RESUMO
Thiazolidinediones (TZD), benzopyrans are the proven scaffolds for inhibiting Aldose reductase (ALR2) activity and their structural confluence with the retention of necessary fragments helped in designing a series of hybrid compounds 2-(5-cycloalkylidene-2,4-dioxothiazolidin-3-yl)-N-(2-oxo-2H-chromen-3-yl)acetamide (10a-n) for better ALR2 inhibition. The compounds were synthesized by treating substituted 3-(N-bromoacetyl amino)coumarins (9a-d) with potassium salt of 5-cyclo alkylidene-1,3-thiazolidine-2,4-diones (4a-d). The inhibition activity against ALR2 with IC50 values range from 0.012 ± 0.001 to 0.056 ± 0.007 µM. N-[(6-Bromo-3-coumarinyl)-2-(5-cyclopentylidene-2,4-dioxothiazolidin-3-yl)] acetamide (10c) with cyclopentylidene group on one end and the 6-bromo group on the other end showed better inhibitory property (IC50 = 0.012 µM) and selectivity index (324.166) against the ALR2, a forty fold superiority over sorbinil, a better molecule over epalrestat and rest of the analogues exhibited a far superior response over sorbinil and slightly better as compared with epalrestat. It was further confirmed by the insilico studies that compound 10c showed best inhibition activity among the synthesized compounds with a high selectivity index against the ALR2. In invivo experiments, supplementation of compound 10c to STZ induced rats delayed the progression of cataract in a dose-dependent manner warranting its further development as a potential agent to treat thediabetic secondary complications especially cataract.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Cumarínicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/uso terapêutico , Aldeído Redutase/metabolismo , Animais , Catarata/prevenção & controle , Cumarínicos/síntese química , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacocinéticaRESUMO
BACKGROUND: Millions of people today use herbs either as food or in the form of medicine along with other medications. Many of the herbs can interact with these medications, causing either potentially dangerous side effects or improved or reduced benefits from the medication. OBJECTIVE: The present study was performed to determine the influence of cinnamon, on the pharmacokinetics and pharmacodynamics of pioglitazone. METHOD: Studies were conducted in normal and alloxan induced diabetic rats and rabbits with oral administration of selected doses of pioglitazone, cinnamon and their combination. Blood samples were collected at regular intervals of time and were analysed for glucose by GOD/POD method and for pioglitazone by HPLC method respectively. Body weights were also measured every week. RESULTS: Significant differences were seen in pharmacokinetic parameters of pioglitazone like AUC, t1/2, Ke, Cl/F, Vd/F when given in combination with cinnamon in normal and diabetic rabbits. The combination of pioglitazone and cinnamon was found to reduce the glucose levels and body weights significantly than pioglitazone. The results indicating increased AUC of pioglitazone on pretreatment with cinnamon suggest an interaction indicating decreased metabolism of pioglitazone as a result of CYP 3A4 inhibition and thereby producing a potentiating effect. CONCLUSION: Cinnamon enhanced the bioavailability of pioglitazone by inhibiting the CYP3A4 enzyme. Hence, cinnamon might be beneficial when used in combination with pioglitazone in diabetic patients and an adjustment of dose of pioglitazone may be necessary.
Assuntos
Glicemia/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Interações Ervas-Drogas , Hipoglicemiantes/farmacocinética , Extratos Vegetais/farmacologia , Tiazolidinedionas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Biomarcadores/sangue , Glicemia/metabolismo , Cinnamomum/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/isolamento & purificação , Inibidores do Citocromo P-450 CYP3A/toxicidade , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/administração & dosagem , Masculino , Pioglitazona , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Coelhos , Ratos Sprague-Dawley , Tiazolidinedionas/administração & dosagem , Redução de Peso/efeitos dos fármacosRESUMO
Although many studies have evaluated the effects of type 2 diabetes mellitus (T2DM) on the pharmacokinetics (PK) of low molecular weight molecules, there is limited information regarding effects on monoclonal antibodies. Our previous studies have reported significant increases in total (2-4 fold) and renal (100-300 fold) clearance of human IgG, an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Pioglitazone treatment incompletely reversed the disease-related PK changes. The objective of this study was to construct a mechanistic model for simultaneous fitting plasma and urine data, to yield physiologically relevant PK parameters. We propose an extended minimal physiologically based PK (mPBPK) model specifically for IgG by classifying organs as either leaky or tight vascular tissues, and adding a kidney compartment. The model incorporates convection as the primary mechanism of IgG movement from plasma into tissues, interstitial fluid (ISF) in extravascular distribution space, and glomerular filtration rate (GFR), sieving coefficient and fraction reabsorbed in the kidney. The model captured the plasma and urine PK profiles well, and simulated concentrations in ISF. The model estimated a 2-4 fold increase in nonrenal clearance from plasma and 30-120 fold increase in renal clearance with T2DM, consistent with the experimental findings, and these differences in renal clearance were related to changes in GFR, sieving coefficient, and proximal tubular reabsorption. In conclusion, the mPBPK model offers a more relevant approach for analyzing plasma and urine IgG concentration-time data than conventional models and provides insight regarding alterations in distributional and elimination parameters occurring with T2DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Hipoglicemiantes/farmacocinética , Imunoglobulina G/metabolismo , Modelos Biológicos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pioglitazona , Ratos , Ratos Zucker , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/uso terapêuticoRESUMO
