Pharmacokinetics and drug-likeness of antidiabetic flavonoids: Molecular docking and DFT study.

Computer aided toxicity and pharmacokinetic prediction studies attracted the attention of pharmaceutical industries as an alternative means to predict potential drug candidates. In the present study, in-silico pharmacokinetic properties (ADME), drug-likeness, toxicity profiles of sixteen antidiabetic flavonoids that have ideal bidentate chelating sites for metal ion coordination were examined using SwissADME, Pro Tox II, vNN and ADMETlab web tools. Density functional theory (DFT) calculations were also employed to calculate quantum chemical descriptors of the compounds. Molecular docking studies against human alpha amylase were also conducted. The results were compared with the control drugs, metformin and acarbose. The drug-likeness prediction results showed that all flavonoids, except myricetin, were found to obey Lipinski's rule of five for their drug like molecular nature. Pharmacokinetically, chrysin, wogonin, genistein, baicalein, and apigenin showed best absorption profile with human intestinal absorption (HIA) value of ≥ 30%, compared to the other flavonoids. Baicalein, butein, ellagic acid, eriodyctiol, Fisetin and quercetin were predicted to show carcinogenicity. The flavonoid derivatives considered in this study are predicted to be suitable molecules for CYP3A probes, except eriodyctiol which interacts with P-glycoprotein (p-gp). The toxicological endpoints prediction analysis showed that the median lethal dose (LD50) values range from 159-3919 mg/Kg, of which baicalein and quercetin are found to be mutagenic whereas butein is found to be the only immunotoxin. Molecular docking studies showed that the significant interaction (-7.5 to -8.3 kcal/mol) of the studied molecules in the binding pocket of the α-amylase protein relative to the control metformin with the crucial amino acids Asp 197, Glu 233, Asp 197, Glu 233, Trp 59, Tyr 62, His 101, Leu 162, Arg 195, His 299 and Leu 165. Chrysin was predicted to be a ligand with high absorption and lipophilicity with 84.6% absorption compared to metformin (78.3%). Moreover, quantum chemical, ADMET, drug-likeness and molecular docking profiles predicted that chrysin is a good bidentate ligand.

Pharmacodynamic comparison of acarbose tablets in Chinese healthy volunteers under chewing and swallowing conditions.

WHAT IS KNOWN AND OBJECTIVE: Acarbose can efficiently block glucose absorption in the intestine as an alpha-glucosidase inhibitor. It is currently manufactured in several oral dosage forms, with the most common types being tablets and chewable tablets. The acarbose tablet (Glucobay® , 50 mg, Bayer) package insert gives instructions for either directly swallowing or chewing then swallowing. This study compared the pharmacodynamic effects of a single formulation of acarbose tablets under these two different administration routes. METHODS: This randomized, crossover study enrolled 24 healthy subjects who were instructed to chew (C group) or swallow (S group) the acarbose tablet. Glucose levels were monitored in subjects for up to 4 h following administration of 75 g of sucrose to establish a baseline firstly, after which subjects in the C and S groups were administered 50- or 100- mg of acarbose along with 75 g of sucrose. Then, subjects entered a 1-week washout period before being crossed over to the alternate dosing route. RESULTS AND DISCUSSION: Compared with the S group, the C group had a lower maximum concentration of serum glucose (Cmax ) and areas under the concentration-time curve (AUC0-2 , AUC0-1.5 ). In addition, the maximum reduction in serum glucose (ΔCmax ) and the reduction in the AUC (AUEC0-1.5 ) were both increased in the S group. This occurred at both the 50 mg and 100 mg dosages. These results indicate that fluctuations in blood glucose were lower following chewing of the acarbose tablet. Both administration routes exhibited similar safety and tolerance profiles. WHAT IS NEW AND CONCLUSION: In summary, chewing acarbose tablets appears to induce a superior glycaemic-controlling effect compared with swallowing them directly, at least with a single dose. It will be important to inform both clinicians and patients about these differences between the two administrations so that informed clinical decisions can be made, as numerous patients with diabetes are inclined to directly swallow acarbose tablets for convenience.

