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Objective: While the pathogenesis of sudden sensorineural hearing loss is thought to be localised to the cochlea, recent microRNA findings suggest a neuro-topic localisation in some patients. This study distinguishes if neural and non-neural groups differ in hearing recovery., Methods: Neural-type hearing loss was defined as a presenting word recognition score less than 60 per cent, with a word recognition score reduction greater than 20 per cent than expected based on the averaged pure tone audiometry. Hearing recovery was defined as an improvement of greater than or equal to 10 decibels in pure tone audiometric thresholds., Results: Eight of 12 and 24 of 36 of neural and non-neural hearing loss patients demonstrated hearing recovery, respectively. The affected ear's word recognition score (per cent) change with treatment were different between the neural and non-neural groups (46.9 ± 29.8 vs 3.2 ± 25.8 ( p < 0.0001))., Conclusion: The hearing recovery rate in neural and non-neural hearing loss groups was similar. Patients with neural-type hearing loss demonstrated greater word recognition score recovery post treatment than those in the sensory group.

Despite significant progress achieved in artificial self-sorting in solution, operating self-sorting in the body remains a considerable challenge. Here, we report an in vivo self-sorting peptide system via an in situ assembly evolution for combined cancer therapy. The peptide E3C16-SS-EIY consists of two disulfide-connected segments, E3C16SH and SHEIY , capable of independent assembly into twisted or flat nanoribbons. While E3C16-SS-EIY assembles into nanorods, exposure to glutathione (GSH) leads to the conversion of the peptide into E3C16SH and SHEIY , thus promoting in situ evolution from the nanorods into self-sorted nanoribbons. Furthermore, incorporation of two ligand moieties targeting antiapoptotic protein XIAP and organellar endoplasmic reticulum (ER) into the self-sorted nanoribbons allows for simultaneous inhibition of XIAP and accumulation surrounding ER. This leads to the cytotoxicity toward the cancer cells with elevated GSH levels, through activating caspase-dependent apoptosis and inducing ER dysfunction. In vivo self-sorting of E3C16-SS-EIY decorated with ligand moieties is thoroughly validated by tissue studies. Tumor-bearing mouse experiments confirm the therapeutic efficacy of the self-sorted assemblies for inhibiting tumor growth, with excellent biosafety. Our findings demonstrate an efficient approach to develop in vivo self-sorting systems and thereby facilitating in situ formulation of biomedical agents.

Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a β-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via β-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing β-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future., (© 2024 Wiley-VCH GmbH.)

Background/purpose(s): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation., Methods: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples., Results: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA., Conclusion: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies., (© 2024. The Author(s).)

In order to reveal the influence of urban transportation systems on the quality of urban ecological environment, this study selected surface dust from bus stops, which is strongly disturbed by transportation, as the research object. The contents of eight heavy metals (V, Cr, Co, Ni, Cu, Zn, Cd, and Pb) in the dust were determined through inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectroscopy (ICP-ASE). The spatial distribution characteristics and pollution levels of the eight heavy metals in the dust were analyzed using the geo-accumulation index method. A combined qualitative (correlation analysis and principal component analysis) and quantitative (absolute principal component scores-multiple linear regression model (APCS-MLR)) method was used to explore the sources of heavy metals in surface dust near bus stops. The spatial distribution characteristics of heavy metals from different sources were elucidated using the Kriging interpolation method. The health risk assessment model proposed by the United States Environmental Protection Agency was used to evaluate the human health risks. The results showed that the average values of ω (V), ω (Cr), ω (Co), ω (Ni), ω (Cu), ω (Zn), ω (Cd), ω (Pb), and ω (As) in the bus stop surface dust were 68.36, 59.73, 5.81, 19.34, 40.10, 208.32, 1.01, and 49.46 mg·kg -1 , respectively. The concentrations of heavy metals (Cd, Zn, Pb, Cu, and Cr) in the dust were all higher than the background values in the surrounding dust, exceeding them by 3.37, 2.70, 2.01, 1.95, and 1.28 times, respectively. The order of the geo-accumulation index for the eight heavy metals was Cd &gt; Zn &gt; Pb &gt; Cu &gt; Cr &gt; V &gt; Ni &gt; Co, with Cd, Zn, Cu, and Pb in the dust indicating mild pollution levels and the others showing no pollution. The source analysis results showed that Cr, Co, and Ni were natural sources, whereas Cu, Zn, Pb, and Cd were traffic sources, and V was derived from a combination of industrial and natural sources. The APCS-MLR results indicated that the average contribution rates of the four sources were as follows:natural source (34.17 %), traffic source (29.84 %), industrial-natural mixed source (14.64 %), and unknown source (21.35 %). The spatial distribution map of the contribution rate of the traffic source was consistent with the trends of traffic volume and bus route density distribution. According to the health risk assessment, the cancer risk and non-cancer risk for children were both higher than those for adults. Cr was the main non-cancer factor, and Cd was the main cancer-causing factor. Natural and traffic sources contributed the most to non-cancer risk and cancer risk, respectively.

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.

