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PURPOSE: Community health workers (CHWs) play integral roles in primary health care provision in low- and middle-income countries (LMICs). This is particularly true in underdeveloped areas where there are acute shortages of health workers. In this study, we evaluated the development and community utilization of a CHW training program in the Loreto province of Peru. Additionally, a community-oriented training model was designed to augment access to basic health information in underserved and isolated areas of the Amazon. METHODS: Health resource utilization was compared in each community by surveying community members before and after implementation of the CHW training program, which utilized a community participatory program development (CPPD) model. RESULTS: All communities demonstrated significantly increased CHW utilization (p = 0.026) as their initial point of contact for immediate health concerns following CHW training implementation. This increase in CHW utilization was accompanied by trends toward decreased preferences for local shamans or traveling to the closest health post as the initial health resource. CONCLUSION: The community-focused, technology-oriented model utilized in this study proved an effective way to promote the use of CHWs in the Amazon region of Loreto, and could prove valuable to CHW capacitation efforts within other Peruvian provinces and in other LMICs around the world.
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A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
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Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/síntesis química , Fenetilaminas/síntesis química , Pirrolidinas/síntesis química , Animales , Glucemia/metabolismo , Ciclohexenos/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Inhibidores Enzimáticos/química , Femenino , Hipoglucemiantes/farmacología , Modelos Químicos , Conformación Molecular , Fenetilaminas/química , Pirrolidinas/química , RatasRESUMEN
It is unclear how hepatic glucocorticoid receptor (GR) function and hypothalamic-pituitary-adrenal axis tone contribute to the diabetic state and in particular whole-body glucose fluxes. We have previously demonstrated that long-term exposure to hepatic GR inhibition lowers glucose levels in ob/ob mice (J Pharmacol Exp Ther 2005;314:191). The purpose of this study was to determine the effects of a novel GR antagonist (A-348441) on whole-body glucose fluxes in a model of insulin resistance, the Zucker fatty (fa/fa) rat. After an overnight fast, euglycemic-hyperinsulinemic clamp studies were performed 2 hours after single oral dosing as follows: (1) A-348441 at 100 mg/kg or (2) vehicle. Furthermore, effects of 1 week of treatment with either vehicle or A-348441 (3, 10, 30, or 100 mg/kg PO, once per day) were investigated in separate groups of rats fasted overnight and given a final dose of their respective compound, followed 2 hours later by a euglycemic-hyperinsulinemic clamp. One week after catheter implantation, body weight returned to presurgery levels, with no difference between groups. A single, 100-mg/kg dose of A-348441 significantly increased glucose infusion rate 4-fold (P < .05) and reduced endogenous glucose production by 37% (P < .05) but did not change glucose disposal. After 1 week of sub-long-term dosing, fasting glucose levels were reduced dose-dependently with A-348441 vs vehicle (-8%, not significant; -14%, -20%, and -25%, P < .05, at 3, 10, 30, and 100 mg/kg, respectively) with no observed hypoglycemia or change in fasting insulin levels. A-348441 increased the glucose infusion rates after 1-week treatment by 1.3-, 5.7-, 7.3-, and 6.4-fold (P < .05). Endogenous glucose production was decreased (-25%, -44%, -50%, and -61%, P < .05), whereas glucose disposal was increased (29% and 13%, not significant; 23% and 34%, P < .05), with A-348441. In summary, single-dose treatment with the liver-selective GR antagonist A-348441 decreases glucose production with no effect on glucose disposal or fasting glucose levels. After 1 week of treatment with A-348441, (1) there was no effect on body weight, (2) fasting glucose levels decreased, (3) both glucose disposal and glucose infusion rate increased during clamping, and (4) endogenous glucose production was greatly reduced. In addition, hepatic glucose production was highly correlated with fasting glucose levels (r = 0.97). In conclusion, these results indicate that A-348441 increases insulin sensitivity at both the liver and peripheral tissues, leading toward a normalization of the insulin resistant state. Furthermore, with 1-week vs single-dose liver-selective glucocorticoid antagonism, we have determined that the peripheral effect is secondary to the primary event of reduced hepatic glucose production. The approach of inhibiting the hepatic GR may be an advantageous treatment paradigm for individuals with type 2 diabetes mellitus.
