewise, mean postprandial incremental area under the curve (AUCpp)and mean amplitude of glycemic excursions (MAGE) were comparable across treatments and across combinations of day and treatment, although the Glimepiride group showed relatively higher MAGE values.CONCLUSION: Vildaglipitin and glimepiride both improved glycemia of patients with uncontrolled blood sugar on monotherapy with metformin as both groups showed downward glucose trend, although vildagliptin showed relatively less abrupt glucose lowering effect suggesting lesser risk of hypoglycemia. Mean postprandial glucose excursions of the two groups were also comparable but the vildagliptin arm had lower MAGE and may suggest an improvement in both ?- and ?-cell function.

Comparison of DPP-4 Inhibitors / 임상당뇨병

During past several years, a novel class of antihyperglycemic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors, has become one of the most important options in the management of type 2 diabetes. These agents have unique insulinotropic actions as well as other advantages such as lower hypoglycemia and a weight-neutral effect compared to traditional insulin secretagogues. To date, 6 different DPP-4 inhibitors have been introduced: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin and gemiglitin. This review provides a summary of the clinical data for each DPP-4 inhibitor, and discusses the similarities and differences between them.

The Efficacy of Vildagliptin in Korean Patients with Type 2 Diabetes

No abstract available.

Predictive Clinical Parameters and Glycemic Efficacy of Vildagliptin Treatment in Korean Subjects with Type 2 Diabetes

BACKGROUND: The aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes. METHODS: In this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics. RESULTS: Ultimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (DeltaHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P<0.05). Of the variables, initial HbA1c levels (P=0.032) and history of sulfonylurea use (P=0.026) were independently associated with responsiveness to vildagliptin treatment. CONCLUSION: Vildagliptin was effective when it was used in subjects with poor glycemic control. It controlled fasting plasma glucose levels as well as sulfonylurea treatment in Korean type 2 diabetic subjects.

Clinical Characteristics of the Responders to Dipeptidyl Peptidase-4 Inhibitors in Korean Subjects with Type 2 Diabetes

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (DeltaHbA1c). The Student's t-test between good responders (GR: DeltaHbA1c > 1.0%) and poor responders (PR: DeltaHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with DeltaHbA1c. In the multivariate analysis, age (r2 = 0.006), duration of diabetes (r2 = 0.019), HbA1c (r2 = 0.296), and creatinine levels (r2 = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Custo-efetividade e impacto orçamentário da saxagliptina como terapia adicional à metformina para o tratamento do diabetes mellitus tipo 2 no sistema de saúde suplementar do Brasil / Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the brazilian private health system

OBJETIVOS: Comparar custos e benefícios clínicos de três terapias adicionais à metformina (MF) para pacientes com diabetes mellitus tipo 2 (DMT2). MÉTODOS: Um modelo de simulação de eventos discretos foi construído para estimar a relação custo-utilidade (custo por QALY) da saxagliptina como uma terapia adicional à MF comparada à rosiglitazona ou pioglitazona. Um modelo de impacto orçamentário (BIM - Budget Impact Model) foi construído para simular o impacto econômico da adoção de saxagliptina no contexto do Sistema Suplementar de Saúde brasileiro. RESULTADOS: O custo de aquisição da medicação para o grupo de pacientes hipotéticos analisados, para o horizonte temporal de três anos, foi de R$ 10.850.185,00, R$ 14.836.265,00 e R$ 14.679.099,00 para saxagliptina, pioglitazona e rosiglitazona, respectivamente. Saxagliptina exibiu menores custos e maior efetividade em ambas as comparações, com economias projetadas para os três primeiros anos de -R$ 3.874,00 e -R$ 3.996,00, respectivamente. O BIM estimou uma economia cumulativa de R$ 417.958,00 com o reembolso da saxagliptina em três anos a partir da perspectiva de uma operadora de plano de saúde com 1 milhão de vidas cobertas. CONCLUSÃO: Da perspectiva da fonte pagadora privada, a projeção é de que o acréscimo de saxagliptina à MF poupe custos quando comparado ao acréscimo de rosiglitazona ou pioglitazona em pacientes com DMT2 que não atingiram a meta de hemoglobina glicada (HbA1c) com metformina em monoterapia. O BIM, para a inclusão de saxagliptina nas listas de reembolso das operadoras de planos de saúde, indicou uma economia significativa para o horizonte de 3 anos.