Morphology-transformational self-assembly of peptides allows for manipulation of the performance of nanostructures and thereby advancing the development of biomaterials. Acceleration of the morphological transformation process under a biological microenvironment is important to efficiently implement the tailored functions in living systems. Herein, we report redox-regulated in situ seed-induced assembly of peptides via design of two co-assembled bola-amphiphiles serving as a redox-resistant seed and a redox-responsive assembly monomer, respectively. Both of the peptides are able to independently assemble into nanoribbons, while the seed monomer exhibits stronger assembling propensity. The redox-responsive monomer undergoes morphological transformation from well-defined nanoribbons to nanoparticles. Kinetics studies validate the role of the assembled inert monomer as the seeds in accelerating the assembly of the redox-responsive monomer. Alternative addition of oxidants and reductants into the co-assembled monomers promotes the redox-regulated assembly of the peptides facilitated by the in situ-formed seeds. The reduction-induced assembly of the peptide could also be accelerated by in situ-formed seeds in cancer cells with a high level of reductants. Our findings demonstrate that through precisely manipulating the assembling propensity of co-assembled monomers, the in situ seed-induced assembly of peptides could be achieved. Combining the rapid assembly kinetics of the seed-induced assembly with the common presence of redox agents in a biological microenvironment, this strategy potentially offers a new method for developing biomedical materials in living systems.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, and several studies have evaluated the efficacy of extracellular vesicles (EVs) in the treatment of IVDD. The databases PubMed, Embase, and Cochrane Library were systematically searched from inception to the end of 2022 to identify studies investigating the therapeutic potential of cell-derived EVs for IVDD treatment. The following outcome measures were utilized: magnetic resonance imaging (MRI) Pfirrmann grading system, disc height index (DHI), histological grading, and apoptosis rate. A comprehensive meta-analysis was conducted, including a total of 13 articles comprising 19 studies involving 218 experimental animals. Comparative analysis between normal cell-derived EVs and placebo revealed significant reductions in MRI grade, increased DHI values, decreased nucleus pulposus cell apoptosis rates, and improved tissue grades. These findings collectively demonstrate the effective inhibition of IVDD through the application of EVs derived from cells. In conclusion, this study provides an updated synthesis of evidence supporting the efficacy of EVs as a promising therapeutic approach for IVDD treatment.

The presence of disordered region or large interacting surface within proteins significantly challenges the development of targeted drugs, commonly known as the "undruggable" issue. Here, we report a heterogeneous peptide-protein assembling strategy to selectively phosphorylate proteins, thereby activating the necroptotic signaling pathway and promoting cell necroptosis. Inspired by the structures of natural necrosomes formed by receptor interacting protein kinases (RIPK) 1 and 3, the kinase-biomimetic peptides are rationally designed by incorporating natural or D -amino acids, or connecting D -amino acids in a retro-inverso (DRI) manner, leading to one RIPK3-biomimetic peptide PR3 and three RIPK1-biomimetic peptides. Individual peptides undergo self-assembly into nanofibrils, whereas mixing RIPK1-biomimetic peptides with PR3 accelerates and enhances assembly of PR3. In particular, RIPK1-biomimetic peptide DRI-PR1 exhibits reliable binding affinity with protein RIPK3, resulting in specific cytotoxicity to colon cancer cells that overexpress RIPK3. Mechanistic studies reveal the increased phosphorylation of RIPK3 induced by RIPK1-biomimetic peptides, elucidating the activation of the necroptotic signaling pathway responsible for cell death without an obvious increase in secretion of inflammatory cytokines. Our findings highlight the potential of peptide-protein hybrid aggregation as a promising approach to address the "undruggable" issue and provide alternative strategies for overcoming cancer resistance in the future., (© 2023 Wiley-VCH GmbH.)

Most microbiome studies regarding the ruminant digestive tract have focused on the rumen microbiota, whereas only a few studies were performed on investigating the gut microbiota of ruminants, which limits our understanding of this important component. Herein, the gut microbiota of 30 Caprinae animals (sheep and goats) from six provinces in China was characterized using ultradeep (>100 Gbp per sample) metagenome shotgun sequencing. An inventory of Caprinae gut microbial species containing 5,046 metagenomic assembly genomes (MAGs) was constructed. Particularly, 2,530 of the genomes belonged to uncultured candidate species. These genomes largely expanded the genomic repository of the current microbes in the Caprinae gut. Several enzymes and biosynthetic gene clusters encoded by these Caprinae gut species were identified. In summary, our study extends the gut microbiota characteristics of Caprinae and provides a basis for future studies on animal production and animal health. IMPORTANCE We constructed a microbiota catalog containing 5,046 MAGs from Caprinae gut from six regions of China. Most of the MAGs do not overlap known databases and appear to be potentially new species. We also characterized the functional spectrum of these MAGs and analyzed the differences between different regions. Our study enriches the understanding of taxonomic, functional, and metabolic diversity of Caprinae gut microbiota. We are confident that the manuscript will be of utmost interest to a wide range of readers and be widely applied in future research.

Objective: External ventricular drainage (EVD) catheters are associated with complications such as EVD catheter infection (ECI), intracranial hemorrhage (ICH), and suboptimal placement. The aim of this study was to investigate the rates of EVD catheter complications and their associated risk factor profiles in order to optimize the safety and accuracy of catheter insertion., Methods: A total of 348 patients with urgently placed EVD catheters were included as a part of a prospective multicenter observational cohort. Strict definitions were applied for each complication category., Results: The rates of misplacement, ECI/ventriculitis, and ICH were 38.6%, 12.2%, and 9.2%, respectively. Catheter misplacement was associated with midline shift (p = 0.002), operator experience (p = 0.031), and intracranial length (p < 0.001). Although mostly asymptomatic, ICH occurred more often in patients receiving prophylactic low-molecular-weight heparin (LMWH) (p = 0.002) and those who required catheter replacement (p = 0.026). Infectious complications (ECI/ventriculitis and suspected ECI) occurred more commonly in patients whose catheters were inserted at the bedside (p = 0.004) and those with smaller incisions (≤ 1 cm) (p < 0.001). ECI/ventriculitis was not associated with preinsertion antibiotic prophylaxis (p = 0.421), catheter replacement (p = 0.118), and catheter tunneling length (p = 0.782)., Conclusions: EVD-associated complications are common. These results suggest that the operating room setting can help reduce the risk of infection, but not the use of preoperative antibiotic prophylaxis. Although EVD-related ICH was associated with LMWH prophylaxis for deep vein thrombosis, there were no significant clinical manifestations in the majority of patients. Catheter misplacement was associated with operator level of training and midline shift. Information from this multicenter prospective cohort can be utilized to increase the safety profile of this common neurosurgical procedure.

Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK] 2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC 50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy., (© 2021 Wiley-VCH GmbH.)

Purpose of Review: The triquetrum is the second most commonly fractured carpal bone, comprising 15-18% of all carpal bone fractures. This review summarizes the current knowledge of triquetral fractures, including the anatomy and pathophysiology, evaluation and diagnosis, treatment and management, post-treatment outcomes, and complications., Recent Findings: Triquetral fractures are frequently caused by impaction of the ulnar wrist after a fall on an outstretched hand or by avulsion of attached ligaments. There are three main types of triquetral fractures: dorsal cortical fractures, triquetral body fractures, and volar cortical fractures. Dorsal cortical fractures are the most common and are usually benign, while volar cortical fractures are the least common and can be problematic. Nonsurgical management is indicated for most triquetral fractures, which usually results in good outcomes. Surgical treatment is indicated for fractures with significant displacement or evidence of instability. Complications of triquetral fractures include non-union, triangular fibrocartilage complex injury, and pisotriquetral arthritis. While less common than scaphoid fractures, triquetral fractures should remain in the differential diagnosis for patients with ulnar-sided wrist pain after falling on an outstretched hand. Most triquetral fractures can be treated with immobilization, though they should be thoroughly evaluated due to their potential to result in instability, loss of motion, and arthrosis. Further research is needed to determine the best method of surgical treatment.

Peptides have shown great potential in cancer treatment due to their good biocompatibility and low toxicity. However, the bioavailability and adverse immune response of peptides limit their further translation from bench to bedside. Over the past few decades, various peptide-based nanomaterials have been developed for drug delivery and cancer treatment. Compared with therapeutic peptides alone, self-assembled peptide nanomaterials have obvious advantages, such as improved stability and biodistribution for high-performance cancer therapy. In this review, we have described the synthesis, self-assembly and the anti-cancer application of therapeutic peptides and their conjugates, particularly polymer-peptide conjugates (PPCs).

Objective: To analysis the change of brain functional activity in the left and right peripheral facial paralysis by using resting-state functional magnetic resonance imaging (R-fMRI) of fraction amplitude of low frequency fluctuation(fALFF) measurement technique, and research the abnormal brain region with different side patients whether there are differences. Methods: A total of 43 patients with peripheral facial paralysis patients (patient groups, divided into left / right two subgroups) and 21 healthy volunteers (control group) in this study.Resting-state fMRI were acquired for each volunteer and patient. The fALFF approach was used to compare the peripheral facial paralysis groups to healthy group.Functional analysis was performed with brain function analysis software REST and DPARSFA , and then analysis the difference of two groups of patients and control group in two sample t test.At the same time, the correlation analysis between fALFF parameters map of the left and right side of two groups of patients and corresponding facial nerve grading TFGS score.Ultimately obtain a statistically significant brain regions. Results: Compared to healthy group, the decreased fALFF areas in the left side facial paralysis were showed in the right superior temporal gyrus , the pole of the right temporal, right middle temporal gyrus, the left occipital gyrus, and left medial cingulate gyrus, left paracentral lobule, and the left supplementary motor area; while the increased brain regions have the right superior frontal gyrus, right middle frontal gyrus, the right precentral gyrus, bilateral inferior temporal gyrus and middle temporal gyrus.Compared to healthy group, the decreased fALFF areas in the right side facial paralysis were showed in the right inferior temporal gyrus and fusiform gyrus, the left inferior occipital gyrus, the left superior parietalgyrus, the left inferior parietalgyrus, left precuneus, left paracentral lobule, the left supplementary motor area; while the increased brain regions have the left Calcarine, right lingual gyrus, corpus callosum, right medial cingulum gyrus.In the left facial paralysis group TFGS score was positively correlated with brain regions have left middle frontal gyrus, left precuneus and left cuneus, while the negatively related brain area on the right lingual gyrus.In the right facial paralysis groups TFGS score was positively correlated with brain areas have right inferior temporal gyrus and middle temporal gyrus, left inferior parietalgyrus; while the negatively correlated brain area on the left superior temporal gyrus, the right medial frontal gyrus. Conclusion: The left and right side facial paralysis patient's mood and motor function integration mechanism may be different, and the patient's emotional and psychological changes may be associated with disease severity.