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Ácidos Cólicos/farmacología , Estrona/análogos & derivados , Glucosa/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Glucemia/análisis , Relación Dosis-Respuesta a Droga , Estrona/farmacología , Insulina/sangre , Ratas , Ratas ZuckerRESUMEN
Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
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Compuestos de Bifenilo/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/farmacología , Inhibidores de Serina Proteinasa/farmacología , Triazoles/farmacología , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Ciclohexenos/química , Diabetes Mellitus Tipo 2/genética , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Modelos Moleculares , Ratas , Ratas Zucker , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacocinética , Difracción de Rayos XRESUMEN
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
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Inhibidores de la Adenosina Desaminasa , Inhibidores de la Dipeptidil-Peptidasa IV , Glicoproteínas/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Piridinas/síntesis química , Pirrolidinas/síntesis química , Adenosina Desaminasa/química , Administración Oral , Animales , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/química , Perros , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Glicoproteínas/química , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Macaca fascicularis , Modelos Moleculares , Estructura Molecular , Piridinas/farmacocinética , Piridinas/farmacología , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Diets rich in monounsaturated fatty acids (MUFA) are recommended for individuals with type 2 diabetes mellitus (T2DM). The American Heart Association recommends increasing intakes of n-3 polyunsaturated fatty acids (PUFA) to reduce the risk of vascular disease in high-risk individuals; however, the long-term effects of these bioactive fatty acids on glucose metabolism in insulin resistance are controversial. The present studies were conducted to evaluate the effects of diets rich in both MUFA and alpha linolenic acid (C18:3n-3, ALA), eicosapentaenoic acid (C20:5n-3, EPA), or docosahexaenoic acid (C22:6n-3, DHA), on glycemic control and other parameters related to vascular health in a mouse model of T2DM and insulin resistance. Male ob/ob mice (n = 15 per treatment) were fed 1 of 4 lipid-modified formula diets (LFDs) for 4 weeks: (1) MUFA control, (2) ALA blend, (3) EPA blend, and (4) DHA blend. A portion of a MUFA-rich lipid blend in the control LFD was replaced with 11% to 14% energy as n-3 PUFA. After 4 weeks, plasma glucose response to a standard meal (1.5 g carbohydrate/kg body weight) and insulin challenge (2 U/kg body weight, IP) was assessed, and samples were collected for analysis of glucose, insulin, and lipids. Vascular reactivity of isolated aortic rings was assessed in an identical follow-up study. The results showed that insulin-resistant mice fed an LFD with EPA and/or DHA blends had significantly (P < .05) lower triglycerides and free fatty acids, but insulin sensitivity and fasting plasma glucose were not improved. However, mice fed with the ALA blend had significantly improved insulin sensitivity when compared to those fed with other LFD (P < .05). Animals fed an LFD with n-3 PUFA from marine or plant sources showed significantly improved vascular responses as compared with the MUFA-rich LFD (E(max), P < .05) and ob/ob reference mice consuming chow (E(max) and pEC(50), P < .05). In summary, long-term consumption of LFD with n-3 PUFAs improved blood lipids and vascular function in an animal model of insulin resistance and T2DM; however, only MUFA-rich LFD with ALA also improved both insulin sensitivity and glycemic responses. Further studies of MUFA-rich LFD with ALA with individuals who have T2DM are warranted.
