Multiple-dose escalation,safety, and tolerability study of wood creosote,the principal active ingredient of seirogan,an herbal antidiarrheal medication,in healthy subjects

Seirogan, an herbal medicine containing wood creosote (CAS 8021-39-4), a mixture of simple phenolic compounds, has been marketed for the past century in Asia for the treatment of acute diarrhea and associated symptoms, such as abdominal discomfort and cramping. The present study was designed to assess the safety and tolerability of an anticipated acute antidiarrheal dosing regimen. Sixty healthy males were randomized into five groups of 12 subjects each (9 wood creosote; 3 placebo) to receive 45-, 90-, 135-, 180-, and 225-mg tablets every 2 hours for five doses. Serial sitting and standing vital signs, ECG rhythm strips, and continuous telemetry monitoring were obtained predose and for 24 hours after the first dose. Clinical laboratory tests and 12-lead resting ECGs were obtained predose and 24 hours postdose. Of the subjects, 27% (12/45) receiving wood creosote and 27% (4/15) receiving placebo reported adverse events. The most common adverse events were altered taste and somnolence, reported more often with 180- and 225-mg doses. Wood creosote had no clinically significant effects on vital signs, ECG intervals or interpretations, or clinical laboratory tests. No clinically significant or serious dysrhythmias were reported on continuous telemetry monitoring. It was concluded that oral doses of wood creosote 45 to 225 mg every 2 hours for up to five doses were safe and well tolerated in 45 healthy subjects. Wood creosote doses ranging from 45 to 135 mg per dose, which are commonly administered antidiarrheal doses in Asia, were associated with minimal side effects.     

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

AimsThe immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus.MethodsThree single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova.ResultsSublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration.ConclusionsSublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.     

Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects

An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.     

Development of active safety surveillance system for traditional Chinese medicine: an empirical study in treating climacteric women

PURPOSE: Traditional Chinese medicines (TCM) prescribed by doctors are regularly reimbursed by the National Health Insurance (NHI) in Taiwan. The safety of TCM should undergo the same scrutiny that most western medicines do. This study was to monitor adverse events (AEs) associated with a new mixture of TCM, TMN-1, used to treat climacteric symptoms. METHODS: For this multi-center, prospective observational study, we recruited 134 women with climacteric symptoms. During this 12-week study, the subjects made nine visits, took TMN-1 three times a day, and received routine hematologic tests, biochemical tests, and tests for gynecologically relevant hormones at baseline and after 4 and 12 weeks of beginning medication. At every visit, the subjects were asked by questionnaire about any AEs. All AEs were examined through a process of causality assessment (CA) by a research team. RESULTS: In total, we recorded 203 AEs, in order of decreasing incidences--cough, pharyngitis, rhinitis, abdominal pain, abdominal fullness, diarrhea, and pruritus with incidence rates of 2.57, 2.47, 1.88, 1.78, 1.68, 1.58, and 1.58 per 10(3) person-days, respectively. Most AEs were tolerable. Five of the AEs were judged to be "probable" adverse drug reactions (ADRs): Two events of diarrhea and one event each of nausea, abdominal pain, and abdominal fullness. CONCLUSION: This study demonstrates the effectiveness using active safety surveillance to document safety of TCMs. This surveillance system could probably be useful to document the safety of other alternative or complementary medicines.     

维药家独行菜子的药效学研究

目的 研究维吾尔传统药家独行菜子水浸液对实验性胃溃疡镇痛作用及对小鼠小肠运动的影响.方法 制作小鼠胃溃疡模型,以家独行菜子水浸液灌胃给药,观察实验组和对照组小鼠胃黏膜的溃疡指数,探讨其对胃的保护作用;以炭末推进法观察家独行菜子水浸液对小肠运动的影响并通过离体实验观察其对小鼠小肠平滑肌的作用;以热板法观察家独行菜子水浸液对实验动物的镇痛作用.结果 家独行菜子水浸液对小鼠实验应激性胃溃疡黏膜具有修复作用,小鼠胃溃疡指数从30±10.12下降到22.7±5.54,可减少溃疡出血点(P<0.05);对小肠运动的抑制率为18.54%,拮抗硝酸毛果芸香碱致小肠蠕动振幅的加大,并显著延缓小鼠热刺激的痛反应时间(P<0.01).结论 家独行菜子水浸液具有抗实验性胃溃疡的作用,能促进溃疡愈合、抑制小肠运动,并具有显著的止痛作用.     

