Factors associated to adequate time in therapeutic range with oral vitamin K antagonists in Tunisia.

INTRODUCTION:   The quality of chronic anticoagulation and predictor factors of poor anticoagulant control in patients under acenocoumarol were unknown in North Africa. METHODS: It is an observational study, carried out between November 2015 and November 30, 2016. The international normalized ratio (INR) values were prospectively obtained, and TTR was calculated using the Rosendaal method. RESULTS: Overall, 215 patients were included in this study, with a mean age of 63±0,8 years. The prevalence of poor anticoagulation control was 78.1%; 95% CI [72.2-83.2] (168 patients with TTR less than 65%). The median TTR with the Rosendaal method was 44.4%. After multivariate adjustment, variables significantly associated with adequate anticoagulation level were: history of ischemic stroke (Adjusted OR equal to 4.3, 95% CI: 1.4-12.9), associated prescription of antiplatelet therapy (Adjusted OR equal to 3.5, 95% CI: 1.1-11.2), daily prescribed dose of coumarins less than 6 mg (Adjusted OR equal to 6.4, 95% CI: 1.1- 36) and lower risk of bleeding assessed as HAS-BLED score (Adjusted OR: 0.5, 95% CI: 0.3-0.8). CONCLUSION: The quality of anticoagulation management with VKA among outpatients who received acenocoumarol was suboptimal. Strategies should be undertaken by clinicians and patients to improve the quality of anticoagulation, to address challenges to adverse cardiovascular outcomes in individuals treated with chronic anticoagulation.

LC-MS/MS method for simultaneous determination of ramelteon and its metabolite M-II in human plasma: Application to a clinical pharmacokinetic study in healthy Chinese volunteers.

A sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of ramelteon and its active metabolite M-II in human plasma. After extraction from 200 µL of plasma by protein precipitation, the analytes and internal standard (IS) diazepam were separated on a Hedera ODS-2 (5 µm, 150 × 2.1 mm) column with a mobile phase consisted of methanol-0.1% formic acid in 10 mm ammonium acetate solution (85:15, v/v) delivered at a flow rate of 0.5 mL/min. Mass spectrometric detection was operated in positive multiple reaction monitoring mode. The calibration curves were linear over the concentration range of 0.0500-30.0 ng/mL for ramelteon and 1.00-250 ng/mL for M-II, respectively. This method was successfully applied to a clinical pharmacokinetic study in healthy Chinese volunteers after a single oral administration of ramelteon. The maximum plasma concentration (Cmax ), the time to the Cmax and the elimination half-life for ramelteon were 4.50 ± 4.64ng/mL, 0.8 ± 0.4h and 1.0 ± 0.9 h, respectively, and for M-II were 136 ± 36 ng/mL, 1.1 ± 0.5 h, 2.1 ± 0.4 h, respectively.

Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers.

The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

Effect of ramadan fasting on acenocoumarol-induced antocoagulant effect.

Eating patterns, food intake and type of alimentation vary greatly during the month of ramadan. Furthermore, fasting, which practiced during the month of ramadan, can have an impact on drug's metabolism. These two factors, fasting and eating habits changes during the month of ramadan, may impact acenocoumarol anticoagulant effect, translated by variations of INR values. The aim of our study was to see ramadan fasting effects on INR variations in patients treated by acenocoumarol. A prospective monocentric study was conducted during the ramadan month on fasting outpatients that were treated by acenocoumarol. Baseline INR values (e.i. most recent available value before the month of ramadan) were compared to INR values obtained during the month of ramadan. All patients were monitored for signs of secondary haemorrhagic complications linked to treatment by anti-vitamin K (AVK). Thirty patients were included in the study with a sex ratio 1. Patients mean age was 65 years. Around two thirds of the patients were treated by AVK for atrial fibrillation. The majority of patients (94%) have been treated by AVK for more than a year. Mean INR was significantly higher during the month of ramadan than baseline (3.51 vs 2.52; p< 0.0001). There were also more overdoses during the month of ramadan than baseline (9 vs. 0; p=0.014). The increased INR values highlights the need of a close monitoring of INR values during the month of ramadan, particularly in patients with a high haemorrhagic risk.

Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.

Disposition of the Highly Fat Distributed Compound 1-(4-Methoxyphenyl)-4-(2,2,4,6,7-Pentamethyl -2,3-Dihydro-1-Benzofuran-5-yl)Piperazine (TAK-357) in Rats and Dogs.

