Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles.

CONTEXT: As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. OBJECTIVE: The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. MATERIALS AND METHODS: The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. RESULTS: The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5-91.58% and 94.98-99.67%, while for ACT-333679 were 81.21-93.90% and 93.17-99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in Cmax and AUC0-t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. DISCUSSION AND CONCLUSION: The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

Fabrication of Ligusticum chuanxiong polylactic acid microspheres: A promising way to enhance the hepatoprotective effect on bioactive ingredients.

Ligusticum chuanxiong extract-polylactic acid sustained-release microspheres (LCE-PLA) are fabricated in this study for enhancing both duration and hepatoprotective efficacy of the main bioactive ingredients. LCE-PLA in vitro release, cytotoxicity and in vivo hepatoprotective effect were discussed to evaluate its efficiency and functionality. Results demonstrated that the optimal drug-loading rate and encapsulation efficiency of tetramethylpyrazine (TMP, the main active ingredient) were 8.19%, 83.72%, respectively. The LCE-PLA in vitro release of TMP showed prolong 5-fold and in vitro cytotoxicity declined 25.00% compared with naked LCE. After 6 weeks of in vivo intervention in high fat diet mice, both liver aspartate aminotransferase and alanine aminotransferase levels were higher in LCE-PLA group than LCE group. The above results indicated that TMP had a higher bioavailability of hepatoprotection when encapsulation of LCE-PLA was applied. The current study has provided a promising novel way to enhance the efficacy of short half-life ingredients.

Pharmacokinetic comparative study of tetramethylpyrazine and ferulic acid and their compatibility with different concentration of gastrodin and gastrodigenin on blood-stasis migraine model by blood-brain microdialysis method.

Tianma pills, a traditional formula made from Ligusticum chuanxiong and Gastrodia elata, are efficacious for the treatment of primary headache. Tetramethylpyrazine (TMP) and Ferulic acid (FA) are the bioactive ingredients of Ligusticum chuanxiong, while Gastrodin and Gastrodigenin are the bioactive ingredients of Gastrodia elata. Pharmacokinetic assessment of TMP, FA, gastrodin or gastrodigenin in blood or brain interstitial fluid (BIF) has been reported in healthy animals. However, the pharmacokinetic properties of TMP and FA have not been studied when they are co-administered in a blood-stasis migraine model. The present research investigated the pharmacokinetic behavior of TMP and FA after oral administration in the presence of different concentrations of gastrodin and gastrodigenin in a blood-stasis migraine model. Pharmacokinetic parameters were determined using blood-brain microdialysis in combination with the UHPLC-MS method. Compared to the control group, in which TMP and FA were administrated without gastrodin or gastrodigenin, the T1/2, MRT, Cmax and AUC0-∞ of TMP and FA were increased. These results indicate that varying concentrations of gastrodin and gastrodigenin play an important role in affecting the pharmacokinetics of TMP and FA. Low concentrations of gastrodin and gastrodigenin (similar to those found in Tianma pills) were more efficacious, validating the utility of the ancient formulation.

Systems pharmacology-based approach for dissecting the mechanisms of pyrazine components in Maotai liquor.

Maotai liquor is a typical representative of sauce aroma-style flavor liquors and has been considered to be a precious cultural heritage of the oriental spirit culture. Aroma components are largely responsible for the characteristic aroma of liquor. Pyrazine compound is one of the most important categories of aroma components that affect the flavor of Maotai liquor. However, limited information is available regarding the systemic analysis of pyrazine compounds, especially the pharmacological effects of bioactive pyrazine components. Therefore, in the current study, a systemic analysis approach was provided by integrating absorption, distribution, metabolism, and excretion (ADME) screening, target identification, pharmacological evaluation and pathway analysis to explore the pharmacological mechanism of pyrazine compounds in Maotai liquor. As a result, 17 pyrazine components with adequate pharmacokinetic properties were filtered out using ADME models. Thirty eight potential targets of these active compounds were identified through target prediction. The pharmacological evaluation was proposed to uncover the pharmacological effect of pyrazine compounds in Maotai liquor from the holistic perspective. Finally, the pharmacological effects of the pathways perturbed by potential targets were interpreted based on the pathway analysis. Our study lays the foundation for formulating a comprehensive understanding of the pyrazine compounds in Maotai liquor, which would contribute to the development of Chinese liquor.

Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor.

Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical methods. Pharmacodynamic studies for evaluating cMet inhibition and anti-tumor efficacy were conducted in nude mice bearing Hs746t xenograft. PK/PD models were built to link the PD measurements to nude mouse PK. The established integrated preclinical PK/PD model contained a two-compartment non-linear PK model, a biomarker link model and a tumor growth transit model. The IC50 of cMet inhibition and the concentration achieving half of the maximal Hs746t tumor reduction by savolitinib were equal to 12.5 and 3.7 nM (free drug), respectively. Based on the predicted human PK data, as well as the established PK/PD model in nude mouse, the human PD (cMet inhibition) profiles were also simulated. This research supported clinical development of savolitinib. Understanding the preclinical PK/PD relationship of savolitinib provides translational insights into the cMet-targeted drug development.

Alkylpyrazines from Coffee are Extensively Metabolized to Pyrazine Carboxylic Acids in the Human Body.

SCOPE: Coffee is a complex mixture of over 1000 compounds, including diverse heteroaromatic compounds such as alkylpyrazines. Little is known about the intake, metabolism, and bodily distribution of these compounds. Therefore, a human intervention study is conducted to investigate the excretion of alkylpyrazine metabolites in urine after the ingestion of brewed coffee containing alkylpyrazines. METHODS AND RESULTS: After consuming a diet without heat-processed food, ten volunteers consumed 500 mL of freshly brewed coffee prepared from coffee pads, providing intakes of 2-methylpyrazine (2-MeP), 2,5-dimethylpyrazine (2,5-DMeP), and 2,6-dimethylpyrazine (2,6-DMeP) amounting to 17.2, 4.4, and 4.9 µmol, respectively. These alkylpyrazines are metabolized into the corresponding pyrazine carboxylic acids, namely pyrazine-2-carboxylic acid (PA), 5-hydroxypyrazine-2-carboxylic acid (5-OHPA), 5-methylpyrazine-2-carboxylic acid (5-MePA), and 6-methylpyrazine-2-carboxylic acid (6-MePA). In total, 64% of the ingested 2-MeP is excreted as PA, as well as 26% as 5-OHPA, while 91% and 97% of the ingested 2,5-DMeP and 2,6-DMeP are recovered as 5-MePA and 6-MePA, respectively, in urine samples collected after coffee consumption. CONCLUSION: This study provides evidence that alkylpyrazines are rapidly metabolized into the corresponding carboxylic acids and excreted via urine by humans, which is consistent with earlier rodent studies.

Pharmacokinetic behaviors of ligustrazine after single- and multiple-dose intravenous Shenxiong glucose injection in rats by high-performance liquid chromatography.

Shenxiong glucose injection (SXG) is a traditional Chinese medicine that is used for cardio-cerebral vascular diseases on the national essential drug list of China. To date, a comprehensive knowledge concerning the pharmacokinetic profile of SXG-related components, especially following multiple dosing, is still lacking. This study was designed to investigate the pharmacokinetics and tissue distribution of ligustrazine after single- and multiple-dose intravenous administration of SXG in rats. A simple HPLC method was developed for the determination of ligustrazine in biological samples. The pharmacokinetic profiles of ligustrazine in rats were linear after both single- and multiple-dose intravenous administration of SXG, with a half-life of approximately 35 min. Ligustrazine was readily distributed in highly perfused organs and almost eliminated from organs after 90 min of SXG injection. The AUC0-t and C0 of ligustrazine after SXG injection (18 ml/kg, equal to 9.0 mg/kg ligustrazine) were increased significantly compared to those of single ligustrazine administration (9.0 mg/kg), indicating that the pharmacokinetics of ligustrazine in the SXG were affected by other ingredients. This study provided first evidence for the pharmacokinetic characteristics of ligustrazine after both single and multiple-dose SXG in rats, which would be helpful for its clinical application.