First clinical pharmacokinetic dose-escalation study of sagopilone, a novel, fully synthetic epothilone, in Japanese patients with refractory solid tumors

Purpose Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. Methods A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3?weeks (one course) with an initial dose of 12.4?mg/m(2) up to 22.0?mg/m(2) for a maximum of 6 courses. Results The maximum tolerated dose (MTD) was determined to be 16.5?mg/m(2). The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12?weeks. Conclusions Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials.     

Potent inhibition of CYP1A2 by Frutinone A, an active ingredient of the broad spectrum antimicrobial herbal extract from P. fruticosa

Frutinone is an active ingredient extracted from the lipophilic fraction of the Polygala Fruticosa demonstrating various antibacterial and fungal properties. The aim of this study was to characterize its metabolism in an effort to understand metabolism based drug-herb interactions. In vitro metabolic clearance and metabolite identification studies were done using cryopreserved hepatocytes. Reaction phenotyping and inhibition studies were done using human liver microsomes and recombinant cytochrome P450s (CYPs). Frutinone A-CYP1A2 interactions were rationalized using docking simulations. Hepatic clearance was predicted to be low (7.17 mL/min/kg), with reaction phenotyping studies indicating no clearance by the enzymes tested. Frutinone was identified as a potent inhibitor of CYP1A2 with moderate effects on CYP2C19, 2C9, 2D6 and 3A4. CYP1A2 inhibition was reversible and characterised by an IC(50) of 0.56 μM. Inhibition was differential showing mixed (K(i) = 0.48 μM) and competitive (K(i) = 0.31 μM) inhibition with 3-cyano-7-ethoxycoumarin and ethoxyresorufin, respectively. Two binding sites, one for inhibitors and the other for substrates were identified in silico. The potent CYP1A2 inhibition by Frutinone A could be predictive of the potential drug-herb interaction risk in the use of herbal extracts from P. fruticosa. The data suggest future pharmacological research on this chromocoumarin should take metabolic properties into account.     

Validation of a simple bioanalytical method for the determination of DRF-6196, a novel oxazolidinone, in mouse plasma: application to a single-dose pharmacokinetic study

An isocratic simple, specific, sensitive and reproducible high performance liquid chromatography (HPLC) method was developed and validated for the estimation of DRF-6196, a novel oxazolidinone in mouse plasma. This method involves a simple liquid/liquid extraction of DRF-6196 and the internal standard (IS; chlorzoxazone, CAS 95-25-0) from plasma into dichloromethane/ethyl acetate mixture that was evaporated under nitrogen. The HPLC analysis was carried out on an Inertsil ODS 2 column using 0.01 mol/L potassium dihydorgen ortho phosphate (pH 3.2) and acetonitrile (65:35, v/v) as mobile phase. The eluate was monitored using an UV detector set at 266 nm. Ratio of peak area of analyte to IS was used for quantification of plasma samples. The retention time of DRF-6196 and IS were 8.2 and 11.1 min, respectively. The assay was linear (r2 > 0.999) in the concentration range 0.1-50 microg/ml. Absolute recovery for analyte and IS was > 94 % from mouse plasma. The lower limit of quantification (LLOQ) of DRF-6196 was 0.1 microg/ml. The inter- and intra-day precision in the measurement of quality control (QC) samples, 0.1, 0.3, 15.0 and 40.0 microg/ml, were in the range 3.64 to 9.51 % relative standard deviation (RSD) and 0.92 to 6.23 % RSD, respectively. Accuracy in the measurement of QC samples was in the range 88.15 to 106.05 % of the nominal values. The analyte and IS were stable in the stability studies viz., benchtop, autosampler and freeze/thaw cycles. The stability of DRF-6196 was established for 1 month at -80 degrees C. The assay method was successfully applied to a pharmacokinetic study of DRF-6196 in mice.     

Metabolic pathways leading to detoxification of triptolide,a major active component of the herbal medicine Tripterygium wilfordii