Hearing loss is the third leading cause of human disability. Age-related hearing loss, one type of acquired sensorineural hearing loss, is largely responsible for this escalating global health burden. Noise-induced, ototoxic, and idiopathic sudden sensorineural are other less common types of acquired hearing loss. The etiology of these conditions is complex and multi-factorial involving an interplay of genetic and environmental factors. Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss. Short non-coding RNA sequences known as microRNAs (miRNAs) have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response. Sensory hair cell death is a central histopathological finding in sensorineural hearing loss. As these cells do not regenerate in humans, it underlies the irreversibility of human age-related hearing loss. Ovid EMBASE, Ovid MEDLINE, Web of Science Core Collection, and ClinicalTrials.gov databases over the period August 1, 2018 to July 31, 2023 were searched with "hearing loss," "hypoxamiRs," "hypoxia," "microRNAs," "ischemia," and "oxidative stress" text words for English language primary study publications or registered clinical trials. Registered clinical trials known to the senior author were also assessed. A total of 222 studies were thus identified. After excluding duplicates, editorials, retractions, secondary research studies, and non-English language articles, 39 primary studies and clinical trials underwent full-text screening. This resulted in 11 animal, in vitro , and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review. MiRNAs miR-34a and miR-29b levels increase with age in mice. These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator-1-alpha (SIRT1/PGC-1α), SIRT1/p53, and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis. Furthermore, hypoxia and oxidative stress had a similar adverse apoptotic effect, which was inhibited by resveratrol and a myocardial inhibitor-associated transcript, a miR-29b competing endogenous mRNA. Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice - an effect that was corrected by inner ear stem cell-derived exosomes. There is ongoing work seeking to determine if these findings can be effectively translated to humans., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Background. Quaternary structures of proteins are closely relevant to gene regulation, signal transduction, and many other biological functions of proteins. In the current study, a new method based on protein-conserved motif composition in block format for feature extraction is proposed, which is termed block composition. Results. The protein quaternary assembly states prediction system which combines blocks with functional domain composition, called QuaBingo, is constructed by three layers of classifiers that can categorize quaternary structural attributes of monomer, homooligomer, and heterooligomer. The building of the first layer classifier uses support vector machines (SVM) based on blocks and functional domains of proteins, and the second layer SVM was utilized to process the outputs of the first layer. Finally, the result is determined by the Random Forest of the third layer. We compared the effectiveness of the combination of block composition, functional domain composition, and pseudoamino acid composition of the model. In the 11 kinds of functional protein families, QuaBingo is 23% of Matthews Correlation Coefficient (MCC) higher than the existing prediction system. The results also revealed the biological characterization of the top five block compositions. Conclusions. QuaBingo provides better predictive ability for predicting the quaternary structural attributes of proteins.

Many respiration-related interneurons and motoneurons receive a catecholaminergic input, but the extent and distribution of this input to recurrent laryngeal motoneurons that innervate intrinsic muscles of the larynx are not clear. In the present study, we examined the catecholaminergic input to expiratory laryngeal motoneurons in the caudal nucleus ambiguus by combining intracellular labeling of single identified motoneurons, with immunohistochemistry to reveal tyrosine hydroxylase immunoreactive (catecholaminergic) terminal varicosities. Close appositions were found between the two structures, with 18 ± 5 close appositions per motoneuron (n = 7). Close appositions were more frequently observed on distal rather than proximal dendrites. Axosomatic appositions were not seen. In order to determine the source of this input, microinjections of cholera toxin B subunit (1%, 20 nl) were made into the caudal nucleus ambiguus. Retrogradely labeled neurons, located in the ipsilateral nucleus tractus solitarius and the area postrema, were tyrosine hydroxylase-positive. Our results not only demonstrate details of the extent and distribution of potential catecholamine inputs to the expiratory laryngeal motoneuron, but further indicate that the inputs, at least in part, originate from the dorsomedial medulla, providing a potential anatomical basis for previously reported catecholaminergic effects on the laryngeal adductor reflex., (© 2014 Wiley Periodicals, Inc.)

Littoral cell tumors are unique to the spleen and are different from all other primary splenic tumors. These tumors may be divided into three types: "littoral cell angioma," "littoral cell hemangioendothelioma," and "littoral cell angiosarcoma." We present a patient with splenic littoral cell hemangioendothlioma accompanied by hepatic metastases., (Copyright © 2014 Wiley Periodicals, Inc.)

To investigate the pharmacokinetic characteristics of icariside II after a single oral dose administration of YiGu Capsule in healthy -Chinese volunteers. 8 (4 female) healthy Chinese volunteers were involved and administrated for 15 doses of YiGu Capsule after fasting overnight. 4 ml of blood samples were collected at scheduled time before and after administration. Icariside II in human plasma was separated on a Agela Venusil XBP-C18 column (250 mm×4.6 mm, 5 μm), and eluted using acetonitrile-water (containing 0.1% formic acid) (70:30, V/V) as mobile phase. The analytes were detected with a -triple quad HPLC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring mode were m/z 515.1 (precursor ion) to m/z 369.1 (product ion) for icariside II and m/z 321.0 (precursor ion) to m/z 275.0 (product ion) for lorazepam (internal standard).The plasma concentration of icariside II was determined by established HPLC-MS/MS method after disposition and its pharmacokinetic parameters were analyzed and evaluated by PK Solver Software (version 1.0). The Cmax, Tmax, t1/2, AUC0-24, AUC0-∞, MRT0-∞-1, 2.50±1.91 h, 7.61±2.81 h, 12.68±4.86 ng · mL-1 · h, 14.22±5.75 ng · mL-1 · h, 9.55±1.56 h, 12.81±7.94 L · h-1 and 121.70±32.70 L. The established HPLC-MS/MS method was sensitive, selective and rapid for icariside II pharmacokinetic study., (© Georg Thieme Verlag KG Stuttgart · New York.)