Acarbose bioequivalence: Exploration of eligible protocol design.

WHAT IS KNOWN AND OBJECTIVE: Acarbose is a poorly absorbed α-glucosidase inhibitor that acts locally in the intestinal tract. Therefore, the evaluation of its bioequivalence (BE) should be based on pharmacodynamic (PD) rather than pharmacokinetic (PK) endpoints. Currently, there is no consensus on the best method for acarbose BE evaluation. The optimal protocol design regarding dosing time/dose and PD parameters requires further exploration. The aim of the study was to identify an optimum protocol for establishing acarbose BE in healthy Chinese volunteers using PD endpoints. METHODS: Three pilot studies were conducted in healthy Chinese subjects. Study 1 was an open, randomized, two-period crossover study using the reference (R) drug at the dose of 1 × 50 mg. Study 1 aimed to determine appropriate dosing time by comparing the PD effect of acarbose between two administration methods. One method was concomitant administration of sucrose and acarbose, and another method was acarbose administration 10 min before sucrose. Study 2 was an open, randomized, three-period crossover study. Subjects were given the R drug at the dose of 1 × 50 mg, 2 × 50 mg or 3 × 50 mg in a random sequence. The aim of Study 2 was to identify a reasonable dose of acarbose in the BE study. Study 3 was conducted with an open, randomized, three-period crossover design using the test (T) or R drug in an R-T-R sequence at the dose of 2 × 50 mg. Study 3 aimed to compare the BE between the R and T drug and determine intra-individual variation. Twelve subjects were recruited in Study 1, Study 2 and Study 3, respectively, with a one-week washout period. Serum glucose and insulin concentrations were determined after sucrose administration (baseline) and sucrose/acarbose co-administration. RESULTS AND DISCUSSION: In Study 1, no significant differences in PD parameters were found between the two administration methods. The results of Study 2 revealed that the optimal dose was between 1 × 50 mg and 2 × 50 mg. The comparison of PD parameters indicated that the rectifying method could distinguish between different formulations. Study 3 showed that the geometric mean ratios of Cmax, r , AUC0-2 h, r and AUC0-4 h, r were 90.06%, 84.55% and 84.21%, respectively, using the rectifying method. The 90% CIs of Cmax, r were within acceptance limits (80.00%-125.00%), whereas that of AUC0-2 h, r and AUC0-4 h, r were out of the range. The intra-individual variation was approximately 21% for R formulation. Based on the variation, the number of subjects needed to identify formulation differences in the pivotal study would be 55 with 90% power at the 5% level of significance. WHAT IS NEW AND CONCLUSION: The results from our study manifested that a randomized, balanced, two-way crossover design was eligible to evaluate acarbose BE. The appropriate dosing time was concomitant administration of sucrose and acarbose, and the optimal dose was 2 × 50 mg. The rectifying method exhibited preferable sensitivity and applicability in acarbose BE evaluation. A practical sample size of the pivotal study would be 55. These results may help to provide new insights into the protocol design of acarbose BE study.

Synthesis of sandwich-structured magnetic graphene-Zn-MOFs composites for quantitative determination of acarbose in rat plasma.

In this study, sandwich-structured magnetic graphene composites with Zn metal-organic framework layer coated on both two sides (denoted as magG@Zn-MOFs) were synthesized. The composites have large specific surface of 114 m2 g⁻1, uniform porous structure and rapid magnetic separation within 10 s. The magG@Zn-MOFs composites were used for extraction of acarbose in plasma prior to its quantitative analysis by LC-MS/MS. The established method has good linearity (10-1000 ng mL-1), satisfactory recovery (94.3-107.5%), low detection limit (as low as 2.5 ng mL-1), good intra-day precision (RSD 3.5-5.3%) and inter-day precision (RSD 6.3-8.1%). Finally, the method was successfully applied to pharmacokinetic study of acarbose in rats.

Clinical and genetic predictors of diabetes drug's response.

