Comparative Pharmacokinetics and Safety Studies of Dexibuprofen Injection and a Branded Product Ibuprofen Injection in Healthy Chinese Volunteers.

Ibuprofen, a nonsteroidal anti-inflammatory drug, is considered a safe and effective analgesic for treating different types of pain and joint disorders. Dexibuprofen, S-(+)-ibuprofen, is the single pharmacologically active enantiomer of ibuprofen. It is more potent than the racemic formulation of ibuprofen in terms of analgesic and anti-inflammatory properties and causes less acute gastric damage. For the first time, in the present single-dose, randomized, open-label, 2-period crossover study, the safety and pharmacokinetic (PK) characteristics of a single-dose dexibuprofen injection (0.2 g) were evaluated in healthy Chinese subjects and compared with the PK characteristics of a 0.2-g ibuprofen injection. Five consecutive men and women were randomly administered a single dose of the 0.2-g ibuprofen or 0.2-g dexibuprofen injection after fasting in every period during the 5-day interval. Then, plasma samples were collected for liquid chromatography-tandem mass spectrometric analysis. WinNonlin software was used for calculating the PK parameters. The geometric mean ratios of the 0.2-g dexibuprofen injection/ibuprofen injection for maximal plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable time point, and AUC from time 0 to infinity were 184.6%, 136.9%, and 134.4%, respectively. The dexibuprofen plasma exposure of the 0.15-g dexibuprofen injection was comparable to that of the 0.2-g ibuprofen injection, calculated using AUC from time 0 to infinity.

Comparative effect of ciprofloxacin and moxifloxacin on the modulation of bile acid profiles and gut microbiota in rats

Abstract Fluoroquinolones are an important class of antimicrobial agents to manage infectious diseases. However, knowledge about how host bile acids are modified by fluoroquinolones is limited. We investigated and compared the impact of fluoroquinolones on circulating bile acid profiles and gut microbiota from in vivo studies. We administered ciprofloxacin (100 mg/kg/day) or moxifloxacin (40 mg/kg/day) orally to male Wistar rats for seven days. Fifteen bile acids (BAs) from the serum and large intestine were quantified by HPLC-MS/MS. The diversity of gut microbiota after ciprofloxacin and moxifloxacin treatment was analyzed using high-throughput, next-generation sequencing technology. The two fluoroquinolone-treated groups had different BA profiles. Ciprofloxacin significantly reduced the hydrophobicity index of the BA pool, reduced secondary BAs, and increased taurine-conjugated primary BAs in both the serum and large intestine as compared with moxifloxacin. Besides, ciprofloxacin treatment altered intestinal microbiota with a remarkable increase in Firmicutes to Bacteroidetes ratio, while moxifloxacin exerted no effect. What we found suggests that different fluoroquinolones have a distinct effect on the host BAs metabolism and intestinal bacteria, and therefore provide guidance on the selection of fluoroquinolones to treat infectious diseases.

Pharmacokinetics, Pharmacodynamics, and Safety of a Single Escalating Dose and Repeated Doses of Rasagiline Transdermal Patch in Healthy Chinese Subjects.

A rasagiline transdermal patch can be used to offer continuous rasagiline to patients with Parkinson's disease who cannot take their usual oral medications. This was the first study to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects. Thirty subjects were randomized to 3 groups with 10 subjects in each group. The 10 subjects of group 1 received a single 1-mg dose of rasagiline as a tablet; the 20 subjects of groups 2 and 3 received a single transdermal patch (48-hour patch-on period) containing 1.25 mg and 2.5 mg rasagiline, respectively. After a 2-week washout period, the subjects of group 1 were assigned to receive 1 mg of rasagiline tablets every 24 hours for 7 days, and the subjects of group 2 were assigned to receive 1.25-mg rasagiline transdermal patches (48-hour patch-on period) every 72 hours for 5 time periods. The absorption of rasagiline from the transdermal patch was significantly improved, although the peak plasma concentration was obviously reduced. There was slight accumulation of rasagiline dose after multiple administrations. Inhibition of platelet monoamine oxidase-B (MAO-B) activity was dose dependent. The 80% inhibition maintained for at least 48 hours after multiple-dose administration of 1 mg tablets, and for 72 hours after multiple-dose administration of 1.25 mg/48 h patch. Compared with rasagiline tablets, the transdermal patch had a prolonged duration of 80% inhibition and increased maximal inhibition of MAO-B activity. These characteristics permitted an interval of 3 days of dosing, which was convenient for patients to use.

The effect of food intake on the pk of rhein released from diacerein

Diacerein is a symptomatic slow-acting drug used for treating osteoarthritis. This drug is completely metabolized into the active metabolite rhein before reaching the systemic circulation. This study evaluated the effects of food on the pharmacokinetics of rhein released from diacerein in healthy Chinese subjects. This was a single-center, randomized, single-dose, open-label, two-period, cross-over study. Twenty-four healthy subjects were randomly selected to receive a single oral dose of 50 mg diacerein capsule in either fasted or fed state on two separate visits. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters were calculated using WinNonlin software. In the fasted and fed states, the main pharmacokinetic parameters of diacerein capsule were as follows: Cmax were (4471 ± 936), (3225 ± 755) ng/mL, t1/2 were (4.22 ± 0.42), (4.19 ± 1.05) h, tmax were (2.61 ± 1.25), (3.81 ± 1.29) h, AUC0-24 h were (24223 ± 4895), (24316 ± 5856) h·ng/mL, and AUC0-∞ were (24743 ± 5046), (25170 ± 6415) h·ng/mL. The absorption rate of diacerein capsule was obviously delayed by food intake but the absorption degree remained unaffected.