Acalabrutinib and its use in treatment of chronic lymphocytic leukemia.

Acalabrutinib received an accelerated US FDA approval for patients with relapsed/refractory mantle cell lymphoma in 2017 and is currently being evaluated in chronic lymphocytic leukemia (CLL). To date, ibrutinib is the only Bruton tyrosine kinase (BTK) inhibitor that's approved for treatment of CLL. Acalabrutinib is a second generation BTK inhibitor that binds covalently to the Cys481 residue on BTK and has half maximal inhibitory concentration (IC50) of 3 nM. In preclinical mouse models, acalabrutinib significantly reduced proliferation of CLL cells. Results of Phase I/II trials revealed overall response rates (ORR) of 96% in treatment-naive, 93% in relapsed/refractory and 76% in ibrutinib intolerant patients with CLL. The most common adverse effects (>20%) were grade 1-2 comprising constitutional symptoms, GI toxicity, rash and myelosuppression. There were limited grade 3 or 4 toxicities, involving syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.

Pharmacokinetics and bioequivalence study of tetramethylpyrazine phosphate tablets after single-dose administration in healthy Chinese male subjects
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BACKGROUND: Tetramethylpyrazine, isolated from Ligusticum wallichii Franch., is widely used for the treatment of cerebrovascular and cardiovascular diseases in China. OBJECTIVE: To assess and compare the pharmacokinetic characteristics and bioequivalence of two tetramethylpyrazine phosphate (TMPP) tablets in healthy Chinese male subjects. MATERIALS AND METHODS: 20 healthy male subjects were randomly divided into two groups according to a two-period crossover design test. A single oral dose of 200 mg test or reference tablets was given with a 7-day washout period under fasting conditions. Blood samples were taken at scheduled time points, and the concentration of TMPP was measured by LC-MS. Drug And Statistical Software-Version 2.0 was used to calculate the pharmacokinetic parameters and assess bioequivalence of the two formulations. RESULTS: 20 subjects were enrolled in the study, and none dropped out. The main pharmacokinetic parameters of test and reference formulations were as follows: T1/2 was (1.79 ± 0.82) hours and (1.64 ± 0.52) hours, tmax was (0.76 ± 0.37) hours and (0.94 ± 0.44) hours, Cmax was (961.14 ± 309.64) ng/mL and (1,059.09 ± 350.69) ng/mL, AUC0-12h was (1,744.69 ± 643.49) ng×h/mL and (1,726.32 ± 494.11) ng×h/mL, AUC0-∞ was (1,756.95 ± 643.63) ng×h/mL and (1,740.16 ± 504.89) ng×h/mL, respectively. The relative bioavailability of TMPP tablets was 102.4 ± 26.0%, and no serious adverse events were reported. CONCLUSION: This single-dose study in healthy Chinese male fasted subjects showed that the TMPP test and reference tablets were bioequivalent.
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Application of TQSM polypharmacokinetics and its similarity approach to ascertain Q-marker by analyses of transitivity in vivo of five candidates in Buyanghuanwu injection.

