Miglitol, a new alpha-glucosidase inhibitor

Miglitol (Bay m 1099, Bayer) is a second generation alpha-glucosidase inhibitor. It is a derivative of 1-desoxynojirimycin, and binds reversibly to the brushborder alpha-glucosidase enzymes. In contrast to its parent drug (acarbose, Bay g 5421, Bayer), miglitol is almost completely absorbed in the small intestine. It has to be taken with each main meal, and through its effect on carbohydrate digestion it blunts the postprandial blood glucose increase. Miglitol has no or a very small effect on fasting blood glucose levels. The blood-glucose lowering effects of miglitol in patients with Type 2 diabetes are lower than those of the frequently-used sulphonylurea compounds. Long-term studies show that a moderate average reduction of HbA1c of 0.3-0.7% point from baseline can be achieved. An advantage over sulphonylurea is the effect on serum insulin levels: miglitol therapy leads to slightly lower postprandial levels of serum insulin, whereas chronic sulphonylurea treatment usually increases serum insulin levels. This insulin-sparing effect may, in theory, lead to a lesser weight gain or even no weight gain and reduced risk of hypoglycaemia during chronic treatment. Long-term experience in Type 1 diabetic patients is limited. Similarly, miglitol may lead to reduced postprandial glucose excursions, slightly reduced insulin requirements and perhaps, as a consequence, a lower risk of hypoglycaemia. More long-term data are needed to fully assess to the clinical use of miglitol in these patients.     

Acarbose, an alpha-glucosidase inhibitor, improves insulin resistance in fructose-fed rats

Insulin resistance is one of the determinants of postprandial hyperglycemia. Acarbose is an alpha-glucosidase inhibitor that delays the absorption of carbohydrates from the small intestine, thereby suppressing postprandial hyperglycemia. Recently, acarbose has been found to reduce the incidence of cardiovascular disease (CVD) in patients with diabetes. These observations suggest that intervention of postprandial hyperglycemia with acarbose is a promising strategy for the prevention of CVD in diabetic patients. However, the effects of acarbose on insulin sensitivity are not fully understood. In this study, we examined whether oral administration of acarbose could improve insulin sensitivity in fructose-fed rats, a widely used insulin-resistant animal model. Although plasma glucose levels remained unchanged during the experiments, serum insulin levels were significantly increased in fructose-fed rats, which were suppressed by 4 weeks of treatment with acarbose. Acarbose treatment also increased high-density lipoprotein levels in fructose-fed rats. Furthermore, treatment of acarbose inhibited the elevation of systolic blood pressure levels in fructose-fed rats. These results indicate that oral administration of acarbose improves insulin sensitivity in fructose-fed rats. Our present study suggests that the cardioprotecive effects of acarbose could be ascribed, at least in part, to its insulin-sensitizing property.     

In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats

The drug interactions between a new human immune deficiency virus (HIV) protease inhibitor, amprenavir, and four other protease inhibitors which are presently used have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration studies. The metabolic clearance rates (Vmax/Km) of amprenavir, saquinavir, indinavir and nelfinavir in rat liver microsomes were 50.67+/- 3.77, 170.88 +/- 15.34, 73.01 +/- 2.76 and 126.06 +/- 6.23 microLmin(-1) (mg protein)(-1), respectively, and the degree of metabolicclearance was in the order of saquinavir > nelfinavir > indinavir > amprenavir > ritonavir. The inhibition constants (Ki) of ritonavir for amprenavir, indinavir, nelfinavir and saquinavir were 2.29, 0.95, 1.01 and 1.64 microM, respectively, and that of indinavir for amprenavir was 0.67, indicating that amprenavir metabolism in rat liver microsomes was strongly inhibited by indinavir. The Ki values of amprenavir for indinavir, nelfinavir and saquinavir were 7.41, 2.13 and 16.11 microM, respectively, and those of nelfinavirand saquinavirforamprenavirwere 9.15 and 34.57 microM, respectively. The area under the concentration vs time curve (AUC) of amprenavir after oral co-administration with saquinavir, indinavir, nelfinavir or ritonavir (20 mg kg(-1) for each oral dose in rats) was increased by 1.6-, 2.0-, 1.2- and 9.1-fold, respectively. The AUC values of saquinavir, indinavir and nelfinavir by co-administration with amprenavir showed about 7.3-, 1.3-, and 7.9-fold increase, respectively. These observations suggested that the oral bioavailability of amprenavir was not so affected by co-administration with saquinavir, nelfinavir or indinavir, compared with ritonavir, whereas amprenavir markedly affected the oral bioavailability of saquinavir and nelfinavir. In addition, the in-vivo effects after co-administration of two kinds of HIV protease inhibitors cannot always be predicted from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. However, these results provide useful information for the treatment of AIDS patients when they receive a combination therapy with two kinds of HIV protease inhibitor.     