This study was designed to investigate the effect and mechanism of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction in rats. Fifty male Wistar rats were randomly divided into five groups: the normal control rats (NC), the high-methionine-diet rats (Met), the high-methionine-diet rats treated with folic acid, vitaminB₆ and vitaminB₁₂ (Met+F), or with low-dose allicin (Met+L), or with high-dose allicin (Met+H). After 6 weeks, we collected blood samples of all groups to determine plasma endothelin (ET), serum homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and detected the expression of basic fibroblast growth factors (bFGF), transforming growth factor beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in the aorta. The Hcy and the expression of TGF-β in both the Met+L and Met+H groups were significantly lower than the Met and Met+F groups. The ET, ET/NO ratio and the MDA levels of the Met+L and Met+H groups were significantly lower than the Met group. The SOD and NO levels and the expression of bFGF, TNF-α and ICAM-1 of the Met+L and Met+H groups were significantly higher than the Met group. Our data indicate that allicin inhibits lipid peroxidation induced by hyperhomocysteinemia and regulates the excretion and equilibrium of ET and NO, and suggest that allicin might be useful in the prevention of endothelial dysfunction caused by hyperhomocysteinemia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To assess the bioequivalence of a new generic formulation of misoprostol (CAS 59122-46-2) 0.2 mg tablets (test) and the available branded tablet (reference) for the requirement of state regulatory criteria and the marketing of the test product in China., Methods: A randomized-sequence, 2-period crossover study was conducted in 20 healthy Chinese female volunteers in the fasted state. Blood samples were collected at baseline and 0.083, 0.17, 0.25, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4 and 6 h after a single oral dose of 0.6 mg misoprostol test or reference, followed by a 7-day washout period. Misoprostol acid, the active metabolite of misoprostol, was determined by an HPLC-MS/MS method. Drug And Statistics 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the 2 formulations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Tmax, Cmax and AUC0-t were all within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports., Results: The main pharmacokinetics parameters for the test and reference were as follows: t1/2 was (0.680 ± 0.371) h and (0.650 ± 0.264) h; Tmax was (0.415 ± 0.087) h and (0.399 ± 0.097) h; Cmax was (1.941 ± 0.417) ng/mL and (2.047 ± 0.397) ng/mL; AUC0-t was (1.535 ± 0.419) ng·h/mL and (1.652 ± 0.400)ng·h/mL, and the AUC0-∞ was (1.576 ± 0.465) ng·h/mL and (1.686 ± 0.396) ng·h/mL. The mean ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 95.3% ±13.2%, 92.65% ± 17.31%, and 93.61%±18.97%, respectively. No significant (p>0.05) differences in pharmacokinetic parameters were found between preparations, treatments and periods., Conclusions: This single-dose study in healthy Chinese fasted volunteers was shown that the misoprostol test and reference met the requirement of US and China regulatory criterion, and the test and reference were bioequivalent., (© Georg Thieme Verlag KG Stuttgart · New York.)

The aim of this study is to establish an HPLC method for simultaneous determinations of mifepristone and its metabolites, mono-demethylated mifepristone, di-demethylated mifepristone and C-hydroxylated mifepristone in plasma and to evaluate the pharmacokinetic characteristics of mifepristone tablet. Twenty healthy female Chinese subjects were recruited and a series of blood samples were collected before and after 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0, 24.0, 48.0, 72.0 and 96.0 hours administration by a single oral dose of 75 mg mifepristone tablet. Mifepristone and its three metabolites were extracted from plasma using ethyl acetate and determined by high performance liquid chromatography. The main pharmacokinetic parameters of mifepristone and its metabolites, including Cmax, tmax, MRT, t(1/2), V, CL, AUC(0-96 h) and AUC(0-infinity), were calculated by Drug and Statistical Software Version 2.0. The simple, accurate and stable method allows the sensitive determinations of mifepristone and its metabolites in human plasma up to 4 days after oral administration of 75 mg mifepristone tablet and the clinical applications of their pharmacokinetic studies.

Substance P (SP), tyrosine hydroxylase (TH) and serotonin inputs onto laryngeal motoneurons (LMNs) are known to exist, but the distribution of their terminals in the caudal nucleus ambiguus (NA), remains unclear. Using immunofluorescence and confocal microscopy, we assessed simultaneously the distribution of SP, TH, serotonin and synaptophysin immunoreactive (ir) terminals in the caudal NA. SP, TH and serotonin-ir varicosities were considered to represent immunoreactive synapses if, using confocal microscopy, they were co-localized with the presynaptic protein, synaptophysin. Relative to the total number of synapses, we found only a modest number of SP, TH or serotonin-ir synaptic terminals in the caudal NA. The density of SP-ir synaptic terminals was higher than that of TH-ir and serotonin-ir synaptic terminals. Our results suggest that SP, TH, and serotonin-ir inputs may play only a modest role in regulating the activity of LMN. We conclude that SP, TH and serotonin are not always co-localized in terminals forming inputs with LMN and that they arise from separate subpopulations of neurons., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a chronic pain condition characterized by pain during joint use as well as pain at rest (i.e., ongoing pain). Although injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well established model of OA pain that is characterized by changes in weight bearing and hypersensitivity to tactile and thermal stimuli, it is not known if this procedure elicits ongoing pain. Further, the time-course and possible underlying mechanisms of these components of pain remain poorly understood. In these studies, we demonstrated the presence of ongoing pain in addition to changes in weight bearing and evoked hypersensitivity. Twenty-eight days following MIA injection, spinal clonidine blocked changes in weight bearing and thermal hypersensitivity and produced place preference indicating that MIA induces ongoing and evoked pain. These findings demonstrate the presence of ongoing pain in this model that is present at a late-time point after MIA allowing for mechanistic investigation., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The study aimed to compare and evaluate the bioequivalence of Calcigard-10 softgel and Adalat 10 capsule in healthy Chinese volunteers in a randomized, two-way cross over study design with a washout period of 7 days. A sensitive and reproducible electro-spray ionization liquid chromatography-mass spectrometry (ESI-LCMS) assay was developed and validated to determine nifedipine in human plasma using nitrendipine as internal standard. Nifedipine and nitrendipine were extracted from plasma using liquid-liquid extraction with methylene chloride as extraction solvent. The separation was performed by a Diamonsil ODS column (150 x 4.6 mm, 5 microm). The mobile phase was consisted of acetonitrile-5 mM ammonium acetate (52:48, v/v), delivered at flow rate of 1 mL/min. The 90% confidence intervals for the ratio values of logarithmic transformed Cmax and AUC were calculated to evaluate the bioequivalence of two preparations. The values of Cmax (92.3-112.7%), AUC0-t (84.5-95.1%) and AUC0-inf (84.4-95.5%) are within the interval criterion of 70-143% for Cmax and 80-125% for AUC. The Calcigard-10 softgel and Adalat 10 capsule are bioequivalent.