BACKGROUND: It is well-known that the public still have been facing on a severe issue about the inconsistency of quality and therapeutic efficacy of traditional medicines. Recently, Professor Chang-Xiao Liu has created a new promising concept for identifying relevant quality-markers (Q-marker) from herbs, their formulas and manufacturing products. Therefore, building up a new approach is necessary for us to bridge over quality to efficacy of pharmaceutical products. STUDY DESIGN: In this paper, five candidate Q-markers, astragaloside IV, paeonflorin, amygdalin, tetramethylpyrazine, ferulic acid in Buyanghuanwu injection (BYHWI) had been designed to carry out in rat by using single and polypharmacokinetic models for total quanta to ascertain adequate Q-marker. METHODS: The Q-marker transitivity in vivo was studied with polypharmacokinetic model and its similarity approach, which were modeled with TQSM principle. The Q-marker was ascertained with transitive similarity and bioavailability in polypharmacokinetics. Their concentrations in plasma sample of white rat were determined by RP-HPLC. Data analyses were used by the DAS software for singles and myself-written-program with EXCEL for multiples. RESULTS: In BYHWI, five candidate Q-marker pharmacokinetic profiles were singly fixed to two compartmental models in rat using classical compartmental analysis, but there were tremendous differences among which the candidate parameters were fluctuated from nearly 3552 folds to equivalency. The theoretical value of TQSM polypharmacokinetic parameters such as AUCT, MRTT, VRTT, CLT, VT over the mixure of five drugs were 110.8 ±â€¯51.91 mg min ml-1, 176.0 ±â€¯36.5 min, 39,921 ±â€¯4311 min2, 0.3116 ±â€¯0.02347 ml min-1 kg-1, 54.83 ±â€¯7.683 ml kg-1 respectively. The TQSM polypharmacokinetic parameters in astragaloside Ⅳ ordered by AUCT, MRTT, VRTT, CLT, VT were 110.8 ±â€¯51.91 mg min ml-1, 176.0 ±â€¯36.5 min, 39,921 ±â€¯4311 min2, 0.3116 ±â€¯0.02347 ml min-1 kg-1, 54.83 ±â€¯7.683 ml kg-1, respectively, which were closed to the theoretical values. TQSM similarity versus astragaloside Ⅳ was 0.9661. CONCLUSION: The results represented that the optimum Q-marker in BYHWI is astragaloside Ⅳ, whose transitivity in vivo similarity was close to the behavior of polypharmacokinetics with maximum bioavailability to the total quanta. It is feasible for Q-marker in CMMs to screen on the comparison of single pharmacokinetic behavior and bioavailability to the total quanta.

An UHPLC-MS/MS method for simultaneous determination of quercetin 3-O-rutinoside, kaempferol 3-O-rutinoside, isorhamnetin 3-O-rutinoside, bilobalide and ligustrazine in rat plasma, and its application to pharmacokinetic study of Xingxiong injection.

The present study was designed to develop and validate a rapid, sensitive, and reliable ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of five major active constituents in the traditional Chinese medicinal preparation Xingxiong injection (XXI) in rat plasma, including quercetin 3-O-rutinoside (QCR), kaempferol 3-O-rutinoside (KFR), isorhamnetin 3-O-rutinoside (ISR), bilobalide (BB), and ligustrazine (LGT). The plasma samples were pretreated by protein precipitation with acetonitrile. The chromatographic separation was achieved on a Waters Symmetry C18 analytical column (2.1 mm × 100 mm, 3.5 µm) with a mobile phase of 0.1% aqueous formic acid (A)-acetonitrile (B). Quantitation of the five bioactive constituents was achieved. Naringin was used as the internal standard (IS). All the calibration curves showed good linearity (r > 0.996) over the concentration range, with the lowest limit of quantification (LLOQ) between 2-18 ng·mL-1. The intra- and inter-day accuracy and precision of the analytes were both within acceptable limits. Moreover, satisfactory extraction recoveries (90.92%-104.03%) were obtained by protein precipitation. The validated method was successfully applied to a pharmacokinetic study of XXI in rats after intravenous administration at three doses. The pharmacokinetic parameters of the five compounds varied in a dose-dependent manner within the tested dosage range. The present study was the first report of pharmacokinetic study for XXI.

Effect of ferulic acid on the brain pharmacokinetics of tetramethylpyrazine in conscious rats.