Effectiveness of acarbose,an alpha-glucosidase inhibitor,in uncontrolled non-obese non-insulin dependent diabetes

Summary The effect of acarbose, an alpha-glucosidase inhibitor, on glycaemic control, was compared with placebo in a double-blind, randomised, group comparison study during 16 weeks in 20 non-obese non-insulin dependent diabetic patients in whom sulphonylurea treatment had been withdrawn.There was significant deterioration in glycaemic control as assessed by HbA₁ following withdrawal of the sulphonylurea. There was no significant improvement in HbA₁ between weeks 0 and 16 in either the acarbose (11.3% and 12.4% respectively) or the placebo group (10.6% and 12.2% respectively). In both the acarbose and placebo treated groups fasting glucose and insulin concentrations were unaltered.This study also suggests that acarbose was not an effective substitute for sulphonylureas in non-obese Type 2 diabetes uncontrolled by diet alone.     

Castanospermine: an apparent tight-binding inhibitor of hepatic lysosomal alpha-glucosidase

Castanospermine is a potent inhibitor of rat hepatic lysosomal alpha-glucosidase in vitro. The alkaloid showed time-dependent inhibition with an IC50 of 5 X 10(-6) M without preincubation and 1 X 10(-7) M with 1 hr of preincubation. Inhibition appeared competitive without preincubation but noncompetitive after preincubation. The time-dependent inactivation of the enzyme followed pseudo-first-order kinetics with an inactivation constant of 1.2 X 10(3) M-1 sec-1. The apparent irreversibility of enzyme inhibition by castanospermine is postulated to be by tight-binding inhibition.     

A theoretical study on interactions between mitoxantrone as an anticancer drug and DNA: application in drug design

This research is an effort to further understand the physicochemical interaction between the novel drug, mitoxantrone (MTX) and its biologic receptor, DNA. The ultimate goal is to design drugs that interact more with DNA. Understanding the physicochemical properties of the drug as well as the mechanism by which it interacts with DNA, it should ultimately allow the rational design of novel anti-cancer or anti-viral drugs. Molecular modelling on the complex formed between MTX and DNA presented that this complex was indeed fully capable of participating in the formation of a stable intercalation site. Furthermore, the molecular geometries of MTX and the DNA bases (adenine, guanine, cytosine and thymine) were optimized with the aid of the B3LYP/6-31G* method. The properties of the isolated intercalator and its stacking interactions with the adenine...thymine (AT) and guanine...cytosine (GC) nucleic acid base pairs were studied with the DFTB method (density functional tight-binding), an approximate version of the DFT method, that was extended to cover the London dispersion energy. The B3LYP/6-31G* stabilization energies of the intercalator...base pair complexes were found 10.06 kcal/mol and 21.64 kcal/mol for AT...MTX and GC...MTX, respectively. It was concluded that the dispersion energy and the electrostatic interaction contributed to the stability of the intercalator.DNA base pair complexes. The results concluded from the comparison of the DFTB method and the Hartree-fock method point out that these methods show close results and support each other.     

Inhibition constants, inhibitor concentrations and the prediction of inhibitory drug drug interactions: pitfalls, progress and promise

Strategies and standards for predicting the likelihood of pharmacokinetically significant inhibitory drug-drug interactions for drug development purposes which rely primarily on projected in vivo concentrations of cytochrome P450 (CYP) or transporter inhibitors, [I], and in vitro estimates of their inhibitory constants, K(i), were specified in several commentaries based upon a conference held by the European Federation of Pharmaceutical Sciences (EUFEPS) several years ago. Since then the application of those strategies and standards has met with varying degrees of success. Many of the vexing issues that were identified in the EUFEPS Conference Report remain, while other issues are systematically being resolved. This article briefly reviews the underlying strategy in the prediction of the significance of inhibitory DDIs using [I]/K(i) ratios; some of the difficulties or pitfalls associated with the predictive application of [I]/K(i) ratios; and some of the recent refinements of the general strategy.     