The non-clinical pharmacokinetics (PK) of TAK-357, a highly lipophilic (clogP>6) potential agent for the amelioration of Alzheimer's disease, was investigated in rats and dogs. A long half-life (t1/2) in plasma was observed in animals and a low total body clearance with high distribution volume was consistent with the long t1/2. The absorption, distribution, metabolism and excretion (ADME) studies using radiolabeled TAK-357 revealed that the total radioactivity was highly distributed to the adipose tissues and sustained with high concentration for over 4 weeks after oral administration. The metabolite analysis also revealed that the main component in the plasma and adipose tissues was unchanged TAK-357. The major elimination route of absorbed TAK-357 was suggested to be by metabolism. An ADME study indicated that the adipose tissue is the main depot of remaining TAK-357 in the body and slow release from the adipose tissues contributes to the long t1/2. The PK of highly lipophilic compounds have a tendency to be affected by body weight changes especially changes in the adipose tissues. Therefore, it is considered that the relationship between the plasma levels of TAK-357 and the body weight should be evaluated carefully during the clinical trials.

Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants.

Co-administration of fluvoxamine (FLV) (perpetrator) and ramelteon (victim, high-clearance CYP1A2 substrate) reportedly showed a 130-fold increase in the area under blood-ramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional well-stirred hepatic extraction (Eh ) model. Thus, in order to predict this drug interaction (DDI), a mathematical method that allows simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tools, was derived using hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI could be simulated in comparison with other victim DDIs, assuming a consistent FLV dosing regimen. Despite large differences in AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki , around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki s estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in blood perpetrator levels were demonstrated to have a small effect on DDI, thus suggesting the usefulness of a tube-based static method for DDI prediction.

Pharmacokinetic and pharmacodynamic evaluation of ramelteon : an insomnia therapy.

INTRODUCTION: Ramelteon , a selective melatonin receptor agonist, is the first member of a novel class of hypnotics. It is approved for the treatment of insomnia characterized by sleep onset difficulties in the US and Japan, but not in Europe. AREAS COVERED: The main clinical properties as well as safety issues of ramelteon are described. Relevant publications reporting ramelteon characteristics and its use in insomnia disorder were identified using PubMed and SciFinder databases up to January 2015. Additional information was collected from the US clinical trials database and from Takeda website. EXPERT OPINION: Despite its high prevalence and economic burden, insomnia disorder remains mostly untreated. Ramelteon has demonstrated sleep-promoting effects in clinical trials and clinical practice, and it is not associated with the adverse effects typical of other class of hypnotics. Its efficacy appears to be relatively modest compared to current insomnia therapeutics, and its use seems restricted to patients with sleep onset difficulties. Assessment of ramelteon effects on sleep quality and maintenance, daytime function and of improvements in comorbid insomnia conditions deserves further studies. The potential application of ramelteon in other pathological conditions could open the way to novel therapeutic approaches as well as to new market opportunities.

A global quality control system to check PT-INR portable monitor for Antivitamin K antagonists.

INTRODUCTION: Although most guidelines for quality assessment of INR PMs recommend specific procedures, no clear regulation or methodology is required for outpatients in our country. We have developed a specific INR portable monitor (PM) quality control system within our telemedicine organization to check over time quality performances and plan corrective actions. METHODS: Based on current guidelines for laboratory QC, the following aspects were assessed: suitability of PM, defined in terms of imprecision and accuracy; intra-assay imprecision, defined according to monthly revision of Levey-Jennings cards with data from each peripheral healthcare unit (PHU), using an internal QC provided by the manufacturer (CV ± 20% considered as acceptable); quarterly accuracy study, for assessing agreement between analytical instruments, based on duplicate analysis of three samples with INR values reflecting different therapeutic ranges (differences ± 0.5 considered as acceptable); external quality assessment (NEQAS). RESULTS: In the nine PHU, 18 portable monitors were used to perform 22 929 test during year 2010. Analytical imprecision was low, showing CVs always <5%. Accuracy check showed two of 216 results out of range (0.92%), thus providing timely indication for instrument replacement. The external QC NEQAS showed optimal performance. CONCLUSION: The current protocol for INR PMs quality assessment was effective to establish and maintain a reliable control of devices, ensuring the quality of analytical data over time. National authorities should be prompted to guarantee and apply correct protocols for INR-PM use.

JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease.

Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.

The anxiolytic effects of a Valerian extract is based on valerenic acid.

BACKGROUND: Valerian is commonly used for the treatment of insomnia and anxiety. Valerian extracts allosterically modulate GABA-A receptors and induced an anxiolytic activity. This activity is closely related to valerenic acid. In the present experiments it was investigated whether acetoxy valerenic acid may interfere with the anxiolytic action of valerenic acid. METHODS: Situational anxiety was measured using male CD-1 mice in the elevated plus maze test after oral administration of the test substances. In addition the body core temperature was measured. For the 3H-GABA binding assay dissected tissue from frontal cortex of male RjHan:WI rats were used. Statistical evaluation was performed by means of the non-parametric Kruskal-Wallies H-test, followed by the two-tailed Mann-Whitney U-test. RESULTS: Adding of acetoxy valerenic acid abolished the anxiolytic action of valerenic acid. There was no effect on body core temperature. Moreover, the valerian extract did not show any affinity to benzodiazepine binding sites. CONCLUSION: The determining compound for the observed anxiolytic effect of the valerian extract is its content of valerenic acid.

