The therapeutic role of lactobacillus and montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress.

Male reproductive dysfunction is one of the overlooked findings of diabetes mellitus (DM) that deserves greater scientific attention. This study is designed to explore the therapeutic potential of metformin and montelukast, in combination with Lactobacillus, for modulation of intestinal flora and suppression of oxidative stress in testicular and liver damage in diabetic male rats. A DM model was induced by streptozotocin (STZ)which caused functional, biochemical, and inflammatory injuries to the testicular and liver tissues. The experimental panel included nine rat groups: normal control, normal control plus metformin, normal control plus montelukast, DM control, DM plus montelukast, DM plus a combination of metformin and Lactobacillus, DM plus a combination of montelukast and Lactobacillus, and DM plus a combination of metformin and montelukast. In parallel, clinical evaluation of microscopic examination scoring, and hepatic and testicular injuries, were evaluated. Biochemical markers including glucose level, lipid profile, inflammatory markers (tumor necrosis factor- (TNF-α) and interleukin-17 (IL-17), Caspase-3, and Bax proteins expressions were measured. The change in the microbiota abundance was investigated using conventional and real-time PCR. The current study revealed a significant difference in the relative abundance of microbiota, where DM is associated with an enormous increase of Bacteroides spp., Clostridium spp., E. coli, and Fusobacterium spp., and a significant decrease in Bifidobacteria spp., and Lactobacillus spp., in contrast with normal control. Metformin and montelukast, in combination with Lactobacillus, significantly reversed the testicular and liver damage caused by STZ. Moreover, the drugs significantly reduced the oxidative, inflammatory, and apoptotic activities induced by STZ.

Antiviral activity against Middle East Respiratory Syndrome coronavirus by Montelukast, an anti-asthma drug.

Middle East Respiratory Syndrome (MERS) is a respiratory disease caused by a coronavirus (MERS-CoV). Since its emergence in 2012, nosocomial amplifications have led to its high epidemic potential and mortality rate of 34.5%. To date, there is an unmet need for vaccines and specific therapeutics for this disease. Available treatments are either supportive medications in use for other diseases or those lacking specificity requiring higher doses. The viral infection mode is initiated by the attachment of the viral spike glycoprotein to the human Dipeptidyl Peptidase IV (DPP4). Our attempts to screen antivirals against MERS led us to identify montelukast sodium hydrate (MSH), an FDA-approved anti-asthma drug, as an agent attenuating MERS-CoV infection. We showed that MSH directly binds to MERS-CoV-Receptor-Binding Domain (RBD) and inhibits its molecular interaction with DPP4 in a dose-dependent manner. Our cell-based inhibition assays using MERS pseudovirions demonstrated that viral infection was significantly inhibited by MSH and was further validated using infectious MERS-CoV culture. Thus, we propose MSH as a potential candidate for therapeutic developments against MERS-CoV infections.

Use of phenytoin for treatment of tacrolimus toxicity with superimposed sepsis.

A 40-year-old woman with a history of chronic graft-versus-host-disease on immunosuppression with tacrolimus presented to the hospital with somnolence, confusion and muscle cramps over a few days. She was found to have hypertension, hyperglycaemia and acute kidney injury with an elevated blood tacrolimus level of greater than 120 ng/mL (reference range 5-15 ng/mL). Discontinuation of tacrolimus with concomitant administration of intravenous phenytoin led to the successful reduction of elevated tacrolimus concentrations and the resolution of her symptoms. Tacrolimus is metabolised by the cytochrome P (CYP) 450 3A enzyme system, and utilisation of CYP 3A inducers to accelerate its clearance may be used as a successful therapy to treat tacrolimus toxicity.

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs. PATIENTS AND METHODS: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion. RESULTS: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations. CONCLUSION: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 2: systemic therapies.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Effect of High-Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long-lasting Inhibition of CYP2C19.

In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half-life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in ~ 3-4 days after discontinuation of esomeprazole treatment.

Impact of AhRR (565C > G) polymorphism on dioxin dependent CYP1A2 induction.

