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2.
Vitae (Medellín) ; 28(3): 1-14, 2021-08-11. Ilustraciones
Article in English | LILACS, COLNAL | ID: biblio-1363261

ABSTRACT

Background: Milk-derived biopeptides have reported in vitro dipeptidyl-peptidase IV (DPP-IV) inhibition, suggesting a glycemic-regulatory effect in Type 2 Diabetes Mellitus (T2DM). Nonetheless, the therapeutic application of these nutraceuticals is limited by the scarcity of knowledge regarding their pharmacokinetic profile. Objective: This study aimed to characterize and assess the pharmacokinetics of milk-derived biopeptides. Through an in silico comparative analysis with gliptins, we expected to identify enhanced properties in food-hydrolysates and suitable DPP-IV inhibiting peptides as candidates for T2DM therapy. Methods: A comparison between gliptins and biopeptides was conducted based on in silico evaluation of drug-likeness, physicochemical properties, pharmacokinetics, and synthetic accessibility. Suitable target proteins for gastrointestinal-absorbable biopeptides were determined as well. Data collection was performed on SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes, and BIOPEP-UWM platforms. Statistical analysis was carried out using a one-way ANOVA test. Results: Drug-likeness compliance showed no significant difference between gliptins and biopeptides (p>0.05) in three out of nine assessed rules, though gastrointestinal-absorbable biopeptides exhibited no significant difference with gliptins in five drug-likeness guidelines. The physicochemical evaluation revealed a significant difference (p<0.05) between both groups, with peptides exhibiting enhanced solubility, flexibility, and polarity. Nine out of thirty-six assessed biopeptides reported being likely gastrointestinal-absorbable molecules, from which six displayed ≥30% predicted bioavailability, two reported CYP450 interactions, and all were determined to be blood confined. Biopeptides showed a slightly lower clearance than gliptins yet counteracted by a significantly lower half-life. Moreover, synthetic accessibility scores indicated higher synthetic ease for biopeptides. In addition, absorbable bioactive peptides reported a considerable binding affinity to DPP-IV and Calpain-I. Conclusions: Compared to gliptins, gastrointestinal-absorbable biopeptides exhibit superior physicochemical properties (higher solubility, flexibility, and polarity), lesser CYP450 interactions, higher synthetic ease, and some reported an important affinity for DPP-IV and Calpain-I. Only a small fraction of milk-derived biopeptides are suitable drug-like compounds and feasible candidates for T2DM therapy; yet, testing their therapeutic potency remains subject to further studies


Antecedentes: Los biopéptidos derivados de la leche han mostrado inhibir la dipeptidil-peptidasa IV (DPP-IV) en ensayos in vitro, lo que sugiere una regulación de la glicemia en la Diabetes Mellitus Tipo 2 (DM2). Sin embargo, su uso terapéutico está limitado por el escaso conocimiento de sus propiedades farmacológicas. Objetivo: Caracterizar y evaluar el perfil farmacocinético de los biopéptidos derivados de la leche. Por medio de un análisis comparativo in silico, se buscó identificar propiedades de carácter superior a las gliptinas en los biopéptidos inhibidores de DPP-IV, así como posibles candidatos a agentes terapéuticos en la DMT2. Métodos: Se llevó a cabo una comparación entre las Gliptinas y los biopéptidos basada en la evaluación in silicode las características "d r ug - li ke", propiedades fisicoquímicas, farmacocinética y accesibilidad sintética. Adicionalmente, se determinaron posibles proteínas diana para los biopéptidos de alta probabilidad de absorción gastrointestinal. Los datos se obtuvieron en SwissADME, ADMETlab, DrugBank, SwissTargetPrediction, ChemDes y BIOPEP-UWM. El análisis estadístico se basó en un análisis de varianza (one-way ANOVA test). Resultados: El cumplimiento de las reglas de "drug-likeness" no mostró diferencias significativas entre las gliptinas y los biopéptidos (p>0.05) en tres de las nueve normas evaluadas, empero, los biopéptidos absorbibles no mostraron diferencias significativas con las gliptinas en cinco de estas. La evaluación fisicoquímica reveló una diferencia significativa (p>0.05) entre ambos grupos y una mayor solubilidad, flexibilidad y polaridad para los biopéptidos. Nueve de los treinta y seis biopéptidos estudiados reportaron alta probabilidad de absorción gastrointestinal, de los cuales seis presentaron una biodisponibilidad predicha ≥30%, dos reportaron interacciones con el CYP450, y todos mostraron permanecer confinados en sangre. Los biopéptidos mostraron una tasa de aclaramiento inferior a las gliptinas, sin embargo, contrarrestado por una vida-media significativamente menor. Los valores de accesibilidad sintética indicaron una mayor facilidad de síntesis para los biopéptidos. Por último, los biopéptidos absorbibles mostraron una considerable afinidad por la DPP-IV y la Calpaína-I. Conclusiones: Frente a las gliptinas, los biopéptidos absorbibles presentan: propiedades fisicoquímicas superiores (mayor solubilidad, flexibilidad y polaridad), menores interacciones con el CYP450, mayor facilidad de síntesis y algunos una importante afinidad por la DPP-IV y la Calpaína-I. Una mínima fracción de biopéptidos derivados de la leche son candidatos viables para la terapia de DM2; sin embargo, la determinación de su efectividad terapéutica permanece sujeta a futuros estudios