Raw Radix Rehmanniae (RRR) is a frequently used traditional Chinese medicine in the treatment of diabetes mellitus according to the statistics on all of the anti-diabetic formulas recorded in New National Traditional Chinese Medicine. Pioglitazone and RRR may be co-administrated for presumably enhanced therapeutic effects because of the common indications. Therefore, the aim of the study was to evaluate the effect of RRR on the pharmacokinetics of pioglitazone in healthy rats and type 2 diabetic rats. The pharmacokinetic effect of RRR on pioglitazone was studied in healthy rats and type 2 diabetic rats. A validated UPLC-MS/MS method was used to analyze the concentration of pioglitazone in blood samples. The pharmacokinetic parameters were calculated using non-compartmental analyses by Winnonlin 5.0.1. In healthy group, the pre-treatment of RRR significantly (P<0.05) reduced the C(max) but enhanced the V/F of pioglitazone; whereas in T2DM group, signiï¬cant increase of C(max) and decrease of V/F and T½ were found after the rats were pre-treated with RRR. However, AUC(0-t) and CL/F remained unchanged in both healthy group and T2DM group. In conclusion, co-administration with RRR could alter the pharmacokinetic profiles of pioglitazone to statistically significant levels.
Assuntos
Interações Ervas-Drogas , Hipoglicemiantes/farmacocinética , Medicina Tradicional Chinesa , Rehmannia , Tiazolidinedionas/farmacocinética , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Pioglitazona , Ratos , Ratos WistarRESUMO
The objective of the current study was to assess the possible pharmacokinetic interactions of spirulina with glitazones in an insulin resistance rat model. Wistar male albino rats were equally divided into five groups: insulin resistant rats+spirulina (500 mg/kg)+pioglitazone (10 mg/kg), insulin resistant rats+pioglitazone (10 mg/kg), insulin resistant rats+spirulina (500 mg/kg)+rosiglitazone (10 mg/kg), insulin resistant rats+rosiglitazone (10 mg/kg), and insulin resistant rats+spirulina (500 mg/kg). Described doses of pioglitazone, rosiglitazone, or spirulina were per orally administered and the plasma drug concentrations were determined. The pharmacokinetic parameters such as Tmax, Cmax, AUC(0-α), t1/2, and Kel were determined by plotting the drug concentration as a function of time. The data observed in this acute study indicated that there was no statistically significant difference in any of the pharmacokinetic parameters (Tmax, Cmax, AUC(0-α), t1/2, and Kel) of glitazones (pioglitazone, rosiglitazone) or spirulina, when they were coadministered. Given the promising results, this study concludes that the coadministration of spirulina does not influence the pharmacokinetics of glitazones in a type 2 diabetes rat model. Further chronic in vivo studies are recommended to assess the real time effect.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Spirulina , Tiazolidinedionas/farmacocinética , Animais , Dexametasona , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Masculino , Pioglitazona , Ratos , Ratos Wistar , Rosiglitazona , Tiazolidinedionas/administração & dosagemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Radix astragali (RA) was the most frequently used traditional Chinese medicine (TCM) according to the statistics on 52 anti-diabetic formulas recorded in New National Traditional Chinese Medicine; it was employed in 34 out of the 52 formulas. The aim of this study was to elucidate potential pharmacokinetic interaction between RA and pioglitazone, and to provide guidance for clinical medicine safety. MATERIALS AND METHODS: A specific and rapid UPLC-MS/MS method was established to quantify pioglitazone in rat plasma. Then healthy and type 2 diabetes mellitus (T2DM) rats were each divided into control and RA decoction (RAD) administration groups-healthy, healthy-RAD, T2DM, T2DM-RAD; pharmacokinetics of pioglitazone was carried out after RAD was administrated to rats for 7 days. RESULTS: The established UPLC-MS/MS method was rapid, specific, and precise. Between healthy and healthy-RAD groups, half-life (T(1/2)), area under the curve (AUC (0-t)), Vz/F, and Cl/F showed mild yet statistically significant differences; no significant difference for any above parameter was detected between T2DM and T2DM-RAD groups. CONCLUSION: RAD co-administration did not affect the pharmacokinetics of pioglitazone especially in diabetic groups; RA and pioglitazone might be feasible herb-drug co-effectiveness.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacocinética , Animais , Astrágalo , Astragalus propinquus , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Pioglitazona , Ratos , Ratos WistarRESUMO
The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the ß-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the ß-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.