Novel organic cation transporter-2 (OCTN2), a member of the organic cation transporter family, may transport carnitine and multiple organic cationic drugs. Thus OCTN2 possesses substantial roles in physiology and pharmacology. A number of researches have proven that many factors can regulate the expression and/or function of OCTN2 via different pathways, and then may affect the homeostasis and disposition of drugs. This paper reviews recent progresses in this field.

A remarkably large species difference in cinchonidine oxidation activity catalyzed by aldehyde oxidase (AO) has been known, in particular between rabbit and monkey. As the first step in clarifying the phenomenon from the view point of structures of the active site, we attempted to construct an expression system of rabbit AO cDNA. The nucleotide sequences of cloned full-length rabbit AO cDNA were determined and confirmed to agree completely with those of genome DNA. The expression system in Escherichia coli was constructed in reference to the previously established method for monkey AO. Both expressed rabbit and monkey AO proteins correctly reproduced the remarkable species differences observed in their liver cytosols towards cinchonidine and methotrexate. Namely, the expressed rabbit AO protein showed extremely high activities than did that of monkey AO. A difference in the structure of the active site might be responsible for the substrate-dependent species difference towards the relatively bulky molecules of cinchonidine and methotrexate. The use of molecular biology techniques will be very useful to verify the hypothesis.

We developed and validated a sensitive and low sample volume liquid chromatographic-mass spectrometric (LC-MS) method for determination of Promethazine hydrochloride in human plasma (0.5 ml) or urine (0.1 ml). The lower limit of quantification in human plasma and urine was 1.00 ng/ml. The inter- and intra-day precisions (CV %) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations were more than 97%. The developed method was successfully applied to determine Promethazine hydrochloride in human plasma and urine, and proved suitable to clinical pharmacokinetic study.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS) method was developed and validated for the determination of Tramadol in human plasma and urine. The analyte was separated on a Diamonsil C18 column with ammonium acetate (5 mmol x L(-1))-methanol (50:50,v:v) adjusted PH by caustic soda at a flow rate of 0.8 ml min(-1), and analyzed by mass spectrometry is in positive ion mode. The ion mass spectrum of m/z were 264.1 for Tramadol and 248.0 for Tinidazole (I.S.), respectively. The weighted (1/x2) calibration curve was linear over plasma concentration range 1.00-400.00 ng/ml and urine concentration range 0.01-16.00 microg/ml, with a correlation coefficient (r) of 0.9995 and 0.9997, respectively. The lower limit of quantification in human plasma was 1.00 ng/ml. The inter-and intra-day precisions (CV%) in both plasma and urine were lower than 10%, the mean method accuracies and recoveries from spiked plasma samples at three concentrations ranged from 98.2 to 100.1% and 61.6 to 62.9%, respectively. The developed method was successfully applied to determine Tramadol in human plasma and urine, and provided suitable profiles for clinical pharmacokinetic study of Tramadol.

The pharmacokinetics of Tramadol and Promethazine after a single dose of 40, 80 and 120 mg intramuscular injecting CTHI was evaluated in healthy volunteers. Physical exam, vital signs, clinical laboratory tests and electrocardiogram measurements were monitored to assess the safety and tolerance of the drug. The plasma levels of Tramadol and Promethazine in serial samples were measured by a validated HPLC-MS method. No subject showed any drug-related clinically significant changes on physical examination, vital signs or laboratory tests.

2,3-Dimercaptosuccinic acid (DMSA) is an orally effective chelating agent for the treatment of heavy metal poisoning. The increasing therapeutic use of DMSA has stimulated the need for sensitive and selective methods for its determination in biological samples, as well as study on pharmacokinetics and tissue distribution. According to the previously reported method, an improved method was established for the determination of DMSA in mice blood and tissues, in which oxidized DMSA was reduced by the disulfide-reducing agent, dithiothreitol (DTT), and DMSA was converted to a highly fluorescent and stable derivative by reaction with monobromobimane (mBBr) in alkaline solution. Acetonitrile was used for deproteinization and dichloromethane was used for condensation and purification, which significantly shortened the amount of time used to process the sample. Meanwhile isocratical elution was performed and excellent separation of the DMSA derivative was obtained, this enabled a run finish within 20 min. The limits of quantitation were 0.025 microg/ml in brain and 0.1 microg/ml in blood, lung, heart, intestine, liver, spleen and kidney, respectively. The calibration curves were linear in all samples (r(2)>0.992) with a range of 0.025-1.6 microg/ml for brain homogenate and 0.1-6.4 microg/ml for blood and homogenates of lung, heart, intestine, liver, spleen and kidney, respectively. Therefore, the method is simple, rapid and sensitive, and it could be applicable to the studies in an animal model to evaluate the distribution of DMSA in blood and tissues.