Subject(s)
Humans , Pharmacokinetics , Peptides , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors
3.
Prensa méd. argent ; 107(5): 258-263, 20210000. tab, ilus
Article in Spanish | LILACS, BINACIS | ID: biblio-1359193

ABSTRACT

El Penfigoide Ampollar por fármacos es una variedad de penfigoide ampollar en la que un medicamento actúa como causa o desencadenante de la enfermedad. Clínicamente se manifiesta como ampollas tensas de contenido seroso localizadas fundamentalmente en abdomen, miembros superiores y raíz de muslos. El estudio histopatológico evidencia ampollas subepidérmicas e infiltrado dérmico mixto con eosinófilos. La inmunofluorescencia directa de piel sana perilesional muestra depósitos lineales de IgG y/o C3. Sin embargo, en hasta 15% de los casos puede ser negativa. Los pacientes diabéticos que reciben tratamiento con fármacos del grupo de los inhibidores de la dipeptidilpeptidasa 4, también conocidos como gliptinas, tienen 3 veces más riesgo de desarrollar esta patología. El tiempo de latencia entre el inicio de la medicación y la aparición de los síntomas es variable, con una media de 10 meses. El tratamiento radica en la suspensión inmediata del fármaco causal y la administración de prednisona oral 0,5 mg/kg/día. El tiempo medio de respuesta es de 10 días. Se presenta un varón de 82 años con una dermatosis ampollar pruriginosa de 3 semanas de evolución posterior al inicio de teneligliptina, cuyo estudio histopatológico fue característico de penfigoide ampollar, y que evolucionó satisfactoriamente al suspender el hipoglucemiante oral, sin aparición de nuevas lesiones a más de un año de seguimiento clínico


Drug-induced bullous pemphigoid is a variety of bullous pemphigoid in which a drug is the cause of the disease. It manifests as serous tense blisters located mainly on the abdomen, upper limbs and root of the tights. The histopathology shows subepidermal bullae and mixed dermal infiltrate with eosinophils. Direct immunofluorescence of healthy perilesional skin shows linear IgG and/or C3 deposits. However, it can be negative in up to 15% of the cases. Diabetic patients receiving dipeptidylpeptidase 4 inhibitors have a 3 times increased risk of developing drug-induced bullous pemphigoid. The mean time between the beginning of the medication and the appearance of the dermatosis is 10 months. Immediate suspension of the offending drug and administration of prednisone 0,5 mg/kg/day is the standard treatment. Average response time is 10 days. We present an 82-year-old-man with a 3-week itchy bullous dermatosis that started 8 months after treatment with teneligliptin, whose histopathological study resembled bullous pemphigoid, and which evolved satisfactorily when the drug was discontinued. No new lesions have been detected after more than one year of clinical follow-up. Key words: bullous pemphigoid, drug-induced bullous pemphigoid, gliptins, teneligliptin, dipeptidylpeptidase 4 inhibitors


Subject(s)
Humans , Male , Aged, 80 and over , Skin Diseases/immunology , Prednisone/therapeutic use , Pemphigoid, Bullous/drug therapy , Pemphigoid, Bullous/therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
4.
Salud(i)ciencia (Impresa) ; 24(5): 232-237, mar.-abr. 2021. tab.
Article in Spanish | LILACS, BINACIS | ID: biblio-1283796