Assuntos
Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Aumento de Peso , Células 3T3-L1 , Animais , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Ligantes , Camundongos , Células NIH 3T3 , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Estrutura Secundária de Proteína , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Células U937RESUMO
The need for a reliable bioanalytical method is of primary importance during preclinical studies. The aim of the present study was simultaneous determination of pioglitazone (CAS 111025-46-8) (PIO) and glimepiride (CAS 93479-97-1) (GLM) in plasma of rats. A high-performance liquid chromatographic method has been developed and validated using C18 column and UV detector. A mobile phase composed of acetonitrile and ammonium acetate buffer pH 4.5 in the ratio of 55:45%. The plasma samples clean-up was carried out using solid phase cartridges. The method was in the linear range of 50-8000 ng/mL for PIO and 50-2000 ng/mL for GLM. The coefficient of regression was found to be > or = 0.99. Precision and accuracy were within the acceptable limits, as indicated by relative standard deviation varying from 1.5 to 6.1% for PIO and 3.1 to 7.0% for GLM whereas the accuracy ranged from 97.0 to 106.4% for PIO and 96.5 to 106.4% for GLM. The mean extraction recovery was found to be 90.2 +/- 4.5, 76.8 +/- 2.8 and 85.2 +/- 5.2% for PIO, GLM and internal standard, respectively. Moreover, PIO and GLM were stable in plasma, up to 30 days of storage at -70 degrees C and after being subjected to bench top, auto-sampler, and three freeze-thaw cycles. The developed method was applied for preclinical pharmacokinetic studies.
Assuntos
Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Compostos de Sulfonilureia/sangue , Compostos de Sulfonilureia/farmacocinética , Tiazolidinedionas/sangue , Tiazolidinedionas/farmacocinética , Animais , Área Sob a Curva , Calibragem , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Meia-Vida , Masculino , Pioglitazona , Ratos , Ratos Wistar , Padrões de Referência , Reprodutibilidade dos Testes , Extração em Fase Sólida , Espectrofotometria UltravioletaRESUMO
Micelles formed in the GI tract by bile acid and lecithin play an important role in oral absorption of poorly soluble drugs. In this situation, the drug molecules are present in equilibrium between the free and micellar states. In this study, the relationship between the free drug concentration and the membrane permeability of poorly soluble drugs was examined. Permeability across a Caco-2 monolayer and a dialysis membrane were measured in a side-by-side chamber system. The concentrations of sodium taurocholate (NaTC) and lecithin were varied to allow measurement of membrane permeability at different concentrations of free drugs. For troglitazone, hexylparaben, and heptylparaben, an increase in the NaTC and lecithin concentrations caused the permeability across the Caco-2 monolayer to decrease slightly, whereas the permeability across the dialysis membrane decreased markedly. In contrast, the changes in permeability of griseofulvin with an increased micelle concentration were similar for the Caco-2 monolayer and the dialysis membrane. Assuming that the permeability for the dialysis membrane reflects the free drug concentration in the medium, these results suggest that troglitazone and alkylparabens, but not griseofulvin, can partition directly from micelles to Caco-2 monolayers. This mechanism may contribute to oral absorption of drugs that are poorly soluble in water.
Assuntos
Micelas , Administração Oral , Células CACO-2 , Permeabilidade da Membrana Celular , Fenômenos Químicos , Cromanos/farmacocinética , Diálise/métodos , Griseofulvina/farmacocinética , Humanos , Técnicas In Vitro , Absorção Intestinal , Lecitinas/química , Parabenos/farmacocinética , Solubilidade , Ácido Taurocólico/química , Teofilina/farmacocinética , Tiazolidinedionas/farmacocinética , TroglitazonaRESUMO
BACKGROUND: Various approaches have been used to retain the dosage form in stomach as a way of increasing the gastric residence time, including floatation systems; high-density systems; mucoadhesive systems; magnetic systems; unfoldable, extensible, or swellable systems; and superporous hydrogel systems. AIM: The objective of this study was to prepare and evaluate floating microspheres of rosiglitazone maleate for the prolongation of gastric residence time. METHOD: The microspheres were prepared by solvent diffusion-evaporation method using ethyl cellulose and hydroxypropylmethylcellulose. A full factorial design was applied to optimize the formulation. RESULTS: Preliminary studies revealed that the polymer:drug ratio, concentration of polymer, and stirring speed significantly affected the characteristics of microspheres. The optimum batch exhibited a prolonged drug release, remained buoyant for >12 hours, high entrapment efficiency, and particle size in the order of 350 microm. CONCLUSION: The results of 32 full factorial design revealed that the concentration of ethylcellulose 7 cps (X(1)) and stirring speed (X(2)) significantly affected drug entrapment efficiency, percentage release after 8 h and particle size of microspheres.