The current study uses the metabolic probe, antipyrine, and AhRR transcript expression (qRT-PCR) to examine the impact of the AhRR (565C > G or Pro185Ala, rs2292596) genetic polymorphism upon CYP1A2 inducibility in an established cohort of male firefighters with exposure to dioxin-like chemicals. The lipid adjusted concentrations of 29 dioxin and dioxin-like congeners were measured in serum. Possession of the G allele (CG and GG genotypes) was correlated with high expression AhRR transcript and lower CYP1A2 induction than found in individuals homozygous for CC. The induction of CYP1A2 was dioxin-dependent among carriers of the G allele. Multivariate models indicated that CYP1A2 activity, detected as urinary 3-hydroxymethylantipyrine, was significantly correlated with cotinine concentration and for those currently working as firefighters, dioxin body burden (ß = 0.54, p = 0.041). The efficacy of the AhRR in regulating the AhR signaling pathway is influenced by the AhRR (565C > G) polymorphism. Our study of firefighters using the induction of CYP1A2 as an indicator suggest that G allele proteins have variable AhR repressor activity which is manifested in a dioxin-dependent manner. These results provide evidence of metabolic differences that may affect susceptibility to dioxin-mediated health effects.

Comparison of the toxicity of sulfur mustard and its oxidation products in vitro.

The molecular toxicology of the chemical warfare agent sulfur mustard (SM) is still not completely understood. It has been suggested that in addition to SM itself also biotransformation products thereof mediate cytotoxicity. In the current study, we assessed this aspect by exposing a human hepatocyte cell line (HepG2) to SM or to its oxidation products sulfur mustard sulfoxide (SMO), sulfur mustard sulfone (SMO2), and divinyl sulfone (DVS). Cytotoxicity, determined with the XTT assay, revealed a significant higher toxicity of SMO2 and DVS compared to SM while SMO had no effect at any concentration. The exact biotransformation of SM leading to SMO, SMO2 and finally DVS is unknown so far. Involvement of the CYP450 system is discussed and was also investigated in the presented study. Modulation of CYP1A2 activity, taken as a model enzyme for CYP450, affected cytotoxicity of SM, SMO2 or DVS significantly. Induction of CYP1A2 with omeprazole led to decreased cytotoxicity for all compounds whereas inhibition with cimetidine resulted in an increased cytotoxicity for SM, but not for SMO2 and DVS. Our results indicate a distinctive role of the CYP450 system in SM poisoning. Future studies should address the metabolic conversion of SM in more detail. Our data may suggest the well-tolerated drug omeprazole as a potential co-treatment after contact to SM.

A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles.

Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure-activity-relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags.

Montelukast in chronic lung allograft dysfunction after lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a major cause of post‒lung transplant mortality, with limited medical treatment options. In this study we assessed the association of montelukast treatment with pulmonary function and outcome in lung transplant recipients with progressive CLAD. METHODS: We performed a retrospective study of all lung transplant recipients transplanted between July 1991 and December 2016 at our center and who were treated for at least 3 months with montelukast for progressive CLAD, despite at least 3 months of prior azithromycin therapy. Main outcome parameters included evolution of pulmonary function and progression-free and overall survival. RESULTS: A total of 153 patients with CLAD (115 with bronchiolitis obliterans syndrome and 38 with restrictive allograft syndrome) were included, of whom 46% had a forced expiratory volume in 1 second (FEV1) measure of between 66% and 80%, 31% an FEV1 between 51% and 65%, and 23% an FEV1 ≤50% of best post-operative FEV1 at start of montelukast. Montelukast was associated with attenuation in rate of FEV1 decline after 3 and 6 months, respectively (both p < 0.0001). Patients in whom FEV1 improved or stabilized after 3 months of montelukast (81%) had significantly better progression-free (p < 0.0001) and overall (p = 0.0002) survival after CLAD onset, as compared to those with further decline of FEV1 (hazard ratio [HR] 2.816, 95% confidence interval [CI] 1.450 to 5.467, p = 0.0022 for overall survival after CLAD onset in risk-adjusted multivariate analysis). CONCLUSIONS: Montelukast was associated with a significant attenuation in rate of FEV1 decline in a substantial proportion of patients with established CLAD, which correlated with better outcome. Further study is required regarding use of montelkast.

Phenytoin-induced hypothermia.

A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?

Is there any effect of montelukast on prevention of myringosclerosis after myringotomy in a rat model?