ABSTRACT

Background: In December 2019, a series of cases occurred in Wuhan (China), caused by a new coronavirus. On March 11, 2020, the WHO declared the COVID-19 disease, caused by SARS-CoV-2, as a pandemic. In Peru, the first person infected with SARS-CoV-2 was confirmed on March 6, 2020. The number of infected has been constantly increasing to this day. Purpose: It is relevant to the current pandemic, understanding the mechanism of infection of SARS-CoV-2 in diabetic patients and in this way to be able to provide natural alternatives to reduce the complications that these patients can carry out until death. Methodology: An information search was carried out between April 6 and August 25 of 2020 in databases and indexed journals, whose articles have been published between 2011 and 2020. Results: It was found regarding inhibitors of dipeptidyl peptidase (DPP-4) evaluated in in vitro tests, that the Berberis aristata species has a metabolite called "berberine", which has the highest inhibitory capacity among the mentioned species, and, concerning furine inhibition, among the in vitro tests, catechin has a significant inhibitory capacity; it also has DPP-4 inhibitory activity. Conclusion: There is a great variety of medicinal plants with inhibitory properties for DPP-4 and some for furin. These properties are beneficial in patients with type 2 diabetes, since they reduce the activity of these proteases and, consequently, the complications in SARS-CoV-2 infection


Antecedentes: En diciembre de 2019, se registraron una serie de casos producidos por un nuevo coronavirus en Wuhan (China). El 11 de marzo de 2020, la Organización Mundial de la Salud declaró a la COVID-19, provocada por el coronavirus 2 causante del síndrome respiratorio agudo grave (SARS-CoV-2), como una pandemia. En el Perú, la primera persona infectada por SARS-CoV-2 fue confirmada el 6 de marzo de 2020; desde entonces, la cifra de infectados ha ido en constante aumento hasta el día de hoy. Propósito: Es relevante, ante la actual pandemia, entender el mecanismo de infección del SARS-CoV-2 en pacientes diabéticos, para, de esta manera, poder dar alternativas naturales para disminuir las complicaciones que pueden llevar a estos pacientes hasta la muerte. Metodología: se realizó una búsqueda de información entre el 6 de abril y el 25 de agosto de 2020, en bases de datos y revistas indexadas, cuyos artículos han sido publicados entre 2011 y 2020. Resultados: Se encontró, en cuanto a los inhibidores de la dipeptidilpeptidasa 4 (DPP-4) evaluados en ensayos in vitro, que la especie Berberis aristata posee un metabolito denominado "berberina", el cual presentó la mayor capacidad inhibitoria entre las especies analizadas. Con respecto a la inhibición de la furina, en los ensayos in vitro, la catequina posee una capacidad inhibitoria significativa; además de actividad inhibitoria para la DPP-4. Conclusión: Existe una gran variedad de plantas medicinales con propiedades inhibitorias para la DPP-4, y algunas de ellas para la furina. Estas propiedades son beneficiosas en pacientes con diabetes tipo 2, dado que reducen la actividad de estas proteasas y, por consiguiente, las complicaciones causadas por la infección por SARS-CoV-2


Subject(s)
Furin , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , COVID-19
5.
s.l; s.n; 29 maio 2020.
Non-conventional in Portuguese | LILACS, BRISA, PIE | ID: biblio-1099466

ABSTRACT

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 13 artigos e 13 protocolos.


Subject(s)
Humans , Pneumonia, Viral/drug therapy , Coronavirus Infections/drug therapy , Betacoronavirus/drug effects , Renin-Angiotensin System , Technology Assessment, Biomedical , Zinc/therapeutic use , Ivermectin/therapeutic use , Chloroquine/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Azithromycin/therapeutic use , Ritonavir/therapeutic use , Oseltamivir/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Wharton Jelly , Lopinavir/therapeutic use , Atazanavir Sulfate/therapeutic use , Sofosbuvir/therapeutic use , Interferon alpha-2/therapeutic use , Hydroxychloroquine/therapeutic use
6.
Rev Assoc Med Bras (1992) ; 66(4): 458-465, 2020. tab, graf
Article in English | LILACS, SES-SP | ID: biblio-1136227