Diabetes is a major health problem worldwide. Glycemic control is the main goal in the management of type 2 diabetes. While many anti-diabetic drugs and guidelines are available, almost half of diabetic patients do not reach their treatment goal and develop complications. The glucose-lowering response to anti-diabetic drug differs significantly between individuals. Relatively little is known about the factors that might underlie this response. The identification of predictors of response to anti-diabetic drugs is essential for treatment personalization. Unfortunately, the evidence on predictors of drugs response in type 2 diabetes is scarce. Only a few trials were designed for specific groups of patients (e.g. patients with renal impairment or older patients), while subgroup analyses of larger trials are frequently unreported. Physicians need help in picking the drug which provides the maximal benefit, with minimal side effects, in the right dose, for a specific patient, using an omics-based approach besides the phenotypic characteristics.

Acarbose plus metformin fixed-dose combination in the management of type 2 diabetes.

INTRODUCTION: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Concerns in the management of diabetes include drug-induced hypoglycemia, poor control of postprandial blood glucose level and weight gain. A carbohydrate-rich diet can cause more load on the intestinal cells producing α-glucosidase. Many patients need combination treatment based on their level of glycemic control and other associated parameters. In such cases, a therapy that provides effective glycemic control with minimal or no risk of adverse events like hypoglycemia or weight gain is highly desired. The chances of cardiovascular events are high in diabetes patients; hence, medicines providing benefits beyond glycemic control such as reduced cardiovascular risk factors may be ideal in such patients. AREAS COVERED: Current available data are related to the rationale and clinical trials on the fixed-dose combination of acarbose plus metformin in management of type 2 diabetes. EXPERT OPINION: Combination therapy is routinely prescribed in the management of T2DM. Drugs with complimentary mechanisms should be used to maximize the efficacy of combination therapy. The combination of metformin and acarbose is a rational therapy because of their different and complimentary mechanisms of action, which provides effective glycemic control with additional cardiovascular benefits and minimizes adverse events.

Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects.

WHAT IS KNOWN AND OBJECTIVE: Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. METHODS: A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8-1·25). RESULTS AND DISCUSSION: Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. WHAT IS NEW AND CONCLUSION: These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs.

Acarbosa y propofol: ¿una peligrosa combinación? / Acarbose and propofol: A dangerous combination?

La hepatotoxicidad es una complicación infrecuente tras el empleo de propofol, que puede ser potencialmente grave en caso de no realizarse un diagnóstico precoz. El propofol es un fármaco cada vez más empleado en la práctica diaria no solo en cirugía sino también en la sedación de procedimientos invasivos ambulatorios tales como la endoscopia. Acarbosa es un fármaco clásico en el tratamiento de la diabetes tipo 2 en estadios iniciales que puede causar de forma infrecuente hepatitis tóxica. Se presenta el caso de una paciente que sufrió una hepatitis aguda secundaria al empleo de propofol como anestesia oftalmológica, hepatitis probablemente potenciada por el uso previo de acarbosa. El cuadro se diagnosticó de forma precoz y se resolvió sin complicaciones. El conocimiento de esta complicación en el ámbito de la anestesiología se revela cada vez más importante para mejorar la valoración preanestésica de los pacientes que vayan a ser sedados con propofol y así evitar en lo posible su aparición (AU)

Hepatotoxicity is a rare complication following the use of propofol and can be potentially serious if an early diagnosis is not made. Propofol is being increasingly used in daily practice, not only in surgery, but also in outpatient sedation procedures, such as endoscopy. Acarbose is a well-known drug used in type 2 diabetes treatment, particularly in the early phase. A case is reported on a patient who suffered an acute hepatitis secondary to the use of propofol in ophthalmology surgery, a hepatitis probably enhanced by prior use of acarbose, a drug that also can cause hepatotoxicity. An early diagnosis and it was resolved without complications. This case could contribute to improve pre-anesthetic evaluation of patients who will be undergoing sedation with propofol in order to avoid the possible appearance of hepatitis (AU)

[Acarbose and propofol: a dangerous combination?]. / Acarbosa y propofol: ¿una peligrosa combinación?