Investigation of drug-porous adsorbent interactions in drug mixtures with selected porous adsorbents

The adsorption of drugs onto porous substrates may prove to be a convenient method by which to enhance the dissolution rate of certain poorly water-soluble drugs in body fluids. The purpose of this research is to provide a better understanding of the type of interactions occurring between drugs and certain pharmaceutically acceptable porous adsorbents that leads to enhanced drug dissolution rates. The interactions between ibuprofen (acidic drug), acetaminophen (acidic drug), dipyridamole (basic drug), and the porous adsorbents used (calcium silicate and silica gel) were investigated using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier Transform infrared spectroscopy (FTIR). DSC and PXRD results indicated a significant loss of crystallinity of both ibuprofen and acetaminophen but not dipyridamole. In the case of ibuprofen, FTIR results indicated the ionization of the carboxylic group based on the shift in the FTIR carboxylic band. Dissolution of ibuprofen from its mixtures with porous adsorbents was found to be significantly higher compared to the neat drug, whereas dipyridamole dissolution from its mixtures with porous adsorbents was not significantly different from that of the neat drug.     

Metabolic drug interactions between angiogenic inhibitor, TNP-470 and anticancer agents in primary cultured hepatocytes and microsomes.

The potential metabolic drug interactions between TNP-470, a potent inhibitor of angiogenesis, and several commonly used anticancer agents, such as cyclophosphamide, taxol, and minocycline, were investigated in vitro using primary cultured hepatocytes and microsomes of rhesus monkeys. After incubation of hepatocytes with 5 microM [3H]TNP-470, rapid and extensive formation of six metabolites was observed, with M-II and M-IV being the predominant metabolites. After 30 min of incubation in the presence of 250 microM cyclophosphamide, concentrations of unchanged TNP-470 and M-IV were increased with values of 1.00 +/- 0.02 and 1.49 +/- 0.01 microM compared with control values of 0.67 +/- 0.09 (p =.02), 1.39 +/- 0. 03 microM (p <.01), respectively. In contrast, the concentration of M-II was substantially decreased from 1.69 +/- 0.86 to 1.02 +/- 0.16 microM (p =.01). Combination of taxol with TNP-470 led to a 50% decrease of M-II levels (p <.01), whereas unchanged TNP-470 and M-IV levels were increased by at least 2.5-fold compared with control (p =.08 and 0.01). Exposure of cells to TNP-470 with 250 microM minocycline had no effect on TNP-470 metabolism in monkey hepatocytes. In vitro studies with isolated monkey liver microsomes confirmed these drug-drug metabolic interactions detected at the cellular level. A detailed understanding of the potential drug interactions in TNP-470 metabolism occurring with taxol or cyclophosphamide is critical to fully elucidate the potentiation of the antitumor activity observed in vivo after coadministration of these two agents with TNP-470.     

Monoamine oxidase inhibitor update. Potential adverse food and drug interactions

Monoamine oxidase inhibitors (MAOIs) are medicines with potential for therapeutic gains, but they may also have adverse consequences. The risk: benefit ratio is assessed and, in appropriately selected cases, efficacy should outweigh disadvantages. Hypotension is the most prominent side-effect; yet the primary concern in the MAOI-treated person is to prevent co-exposure to substances with indirectly-acting sympathomimetic properties. Such co-utilisations from certain foods or drugs can result in dangerous hypertensive and hyperpyretic crises. A responsible individual should be involved in the administration of these drugs. The patient and family must fully understand the self-discretionary diet avoidance rules, which stress abstinence from high-tyramine foods. Drug prohibitions also emphasise elimination of indirect action sympathomimetics, but all pharmaceutical applications are always strictly controlled by the well informed physician who prescribes MAOIs. Treatment of the hypertensive crisis is urgent and includes alpha-blockade. Overdoses require supportive therapies and may necessitate acidification of the urine.     