ABSTRACT

SUMMARY After metformin failure in treatment for diabetes type 2, there is no trivial option for adjuvant medication. The last two oral class medications, gliflozins and gliptins, have different mechanisms of action but have never been compared in long run studies. The aim of the present meta-analysis is to assess the overall long-term efficacy of these drugs after metformin failure. A systematic review and meta-analysis were performed, including all trials with a duration of over 2 years, comparing gliflozins or gliptins after metformin failure in type 2 diabetes. Data Sources: Pubmed (Medline), Embase, Lilacs, and the Cochrane Library from inception through July 2016 without language restrictions. The longest study period found in the literature was 4 years. We selected 1 article on empagliflozin, 1 on dapagliflozin, and 1 on saxagliptin with missing data. After one year of treatment, over 50% of the patients presented HbA1c > 7%. Efficacy rate after 4 years of empagliflozin (23%) was better than dapagliflozin (5%) and saxagliptin (7%); however, it presented statistically non-significant values for HbA1c (7.4 and 7.3% between gliflozins), and missing data for saxaglifozin. Nonetheless, empagliflozin performed better than glimepiride in the 4-year period (standardized mean difference SMD 0.4, confidence interval CI 95% 0.23 to 0.56). The failure of the secondary treatment using gliflozins occurs in less than one year of treatment (less than 50% of the patients presenting HbA1c > 7 %). Empagliflozin offered better glycemic control compared to sulfonylureas but was similar to dapagliflozin.


RESUMO Após a falha da metformina no tratamento do diabetes tipo 2, não existe uma opção trivial para a medicação adicional. Os dois últimos medicamentos de classe oral, gliflozinas e gliptinas, têm mecanismos de ação diferentes, mas nunca foram comparados em estudos de longo prazo. O objetivo da presente meta-análise é a avaliação da eficácia global em longo prazo desses medicamentos após a falha da metformina. Uma revisão sistemática e meta-análise foram realizadas, incluindo todos os ensaios com uma duração de mais de dois anos, comparando gliflozinas ou gliptinas após a insuficiência de metformina no diabetes tipo 2. Fontes de dados: PubMed (Medline), Embase, Lilacs e a Biblioteca Cochrane desde o início até julho de 2016, sem restrições de idioma. O período mais longo de estudo encontrado na literatura foi de quatro anos. Foi selecionado um artigo sobre empagliflozina, um artigo sobre dapagliflozina e um artigo sobre saxagliptina com dados faltantes. Após um ano de tratamento, mais de 50% dos pacientes apresentavam HbA1c >7%. A taxa de eficácia em quatro anos de empagliflozina (23%) foi melhor que dapagliflozina (5%) e saxagliptina (7%), porém com valores estatisticamente não significativos para HbA1c (7,4% e 7,3% entre gliflozinas) e dados ausentes para a saxaglifozina. No entanto, a empagliflozina teve um desempenho melhor do que a glimepirida no período de quatro anos (diferença média padronizada SMD 0,4, intervalo de confiança IC 95% 0,23 a 0,56). A falha do tratamento secundário com gliflozinas ocorre em menos de um ano de tratamento (menos de 50% dos pacientes com HbA1c >7%). A empagliflozina ofereceu melhor controle glicêmico em comparação com as sulfonilureias, mas semelhante à dapagliflozina.


Subject(s)
Humans , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Metformin , Benzhydryl Compounds , Network Meta-Analysis , Hypoglycemic Agents
7.
Article in English | WPRIM | ID: wpr-811147

ABSTRACT

BACKGROUND: There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM.METHODS: This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement.RESULTS: Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: −0.81%, P<0.001; glimepiride: −1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001).CONCLUSION: Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.


Subject(s)
Cholesterol, HDL , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Drug Therapy, Combination , Glycated Hemoglobin A , Humans , Hypoglycemia , Insulin Resistance , Metformin , Sulfonylurea Compounds , Thiazolidinediones , Treatment Failure
8.
Article in English | WPRIM | ID: wpr-811137

ABSTRACT

Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-β/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.


