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.

Calpain inhibition improves erectile function in diabetic mice via upregulating endothelial nitric oxide synthase expression and reducing apoptosis / 亚洲男科学杂志(英文版)

Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice. Thirty-eight-week-old male C57BL/6J mice were divided into three groups: (1) nondiabetic control group, (2) diabetic mice + vehicle group, and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg-1 body weight for 5 consecutive days. Thirteen weeks later, diabetic mice were treated with MDL28170 or vehicle for 4 weeks. The erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis. Caspase-3 expression and activity were also measured to determine apoptosis. Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group. No differences in calpain-1 and calpain-2 expressions were observed among the three groups. However, calpain activity was increased in the diabetic group and reduced by MDL28170. The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice. Additionally, MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum. Inhibition of calpain could improve erectile function, probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.

Alanyl-glutamine attenuates 5-fluorouracil-induced intestinal mucositis in apolipoprotein E-deficient mice

Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/--challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.

Nuevas estrategias en el tratamiento del síndrome antifosfolípido / New alternatives for the treatment of antiphospholipid syndrome. A literature review

For years the mainstay of antiphospholipid syndrome treatment has been anticoagulation and antiplatelet therapy, but the autoimmune nature of the disease, and complications of these therapies, created the need to develop new therapeutic strategies. New therapeutic alternatives inhibit at different levels, the cascade of events leading to the pro-thrombotic state characteristic of the antiphospholipid syndrome. We conducted a literature review of these new treatments, focusing on the pathophysiological bases that support them and their possible clinical applications.

IMPROVEMENT OF INTESTINAL PERMEABILITY WITH ALANYL-GLUTAMINE IN HIV PATIENTS: a randomized, double blinded, placebo-controlled clinical trial

Context Glutamine is the main source of energy of the enterocyte and diarrhea and weight loss are frequent in HIV infected patients. Objective To determine the effect of alanyl-glutamine supplementation on intestinal permeability and absorption in these patients. Methods Randomized double-blinded, placebo-controlled study using isonitrogenous doses of alanyl-glutamine (24 g/day) and placebo (glycine, 25 g/day) during 10 days. Before and after this nutritional supplementation lactulose and mannitol urinary excretion were determined by high performance liquid chromatography. Results Forty six patients with HIV/AIDS, 36 of whom were male, with 37.28 ± 3 (mean ± standard error) years were enrolled. Twenty two and 24 subjects were treated with alanyl-glutamine and with glycine respectively. In nine patients among all in the study protocol that reported diarrhea in the 14 days preceding the beginning of the study, mannitol urinary excretion was significantly lower than patients who did not report this symptom [median (range): 10.51 (3.01–19.75) vs. 15.37 (3.93–46.73); P = 0.0281] and lactulose/mannitol ratio was significantly higher [median (range): 0.04 (0.00–2.89) vs. 0.02 (0.00–0.19); P = 0.0317]. There was also a significant increase in mannitol urinary excretion in the group treated with alanyl-glutamine [median (range): 14.38 (8.25–23.98) before vs 21.24 (6.27–32.99) after treatment; n = 14, P = 0.0382]. Conclusion Our results suggest that the integrity and intestinal absorption are more intensely affected in patients with HIV/AIDS who recently have had diarrhea. Additionally, nutritional supplementation with alanyl-glutamine was associated with an improvement in intestinal absorption. .