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Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Ácidos Grasos Omega-3/farmacología , Animales , Área Bajo la Curva , Glucemia/metabolismo , Peso Corporal/fisiología , Dieta , Relación Dosis-Respuesta a Droga , Ácidos Grasos/análisis , Ácidos Grasos no Esterificados/sangre , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Resistencia a la Insulina , Ratones , Ratones Obesos , Fosfolípidos/sangre , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
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Fármacos Antiobesidad/síntesis química , Dipeptidil Peptidasa 4/metabolismo , Hipoglucemiantes/síntesis química , Nitrilos/síntesis química , Inhibidores de Proteasas/síntesis química , Pirrolidinas/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Glucemia/análisis , Dominio Catalítico , Cristalografía por Rayos X , Estabilidad de Medicamentos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Modelos Moleculares , Nitrilos/farmacocinética , Nitrilos/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (K(i) = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses approximately 2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.
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Indazoles/farmacología , Indoles/farmacología , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Indazoles/química , Indazoles/uso terapéutico , Indoles/química , Indoles/uso terapéutico , Ratones , Ratones SCID , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Piridinas/química , Piridinas/farmacología , Sensibilidad y Especificidad , Especificidad por SustratoRESUMEN
Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
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Glucemia/metabolismo , Ácidos Cólicos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Estrona/análogos & derivados , Glucosa/metabolismo , Hígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Células 3T3 , Adipocitos/metabolismo , Animales , Biotransformación/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ácidos Cólicos/metabolismo , Diabetes Mellitus Tipo 2/sangre , Perros , Sinergismo Farmacológico , Estrona/metabolismo , Estrona/farmacología , Glucocorticoides/farmacología , Glutamato-Amoníaco Ligasa/metabolismo , Hipoglucemiantes/farmacología , Masculino , Ratones , Obesidad/metabolismo , Prednisolona/farmacología , Ratas , Ratas Zucker , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Tiazolidinedionas/farmacología , Tirosina Transaminasa/metabolismoRESUMEN
In order to determine the effects of increasing insulin resistance on endothelin-1 (ET-1) levels, Zucker lean and fatty rats were studied at basal and during a complete nutrient meal tolerance test (MTT) at 7, 12, and 15 weeks of age. The fatty rats were mildly hyperglycemic, severely hyperinsulinemic and glucose-intolerant at all ages versus lean animals and this progressed with age within groups, as previously published. Basal ET-1 levels, at 7 weeks, were significantly increased in fatty versus lean rats (3.2+/-0.5 v 2.0+/-0.3 pg/mL, respectively; P<.05); however, we did not observe any significant basal difference at 12 or 15 weeks. At 7 weeks, ET-1 levels between fatty and lean rats were not different during the MTT (15 minutes: 2.9+/-0.4 v 2.7+/-0.7; 120 minutes: 6.5+/-0.8 v 6.6+/-0.5 pg/mL, fatty v lean, respectively). At 12 weeks, though there was no difference in basal levels, fatty rats had higher ET-1 levels during the MTT compared to lean animals (15 minutes: 6.9+/-1.4 v 1.8+/-0.4; 120 minutes: 9.4+/-1.7 v 3.2+/-0.5 pg/mL, respectively; P<.01). At 15 weeks, ET-1 levels during the MTT receded to levels similar to those observed at 7 weeks, which were significantly higher in fatty versus lean rats 15 minutes following the challenge (3.4+/-0.4 v 2.4+/-0.2 pg/mL, respectively; P<.05). In conclusion, ET-1 levels in the Zucker fatty rat: (1) were increased in the early stages of the progression of insulin resistance at 7 weeks, but were unchanged under basal conditions with age thereafter, and (2) were increased under nutrient challenge conditions with advanced insulin resistance up to 12 weeks, and were still significantly but to a lesser degree increased at 15 weeks of age. The explanation for these results and their relationship to the observed insulin resistance is unclear and will require further investigation.
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Endotelina-1/sangre , Resistencia a la Insulina , Obesidad/sangre , Envejecimiento , Animales , Glucemia/análisis , Ayuno , Alimentos , Intolerancia a la Glucosa/epidemiología , Hiperglucemia/epidemiología , Hiperinsulinismo/epidemiología , Insulina/análisis , Ratas , Ratas ZuckerRESUMEN
Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.