RESUMO
Among the strategies for bioavailability improvement of poorly soluble drugs, co-amorphous systems have revealed to have a significant impact in the increase of the aqueous solubility of the drug, and at the same time increasing the amorphous state stability and dissolution rate when compared with the neat drug. Tolbutamide (TBM) is an oral hypoglycemic drug largely used in the treatment of type II Mellitus diabetes. TBM is a class II drug according to the Biopharmaceutical Classification System, meaning that it has low solubility and higher permeability. The aim of this study was to synthesize a co-amorphous material of tolbutamide (TBM) with tromethamine (TRIS). Density functional theory (DFT), allowed to study the structural, electronic, and thermodynamic properties, as well as solvation effects. In same theory level, several interactions tests were performed to obtain the most thermodynamically favorable drug-coformer intermolecular interactions. The vibrational spectra (mid infrared and Raman spectroscopy) are in accordance with the theoretical studies, showing that the main molecular interactions are due to the carbonyl, sulfonyl, and amide groups of TMB and the alcohol and amine groups of TRIS. X-ray powder diffraction was used to study the physical stability in dry condition at 25 °C of the co-amorphous system, indicating that the material remained in an amorphous state up to 90 days. Differential scanning calorimetry and thermogravimetric results showed a high increase of the Tg when compared with the amorphous neat drug, from 4.3 °C to 83.7 °C, which generally translated into good physical stability. Solubility studies demonstrated an increase in the solubility of TBM by 2.5 fold when compared with its crystalline counterpart.
Assuntos
Diabetes Mellitus , Tolbutamida , Varredura Diferencial de Calorimetria , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Humanos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Insulin resistance during pregnancy is counteracted by enhanced insulin secretion. This condition is aggravated by obesity, which increases the risk of gestational diabetes. Therefore, pancreatic islet functionality was investigated in control nonpregnant (C) and pregnant (CP), and cafeteria diet-fed nonpregnant (Caf), and pregnant (CafP) obese rats. Isolated islets were used for measurements of insulin secretion (RIA), NAD(P)H production (MTS), glucose oxidation ((14)CO(2) production), intracellular Ca(2+) levels (fura-2 AM), and gene expression (real-time PCR). Impaired glucose tolerance was clearly established in Caf and CafP rats at the 14th wk on a diet. Insulin secretion induced by direct depolarizing agents such as KCl and tolbutamide and increasing concentrations of glucose was significantly reduced in Caf, compared with C islets. This reduction was not observed in islets from CP and CafP rats. Accordingly, the glucose oxidation and production of reduced equivalents were increased in CafP islets. The glucose-induced Ca(2+) increase was significantly lower in Caf and higher in CafP, compared with all other groups. CP and CafP islets demonstrated an increased Ca(2+) oscillation frequency, compared with both C and Caf islets, and the amplitude of oscillations was augmented in CafP, compared with Caf islets. In addition, Ca(v)alpha1.2 and SERCA2a mRNA levels were reduced in Caf islets. Ca(v)alpha1.2, but not SERCA2a, mRNA was normalized in CafP islets. In conclusion, cafeteria diet-induced obesity impairs insulin secretion. This alteration is related to the impairment of Ca(2+) handling in pancreatic islets, in especial Ca(2+) influx, a defect that is reversed during pregnancy allowing normalization of insulin secretion.