Contexto A glutamina é a principal fonte de energia do enterócito e diarreia e perda de peso são frequentes em pacientes infectados pelo HIV. Objetivo Determinar o efeito da alanil-glutamina sobre a permeabilidade e a absorção intestinais nesses pacientes. Métodos Estudo duplo-cego, randomizado, controlado por placebo, utilizando doses isonitrogênicas de alanil-glutamina (24 g/dia) e de placebo (glicina, 25 g/dia) durante 10 dias. Antes e depois dessa suplementação nutricional a excreção urinária de lactulose e manitol foi determinada por cromatografia líquida de alta performance. Resultados Quarenta e seis pacientes com HIV/AIDS, sendo 36 do sexo masculino, com 37,28 ± 3 anos (média ± erro padrão) foram incluídos. Vinte e dois e 24 indivíduos foram tratados com alanil-glutamina e com glicina, respectivamente. Nos nove pacientes que relataram ter apresentado diarreia nos 14 dias anteriores ao início do estudo, a excreção urinária de manitol foi significativamente menor do que nos pacientes que não referiram essa queixa [mediana (intervalo): 10,51 (3,01-19,75) vs 15,37 (3,93-46,73), P = 0,0281] e a razão lactulose/manitol foi significativamente mais elevada [mediana (intervalo): 0,04 (0,00-2,89) vs 0,02 (0,00-0,19), P = 0,0317]. Constatou-se também aumento significativo na excreção urinária de manitol no grupo tratado com alanil-glutamina [mediana (intervalo): 14,38 (8,25-23,98), antes vs 21,24 (6,27-32,99) após o tratamento, n = 14, P = 0,0382]. Conclusão Os resultados do presente estudo sugerem que a integridade e a absorção intestinais são mais intensamente afetadas em pacientes com HIV/AIDS que tiveram diarreia recentemente. Adicionalmente, a suplementação ...

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.

A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment / Uma análise crítica dos estudos de avaliação do L-ornitina-L-aspartato (LOLA) no tratamento da encefalopatia hepática

CONTEXT: Experimental and clinical studies suggest that LOLA may have a favorable influence on hepatic encephalopathy due to the effect on the reduction of ammonia, and improvement of the symptoms and laboratory findings. OBJECTIVES: To evaluate and to critically analyze the efficacy and/or effectiveness results of the use of LOLA when compared to placebo in the treatment of hepatic encephalopathy. DATA SOURCES: LILACS, SciELO, MEDLINE, PubMed database and Cochrane Collaboration Register of Controlled Trials were searched from 1966 to September of 2006. The review has included all the randomized controlled double-blind clinical trials performed in humans in English language. RESULTS: Four studies published between 1993 and 2000 were selected and reviewed. LOLA was showed as being able to reduce hyperammonemia in patients with hepatic encephalopathy, when compared to patients in the placebo group. CONCLUSIONS: Although the trials have shown efficacy of LOLA in reducing hyperammonemia of hepatic encephalopathy, sufficient evidence of a significant beneficial effect of LOLA on patients with hepatic encephalopathy was not found. The studies performed in this area were small, with short follow-up periods and half of them showed low methodological quality.

CONTEXTO: Estudos experimentais e clínicos sugerem que a L-ornitina-L-aspartato pode ter uma influência favorável na encefalopatia hepática em virtude do seu efeito na redução da amônia, e melhora dos sintomas e achados laboratoriais. OBJETIVOS: Avaliar e analisar criticamente os estudos de eficácia e/ou efetividade do uso de L-ornitina-L-aspartato quando comparado com placebo no tratamento da encefalopatia hepática. FONTES DE INFORMAÇÃO: Foram pesquisadas as bases de dados LILACS, SciELO, MEDLINE, PubMed e o Registro de Ensaios Controlados da Colaboração Cochrane no período de 1966 até setembro de 2006. A revisão incluiu todos os ensaios clínicos controlados randomizados, duplo-cego, em seres humanos, no idioma inglês. RESULTADOS: Foram selecionados e revisados quatro estudos publicados entre 1993 e 2000, que mostraram que a L-ornitina-L-aspartato foi capaz de reduzir a hiperamonemia em portadores de encefalopatia hepática, quando comparados ao grupo que utilizou placebo. CONCLUSÕES: Embora os estudos tenham demonstrado eficácia da L-ornitina-L-aspartato em reduzir a hiperamonemia da encefalopatia hepática, não foi encontrada evidência suficiente que a L-ornitina-L-aspartato tenha um efeito clínico benéfico significativo em pacientes com encefalopatia hepática. Os ensaios realizados neste campo foram pequenos com períodos curtos de acompanhamento e a metade deles com baixa qualidade metodológica.

Two approaches to discovering and developing new drugs for Chagas disease

This review will focus on two general approaches carried out at the Sandler Center, University of California, San Francisco, to address the challenge of developing new drugs for the treatment of Chagas disease. The first approach is target-based drug discovery, and two specific targets, cytochrome P450 CYP51 and cruzain (aka cruzipain), are discussed. A "proof of concept" molecule, the vinyl sulfone inhibitor K777, is now a clinical candidate. The preclinical assessment compliance for filing as an Investigational New Drug with the United States Food and Drug Administration (FDA) is presented, and an outline of potential clinical trials is given. The second approach to identifying new drug leads is parasite phenotypic screens in culture. The development of an assay allowing high throughput screening of Trypanosoma cruzi amastigotes in skeletal muscle cells is presented. This screen has the advantage of not requiring specific strains of parasites, so it could be used with field isolates, drug resistant strains or laboratory strains. It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits.