Subject(s)
Animals , Atrophy , Blotting, Western , Diabetic Nephropathies , Dipeptidyl-Peptidase IV Inhibitors , Extracellular Matrix , Fibrosis , Gene Expression , Immunohistochemistry , In Vitro Techniques , Kidney Diseases , Kidney Failure, Chronic , Mice , Renal Insufficiency, Chronic , Transforming Growth Factor beta , Ureter , Ureteral Obstruction
9.
Article in English | WPRIM | ID: wpr-876408

ABSTRACT

@#Introduction: Bullous pemphigoid (BP) is a chronic, autoimmune blistering disease occurring primarily in the elderly population. The pathogenesis of this condition has been strongly linked to the presence of circulating and tissue-bound autoantibodies against the basement membrane antigens BP180 and BP230. In most cases, the causative agent remains unidentified, but in a selected few, certain medications have been implicated in the pathogenesis of the disease. Dipeptidyl peptidase-4 inhibitors (-gliptins), in particular, which are used primarily in the treatment of diabetes mellitus, have been increasingly suspected to be a prime aggravating drug in the incidence of BP. Case summary: Bullous pemphigoid (BP) is a chronic autoimmune blistering disease mainly affecting the elderly population. While the pathogenesis has not yet been fully elucidated, it has been suggested that there is a correlation observed with certain groups of medications. Among drugs correlated with bullous pemphigoid, the group of dipeptidyl peptidase-4 inhibitors (-gliptins) used in the treatment of diabetes mellitus has been one of the most strongly associated. This is a case of a 64-year-old female on regular maintenance medications including linagliptin who developed generalized pruritus followed a week after by appearance of localized fluid-filled vesicles and bullae on the right lower leg. BP associated with dipeptidyl peptidase-4 inhibitors is characterized as “non-inflammatory” – lesions are localized and associated with less erythema compared to the classic presentation. Serum eosinophilia was absent, and serum autoantibody against BP180 was positive. Histopathologic and immunohistologic results revealed characteristics similar to classic bullous pemphigoid. The association of dipeptidyl peptidase-4 inhibitors to the development of BP was observed to have a long latency period between initiation of drug to onset of lesions. There was significant improvement after both withdrawal of the drug and standard steroids and doxycycline. Unlike other drug-induced BP, dipeptidyl peptidase-4 inhibitor-associated BP was found to have similar prognosis with the classic manifestation as the patient noted recurrence one month after remission despite withdrawal of inciting drug. Conclusion: There has been increasing incidence in DPP-4 inhibitor-associated BP. Though its clinical course is similar to classic BP, a non-inflammatory and more localized presentation would prompt suspicion of association with drug. The long latency in DPP-4 inhibitor and lesion onset suggests that rather than being simply an adverse reaction to treatment, DPP-4 inhibitor-associated BP should be viewed as a drug-associated or drug-aggravated disease. Determining the association of BP to DPP4-inhibitors is significant as the management for these patients not only entails standard management of BP but also withdrawal of the suspect drug, which in this case was found to significantly improve the patient’s lesions after one month. Unlike other drug-induced BP, however, DPP-4 inhibitor associated BP was found to have the same prognosis with classic BP as the patient noted recurrence one month after remission.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Pemphigoid, Bullous , Pharmaceutical Preparations , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents
10.
Braz. J. Pharm. Sci. (Online) ; 56: e18482, 2020. graf
Article in English | LILACS | ID: biblio-1249142

ABSTRACT

Up to date, the management of hepatotoxicity induced by a suicidal or unintentional overdose of acetaminophen (APAP) remains a therapeutic challenge. The present study aimed to elucidate the potential effect of sitagliptin, a DPP-4 inhibitor, to ameliorate the acute injurious effects of acetaminophen on the liver. APAP toxicity was induced in mice by an intraperitoneal injection of APAP (400 mg/kg). The effect of treatment with sitagliptin, initiated 5 days prior to APAP injection, was evaluated. Serum indices of hepatotoxicity, oxidative stress markers in liver tissues, serum IL-1ß, and TNF-α in addition to hepatic- NF-E2-related factor-2 (Nrf2) were determined. Our results showed that APAP induced marked hepatic injury as evidenced by an increase in serum levels of ALT and AST, in addition to the deterioration of histological grading. Oxidative stress markers, serum TNF-α, and IL-1ß were also elevated. Sitagliptin successfully ameliorated the histological changes induced by APAP, improving liver function tests and liver oxidant status accompanied with a marked increase in Nrf2 level in hepatic tissues. Thus, the hepatoprotective effects of sitagliptin in this animal model seem to involve Nrf2 modulation, coincidental with its anti-inflammatory and antioxidant effects


Subject(s)
Animals , Male , Mice , Therapeutics/adverse effects , Sitagliptin Phosphate/analysis , Acetaminophen/adverse effects , Wounds and Injuries/classification , Oxidative Stress , Models, Animal , Dipeptidyl-Peptidase IV Inhibitors , Liver/abnormalities , Liver Function Tests , Antioxidants/administration & dosage
11.
Rev. chil. endocrinol. diabetes ; 12(2): 124-132, abr. 2019. tab, ilus
Article in Spanish | LILACS | ID: biblio-995453

ABSTRACT

La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.


Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.


Subject(s)
Humans , Diabetes Mellitus, Type 1/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Chemotherapy, Adjuvant , Glucagon-Like Peptide 1/therapeutic use , Sodium-Glucose Transporter 2/antagonists & inhibitors , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Metformin/therapeutic use
12.
Article in English | WPRIM | ID: wpr-739217

ABSTRACT

BACKGROUND: We aimed to retrospectively analyze the efficacy of 10 mg dapagliflozin (DAPA), which is a sodium-glucose cotransporter-2 inhibitor, in Korean patients with type 2 diabetes who visited a primary diabetes clinic. METHODS: In total, 83 patients with type 2 diabetes, who received treatment with DAPA for the first time in a primary diabetes clinic between January 2015 and October 2015, were included in the study. The effect of DAPA in lowering glycosylated hemoglobin (HbA1c) levels was evaluated via chart review at 6 months follow-up. The patients were categorized into five groups according to add-on to or switched from other glucose-lowering agents: add-on to metformin (MET, n=10), add-on to MET+dipeptidyl peptidase 4 inhibitor (DPP4i, n=12), switched from sulfonylurea (SU, n=13), switched from DPP4i (n=11), and switched from thiazolidinedione (TZD, n=37). All the participants had already used MET for their regimen. RESULTS: Treatment with DAPA reduced HbA1c level by 1.2%±0.8%. Moreover, a significant decrease was observed in all subgroups: add-on to MET, −1.2%±0.7%; add-on to MET+DPP4i, −1.4%±0.8%; switched from SU, −1.4%±0.7%; switched from DPP4i, −0.5%±0.7%; and switched from TZD, −1.2%±0.9% (P<0.01). A significant decrease in body weight (−3.1±2.6 kg, P<0.001) was observed after DAPA administration. Estimated glomerular filtration rate and urine microalbumin were significantly decreased after 6 months of treatment with DAPA (−4.0±13.5 mL/min/1.73 m2, P=0.03; −23.6±45.9 mg/L, P<0.001). CONCLUSION: Treatment with DAPA, whether added to or switched from other glucose-lowering agents, significantly decreased HbA1c levels in Korean patients with type 2 diabetes who visited a single primary diabetes clinic. DAPA can be considered as an optimal second-line treatment for patients with type 2 diabetes, as supported by real-world evidence studies.


Subject(s)
Body Weight , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Follow-Up Studies , Glomerular Filtration Rate , Glycated Hemoglobin A , Humans , Korea , Metformin , Primary Health Care , Retrospective Studies
13.
Article in English | WPRIM | ID: wpr-739216

ABSTRACT

BACKGROUND: To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. RESULTS: We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, −1.11 mL/min/1.73 m2; 95% CI, −1.78 to −0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475). CONCLUSION: DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents.


Subject(s)
Albuminuria , Diabetes Complications , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Dipeptidyl-Peptidase IV Inhibitors , Glomerular Filtration Rate , Humans , Hypoglycemic Agents , Kidney Failure, Chronic
14.
Journal of Stroke ; : 139-150, 2019.
Article in English | WPRIM | ID: wpr-766252