Assuntos
Dieta , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Obesidade/metabolismo , Prenhez/fisiologia , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Cálcio/metabolismo , Canais de Cálcio/biossíntese , Canais de Cálcio/genética , DNA/biossíntese , DNA/genética , Feminino , Expressão Gênica/fisiologia , Teste de Tolerância a Glucose , Homeostase/fisiologia , Hipoglicemiantes/farmacologia , Lipídeos/sangue , Obesidade/etiologia , Tamanho do Órgão/fisiologia , Oxirredução , Cloreto de Potássio/farmacologia , Gravidez , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Tolbutamida/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Tecoma stans aqueous extract (TAE) is widely used as a traditional antidiabetic remedy in Mexico; its rational use is controversial. We provide evidence of its main antidiabetic activities. AIM OF THE STUDY: To evaluate in vivo and in vitro intestinal alpha-glucosidases inhibition as the possible mode of action of TAE on type 2 diabetes mellitus (DM2) animal models, and to test the effects of its sub-chronic administration on lipids and glucose blood levels. MATERIALS AND METHODS: In healthy and streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats, glucose or cornstarch was administered after an oral dose of TAE, acarbose, tolbutamide or vehicle, in order to build starch and glucose tolerance curves (STC and GTC). An intestinal brush border preparation was used to evaluate the TAE alpha-glucosidases inhibitory activity. Moreover, in STZ-induced diabetic rats TAE, tolbutamide or vehicle was administered for 21 days for evaluate their effects on fasting glucose cholesterol and triglycerides. Also, TAE total phenolic compounds were quantified. RESULTS: In STC, TAE decreased hyperglycemic peak values in both healthy and STZ-treated rats, in a magnitude similar to that of acarbose. The in vitro preparation showed a dose-dependent inhibition of glucose release from starch. Sub-chronic administration of TAE significantly reduced cholesterol and triglycerides levels. Moreover, we confirmed that acute and sub-chronic administration of TAE (500mg/kg) in both rat models did not diminish fasting glucose and did not modify the GTC. CONCLUSIONS: The study present evidence that the main antidiabetic effect of TAE is due to intestinal alpha-glucosidase inhibition by decreasing the postprandial hyper-glycaemia peak; in addition, TAE sub-chronic administration reduces triglycerides and cholesterol, without modifying fasting glucose.
Assuntos
Bignoniaceae , Colesterol/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Triglicerídeos/sangue , Acarbose/farmacologia , Animais , Bignoniaceae/química , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Feminino , Teste de Tolerância a Glucose , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fenóis/análise , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Amido , Tolbutamida/farmacologiaRESUMO
Islet Neogenesis Associated Protein (INGAP) increases pancreatic beta-cell mass and potentiates glucose-induced insulin secretion. Here, we investigated the effects of the pentadecapeptide INGAP-PP in adult cultured rat islets upon the expression of proteins constitutive of the K(+)(ATP) channel, Ca(2+) handling, and insulin secretion. The islets were cultured in RPMI medium with or without INGAP-PP for four days. Thereafter, gene (RT-PCR) and protein expression (Western blotting) of Foxa2, SUR1 and Kir6.2, cytoplasmic Ca(2+) ([Ca(2+)](i)), static and dynamic insulin secretion, and (86)Rb efflux were measured. INGAP-PP increased the expression levels of Kir6.2, SUR1 and Foxa2 genes, and SUR1 and Foxa2 proteins. INGAP-PP cultured islets released significantly more insulin in response to 40 mM KCl and 100 muM tolbutamide. INGAP-PP shifted to the left the dose-response curve of insulin secretion to increasing concentrations of glucose (EC(50) of 10.0+/-0.4 vs. 13.7+/-1.5 mM glucose of the controls). It also increased the first phase of insulin secretion elicited by either 22.2 mM glucose or 100 microM tolbutamide and accelerated the velocity of glucose-induced reduction of (86)Rb efflux in perifused islets. These effects were accompanied by a significant increase in [Ca(2+)](i) and the maintenance of a considerable degree of [Ca(2+)](i) oscillations. These results confirm that the enhancing effect of INGAP-PP upon insulin release, elicited by different secretagogues, is due to an improvement of the secretory function in cultured islets. Such improvement is due, at least partly, to an increased K(+)(ATP) channel protein expression and/or changing in the kinetic properties of these channels and augmented [Ca(2+)](i) response. Accordingly, INGAP-PP could potentially be used to maintain the functional integrity of cultured islets and eventually, for the prevention and treatment of diabetes.