Hepatotoxicity is a rare complication following the use of propofol and can be potentially serious if an early diagnosis is not made. Propofol is being increasingly used in daily practice, not only in surgery, but also in outpatient sedation procedures, such as endoscopy. Acarbose is a well-known drug used in type 2 diabetes treatment, particularly in the early phase. A case is reported on a patient who suffered an acute hepatitis secondary to the use of propofol in ophthalmology surgery, a hepatitis probably enhanced by prior use of acarbose, a drug that also can cause hepatotoxicity. An early diagnosis and it was resolved without complications. This case could contribute to improve pre-anesthetic evaluation of patients who will be undergoing sedation with propofol in order to avoid the possible appearance of hepatitis.

Acarbose bioequivalence: exploration of new pharmacodynamic parameters.

To investigate bioequivalence (BE) testing of an acarbose formulation in healthy Chinese volunteers through the use of recommended and innovative pharmacodynamic (PD) parameters. Following the Food and Drug Administration (FDA) guidance, a randomized, cross-over study of acarbose test (T) and reference (R) (Glucobay®) formulations was performed with a 1-week wash-out period. Preliminary pilot studies showed that the appropriate dose of acarbose was 2 × 50 mg, and the required number of subjects was 40. Serum glucose concentrations after sucrose administration (baseline) and co-administration of sucrose/acarbose on the following day were both determined. Three newly defined PD measures of glucose fluctuation (glucose excursion (GE), GE' (glucose excursion without the effect of the homeostatic glucose control), and fAUC (degree of fluctuation of serum glucose based on AUC)), the plateau glucose concentration (C(ss)), and time of maximum reduction in glucose concentration (T (max)) were tested in the evaluation. The adequacy of the two parameters recommended by the FDA, ΔC(SG,max) (maximum reduction in serum glucose concentration) and AUEC((0-4h)) (reduction in the AUC((0-4h)) of glucose between baseline and acarbose formulation) was also evaluated. The T (max) values were comparable, and the 90% confidence intervals of the geometric test/reference ratios (T/R) for ΔC(SG,max), C(ss), GE, and fAUC were all within 80-125%. The parameter GE' was slightly outside the limits, and the parameter AUEC((0-4h)) could not be computed due to the presence of negative values. In acarbose BE evaluation, while the recommended parameter ΔC(SG,max) is valuable, the combination of C(ss) and one of the newly defined glucose fluctuation parameters, GE, GE', and fAUC is preferable than AUEC((0-4h)). The acarbose test formulation can be initially considered to be bioequivalent to Glucobay®.

Pharmacodynamic bioequivalence testing.

WHAT IS KNOWN AND OBJECTIVE: The assessment of bioequivalence of drugs intended for local action/targeted delivery and with poor systemic absorption presents unique challenges. Approaches such as pharmacodynamic (PD) bioequivalence testing have been proposed as alternatives to pharmacokinetic (PK) bioequivalence studies. Our objective is to comment on when PD bioequivalence testing might be considered appropriate and whether the acceptance criteria for bioequivalence could be adjusted based on observed variability in PD response. COMMENT: Pharmacokinetic bioequivalence studies are generally conducted to evaluate the rate and extent of drug absorption of a test drug as compared to a reference drug. However, this may not be appropriate for locally acting drugs, when the plasma drug concentrations, if measurable, are not correlated with the clinical therapeutic effect. Systemic absorption may in fact be undesirable for such drugs. The US Food and Drug Administration (FDA) recommends alternative approaches for evaluating the bioequivalence of acarbose, including a bioequivalence study with a PD endpoint. For the evaluation of therapeutic equivalence of highly variable drugs, adjusting the acceptance interval for the PK parameters has been discussed by the FDA and the European Medicines Agency (EMEA). However, it is still not clear whether the newly proposed methodology is applicable to PD bioequivalence testing. WHAT IS NEW AND CONCLUSION: Although no consensus has been reached on the criteria for PD bioequivalence testing, various approaches are currently being investigated. Further studies should be performed to assess whether an adjustment of the acceptance intervals is appropriate based on the within-subject variability of PD responses. This may potentially minimize the unnecessary exposure of a large number of subjects to the test drugs.