The paper is aimed to investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of carvedilol using indirect response and effect-compartment link models, and compare the fitness of PK-PD models. Twenty male healthy Chinese volunteers received a single oral dose of 20 mg of carvedilol. The plasma concentrations of carvedilol were determined by reversed-phase HPLC method with fluorescence detection, and the pharmacokinetic parameters were calculated by DAS2.0. The mean arterial blood pressure was measured and the pharmacodynamics of carvedilol was characterized by tail-cuff manometry. The main pharmacokinetic parameters of carvedilol were as follows, t1/2 (4.56 +/- 2.56) h, Cmax (46.29 +/- 21.07) ng x mL(-1), AUC(0-infinity) (173.76 +/- 87.36) ng x mL(-1) x h. The estimated Kin was (0.41 +/- 0.31)% h(-1), Kout was (0.40 +/- 0.26) h(-1), the IC50 value was (24.40 +/- 21.10) ng x mL(-1) and the area under the effect curve (AUE) was (3.82 +/- 1.46)% h for the indirect response PD model. The Ke0 was (0.35 +/- 0.27) h(-1), the EC50 was (24.30 +/- 24.30) ng x mL(-1), and the AUE was (5.65 +/- 2.54)% h for the effect-compartment model. The HPLC method can be used for the pharmacokinetic study of carvedilol. The proposed effect-compartment link model provided more appropriate and better-fitting PK/PD characteristics than the indirect response model in Chinese healthy volunteers according to Akaike's information criterion values.

A highly sensitive, simple and selective high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and applied to the determination of bergenin concentration in human plasma. Bergenin and the internal standard (IS) thiamphenicol in plasma were extracted with ethyl acetate, separated on a C(18 )reversed-phase column, eluted with mobile phase of acetonitrile-water, ionized by negative ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor --> product ions of m/z 327.1 --> 192 for bergenin and 354 --> 185.1 for the IS, respectively. The linear range of the calibration curve for bergenin was 0.25-60 ng mL(-1), with the lowest limit of quantification of 0.25 ng mL(-1), and the intra/inter-day relative standard deviation (RSD) was less than 10%. The method is suitable for the determination of low bergenin concentration in human plasma after therapeutic oral doses, and has been first and successfully used for its pharmacokinetic studies in healthy Chinese volunteers., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Major advantages of transdermal drug delivery system (TDDS) include avoiding of drug degradation in hepatic and gastrointestinal, predetermining release rate and blood drug level, reducing administration frequency and adverse reactions, and increasing patient compliance. But its application was limited by stratum corneum barrier and low skin permeability of drugs. Terpene penetration enhancers are low toxic and can improve the skin permeability and enhance the permeating veloc both of hydrophilic and lipophilic drugs. Terpenes can also significantly enhance the cumulative release amount of drug at its low concentration comparing with other synthetic penetration enhancers, and play an important role in the TDDS. This review presented the source, classification, mechanism and applications of terpenes, combined use with other enhancers and methods. Optimization, evaluation and prospective applications of terpene penetration enhancers were also discussed.

The study established an HPLC-MS/MS method for determining the concentrations of sodium cromoglycate in human plasma and evaluated the pharmacokinetics of nasal drops and nasal spray. A C18 column was used to separate sodium cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol (involves 50% acetonitrile) (15:85) at a flow rate of 0.4 mL x min(-1). Electronic spray ionization (ESI) and multiple-reaction monitoring (MRM) were used for the determination of sodium cromoglycate in human plasma. The linear range of the standard curve of sodium cromoglycate was from 0.3 to 20 ng x mL(-1), and the minimum concentration of detection was 0.3 ng x mL(-1). The extraction recovery was more than 94.1%, intra-day and inter-day RSD were less than 14.3%. After a single dose of sodium cromoglycate, the main pharmacokinetic parameters of nasal spray and nasal drops were as follows, T(1/2)(1.82 +/- 0.54) h, (1.59 +/- 0.52) h; Tmax (0.47 +/- 0.12) h, (0.44 +/- 0.15) h; Cmax, (9.79 +/- 4.66) ng x mL(-1), (10.88 +/- 4.05) ng x mL(-1); AUC(0-5 h)(11.52 +/- 3.46) ng x mL(-1) x h x h, (12.63 +/- 4.23) ng x mL(-1) x h, Fr(93.6 +/- 13.8)%. The method is sensitive, rapid and accurate. It is suitable for therapeutic drug monitoring and human pharmacokinetic study of sodium cromoglycate.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of sodium cromoglycate (SCG) in human plasma after a nasal dose of 10.4 mg sodium cromoglycate nasal spray, using pravastatin sodium as the internal standard. The method was validated over a linear range of 0.300-20.0 ng/mL. SCG and I.S. were extracted from 1.0 mL of heparinized plasma by C(18) solid-phase extraction cartridges using methanol as eluting solvent. The dried residue was reconstituted with 100 microL of mobile phase, and 10 microL was injected onto the LC-MS/MS system. Chromatographic separation was achieved on a C(18) column (250 x 4.6 mm i.d., 5 microm particle size) with a mobile phase of methanol-acetonitrile-water (containing 2 mmol/L ammonium acetate; 42.5:42.5:15, v/v/v) at a flow rate of 0.4 mL/min. The analytes were detected with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring mode were m/z 469.0 (precursor ion) to m/z 245.0 (product ion) for SCG and m/z 447.2 (precursor ion) to m/z327.1 (product ion) for pravastatin sodium (internal standard) The average recovery of SCG from human plasma was 94.88% and the lower limit of quantitation was 0.3 ng/mL. Results from a 3-day validation study demonstrated excellent precision and accuracy across the calibration range of 0.3-20 ng/mL. The method was successfully applied to the pharmacokinetic study of SCG in healthy Chinese volunteers.