Triptolide (TP) shows promising anti‐inflammatory and antitumor activity but with severe toxicity. TP is a natural reactive electrophile containing three epoxide groups, which are usually linked to hepatotoxicity via their ability to covalently bind to cellular macromolecules. In this study, metabolic pathways leading to detoxification of TP were evaluated in glutathione (GSH)‐depleted (treated with L‐buthionine‐S,R‐sulfoxinine, BSO) and aminobenzotriazole (ABT; a non‐specific inhibitor for P450s)‐treated mice. The toxicity of TP in mice was evaluated in terms of mortality and levels of serum alanine transaminase (ALT). In incubates with NADPH‐ and GSH‐supplemented liver microsomes, seven GSH conjugates derived from TP were detected. In mice, these hydrolytically unstable GSH conjugates underwent γ‐glutamyltranspeptidase/dipeptidases‐mediated hydrolysis leading to two major cysteinylglycine conjugates, which underwent further hydrolysis by dipeptidases to form two cysteine conjugates of TP. In ABT‐treated mice, the hydroxylated metabolites of TP were found at a lower level than normal mice, and their subsequent conjugated metabolites were not found. The level of cysteinylglycine and cysteine conjugates derived from NADPH‐independent metabolism increased in mice treated with both TP and BSO (or ABT), which could be the stress response to toxicity of TP. Compared with normal mice, mortality and ALT levels were significantly higher in TP‐treated mice, indicating the toxicity of TP. Pretreatment of ABT increased the toxicity caused by TP, whereas the mortality decreased in GSH‐depleted mice. Metabolism by cytochrome P450 enzymes to less reactive metabolites implied a high potential for detoxification of TP. The GSH conjugation pathway also contributed to TP's detoxification in mice. Copyright © 2013 John Wiley & Sons, Ltd.     

Evaluation of safety and tolerability,pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled,ascending single-dose study

Rationale

BMS-820836, a novel triple monoamine reuptake inhibitor, is an experimental monotherapy for sufferers of major depressive disorder who have had an inadequate response to an existing antidepressant treatment.

Objectives

This study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK), and serotonin transporter (SERT) and dopamine transporter (DAT) occupancy for single doses of BMS-820836 in healthy subjects.

Methods

Healthy subjects were assigned to seven BMS-820836 dose panels (0.025, 0.1, 0.5, 1, 2, 3, and 5 mg; n?=?8 each), in which subjects were randomly allocated 3:1 to a single BMS-820836 dose or matched placebo. Serial blood samples were collected on Days 1, 2, 3, 4, 7, and 14 to characterize the PK of BMS-820836. Following evaluation of the maximum tolerated dose, SERT occupancy was determined by applying [¹¹C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n?=?3 each) and DAT occupancy by applying [¹¹C]PE2I PET after single-dose BMS-820836 (3 mg; n?=?6).

Results

Single oral doses of BMS-820836 (0.025–3 mg) were generally safe and well tolerated. BMS-820836 had a median T _max of 5.0–7.2 h and a mean apparent terminal T _1/2 of 34–57 h. Mean striatal SERT occupancies were 19?±?9 % and 82?±?8 % after single doses of 0.5 and 3 mg BMS-820836, respectively. The mean striatal DAT occupancy was 19?±?9 % after a single 3 mg BMS-820836 dose.

Conclusions

Single doses of BMS-820836 have meaningful SERT and DAT occupancy and demonstrate an acceptable safety and tolerability profile in healthy control subjects.     

Transport and bioavailability studies of astragaloside IV, an active ingredient in Radix Astragali

Astragaloside IV is an important constituent of Radix Astragali, a herbal remedy widely used in traditional Chinese medicine. Radix Astragali is administered orally but little is known about the transport properties and bioavailability of astragaloside IV. In this paper we report studies of the absorption of astragaloside IV in the perfused rat intestinal model, transport and uptake in Caco-2 cell monolayers and in vivo bioavailability in rat after an oral dose. In the perfused rat intestinal model, absorption of astragaloside IV was low from an aqueous solution but was significantly higher from a solution of Radix Astragali. Absorption was not affected by bile duct ligation. Transport through Caco-2 cells gave a very low permeability value (mean P(app) of 6.7+/-1.0 x 10(-8) cm/sec.) and uptake was unaffected by P-glycoprotein inhibitors. The absolute bioavailability of astragaloside IV in rat was 2.2%. The correlation between low permeability in vitro and poor bioavailability in vivo indicates in vitro absorption studies are useful in the evaluation of traditional Chinese medicines.     

Concentrations of mecillinam and ampicillin determined in serum and renal tissue: a single-dose pharmacokinetic study in patients undergoing nephrectomy

A study was carried out to determine serum and renal tissue concentrations of antibiotics after a single intravenous injection of 1.0 g ampicillin plus 0.4 g mecillinam, given up to 4 hours before surgery, in 13 patients with normal or near normal kidney function who were undergoing nephrectomy. Both antibiotics showed higher tissue concentrations than the corresponding serum levels. The mean kidney:serum ratio was 2.4 for ampicillin and 1.4 for mecillinam. Serum half-lives were calculated to be 57 minutes for ampicillin and 52 minutes for mecillinam. Corresponding elimination half-lives in the kidney were 45 minutes and 44 minutes, respectively.