Pharmacodynamic comparison of two formulations of Acarbose 100-mg tablets.

WHAT IS KNOWN AND OBJECTIVE: Acarbose, an α-glycosidase inhibitor, is used to treat diabetic patients. Pharmacokinetic evaluation of acarbose is difficult because <2% is absorbed systemically. The current investigation evaluated the bioequivalence of two formulations of acarbose through pharmacodynamic comparison. METHODS: This investigation consisted of a pilot study and a main study. The pilot study had an open, single-dose, single-sequence design. Subjects received placebo and then two tablets of reference formulation (Glucobay(®) 100 mg tablet; Bayer Healthcare) on two consecutive days with sucrose. The main study was an open, randomized, two-period, two-sequence crossover study. Subjects randomly received placebo and two tablets of either test formulation (generic acarbose 100-mg tablet) or reference formulation with sucrose on two consecutive days in the first period. In the second period, placebo and alternative formulation were administered. Serial blood samples for pharmacodynamic assessment were taken after each administration. The maximum serum glucose concentration (G(max)) and the area under the serum glucose concentration-time profile (AUC(gluc)) were determined and compared. RESULTS AND DISCUSSION: Five subjects completed the pilot study. The AUC(gluc) from dosing until 1 h post-dose (AUC(gluc,1 h)) was significantly different between the placebo and acarbose. A total of 33 subjects completed the main study. The mean differences in G(max) (ΔG(max)) and AUC(gluc,1 h) (ΔAUC(gluc,1 h)) for the reference formulation compared with placebo were 22·0 ± 18·3 mg/dL and 928·2 ± 756·0 mg min/dL, respectively. The corresponding values for the test formulation were 23·3 ± 21·2 mg/dL and 923·0 ± 991·4 0 mg min/dL, respectively. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for ΔG(max) and ΔAUC(gluc, 1 h) were 1·06 and 1·00, respectively, and the 90% confidence intervals (CIs) corresponding values were 0·79-1·39 and 0·64-1·36, respectively. WHAT IS NEW AND CONCLUSION: The 90% CIs of GMRs for the pharmacodynamic parameters chosen for bioequivalence evaluation of two formulations of acarbose did not meet the commonly accepted regulatory criteria for bioequivalence (0·80-1·25).

Comparación del efecto del FZ con un anthiperglucemiante de mecanismo de acción similar, la acarbosa, en perros beagle / Comparison of FZ and acarbosa anthyperglucemic effct, in beagles

INTRODUCCIÓN. El FZ es una zeolita natural modificadas, la nueva conformación espacial le otorga una selectividad para la captura de glucosa del medio, mostrando un efecto similar al de medicamentos conocidos como antihiperglucemiantes, entre otros la Acarbosa, el Fibraguar y el Miglitol. OBJETIVO. Comparar el efecto antihiperglucemiante del FZ con el de la Acarbosa. MATERIAL Y MÉTODOS. Se utilizaron 20 perros Beagles que se distribuyeron en 5 grupos. A todos los animales se les suministró igual cantidad de pienso; el grupo 1 lo recibió solo, al grupo 2 se adicionó un suplemento de 50 g de sacarosa y los grupos 3, 4 y 5 recibieron además del suplemento de 50g de sacarosa, 200 mg de Acarbosa el grupo 3; 5g de FZ el grupo 4 y la combinación de 5g de FZ mas 200mg de Acarbosa el grupo 5. Se extrajo sangre a todos los animales para realizar determinaciones de glicemia al tiempo 0 y a los 30, 60, 90 y 120 minutos después de la ingestión del alimento y los medicamentos. Con los valores de glicemia se confeccionó una curva de tolerancia a los carbohidratos que permitió la comparación entre los grupos. RESULTADOS. Se observa que los grupos bajo tratamiento (3,4 y 5) presentaron valores inferiores de las áreas bajo la curva que el grupo 2 control positivo y el grupo 1 que ingirió solamente pienso. No se observan diferencias entre el grupo al que se administró la combinación de medicamentos y los grupos que recibieron cada uno por separado. CONCLUSIONES. El FZ y la Acarbosa mostraron un efecto antihiperglucemiante similar (AU)