OBJECTIVES: To compare costs and clinical benefits of three additional therapies to metformin (MF) for patients with diabetes mellitus type 2 (DM2). METHODS: A discrete event simulation model was built to estimate the cost-utility ratio (cost per quality-adjusted life years [QALY]) of saxagliptine as an additional therapy to MF when compared to rosiglitazone or pioglitazone. A budget impact model (BIM) was built to simulate the economic impact of saxagliptine use in the context of the Brazilian private health system. RESULTS: The acquiring medication costs for the hypothetical patient group analyzed in a time frame of three years, were R$ 10,850,185, R$ 14,836,265 and R$ 14,679,099 for saxagliptine, pioglitazone and rosiglitazone, respectively. Saxagliptine showed lower costs and greater effectiveness in both comparisons, with projected savings for the first three years of R$ 3,874 and R$ 3,996, respectively. The BIM estimated cumulative savings of R$ 417,958 with the repayment of saxagliptine in three years from the perspective of a health plan with 1,000,000 covered individuals. CONCLUSION: From the perspective of private paying source, the projection is that adding saxagliptine with MF save costs when compared with the addition of rosiglitazone or pioglitazone in patients with DM2 that have not reached the HbA1c goal with metformin monotherapy. The BIM of including saxagliptine in the reimbursement lists of health plans indicated significant savings on the three-year horizon.

Evaluación económica del tratamiento de diabetes tipo 2 con saxagliptina en Colombia / Economic evaluation of type 2 diabetes treatment with saxagliptin in Colombia

Objetivo: Determinar la relación costo efectividad incremental del agregado de saxagliptina o sulfonilureas en Colombia a personas con DMT2 que no logran alcanzar metas glucémicas con metformina, durante un período máximo de 20 años. Metodología: Se realizó un estudio de costo efectividad, utilizando un modelo de simulación de eventos discretos con incremento de tiempo fijo (Diabetes Cardiff Model). Las características de la cohorte de pacientes y el perfil de eficacia para cada tratamiento se obtuvieron de la literatura. El costo de los medicamentos se obtuvo de SISMED y Farmaprecios. Los costos de los eventos macro y microvasculares se basaron en el POS, Manual Tarifario SOAT y consulta con experto local. La tasa de descuento en costos y beneficios fue 3,5 por ciento. Resultados: En el grupo tratado con saxagliptina registramos menos eventos fatales y no fatales y menos episodios de hipoglucemia. En ambas estrategias los mayores costos correspondieron a los medicamentos, seguidos por los asociados al tratamiento del infarto de miocardio. El costo incremental de la terapia con saxagliptina fue de US$ 555.552 a 20 años. El tratamiento con saxagliptina redundó en un mayor número de Años de Vida Ajustados por Calidad (AVAC) y Años de Vida Ganados (AVG), respecto al obtenido con sulfonilureas. El costo por AVAC fue de US$ 2.190. Los resultados de costo efectividad fueron robustos al análisis de sensibilidad. Conclusión: El agregado de saxagliptina a pacientes que no logran un control glucémico adecuado con metformina, es muy costo efectiva comparada con el agregado de sulfonilureas.

Objective: To determine in Colombia, the cost effectiveness ratio of the saxagliptin or sulphonylureas addition to patients with T2DM who fail to achieve glycemic goals with metformin, for a maximum period of 20 years. Methods: We performed a cost effectiveness analysis, using a discrete event simulation model with fixed time step (Cardiff Diabetes Model). The characteristics of the cohort of patients and efficacy profile for each treatment were obtained from the literature. The cost of medication was obtained from SISMED and Farmaprecios. The costs of macro and microvascular events were based on POS tariffs, SOAT Manual and consultation with local expert. The discount rate on costs and benefits was 3.5 percent. Results: The group treated with saxagliptin had fewer fatal and nonfatal events and fewer episodes of hypoglycemia than the one with sulfonylureas. In both strategies the higher cost corresponds to the drugs, followed by those associated with the treatment of myocardial infarction. The incremental cost of saxagliptin therapy was US$ 555.552 to 20 years. Saxagliptin treatment resulted in a greater number of quality-adjusted life year (QALYs) and life-years gained (LYG) than that obtained with sulfonylureas. The cost per QALY was US$ 2,190. Cost-effectiveness results were robust to sensitivity analysis. Conclusion: Addition of saxagliptin to patients who do not achieve adequate glycemic control with metformin, is highly cost-effective compared with the addition of sulphonylureas.