ABSTRACT

Patients with hyperglycemia are at a high risk of cardio- and cerebrovascular diseases. Diabetes patients also have poor outcomes after cerebrovascular disease development. Several classes of drugs are used for diabetes management in clinical practice. Thiazolidinedione (TZD) was introduced in the late 1990s, and new antidiabetic agents have been introduced since 2000. After issues with rosiglitazone in 2007, the U.S. Food and Drug Administration strongly recommended that trials investigating cardiovascular risk associated with new antidiabetic medications should be conducted before drug approval in the United States, to prove the safety of these new drugs and to determine their superiority to previous medications. Currently, results are available from two studies with TZD focusing on cardiovascular diseases, including stroke, and from 12 cardiovascular outcome trials focusing on major adverse cardiovascular events associated with new antidiabetic agents (four with dipeptidyl peptidase-4 inhibitors, three with sodium-glucose cotransporter-2 inhibitors, and five with glucagon-like peptide-1 analogues). These studies showed different results for primary cardiovascular outcomes and stroke prevention. It is important to determine whether prescription of TZD or new antidiabetic medications compared to conventional treatment, such as sulfonylurea or insulin, is better for stroke management. Furthermore, it is unclear whether drugs in the same class show greater safety and efficacy than other drugs for stroke management.


Subject(s)
Cardiovascular Diseases , Cerebrovascular Disorders , Diabetes Mellitus , Dipeptidyl-Peptidase IV Inhibitors , Drug Approval , Glucagon-Like Peptide 1 , Humans , Hyperglycemia , Hypoglycemic Agents , Insulin , Prescriptions , Stroke , Thiazolidinediones , United States , United States Food and Drug Administration
15.
Article in English | WPRIM | ID: wpr-765067

ABSTRACT

BACKGROUND: There have been equivocal results in studies of the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i) on fractures. In this study, we analyzed the effect of DPP-4i on bone fracture risk in a Korean population. METHODS: We extracted subjects (n = 11,164) aged 50 years or older from the National Health Insurance Service–National Sample Cohort 2.0 from 2009 to 2014. Our control group included subjects without diabetes (n = 5,582), and our treatment groups with diabetes included DPP-4i users (n = 1,410) and DPP-4i non-users (n = 4,172). The primary endpoint was the incidence of a composite outcome consisting of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures. The secondary endpoint was the incidence of each individual component of the composite outcome. Survival analysis was performed with adjustment for age, gender, diabetes complications severity index, Charlson comorbidity index, hypertension medication, and dyslipidemia treatment. RESULTS: The incidence of the composite outcome per 1,000 person-years was 0.089 in DPP-4i users, 0.099 in DPP-4i non-users, and 0.095 in controls. There was no significant difference in fracture risk between DPP-4i users and DPP-4i non-users or controls after the adjustments (P > 0.05). The incidences of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures were not significantly different between DPP-4i users and non-users. The results of subgroup analyses by gender and age were consistent. CONCLUSION: DPP-4i had no significant effect on the risk of fractures in a Korean population.


Subject(s)
Cohort Studies , Comorbidity , Diabetes Complications , Diabetes Mellitus, Type 2 , Diagnosis , Dipeptidyl-Peptidase IV Inhibitors , Dyslipidemias , Femoral Fractures , Fractures, Bone , Hypertension , Incidence , National Health Programs , Osteoporosis , Osteoporotic Fractures
16.
Article in English | WPRIM | ID: wpr-763682

ABSTRACT

BACKGROUND: To investigate the effects of dipeptidyl peptidase-4 inhibitor (DPP4i) as add-on medications to metformin on progression of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus, compared with sulfonylurea (SU) or thiazolidinedione (TZD). METHODS: We identified 4,447 patients with DPP4i, 6,136 with SU, and 617 with TZD in addition to metformin therapy from the database of Korean National Health Insurance Service between January 2013 and December 2015. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for DR progression. The progression of DR was defined by the procedure code of panretinal photocoagulation, intravitreal injection or vitrectomy; or the addition of diagnostic code of vitreous hemorrhage, retinal detachment, or neovascular glaucoma. RESULTS: The age and sex-adjusted HR of DR progression was 0.74 for DPP4i add-on group compared with SU add-on group (95% confidence interval [CI], 0.62 to 0.89). This lower risk of DR progression remained significant after additional adjustments for comorbidities, duration of metformin therapy, intravitreal injections and calendar index year (HR, 0.80; 95% CI, 0.66 to 0.97). CONCLUSION: This population-based cohort study showed that the use of DPP4i as add-on therapy to metformin did not increase the risk of DR progression compared to SU.


Subject(s)
Cohort Studies , Comorbidity , Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Dipeptidyl-Peptidase IV Inhibitors , Glaucoma, Neovascular , Humans , Hypoglycemic Agents , Intravitreal Injections , Light Coagulation , Metformin , National Health Programs , Retinal Detachment , Vitrectomy , Vitreous Hemorrhage
17.
Article in English | WPRIM | ID: wpr-761818

ABSTRACT

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.