1. In traditional Chinese medicine, Angelica sinensis is often coprescribed with Ligusticum chuanxiong Hort for the treatment of ischemic cerebrovascular diseases. Tetramethylpyrazine (TMP) is one of the most important active ingredients isolated from Ligusticum chuanxiong Hort; ferulic acid (FA) is the main water-soluble component of Angelica sinensis. 2. The purpose of this study is to investigate the possible effect of FA on the brain pharmacokinetics of TMP in conscious Sprague-Dawley rats. The pharmacokinetic parameters of TMP were investigated in brain microdialysates after oral and intravenous administration of TMP (4 mg/kg) to rats in the absence and presence of FA (5 mg/kg). Samples were collected at timed intervals for the measurement of TMP by a rapid and sensitive UPLC-MS/MS method. 3. The pharmacokinetic parameters were calculated by noncompartmental analysis for brain microdialysates. The brain pharmacokinetic data for TMP showed significant increases in Cmax, t1/2, AUC0-inf and MRT0-inf after combination with FA. After intragastric administration with FA, there were significant decreases in the Tmax (from 38.33 ± 5.77 to 21 ± 5.48 min; p < 0.01) of TMP. This study indicated that potential drug-drug interaction between TMP and FA should be taken into consideration and the combined administration is beneficial in improving the bioavailability of TMP in the brain.

Pharmacokinetic drug evaluation of selexipag for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy. Areas covered: This review discusses the limitations of non-oral prostacyclin therapy for PAH and describes the factors which led to successful development of selexipag in in vitro and preclinical studies. We review the pharmacokinetics and pharmacodynamics of selexipag. We further discuss the methodology and results of phase II and III trials, which led to approval of selexipag for PAH management. Expert opinion: As compared to previously developed oral prostacyclins, selexipag has limited adverse effects despite similar or better efficacy. Its final place in the treatment paradigm is not yet clear but it does represent a significant advance in the area of oral PAH therapy.

Pharmacokinetic comparative study of gastrodin after oral administration of Gastrodia elata Bl. extract and its compatibility with the different indigents of Ligusticum chuanxiong Hort. to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Da Chuan Xiong Decoction Compound preparation (DCXDCP) is a classic TCM formula of an aqueous extract made from Chuanxiong Rhizoma (Ligusticum chuanxiong Hort., umbelliferae) and Tianma Rhizoma (Gastrodia elata Bl., Orchidaceae). Gastrodin (GAS), a bioactive component of tianma, its pharmacokinetic (PK) behavior significantly changed after oral administration of DCXDCP compared with the extract of tianma. However, little is known about how the ingredients of chuanxiong influenced on the PK of GAS. AIM OF THE STUDY: To study the possible PK behavior differences of GAS after individually oral administration of tianma extract and tianma extract mixed with different active ingredients of chuanxiong to rats, as well as explore whether there were some herb-herb interactions. MATERIALS AND METHODS: Different DCXDCP suspensions were prepared by mixing tianma extract with different active ingredients of chuanxiong. The rats were randomly assigned to six groups and were orally treated with different DCXDCP. At different predetermined time points after administration, the concentrations of GAS in the rat plasma were determined using HPLC, and the main PK parameters were investigated. RESULTS: The results showed that tetramethylpyrazine had no significant effects on the PK parameters of GAS (p>0.05), whereas ferulic acid (FA), total phenolic acids and total alkaloids significantly increased AUC0-∞ (p<0.05). In general the observed changes in the PK parameters of GAS in DCXDCP could be closely related to the total phenolic acids and total alkaloids. CONCLUSION: It could be shown that total phenolic acids and total alkaloids present in Ligusticum chuanxiong in addition to other components not tested yet play an important role in affecting the PK of gastrodin in DCXDCP.

Cardiovascular Actions and Therapeutic Potential of Tetramethylpyrazine (Active Component Isolated from Rhizoma Chuanxiong): Roles and Mechanisms.