Synthesis of a supermolecular nanoparticle γ-hy-PC/Ada-Dox and its antitumor activity / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To synthesize a (2-Hydroxypropyl)-γ-cyclodextrin-polyethylenimine/adamantane-conjugated doxorubicin (γ-hy-PC/Ada-Dox) based supramolecular nanoparticle with host-guest interaction and to identify its physicochemical characterizations and antitumor effect.</p><p><b>METHODS</b>A novel non-viral gene delivery vector γ-hy-PC/Ada-Dox was synthesized based on host-guest interaction. 1H-NMR, NOESY, UV-Vis, XRD and TGA were used to confirm the structure of the vector. The DNA condensing ability of complexes was investigated by particle size, zeta potential and gel retardation assay. Cytotoxicity of complexes was determined by MTT assay in BEL-7402 and SMMC-7721 cells. Cell wound healing assay was performed in HEK293 and BEL-7404 cells. The transfection efficiency was investigated in HEK293 cells. H/E staining and cell uptake assay was performed in BEL-7402 cells.</p><p><b>RESULTS</b>The structure of γ-hy-PC/Ada-Dox was characterized by 1H-NMR, NOESY, UV-Vis, XRD, TGA. The drug loading was 0.5% and 5.5%. Gel retardation assay showed that γ-hy-PC was able to completely condense DNA at N/P ratio of 2; 0.5% and 5.5% γ-hy-PC/Ada-Dox was able to completely condense DNA at N/P ratio of 3 and 4,respectively. The cytotoxicity of polymers was lower than that of PEI25KDa. The transfection efficiency of γ-hy-PC was higher than that of γ-hy-PC/Ada-Dox at N/P ratio of 30 in HEK293 cells; and the transfection efficiency was decreasing when Ada-Dox loading was increasing. Cell uptake assay showed that γ-hy-PC/Ada-Dox was able to carry drug and FAM-siRNA into cells.</p><p><b>CONCLUSION</b>The novel vector γ-hy-PC/Ada-Dox has been developed successfully, which has certain transfection efficiency and antitumor activity.</p>

Effectiveness of adding vildagliptin to the treatment of diabetic patients nonresponsive to the combination of metformin and a sulphonylurea / Eficácia da adição de vildagliptina ao tratamento de pacientes diabéticos não responsivos à combinação de metformina e uma sulfonilureia

OBJECTIVE: To evaluate the effectiveness of adding vildagliptin to the treatment of patients with inadequately controlled type 2 diabetes mellitus (T2DM) treated with a combination of metformin and a sulphonylurea. SUBJECTS AND METHODS: 37 T2DM patients with HbA1c ranging from 7.7 percent to 12.4 percent (mean of 9.30 ± 1.38), despite the use of metformin in combination with a sulphonylurea, were additionally treated with vildagliptin (100 mg/day) for at least 6 months. RESULTS: During triple oral therapy (TOT) HbA1c levels < 7 percent were achieved in 11 patients (29.7 percent), whereas levels of fasting plasma glucose (FPG) < 120 mg/dL were observed in 12 patients (32.4 percent). Both findings were observed in 10 patients (27.0 percent). Compared to nonresponsive subjects, lower mean baseline HbA1c and FPG levels were seen in responsive patients, but the difference was only statistically significant for fasting plasma glucose (FPG). Moreover, there was considerable overlap between the two groups. CONLUSION: Our preliminary results suggest that TOT with metformin, a sulphonylurea and vildagliptin may be useful for some T2DM patients nonresponsive to combination therapy with metformin and sulphonylurea.