LC-MS-based method for the qualitative and quantitative analysis of the novel PPARγ agonist KR-62980.

A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for a novel peroxisome proliferator-activated receptor γ (PPARγ) agonist, KR-62980, in rat plasma. It involves liquid-liquid extraction (LLE) followed by HPLC separation and electrospray ionization tandem mass spectrometry. The linear ranges of the assay were 0.01-10 µg/mL with a correlation coefficient (R (2)) greater than 0.99 and the lower limit of quantification was 0.01 µg/mL. The average recovery was 90.1 and 98.4% from rat plasma for KR-62980 and imipramine, respectively. The coefficients of variation of intra- and inter-assay were 1.2-10.6% and the relative error was 0.8-13.2%. The method was validated and successfully applied to the pharmacokinetic study of KR-62980 in rat.

Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one.

6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.

Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0879 and its metabolite in dog plasma using solid phase extraction.

A liquid-chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0879 and its ketone metabolite (M1) in dog plasma to support preclinical toxicokinetic evaluation. The method consisted of solid phase extraction for sample preparation and LC-MS/MS analysis in positive ion mode using electrospray ionization for analysis. D(4)-GDC-0879 and (13)C(2)-D(2)-M1 were used as internal standards. A quadratic regression (weighted 1/concentration(2)) was used to fit calibration curves over the concentration range of 1-1000 ng/ml for both GDC-0879 and M1. The accuracy (%bias) at the lower limit of quantitation (LLOQ) was 12.0% and 2.0% for GDC-0879 and M1, respectively. The precision (%CV) for samples at the LLOQ was 11.3% and 2.6% for GDC-0879 and M1, respectively. For quality control samples at 3.00, 400 and 800 ng/ml, the between run %CV was ≤3.9% for GDC-0879 and ≤2.4% for M1. Between run %bias ranged from 4.6 to 12.0% for GDC-0879 and from -0.8 to 2.7% for M1. GDC-0879 and M1 were stable in dog plasma for at least 44 days at -70 °C.

Pharmacokinetics of valerenic acid in rats after intravenous and oral administrations.

Valerenic acid (VA), a sesquiterpenoid, is one of the major secondary bioactive metabolites of VALERIANA OFFICINALIS L. Until now IN VIVO studies on the absorption, bioavailability, disposition, and metabolism of VA are limited. We established and validated an LC-MS/MS assay for the determination of VA in rat plasma and successfully used this method for pharmacokinetic studies in rats after intravenous (i. v.) and oral administrations. The plasma concentration-time data was analyzed by both non-compartmental and compartmental approaches using WinNonlin software. Following i. v. administration, the disposition of VA in rat plasma was biphasic, subdivided into a fast distribution and a slow elimination phase. The half-life of the distribution phase was 6-12 min, and that of the terminal elimination phase 6-46 h, indicating a possible large tissue binding. Disposition PK of valerenic acid after oral treatment was also described by a two-compartment model with a clearance (CL/F) of 2-5 L · h (-1) · kg (-1) and volume of distribution of (V (d)) 17-20 L · kg (-1). The extent of absorption (F) after oral administration was estimated to be 33.70 % with a half-life of 2.7-5 h. Dose proportionality was observed in terms of dose and AUCs, suggesting linear pharmacokinetics at the dose levels studied in rats.

Design and characterization of optimized adenosine A2A/A1 receptor antagonists for the treatment of Parkinson's disease.

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia.

The aim of this study was to evaluate the efficacy and safety of ramelteon 4, 8, 16 or 32 mg and placebo in Japanese patients with chronic insomnia using a randomized, double-blind, five-period crossover design. A total of 65 Japanese patients with chronic primary insomnia received ramelteon or placebo for two nights each in sleep laboratories. Changes in sleep parameters were assessed objectively by polysomnography and subjectively by postsleep questionnaires. Safety and tolerability was evaluated by assessment of the occurrence of adverse events, next-day residual effects and laboratory and ECG investigations. Ramelteon 8 and 32 mg significantly shortened the mean latency to persistent sleep in comparison with placebo, and there was a statistically significant trend for linear dose-response for this sleep parameter. Overall changes in sleep architecture were modest (<3% changes vs placebo), with increases in stage 1 and decreases in stage 3/4. Ramelteon was well tolerated, the most common adverse effect being somnolence, which was similar to placebo at doses up to 8 mg, but increased with higher doses. Next-day residual effects occurred no more frequently with ramelteon at any dose than with placebo. When compared with sleep latency data from a similarly-designed US study, there was no evidence of any ethnic differences in the efficacy of ramelteon between Japanese and US patients. Overall, ramelteon 8 mg showed the most favorable balance between sleep-promoting effects and tolerability. The unique efficacy profile of ramelteon, promoting sleep initiation without affecting other sleep parameters, may be due to its circadian shifting effect.

Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6.

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.

Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT(2C) agonists for the treatment of metabolic disorders.

The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.