Brain edema in acute liver failure.

Brain edema and consequent increase in intracranial pressure is a major complication of acute liver failure (ALF) and is a major cause of death in this condition. Rapid accumulation of ammonia in brain has been implicated in the pathogenesis of brain edema in ALF. Increased brain ammonia may cause brain swelling via the osmotic effects of an increase in astrocytic glutamine concentration or by inhibition of glutamate removal from brain extracellular space. Acute liver failure results in altered expression of several genes in the brain, some of which code for proteins involved in central nervous system function such as the glutamate transporter GLT-1, the astrocytic structural protein, glial fibrillary acidic protein, and the water channel protein, aquaporin IV. Loss of expression of GLT-1 results in increased extracellular brain glutamate. Therapeutic measures currently used to prevent and treat brain edema in acute liver failure include mannitol; strategies aimed at lowering of gut ammonia production are generally ineffective. Studies in experimental animals suggest that mild hypothermia or the use of L-ornithine-L-aspartate may be useful in the prevention of brain edema in these patients.

Posibilidades de utilizar dipéptidos parentales en nutrición clínica

En los últimos años se han estudiado a fondo los efectos de los péptidos intravenosos. Las soluciones de dipéptidos son un medio para suministrar determinados aminoácidos que podrían ser inidispensables en ciertas condiciones clínicas. En particular, podría ser díficil administrar aminoácidos tales como la cistina, la glutamina y la tirosina en su forma libre, mientras que su disponiblidad aumenta considerablemente cuando se suministran en forma de dipéptidos. Losestudios en animales y en seres humanos han demostrado que los dipéptidos parentales son eliminados rápidamente del plasma e influyen favorablemente sobre el balance del nitrógeno tanto en individuos sanos como en pacientes catábolicos.(RESUMEN TRUNCADO A 2.500 CARACTERES)

Revisión: Dipéptidos en nutrición parental: de la ciencia básica a las aplicaciones clínicas

Los dipéptidos intravenosos parecen ser un medio muy prometedor para suministrar aminoácidos que de otra manera sería difícil administrar a través de infusiones de nutrientes. Ya se han hecho estudios experimentales y en seres humanos para analizar las propiedades fisicoquimicas y el metabolismo de muchos dipéptidos. Se ha descubierto que estos agentes, al igual que los aminoácidos libres aplicados por via intravenosa, pueden ahorrar nitrógeno y mantener los mismos niveles de proteína sérica. Otro beneficio es la posibilidad de administrar ciertos aminóacidos relativamente inestables o de mala solubilidad en las soluciones acuosas. En esta revisión se describen estos distintos aspectos de los dipéptidos intravenosos

From lysosomes to cells, from cells to Leishmania: amino acid esters as potential chemotherapeutic agents

Amino acid esters can disrupt lysosomes and damage monocytes and certain lymphocyte populations. Lysosomal disruption involves pH trapping of the esters, followed by their hydrolyssis by as yet unidentified enzymes. Accumulation of the more polar amino acids is assumed to cause osmotic lysis of the organelles. we have discovered that certain amino acid esters and amides destroy Leishmania mexicana amazonensis amastigores lodged within macrophages in culture, as well as parasites isolated from mouse lesions. This paper reviews the amino acid specificity of parasite killing, the resistance of amastigotes derived from infection of macrophages with promastigotes, the involvement of an acidified compartment within the parasites, and the protection conferred by other amino acid esters, and the protease inhibitors antipain and chymostatin, aginst the destruction of amastigotes by Leucine-methyl ester. Studies with tritiated esters confirm the critical role of ester hydrolysis for leishmanicidal activity and strengthen the view that similar mechanisms underlie disruption of lysosomes and destruction of Leismania. Characterization of the parasite organelles and of the enzymes involved in the leishmanicidal activity as well as structure-activity studies may permit the design of compounds mor selective for the parasites