A molecular modeling study of the interactions between the antiestrogen drug tamoxifen and several derivatives, and the calcium-binding protein calmodulin.

The interactions of the antiestrogenic drug tamoxifen with the calcium-binding protein calmodulin have been studied by computerized molecular modeling methods. Sites in both the N and C domains of the protein have been established, with one in the C domain having the highest calculated enthalpy of binding. The residues involved in the sites have been detailed. Modeling studies are reported for six tamoxifen derivatives, and their calculated enthalpies of binding are compared with the ability of the analogues to inhibit calmodulin-dependent cyclic AMP phosphodiesterase (PDE) (Rowlands et al. Biochem, Pharmacol. 1990, 40, 283-289). The poor binding properties of the piperazino and C-methyl derivatives are correctly predicted, whereas the superior affinity of 4-iodotamoxifen is not fully explained by the model.     

Pharmacokinetic interactions in mice between irinotecan and MBL‐II‐141, an ABCG2 inhibitor

Purpose . The chromone derivative MBL‐II‐141, specifically designed to inhibit ABCG2, was previously demonstrated to combine strong inhibition potency, low toxicity and good efficiency in reversing resistance to irinotecan in a xenografted mouse model. Here, the pharmacokinetic interactions in mice between irinotecan, its active metabolite SN‐38 and MBL‐II‐141 were characterized quantitatively in the blood and in the brain. Methods. Compartmental models were used to fit the data. Goodness‐of‐fit was assessed by simulation‐based diagnostic tools. Results. Irinotecan increased the MBL‐II‐141 apparent clearance and V ss 1.5‐fold, probably by increasing the MBL‐II‐141 unbound fraction. MBL‐II‐141 decreased the total apparent clearance of irinotecan by 23%, by decreasing its biliary clearance. MBL‐II‐141 increased 3‐fold the brain accumulation of irinotecan, as a result of the rise of systemic exposure combined with the inhibition of ABCG2‐mediated efflux at the blood–brain barrier. Finally, SN‐38 exposure was increased by 1.16‐fold under treatment with MBL‐II‐141, owing to the higher irinotecan exposure with increased metabolism towards the formation of SN‐38. Conclusions . These results may help to anticipate the pharmacokinetic interactions between MBL‐II‐141 and other ABCG2 substrates. The irinotecan‐MBL‐II‐141 interaction is also expected to occur in humans. Copyright © 2017 John Wiley & Sons, Ltd.     

Behaviourally specific interactions between naloxone and beta-phenylethylamine in an operant drug discrimination procedure in rats

Rats were trained to discriminate phenylethylamine (PEA) at 30 mg/kg (IP). In subsequent generalization tests, it was found that naloxone had no effect on the discriminative stimulus (cue) properties of PEA, but it did potentiate PEA's dose-related rate suppressant effects. Thus the potentiation by naloxone of PEA's effects was behaviourally specific and confined to drug effects on motoric behaviours. These data support the results of previous in vivo and in vitro studies, which suggest that interactions between endogenous PEA and endorphin systems may be functionally important. Such interactions could be of significance in stress-related behavioural disorders.     

Pharmacokinetic drug interactions between ampiroxicam and sulfaphenazole in rats

The aim of the present study was to determine the effect of sulfaphenazole (SP) on the pharmacokinetics of ampiroxicam (AM) which is metabolized by cytochrome P-450 (CYP) 2C9, since SP is a potent inhibitor of CYP 2C9, and so a dramatic pharmacokinetic drug interaction between both drugs is assumed after dosing. Single intravenous and oral administrations of AM (5 and 7.5 mg/kg piroxicam equivalent, respectively) and SP (80 and 120 mg/kg, respectively) to rats did not significantly alter the elimination kinetics of AM and piroxicam (PX) converted from AM. When SP was preloaded orally at 2 h before the dosing of AM, and when AM and SP were orally coadministered for 7 d, the elimination of PX from plasma was slightly retarded and the area under the plasma concentration-time curve (AUC) was increased 77 and 53%, respectively, but not significantly, compared with those after AM alone. On the other hand, a significantly decreased metabolic conversion of PX to 5'-hydroxyPX in plasma was observed by these treatments (p<0.05). In order to clarify the mechanism for the interaction, hepatic and intestinal metabolizing enzyme activities, CYP, uridine 5'-diphosphoglucuronyltransferase (UDPGT) and aryl esterase, were assayed after single and multiple oral administrations of AM or AM and SP. The enzyme activities were hardly inhibited by the treatment, indicating that the inhibition of CYP and hydrolytic enzymes by SP was approximately denied. These results suggest that SP does not significantly affect the pharmacokinetics of AM and PX in rats. However, the pharmacokinetic drug interaction between both drugs in man may not always be ignored.     