Subject(s)
Animals , Diet , Dipeptidyl-Peptidase IV Inhibitors , Fatty Liver , Fibrosis , Humans , Hypoglycemic Agents , Inflammation , Insulin , Insulin Resistance , Mice , Non-alcoholic Fatty Liver Disease , Plasma , Triglycerides
18.
Article in English | WPRIM | ID: wpr-785707

ABSTRACT

BACKGROUND: The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.METHODS: We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.RESULTS: Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with thein vivoresults, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.CONCLUSION: The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.


Subject(s)
Animals , Atrophy , Blotting, Western , Diabetic Nephropathies , Dipeptidyl-Peptidase IV Inhibitors , Down-Regulation , Fibrosis , Humans , Hypoglycemic Agents , In Vitro Techniques , Inflammasomes , Inflammation , Kidney , Mice , Ureteral Obstruction
19.
Arch. endocrinol. metab. (Online) ; 62(4): 424-430, July-Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-950077

ABSTRACT

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.


Subject(s)
Humans , Male , Female , Middle Aged , Benzhydryl Compounds/therapeutic use , Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucosides/therapeutic use , Benzhydryl Compounds/adverse effects , Blood Glucose/drug effects , Blood Pressure/drug effects , Body Weight/drug effects , Adamantane/adverse effects , Adamantane/therapeutic use , Double-Blind Method , Diabetes Mellitus, Type 2/blood , Dipeptides/adverse effects , Sodium-Glucose Transporter 2/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use
20.
Rev. chil. cardiol ; 37(1): 42-54, abr. 2018. tab, ilus
Article in Spanish | LILACS | ID: biblio-959338

ABSTRACT

Resumen: En los últimos años, la diabetes mellitus tipo 2 (DM2) ha evolucionado en forma epidémica, experimentando un rápido crecimiento y afectando a millones de individuos a nivel mundial. La cardiopatía isquémica es la principal causa de mortalidad en los pacientes diabéticos, quienes poseen un mayor riesgo cardiovascular respecto a los no diabéticos. La DM2 y la cardiopatía isquémica se caracterizan por ser prevenibles, sin embargo, existen diversos factores de riesgo comunes que contribuyen a su desarrollo. Los mecanismos que explican la ateroesclerosis acelerada y el incremento de riesgo de enfermedades cardiovasculares en los pacientes diabéticos tipo 2 incluyen a la hiperglicemia, dislipidemia y la inflamación del endotelio vascular. La diabetes es resultado de una interacción compleja entre la genética y el medio ambiente. Recientemente se han descrito varios genes implicados en el desarrollo de la diabetes y cardiopatía isquémica y que podrían significar nuevas opciones terapéuticas. En este artículo se revisa la relación entre ambas patologías, los mecanismos moleculares y el descubrimiento de factores de riesgo genéticos comunes y su implicancia en el desarrollo de nuevos blancos terapéuticos.


Abstracts: In recent years, type 2 diabetes mellitus has evolved as a rapidly increasing epidemic and affects millions of people worldwide. Ischemic heart disease (IHD) is the main cause of death among diabetic patients, who have a higher cardiovascular risk than non-diabetics. Both, DM2 and IHD are characterized by being preventable, however there are several common risk factors that contribute to their development. The mechanisms that explain accelerated atherosclerosis and increased risk of cardiovascular diseases in patients with type 2 diabetes mellitus include damage by hyperglycemia, dyslipidemia and inflammation on vascular endothelium. Diabetes is the result of a complex interaction between genetics and the environment, recently, several genes have been identified that appear to be involved in diabetes and ischemic heart disease that could explain its relationship and serve as new therapeutic possibilities. In this article, we review the relationship between diabetes and ischemic heart disease, the molecular mechanisms and the discovery of genetic risk factors common to both diseases and their implication in the development of new therapeutic targets.


Subject(s)
Humans , Myocardial Ischemia/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/genetics , Polymorphism, Genetic/genetics , Genetic Therapy , Myocardial Ischemia/physiopathology , Myocardial Ischemia/genetics , Myocardial Ischemia/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/physiopathology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hyperglycemia/physiopathology , Metformin/therapeutic use
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