OBJECTIVES: In this study, our aim was to identify the possible effects of montelukast sodium (ML) on the prevention of experimentally induced myringosclerosis. MATERIALS AND METHODS: Twenty-eight female Wistar albino rats were used and they were divided into four groups randomly. Tympanic membranes (TM) of all animals were perforated and then group 1 received no treatment (control group), group 2 was treated with a topical saline solution, group 3 received topically ML and group 4 received orally ML. On the 15th day, all animals were euthanized. Tympanic membranes were evaluated otomicroscopically and histopathologically. RESULTS: The histopathological findings, compared against a control and saline groups, showed the topically and orally ML groups had statistically significant differences of degree of myringosclerosis (p < 0.002) and median thickness of the TMs (p < 0.001). Suppression of inflammation was statistically significant only in the oral ML treatment group (p < 0.002). CONCLUSION: Oral and topically administration of ML reduced myringosclerosis formation in myringotomies rats.

Evaluation of the impact of CYP1A2 induction by charbroiled meal on metabolic phenotype.

BACKGROUND & AIMS: The process of grilling food items often generates polycyclic aromatic hydrocarbons which are established inducers of CYP1A2, a human drug metabolising enzyme, known to activate some procarcinogens. The impact of such induction on CYP1A2 metabolic phenotype has been the subject of some discordant findings. This study, while considering some limitations in previous study designs, evaluated the effect of CYP1A2 induction by the consumption of charbroiled meal on its metabolic phenotype. METHODS: Caffeine was administered to 17 healthy subjects before, and after, four consecutive days of charbroiled beef ingestion. Blood and spot urine samples were subsequently collected at the 4th and 6th hour post caffeine-administration, respectively, for the assessment of CYP1A2 activity. An additional caffeine administration and sample collection was repeated 48 h after the cessation of charbroiled-beef intake. CYP1A2 activity, derived as the log-transformed molar ratios of caffeine and its metabolites, was statistically analysed for changes in metabolic phenotype. RESULTS: Urinary and plasma metrics of CYP1A2 activity had mean reference values of 1.53 and 0.38, respectively, in the study subjects. CYP1A2 metabolic phenotype before and after the ingestion of charbroiled meal was not significantly different. However, urinary and plasma metrics of CYP1A2 activity decreased by about 19% (1.53 vs 1.24) and 65% (0.38 vs 0.14), respectively, 48 h after the cessation of charbroiled meal ingestion. CONCLUSIONS: The induction of CYP1A2 by the consumption of charbroiled meals may not portend increased rate of CYP1A2-activation of procarcinogens in humans. However, a potentially significant CYP1A2 inhibition which might result in increased-exposure for drugs predominantly metabolised by this enzyme is likely.

Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability.

Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).

In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects.

Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.

Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.

To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC0-∞ ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10-10 ). UGT1A3*2 was associated with increased AUC0-∞ of montelukast acyl-glucuronide M1 and decreased AUC0-∞ of hydroxymetabolites M5R, M5S, and M6 (P < 10-9 ). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC0-∞ of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC0-∞ of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.

Activated thyroid hormone receptor modulates dioxin-inducible aryl hydrocarbon receptor-mediated CYP1A1 induction in human hepatocytes but not in human hepatocarcinoma HepG2 cells.

Aryl hydrocarbon receptor (AhR) is a transcription factor, the activity of which is modulated by hormones including glucocorticoids and estrogens. In this study, we examined the effects of triiodothyronine (T3), a ligand and activator of thyroid hormone receptor (TR), on transcriptional activity of AhR and the expression of its target gene CYP1A1. Study was carried out in human hepatocellular carcinoma cells HepG2 and primary cultures of human hepatocytes (HH). Gene reporter assay in stably transfected AZ-AhR cells revealed that T3 dose-dependently augmented 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible AhR-dependent luciferase activity. In contrast, T3 had no effect on TCDD-inducible expression of CYP1A1 mRNA, protein and catalytic activity. Incubation of human hepatocytes with T3 had modulatory and inter-individual (7 cell cultures from 7 different liver donors) effects on both basal and dioxin-inducible CYP1A1/2. Since there was no correlation between T3 effects on CYP1A expression and T3-dependent expression of Spot14 mRNA, the involvement of additional factors besides TR is supposed. Overall, the co-incubation of normal and cancer human hepatic cells with TCDD and T3 suggested transcriptional cross-talk between AhR and TR, which may have physiological and toxicological implications.

Hydroxystilbenes and methoxystilbenes activate human aryl hydrocarbon receptor and induce CYP1A genes in human hepatoma cells and human hepatocytes.