Studies on drug interactions between esomeprazole, amoxicillin and clarithromycin in healthy subjects

OBJECTIVE: A combination of esomeprazole, amoxicillin and clarithromycin may be used for Helicobacter pylori eradication. We explored the potential for interactions between these drugs. METHODS: In 2 randomized, 4-way crossover studies, healthy CYP2C19 extensive metabolizers (EMs) received esomeprazole 40 mg once daily (n = 20) or 20 mg twice daily (b.i.d.) (n = 20), clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. or the combination of the 3 drugs for 7 days. In a third randomized, 2-way, crossover study, 6 healthy CYP2C 19 poor metabolizers (PMs) received esomeprazole 40 mg once daily with and without clarithromycin 500 mg b.i.d. for 1 week. RESULTS: Triple therapy with esomeprazole 40 mg increased the area under the plasma concentration-time curve during the dosing interval (AUCtau) from 13.31 micromol x h/l (11.12-15.93) for esomeprazole alone to 22.69 micromol x h/l (18.94-27.17) for triple treatment. Respective AUCtau values with esomeprazole 20 mg b.i.d. were 4.97 micromol.h/l (3.97-6.21) and 11.29 micromol x h/l (9.03-14.12). Clarithromycin and amoxicillin plasma levels were largely unchanged by combination therapy. In PMs, the esomeprazole AUC also approximately doubled when administered in combination with clarithromycin. All treatments were well tolerated. CONCLUSION: Clarithromycin decreases the metabolism rate of esomeprazole, leading to approximately doubled AUC values, both in EMs and PMs.     

In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.     

Assessment of the drug interaction between alteplase and nitroglycerin: an in vitro study

Alteplase is the most commonly administered thrombolytic agent in the United States. However, concurrent therapy with nitroglycerin reduces plasma alteplase concentrations and its clinical efficacy. We sought to determine if this interaction is concentration and pH dependent. Seventy plasma samples were prepared and divided into three groups: alteplase 500 IU/ml alone (group 1), alteplase 500 IU/ml plus nitroglycerin 5 ng/ml (group 2), and alteplase 500 IU/ml plus nitroglycerin 200 ng/ml (group 3). The samples were analyzed at time zero and 3 hours (incubated at 37 degrees C). Group 1 had significantly higher plasma alteplase concentrations than group 3 (p<0.001). When alteplase and nitroglycerin are combined, the degradation of alteplase in plasma is enhanced.     

Lack of drug interactions between mirtazapine and risperidone in psychiatric patients: a pilot study.

An open-label, non-randomized, pilot study has been performed in inpatients in need of treatment with an antipsychotic (risperidone) and an antidepressant (mirtazapine) with the objective to preliminarily assess a possible pharmacokinetic interaction and the tolerability of this combination. A 1-4-week single drug treatment phase (risperidone 1-3 mg bid or mirtazapine 30 mg nocte) was followed by a 2-4-week combined drug treatment phase at unchanged doses. Twelve patients were enrolled, nine of whom were treated with risperidone in the single drug phase. Results of plasma level measurements are available for six patients and indicate that adding mirtazapine to risperidone does not alter steady-state plasma concentrations of risperidone and its 9-hydroxy metabolite. Data from one patient suggest that adding risperidone to mirtazapine does not result in clinically relevant changes in plasma concentrations of either compound. The combination was well tolerated and no major or relevant adverse events were observed. Adding risperidone to mirtazapine probably does not necessitate a change of the dosage of either drug, but more extensive investigations are needed.