Tetramethylpyrazine (TMP), a pharmacologically active component isolated from the rhizome of the Chinese herb Rhizoma Chuanxiong (Chuanxiong), has been clinically used in China and Southeast Asian countries for the prevention and treatment of cardiovascular diseases (CVDs) for about fifty years. The pharmacological effects of TMP on the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TMP prevents atherosclerosis as well as ischemia-reperfusion injury. The cardioprotective effects of TMP are mainly related to its antioxidant, anti-inflammatory, or calcium-homeostasis effects. This review focuses on the roles and mechanisms of action of TMP in the cardiovascular system and provides a novel perspective on TMP's clinical use.

[Pharmacokinetics and brain distribution of NMD/TMP-nanoparticles].

This study aims to prepare nimodipine/tetramethylpyrazine-loaded poly(D, L-lactide-co-glycolide) dual-drug nanoparticles (NMD/TMP-NPs) and investigate pharmacokinetics and brain distribution to evaluate the possibility of enhancing the drug effect of dual-drug nanoparticles. NMD/TMP-NPs were prepared via W/O/W emulsion solvent evaporation. Entrapment efficiency and drug loading of NMD/TMP-NPs were investigated by ultracentrifugation, and drug release behavior in vitro was studied by dialysis method. The pharmacokinetic and brain distribution were studied in SD mice administered intravenously with NMD/TMP-NPs in comparison with NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension. According to the results, the entrapment efficiency and drug loading of NMD were (79.71±0.73)%, (1.74±0.02)%, those of TMP were (40.26±1.51)% and (4.38±0.16)%. The nanoparticles showed the property of sustained release. On the basis of the major parameters for in vivo pharmacokinetic and brain distribution, t1/2ß of NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension, NMD/TMP-NPs were (1.097±0.146), (1.055±0.06), (1.950±0.140), (1.860±0.096), (2.497±0.475） h, CL were (0.778±0.098), (1.133±0.111), (0.247±0.023), (0.497±0.040), (0.297±0.024) h•L-1, AUC0-t in rat plasma were (514.218±60.383), (352.916±33.691), (1 618.429±240.198), (804.110±75.804), (1 349.058±215.497) µg•h•L⁻¹, respectively, and AUC0-t in brain were 0.301 9, 0.624 8, 1.068 6, 1.313 0, 1.046 5 mg•h•L⁻¹, respectively. According to the in vivo study, the pharmacokinetic behavior of NMD were markedly prolonged by adding TMP or prepared dual-drug nanoparticles.

3-(1'-Cyclobutylspiro[4H-1,3-benzodioxine-2,4'-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one (CEP-32215), a new wake-promoting histamine H3 antagonist/inverse agonist.

CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.

Discovery of a novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series promoting neurogenesis of human neural progenitor cells.

A novel neurogenic compound (1), discovered from a mouse neural progenitor cell (NPC) screen, showed profound neurogenic effect on human NPCs. Synthesis and SAR of this novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series are described. Compound 20 is brain penetrable in rodents, and promotes neurogenesis in wild type mice, therefore it is a good tool molecule to study neurogenesis induction as a potential treatment for conditions associated with neurogenesis impairment diseases.

Pharmacokinetics and metabolism of Chf197, a ligustrazine derivative, in rats.

Ligustrazine is the most abundant and bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular diseases. Chf197 is one of the structurally modified ligustrazine derivatives in a purpose of overcoming the rapid metabolism and short half-life of original. The plasma and urine pharmacokinetics of Chf197 in rats were studied after intravenous or intraperitoneal injection of Chf197 with the validated RP-HPLC method. The pharmacokinetic parameters of Chf197 injected intravenously 20 mg/kg were as follows: Cmax , 1.44 ± 0.4 mg/L; Tmax , 0.08 h; t1/2 , 3.03 ± 1.67 h; AUC, 3.85 ± 3.88 h/L; Vd , 31.66 ± 11.79L/kg; and CL, 9.29 ± 4.92 l/h/kg. Dose-dependent pharmacokinetics was observed, and a significantly higher dose-normalized AUC after intravenous administration was obtained than that after intraperitoneal administration. A possible metabolite was detected at about 3.1 min, and full-scan mass spectrum was adopted to predict its possible structure.