Assuntos
Cálcio/metabolismo , Citocinas/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Canais KATP/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Western Blotting , Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Canais KATP/genética , Proteínas Associadas a Pancreatite , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Técnicas de Cultura de Tecidos , Tolbutamida/farmacologiaRESUMO
Neonatal diabetes is a rare condition characterized by hyperglycemia, requiring insulin treatment, diagnosed within the first months of life. The disorder may be either transient, resolving in infancy or early childhood with possible relapse later, or permanent in which case lifelong treatment is necessary. Both conditions are genetically heterogeneous; however, the majority of the cases of transient neonatal diabetes are due to abnormalities of an imprinted region of chromosome 6q24. For permanent neonatal diabetes, the most common causes are heterozygous activating mutations of KCNJ11, the gene encoding the Kir6.2 sub-unit of the ATP-sensitive potassium channel. In this article we discuss the clinical features of neonatal diabetes, the underlying genetic defects and the therapeutic implications.
Assuntos
Diabetes Mellitus/genética , Mutação , Diabetes Mellitus/tratamento farmacológico , Proteínas de Homeodomínio/genética , Humanos , Hipoglicemiantes/uso terapêutico , Recém-Nascido , Insulina/genética , Insulina/uso terapêutico , Canais KATP/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/uso terapêutico , Tolbutamida/uso terapêutico , Transativadores/genéticaRESUMO
O diabetes neonatal (DN) é uma condição rara caracterizada por hiperglicemia, que necessita de tratamento com insulina, diagnosticado nos primeiros meses de vida. Clinicamente pode ser classificado em DN transitório quando ocorre remissão da doença em poucos meses, podendo haver recorrência posterior; ou permanente quando, como o nome indica, não ocorre remissão. Ambas as condições são geneticamente heterogêneas; entretanto a maioria dos casos de DN transitório é decorrente de anormalidades da região de imprinted no cromossomo 6q24. Mutações ativadoras em heterozigose no gene KCNJ11, que codifica a subunidade Kir6.2 do canal de potássio ATP-sensível, são a causa mais comum de DN permanente. No presente artigo, discutimos as características clínicas do DN, os mecanismos moleculares envolvidos e suas implicações terapêuticas.
Neonatal diabetes is a rare condition characterized by hyperglycemia, requiring insulin treatment, diagnosed within the first months of life. The disorder may be either transient, resolving in infancy or early childhood with possible relapse later, or permanent in which case lifelong treatment is necessary. Both conditions are genetically heterogeneous; however, the majority of the cases of transient neonatal diabetes are due to abnormalities of an imprinted region of chromosome 6q24. For permanent neonatal diabetes, the most common causes are heterozygous activating mutations of KCNJ11, the gene encoding the Kir6.2 sub-unit of the ATP-sensitive potassium channel. In this article we discuss the clinical features of neonatal diabetes, the underlying genetic defects and the therapeutic implications.
Assuntos
Humanos , Recém-Nascido , Diabetes Mellitus/genética , Mutação , Diabetes Mellitus/tratamento farmacológico , Proteínas de Homeodomínio/genética , Hipoglicemiantes/uso terapêutico , Insulina/genética , Insulina/uso terapêutico , Canais KATP/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/uso terapêutico , Tolbutamida/uso terapêutico , Transativadores/genéticaRESUMO
A series of chalcone derivatives from 3,4-methylenedioxybenzaldehyde and substituted acetophenones have been synthesized and investigated as antihyperglycemic agents in a glucose loaded animal model. Chalcones with biological activity were compared with lispro, regular insulin and tolbutamide effects on serum glucose levels. Compound 01, without substituent in the A-ring was not able to change glycemic levels. On the other hand, compounds 03, 04, 05, 09 and 10 with substitutions at position 3' and/or 4' in the A-ring caused significant reduction in serum glucose levels. Concerning the antihyperglycemic effect, compounds 03 and 05 (methoxy substituent) inhibited the hyperglycemia induced by glucose around 96% similar to that demonstrated for lispro insulin and tolbutamide at 60 min. A rapid and lasting antihyperglycemic effect was found with compound 09 and 10 (nitro substituent). In conclusion, besides the nature of the functional groups electron-donor substituent, as methoxy and hydroxyl or electron-acceptor, as nitro groups, the position of the group may be mandatory for biological activity.