Assuntos
Química Farmacêutica/métodos , Microesferas , Tiazolidinedionas/química , Avaliação Pré-Clínica de Medicamentos/métodos , Rosiglitazona , Tiazolidinedionas/farmacocinéticaRESUMO
Peroxisome proliferator-activated receptor-gamma (PPARgamma) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPARgamma activation. Administration of the PPARgamma agonist rosiglitazone (15 mg/kg.d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T(4) and T(3)) and mRNA levels of BAT and liver T(3)-generating enzymes iodothyronine type 2 (-40%) and type 1 (-32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms alpha1 (-34%) and beta (-66%) in BAT and isoforms alpha1 (-20%) and alpha2 (-47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPARgamma-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.
Assuntos
Tecido Adiposo/inervação , Fibras Adrenérgicas/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Glândula Tireoide/fisiologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Fibras Adrenérgicas/fisiologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/fisiologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Canais Iônicos/metabolismo , Masculino , Camundongos , Proteínas Mitocondriais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , PPAR gama/fisiologia , Ratos , Ratos Sprague-Dawley , Rosiglitazona , Termogênese/efeitos dos fármacos , Termogênese/genética , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacocinética , Glândula Tireoide/efeitos dos fármacos , Proteína Desacopladora 1 , Regulação para Cima/efeitos dos fármacosRESUMO
The objective of this study was to evaluate a physiologically based pharmacokinetic (PBPK) approach for predicting the plasma concentration-time curves expected after intravenous administration of candidate drugs to rodents. The predictions were based on a small number of properties that were either calculated based on the structure of the candidate drug (octanol:water partition coefficient, ionization constant(s)) or obtained from the typical high-throughput screens implemented in the early drug discovery phases (fraction unbound in plasma and hepatic intrinsic clearance). The model was tested comparing the predicted and the observed pharmacokinetics of 45 molecules. This dataset included six known drugs and 39 drug candidates from different discovery programs, so that the performance of the model could be evaluated in a real discovery case scenario. The plasma concentration-time curves were predicted with good accuracy, the pharmacokinetic parameters being on average two- to three-fold of actual values. Multivariate analysis was used for identifying the candidate properties which were likely associated to biased predictions. The application of this approach was found useful for the prioritization of the in vivo pharmacokinetics screens and the design of the first-time-in-animal studies.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Biológicos , Farmacocinética , Acetamidas/sangue , Acetamidas/química , Acetamidas/farmacocinética , Algoritmos , Animais , Anti-Infecciosos/sangue , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Antidepressivos/sangue , Antidepressivos/química , Antidepressivos/farmacocinética , Benzodiazepinas/sangue , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Cromanos/sangue , Cromanos/química , Cromanos/farmacocinética , Diltiazem/sangue , Diltiazem/química , Diltiazem/farmacocinética , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Linezolida , Fígado/metabolismo , Camundongos , Oxazolidinonas/sangue , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Análise de Componente Principal , Ratos , Roedores , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Distribuição Tecidual , Troglitazona , Zidovudina/sangue , Zidovudina/química , Zidovudina/farmacocinéticaRESUMO
BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. METHODS: In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. RESULTS: In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.
Assuntos
Proteínas Sanguíneas/metabolismo , Glipizida/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Oligorribonucleotídeos/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Oral , Adulto , Interações Medicamentosas , Feminino , Glipizida/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rosiglitazona , Tiazolidinedionas/administração & dosagemRESUMO
1. Peroxisome proliferator activated receptor gamma (PPARgamma) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPARgamma agonists. Therefore, we examined the effect of pioglitazone, a PPARgamma agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2. Mice were treated with placebo or pioglitazone (20 mg x kg(-1) by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3. Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6+/-1.3 vs placebo MI 14.4+/-2.5 mm(2)). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8+/-2.9 mm(2), P=NS vs placebo). 4. Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPARgamma activation. 5. In conclusion, PPARgamma activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.