INTRODUCTION. FZ is a natural zeolite that posses a selective action for the capture of glucose, it show a similar effect to antihypergluemics known drugs, like Acarbosa, Fibraguar and Miglitol. OBJECTIVE. Comparing the antihyperglucemic effect of FZ with Acarbosa. MATERIAL AND METHOD. 20 dogs were distributed in 5 groups. Equal quantity of food was supplied to all of the animals; the group 1 received only food, the group 2, 50g supplement of sucrose and the groups 3, 4 and 5 received besides the supplement of 50g of sucrose, 200mg of Acarbosa the group 3; 5g of FZ the group 4 and the combination of 5g of FZ plus 200mg of Acarbosa the group 5. Glycaemia was determinate in time 0,30,60,90 and 120 minutes after the ingestion of food and medications. A curve of tolerance of carbohydrates was manufactured to comparison the treatments. RESULTS. It is observed inferior values of areas under curved in groups (3.4 and 5). No differences were observed between the group with medications. CONCLUSIONS. FZ and Acarbosa showed similar antihyperglucemic effect (AU)

Comparison of efficacies of a dipeptidyl peptidase IV inhibitor and alpha-glucosidase inhibitors in oral carbohydrate and meal tolerance tests and the effects of their combination in mice.

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase IV (DPP-IV) inhibitor. Since the target of both DPP-IV inhibitors and alpha-glucosidase inhibitors is the lowering of postprandial hyperglycemia, we compared antihyperglycemic effects for E3024 and alpha-glucosidase inhibitors in various oral carbohydrate and meal tolerance tests using normal mice. In addition, we investigated the combination effects of E3024 and voglibose on blood glucose levels in a meal tolerance test using mice fed a high-fat diet. ER-235516-15 (the trifluoroacetate salt form of E3024, 1 mg/kg) lowered glucose excursions consistently, regardless of the kind of carbohydrate loaded. However, the efficacy of acarbose (10 mg/kg) and of voglibose (0.1 mg/kg) varied with the type of carbohydrate administered. The combination of E3024 (3 mg/kg) and voglibose (0.3 mg/kg) improved glucose tolerance additively, with the highest plasma active glucagon-like peptide-1 levels. This study shows that compared to alpha-glucosidase inhibitors, DPP-IV inhibitors may have more consistent efficacy to reduce postprandial hyperglycemia, independent of the types of carbohydrate contained in a meal, and that the combination of a DPP-IV inhibitor and an alpha-glucosidase inhibitor is expected to be a promising option for lowering postprandial hyperglycemia.

Low-dose acarbose does not delay digestion of starch but reduces its bioavailability.

AIMS: Slowly digestible starch is associated with beneficial health effects. The glucose-lowering drug acarbose has the potential to retard starch digestion since it inhibits alpha-amylase and alpha-glucosidases. We tested the hypothesis that a low dose of acarbose delays the rate of digestion of rapidly digestible starch without reducing its bioavailability and thereby increasing resistant starch flux into the colon. METHODS: In a crossover study, seven healthy males ingested corn pasta (50.3 g dry weight), naturally enriched with (13)C, with and without 12.5 mg acarbose. Plasma glucose and insulin concentrations, and (13)CO(2) and hydrogen excretion in breath were monitored for 6 h after ingestion of the test meals. Using a primed continuous infusion of D-[6,6-(2)H(2)] glucose, the rate of appearance of starch-derived glucose was estimated, reflecting intestinal glucose absorption. RESULTS: Areas under the 2-h postprandial curves of plasma glucose and insulin concentrations were significantly decreased by acarbose (-58.1 +/- 8.2% and -72.7 +/- 7.4%, respectively). Acarbose reduced the overall 6-h appearance of exogenous glucose (bioavailability) by 22 +/- 7% (mean +/-se) and the 6-h cumulative (13)CO(2) excretion by 30 +/- 6%. CONCLUSIONS: These data show that in healthy volunteers a low dose of 12.5 mg acarbose decreases the appearance of starch-derived glucose substantially. Reduced bioavailability seems to contribute to this decrease to a greater extent than delay of digestion. This implies that the treatment effect of acarbose could in part be ascribed to the metabolic effects of colonic starch fermentation.