Pharmacokinetics and Safety of Levetiracetam Extended-Release Tablets and Relative Bioavailability Compared with Immediate-Release Tablets in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended-release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses. METHODS: Two panels of 34 healthy subjects were enrolled. Trial 1 was a two-way crossover between levetiracetam ER tablets and immediate-release (IR) tablets under fasting conditions. Trial 2 was a four-way crossover single-dose study between levetiracetam ER fasted and ER with food. RESULTS: Intake of single and multiple levetiracetam ER tablets resulted in a 42.3% lower maximum plasma concentration (Cmax) and a 33.6% lower minimum steady-state plasma concentration (Css min) than IR tablet intake, while the median time to Cmax (tmax) was significantly delayed. The 90% CI of the ER/IR ratios for area under the curve (AUC) from zero to last measurable sample (AUC0-t), AUC from zero to infinity (AUC0-∞), AUC at steady state (AUCss, τ = 24 h), Cmax at steady state (Css max) and average concentration at steady state (Css av) were contained within the 80-125% range of bioequivalence. The Cmax and AUC were dose proportional across the dose cohorts. Following a high-fat meal, levetiracetam ER tablets resulted in a 14.4% higher Cmax. The 90% confidence interval (CIs) of the fed/fasted ratios for Cmax and AUC were entirely contained within the 80-125% range of bioequivalence acceptance, except the tmax was delayed (P < 0.05). The most frequent treatment-emergent adverse events were somnolence, dizziness and thirst. CONCLUSIONS: After single and multiple doses, the absorption of levetiracetam ER was equal to IR, the tmax was significantly delayed, and the Cmax and Css min were significantly decreased. Food did not affect the absorption of the levetiracetam ER tablet, but the Cmax increased and the tmax was delayed. The levetiracetam ER tablet was well tolerated and found to be dose proportional from 500 to 2000 mg in healthy Chinese subjects.

Pharmacokinetics, Pharmacodynamics, and Safety of Rasagiline Transdermal Patch: A Preliminary Study in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Rasagiline tablet is an oral MAO-B inhibitor applied in early or advanced Parkinson's disease (PD). However, when patients with PD cannot take their usual oral medications, a rasagiline transdermal patch can be used as a way to offer continuous rasagiline while avoiding plasma concentration peaks and troughs. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in 15 healthy subjects. Fasted subjects received a single dose of rasagiline (either by transdermal patch-1.25 mg/24 h, 1.25 mg/48 h, 2.5 mg/48 h, or 2.5 mg/72 h, or orally-in the form of a 1-mg tablet) and were monitored over a 168-h observation period to assess pharmacokinetics, pharmacodynamics, and safety. RESULTS: After administration of a single-dose rasagiline transdermal patch, the mean terminal elimination half-life (t 1/2) was 6.06-9.41 h, which was longer than with the 1-mg tablet dose (2.32 ± 0.28 h). The mean dose-normalized maximum plasma concentration (C max,norm(dose)) of the 1-mg tablet dose was twofold higher than that of the transdermal patch groups. The mean dose-normalized areas under the concentration-time curve (AUCnorm(dose)) of 1.25 and 2.5 mg for the rasagiline transdermal patch doses were fourfold and sevenfold higher than that of the 1-mg tablet dose, respectively. Cumulative urinary excretion was about 0.2% of the total dose. Inhibition of MAO-B activity was dose dependent, and the maximal inhibition was 73.9-94.1% at doses ranging from 1.25 to 2.5 mg. The reported adverse events were mild or moderate. CONCLUSION: The prolonged t 1/2, increased AUC0-t , and more stable plasma drug concentration of the rasagiline patch may permit a longer dosing interval compared to the oral tablet. The rasagiline transdermal patch was safe and well tolerated in healthy Chinese subjects.

Pharmacokinetics and safety of repirinast tablets in healthy Chinese subjects

ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects.

Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways.

Our previous studies revealed that berberine-mediated GLP-1 secretion was a possible mechanism for berberine exerting good effects on hyperglycemia. This study was designed to ascertain whether berberine-induced secretion of GLP-1 was related with activation of bitter taste receptors expressed in gastrointestinal tract. Western blotting results showed that TAS2R38, a subtype of bitter taste receptor, was expressed on human enteroendocrine NCI-H716 cells. GLP-1 secretion induced by berberine from NCI-H716 cells was inhibited by incubation with anti-TAS2R38 antibody. We further performed gene silencing using siRNA to knockdown TAS2R38 from NCI-H716 cells, which showed that siRNA knockdown of the TAS2R38 reduced berberine-mediated GLP-1 secretion. We adopted inhibitors of PLC and TRPM5 known to be involved in bitter taste transduction to investigate the underlying pathways mediated in berberine-induced GLP-1 secretion. It was found that PLC inhibitor U73122 inhibited berberine-induced GLP-1 release in NCI-H716 cells, while TRPM5 blocker quinine failed to attenuate berberine-induced secretion of GLP-1. The present results demonstrated that berberine stimulated GLP-1 secretion via activation of gut-expressed bitter taste receptors in a PLC-dependent manner. Because berberine was found to be a ligand of bitter taste receptor, the results of present study may provide an explanation for some bitter taste substance obtain hypoglycemic effect.