Natural polyphenol resveratrol (trihydroxystilbene) is a partial agonist of human aryl hydrocarbon receptor AhR, thereby, displaying a plethora of biological effects. Biological activities of metoxylated and hydroxylated stilbenes were studied in the past. The aim of the current study was to describe the effects of 13 different hydroxy- and methoxystilbenes, including their cis/trans isomers on the transcriptional activity of AhR and the expression of CYP1A genes in hepatic cancer cells HepG2 and in primary human hepatocytes. Techniques of gene reporter assays, qRT-PCR, Simple Western blotting by Sally Sue™ and electrophoretic mobility shift assay EMSA were employed. All compounds activated AhR, but their efficacies, potencies and dose-response profiles differed substantially. The strongest activators of AhR and inducers of CYP1A1 in HepG2 cells were DMU-212 ((E)-3,4,5,4´-tetramethoxystilbene), trans-piceatannol, cis-piceatannol, trans-trismethoxyresveratrol and trans-pinostilbene. While DMU-212 and trans-trismethoxyresveratrol also induced CYP1A1 and CYP1A2 in primary human hepatocytes, the effects of trans-piceatannol, cis-piceatannol and trans-pinostilbene weaned off. On the other hand, trans-4-methoxystilbene was strong CYP1A inducer in hepatocytes but not in HepG2 cells. Differences between effects of stilbenes in HepG2 cells and human hepatocytes are probably due to the extensive phase I and phase II xenobiotic metabolism in human hepatocytes. The data obtained may be of toxicological relevance.

Muscone Induces CYP1A2 and CYP3A4 Enzyme Expression in L02 Human Liver Cells and CYP1A2 and CYP3A11 Enzyme Expression in Kunming Mice.

AIM: To examine the effect of synthetic muscone on the expression of CYP1A2 and CYP3A4 enzymes in human liver L02 cells and in the liver tissue of Kunming mice. METHODS: The L02 hepatic cell line was used to study the effect of low (10-4 µmol/L), middle (10-3 µmol/L), and high concentrations (10-2 µmol/L) of muscone on the expression of CYP1A2 and CYP3A4 enzymes. In addition, the cytochrome P450 (CYP) expression was investigated in Kunming mice after the administration of 10 mg/kg (low), 50 mg/kg (middle), and 100 mg/kg (high) dose of muscone for 6 days. A mixture of phenobarbital (30 mg/kg) and ß-napthoflavone (80 mg/kg) was used as positive control and the effects of the compounds on CYP expression were investigated at the end of 6- and 12-day periods. RESULTS: Muscone induced the expression of CYP1A2 (middle and low concentrations) and of CYP3A4 (high concentration) enzymes in L02 cells. In vivo, administration of muscone in Kunming mice revealed significant weight reduction at the end of 6- and 12-day periods (middle and high doses, respectively), compared to the control group (p < 0.05). Liver toxicity scores indicated that the liver injuries in the positive control and high doses of muscone group were significantly higher in the 6- and 12-day periods, compared to those in the blank control group (p < 0.05). Furthermore, muscone induced CYP1A2 and CYP3A11 expressions in Kunming mice at the middle dose and all doses during the 12-day period as demonstrated by immunoblotting experiments. A low dose of mucone induced the CYP enzyme expression more rapidly, whereas a high dose of muscone caused the longest inductive effect. The results were confirmed by immunohistochemistry experiments and real-time PCR studies, where similar patterns of muscone-mediated inductive effects were noted. CONCLUSIONS: Muscone induces CYP1A2 and CYP3A4 expression in liver cells in vitro and in vivo. In addition, it exhibits liver toxicity in Kunming mice at concentrations higher than 50 mg/kg. The CYP-inductive effect that is caused by muscone encompasses a 6- to 12-day period of activity after drug administration as demonstrated by follow-up in vivo studies.

Development of Left Atrial Thrombus After Coadministration of Dabigatran Etexilate and Phenytoin.

Dabigatran etexilate is a substrate of the P-glycoprotein (adenosine triphosphate-binding cassette subfamily B member 1) transport system and is subject to interactions with medications that induce or inhibit this system. The clinical relevance of the interaction between dabigatran and phenytoin has not been well described. We report a case of left atrial thrombus in a patient receiving concomitant dabigatran etexilate and phenytoin, which is a P-glycoprotein inducer. This case illustrates the potential clinical significance of the interactions of medications that affect P-glycoprotein and dabigatran.