Assuntos
Glicemia/efeitos dos fármacos , Chalcona/análogos & derivados , Chalcona/administração & dosagem , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Administração Oral , Animais , Glicemia/análise , Chalcona/síntese química , Chalcona/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glucose/administração & dosagem , Hiperglicemia/sangue , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Insulina/administração & dosagem , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Estereoisomerismo , Fatores de Tempo , Tolbutamida/administração & dosagemRESUMO
The effect of the crude extract, ethyl acetate and n-butanol fractions from Vitex megapotamica (Spreng) Moldenke on glycemia was investigated in diabetic rats. Oral administration of crude extract significantly reduced serum glucose levels in both normal and diabetic animals. In normal rats, serum glucose lowering was observed with 400 and 800 mg/kg at 2 and 2-3h, respectively after oral crude extract treatment. Nevertheless, the hypoglycemic effect of Vitex megapotamica in diabetic rats was evident at 1 and 2h and from 1 to 3h after treatment with 400 and 800 mg/kg, respectively. The ethyl acetate as well as n-butanol fractions were able to diminish glycemia in diabetic animals. The ethyl acetate fraction (400 and 800 mg/kg) produced the maximum hypoglycemic effect (28 and 20%, respectively) in diabetic rats and the same dose of the n-butanol fraction reduced the hyperglycemia only by 11% at 1h after treatment. Additionally, in hyperglycemic normal rats neither crude extract nor ethyl acetate fraction modified the glucose tolerance and the known tolbutamide effect on insulin release was clearly observed in this group. Thus, this study shows that Vitex megapotamica has an anti-hyperglycemic action, is able to ameliorate the diabetic state and, probably, is a source of hypoglycemic compounds.
Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fitoterapia , Vitex/química , Acetatos , Animais , Glicemia/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Insulina/farmacologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos , Ratos Wistar , Solventes , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Tolbutamida/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Central anti-nociceptive actions of baclofen involve activation of K+ channels. Here we assessed what types of K+ channel might participate in the peripheral anti-nociception induced by baclofen. EXPERIMENTAL APPROACH: Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E2.(PGE2) to induce hyperalgesia were measured 3 h after PGE2 injection. Other agents were also given by intraplantar injection. KEY RESULTS: Baclofen elicited a dose-dependent (15 - 240 microg per paw) anti-nociceptive effect. An intermediate dose of baclofen (60 microg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABAB receptor antagonist saclofen (12.5 - 100 microg per paw) antagonized, in a dose-dependent manner, peripheral antinociception induced by baclofen (60 microg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABAA receptor antagonist (80 microg per paw), or by (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid, GABAC receptor antagonist (20 microg per paw). The peripheral antinociception induced by baclofen (60 microg) was reversed, in a dose-dependent manner, by the voltage-dependent K+ channel blockers tetraethylammonium (7.5 - 30 microg per paw) and 4-aminopyridine (2.5 - 10 microg per paw). The blockers of other K+ channels, glibenclamide (160 microg), tolbutamide (320 microg), charybdotoxin (2 microg), dequalinium (50 microg) and caesium (500 microg) had no effect. CONCLUSIONS AND IMPLICATIONS: This study provides evidence that the peripheral antinociceptive effect of the GABAB receptor agonist baclofen results from the activation of tetraethylammonium-sensitive K+ channels. Other K+ channels appear not to be involved.