Is acarbose equivalent to tolbutamide as first treatment for newly diagnosed type 2 diabetes in general practice? A randomised controlled trial.

We performed a double blind randomised controlled trial in general practice to assess equivalence between tolbutamide and acarbose with respect to the effect on mean HbA(1c) in newly diagnosed patients with type 2 diabetes. Secondary objectives were to compare the effects of both treatments on fasting and post-load blood glucose and insulin levels, lipids, and adverse events. Patients were randomised to receive acarbose, titrated step-wise to a maximum of 100mg three times daily (n=48) or tolbutamide, similarly titrated to a maximum of 2000 mg in three doses (n=48). The two treatments were considered equivalent if the two-sided 90% confidence interval (CI) for the difference in mean HbA(1c) levels was within the range -0.4 to 0.4%. Results were analysed on an intention-to-treat, per-protocol and on worst-case basis. Both agents reduced the HbA(1c) percentage and fasting blood glucose levels. The difference in mean decrease of HbA(1c) was 0.6% in favour of tolbutamide (90% CI 0.3, 0.9; 95% CI 0.2, 1.0). A worst-case analysis, assuming no change in HbA(1c) for dropouts, yielded a difference in mean decrease of 0.9% (90% CI 0.6, 1.2) in favour of tolbutamide. The difference in mean decrease of fasting blood glucose was 1.0 mmol/l in favour of tolbutamide (95% CI 0.3, 1.7). There were no significant differences in post-load blood glucose, fasting and post-load insulin levels, or lipids. In the acarbose group significantly more patients (15 versus 3) discontinued therapy because of adverse effects, mostly of gastrointestinal origin. We conclude that the results of this study favour tolbutamide over acarbose as first treatment for patients with newly diagnosed type 2 diabetes.

Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans.

PURPOSE: To conduct a retrospective evaluation of using dog as an animal model to study the fraction of oral dose absorbed (F) of 43 drugs in humans and to briefly discuss potential factors that might have contributed to the observed differences in absorption. METHODS: Mean human and dog absorption data obtained under fasted state of 43 drugs with markedly different physicochemical and pharmacological properties and with mean F values ranging from 0.015 to 1.0 were obtained from the literature. Correlation of F values between humans and dogs was studied. Based on the same references, additional F data for humans and rats were also obtained for 18 drugs. RESULTS: Among the 43 drugs studied, 22 drugs were virtually completely absorbed in both dogs and humans. However, the overall correlation was relatively poor (r2 = 0.5123) as compared to the earlier rat vs. human study on 64 drugs (r2 = 0.975). Several drugs showed much better absorption in dogs than in humans. Marked differences in the nonliner absorption profiles between the two species were found for some drugs. Also, some drugs had much longer Tmax values and prolonged absorption in humans than in dogs that might be theoretically predicted. Data on 18 drugs further support great similarity in F between humans and rats reported earlier from our laboratory. CONCLUSIONS: Although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, the present study suggests that one may need to exercise caution in the interpretation of data obtained. Exact reasons for the observed interspecies differences in oral absorption remain to be explored.

Lack of interaction between thioctic acid, glibenclamide and acarbose.

AIMS: Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin-dependent diabetes (NIDDM). This study systematically investigated drug-drug interactions between TA and glibenclamide and TA and acarbose. METHODS: Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A-C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(-)-TA as well as glibenclamide concentrations were measured with specific analytical methods. RESULTS: There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide. CONCLUSIONS: Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug-drug interactions.