OBJETIVO: Avaliar a eficácia da adição de vildagliptina ao tratamento de pacientes com diabetes melito tipo 2 (DM2) inadequadamente controlados com a terapia de combinação com metformina e sulfonilureia. SUJEITOS E MÉTODOS: 37 pacientes com DM2 e HbA1c variando entre 7,7 por cento e 12,4 por cento (média, 9,30 ± 1,38), apesar do uso de metformina associada a uma sulfonilureia, foram adicionalmente tratados com vildagliptina (100 mg/dia) durante, pelo menos, 6 meses. RESULTADOS: Durante a terapia oral tripla TOT), níveis de HbA1c < 7 por cento foram alcançados em 11 pacientes (27,9 por cento), enquanto a glicemia de jejum (GJ) < 120 mg/dL foi observada em 12 pacientes (32,4.1 por cento). Ambos os resultados foram descritos em 10 pacientes (27,0 por cento). Em comparação com indivíduos não responsivos, os pacientes responsivos tinham níveis basais mais baixos de HbA1c e GJ, mas a diferença foi estatisticamente significativa somente para glicemia de jejum. Além disso, houve grande sobre-posição entre os dois grupos. CONSLUSÃO: Nossos resultados preliminares sugerem que a TOT com metformina, uma sulfonilureia e vildagliptina pode ser útil para alguns pacientes com DM2 não responsivos à combinação com metformina e uma sulfonilureia.

New Therapeutics for Diabetes Using Incretin Hormone / 대한내과학회지

New therapeutics for type 2 diabetes using incretin hormone were introduced recently. Incretin-based therapies consist of two types: GLP-1 agonists mainly acting on the GLP-1 receptor and dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors). The former is resistant to DPP-4 and injectable. The latter is oral medications raising endogenous GLP-1 by inhibiting the degrading enzyme DPP-4. The incretin based therapies are promising and more commonly used due to their action and safety profile. Stimulation of insulin secretion by these drugs occurs in a glucose-dependent manner. Incretin based therapies have low risk for hypoglycemia. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and vildagliptin.

Comparison of Vildagliptin-Metformin and Glimepiride-Metformin Treatments in Type 2 Diabetic Patients

BACKGROUND: The present study investigated the efficacy and safety of vildagliptin-metformin treatment compared to those of glimepiride-metformin treatment for type 2 diabetes. METHODS: In a randomized, open-label, comparative study, 106 patients with type 2 diabetes were enrolled. The primary endpoint was a reduction in HbA1c from baseline and secondary endpoints included fasting plasma glucose (FPG) or 2-hour postprandial glucose (2h-PPG) reduction from baseline, as well as HbA1c responder rate and HbA1c reduction according to baseline HbA1c category. RESULTS: Comparable HbA1c reduction was observed with a mean+/-standard deviation change from baseline to the 32-week endpoint of -0.94+/-1.15% in the vildagliptin group and -1.00+/-1.32% in the glimepiride group. A similar reduction in 2h-PPG (vildagliptin group 3.53+/-4.11 mmol/L vs. the glimepiride group 3.72+/-4.17 mmol/L) was demonstrated, and the decrements in FPG (vildagliptin group 1.54+/-2.41 mmol/L vs. glimepiride group 2.16+/-2.51 mmol/L) were not different between groups. The proportion of patients who achieved an HbA1c less than 7% at week 32 was 50.1% in the vildagliptin group and 56.0% in the glimepiride group. An average body weight gain of 2.53+/-1.21 kg in the glimepiride group was observed in contrast with the 0.23+/-0.69 kg weight gain noted in the vildagliptin group. A 10-fold lower incidence of hypoglycemia was demonstrated in the vildagliptin group, in addition to an absence of severe hypoglycemia. CONCLUSION: Vildagliptin-metformin treatment provided blood glucose control efficacy comparable to that of glimepiride-metformin treatment and resulted in better adverse event profiles with lower risks of hypoglycemia and weight gain.

Incretin-based Combination Therapy in Type 2 Diabetes Mellitus

While there are many therapies for type 2 diabetes are available including insulin secretagogues, insulin sensitizers and exogenous insulin, many patients are unable to reach recommended therapeutic targets. Incretin-based therapies have recently been introduced into clinical practice, and these novel therapies may make it possible to achieve improved glycemic control either with no weight gain (dipeptidyl peptidase-4 [DPP-4] inhibitors sitagliptin and vildagliptin, or with weight loss (glucagon-like peptide-1 [GLP-1] mimetics exenatide and liraglutide). This article aims to provide an overview of efficacy and safety data regarding incretinbased clinical trials in type 2 diabetic patients, and propose a systematic approach to treatment including patient selection and optimal treatment combination. In addition, preclinical data suggest that incretin-based therapies may also preserve-cell function. Therefore, these agents hold out promise of a truly disease-modifying therapy that would target the progressive nature of type 2 diabetes. Additional clinical trials will be required to test such hypothesis.