Objective: To develop a high performance liquid chromatography mass spectrometry (HPLC-MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations., Methods: The GA in plasma was extracted with ethyl acetate, separated on a C(18) column with a mobile phase of methanol (5 mmol/L ammonium acetate)-water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469.5 for GA and m/z 455.6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively., Results: The calibration curve was linear over the range of 0.5-200 ng/mL (r = 0.9974). The limit of quantification for GA in plasma was 0.5 ng/mL, the recovery was 76.0-80.0%, and the inter- and intra-day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t(1/2)) 9.65 +/- 3.54 h and 9.46 +/- 2.85 h, the time to peak concentration (T(max)) 10.95 +/- 1.32 h and 11.00 +/- 1.30 h, the peak concentration (C(max)) 95.57 +/- 43.06 ng/mL and 103.89 +/- 49.24 ng/mL; the area under time-concentration curve (AUC(0-48) and AUC(0-infinity)) 1281.84 +/- 527.11 ng.h/mL and 1367.74 +/- 563.27 ng.h/mL, 1314.32 +/- 566.40 ng.h/mL and 1396.97 +/- 630.06 ng.h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98.88 +/- 12.98%., Conclusion: The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent.

A sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of betamethasone in human plasma. The analyte was isocratically eluted on a Venusil XBP C8 column (200 mm x 3.9 mm ID, 5 microm) with methanol-water mol x L(-1) ammonium formate) (80:20) at a flow rate of 0.4 mL x min(-1), and detected (containing 5 mmol x L(-1) ammonium formate) (80:20) at a flow rate of 0.4 mL x min(-1), and detected with a triple quad LC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring (MRM) mode were m/z 393.3-->355.2 for betamethasone and m/z 361.3-->343.2 for prednisolone (IS). Betamethasone was extracted from 0.5 mL human plasma with ethyl acetate. The average recovery is 88.24% and the low limit of quantitation (LLOQ) was 0.5 ng x mL(-1). The 3-day validation study demonstrated excellent precision and accuracy across the calibration range of 0.5-80.0 ng x mL(-1). The method was successfully applied to the pharmacokinetic study of compound betamethason injection in healthy Chinese volunteers.

A sensitive, simple and selective high-performance liquid chromatography-tandem mass spectrometry method was developed and applied to the determination of norcantharidin concentration in human serum. Norcantharidin (NCTD) and cyclophosphamide (IS) in serum were extracted with acetone, separated on a C18 reversed-phase column, gradiently eluted with a mobile phase of acetonitrile-water containing 2 mm ammonium acetate and 0.1% formic acid (pH 3), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor-->product ions of m/z 169.3-->123.1 for NCTD and 261.2-->140.2 for IS, respectively. The linear range of the calibration curve for NCTD was 2.5-50 ng/mL, with a lowest limit of quantification of 2.5 ng/mL, and the intra/inter-day RSD was less than 10%. The method was suitable for determination of low NCTD concentration in human serum after therapeutic oral doses, and has been successfully used for pharmacokinetic studies in healthy Chinese volunteers., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

To establish a high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry quantitative detection method for the determination of curcumol, the main ingredient of zedoary turmeric oil fat emulsion, and investigate its pharmacokinetics in Beagle dogs, nine healthy Beagle dogs were divided into three groups, and blood samples were collected at scheduled time points after intravenous injection of 7.5, 10 and 12.5 mg x kg(-1) zedoary turmeric oil fat emulsion. The concentrations of curcumol were determined and pharmacokinetics was calculated. A good linearity was obtained from 0.25 to 100 ng x mL(-1) in plasma. The relative recoveries were from 91.33% to 103.17%, and the absolute recoveries were from 31.61% to 37.20%. The intra-day and inter-day variances (RSD) were < 15%. The main pharmacokinetic parameters of curcumol after intravenous injection of 7.5, 10 and 12.5 mg x kg(-1) zedoary turmeric oil fat emulsion were as follows, T1/2 : (2.0 +/- 0.4), (1.7 +/- 0.2) and (2.3 +/- 0.8) h, AUC(0-infinity): (15.1 +/- 2.7), (18.3 +/- 2.0) and (29.5 +/- 4.0) ng x mL(-1) x h; MRT: (0.9 +/- 0.1), (0.8 +/- 0.2) and (0.8 +/- 0.1) h, CL: (21.9 +/- 4.0), (24.9 +/- 6.0) and (18.4 +/- 1.2) L x h(-1) x kg; Vd : (65.4 +/- 26.5), (62.0 +/- 13.4) and (61.2 +/- 19.8) L x kg(-1), respectively. The developed method was rapid, highly sensitive and specific and could be used in curcumol pharmacokinetic studies in vivo. A three-compartment model was best fit to the plasma concentration--time curves obtained in Beagle dogs and the plasma AUC was increased proportionally with doses.

A single dose of 3H-norcantharidin solution was intragastrically given, blood, tissues, urine and feces were collected as scheduled, and radioactivity in these samples was determined by tritium tracing method to investigate the pharmacokinetics, tissue distribution and excretion of norcantharidin in Kunming mice. The pharmacokinetic characteristics of norcantharidin were evaluated by DAS version 2.0. The blood concentration reached to maximum 0. 5 h after intragastric administration. The radioactivity in tissues was high in small intestine, gallbladder, stomach, adrenal gland, kidney, heart and uterus 15 minutes after administration, descending with time, and high in gallbladder, adrenal gland and uterus 3 hours post dosing. The 24 h accumulative excretion ratio of urine and feces were 65.40% and 1.33% respectively. 3H-norcantharidin was easily absorbed after orally given to mice, the radioactivity was high and existed for a long-time in gallbladder, adrenal gland and uterus, and low but also existed for a long-time in large intestine, thymus and fat tissue. 3H-norcantharidin was declined quickly in small intestine, stomach, kidney and heart, and occurred rarely in brain. Norcantharidin was excreted mainly by urinary route and seldom in feces, which may be the cause of the urinary stimulation side effects observed. Because the radioactivity measured were the sum of 3H labeled norcantharidin and its metabolites, further studies on the disposition of norcantharidin in mammal animals, on the separation or identification of metabolites and, if any, on their activities, are fairly needed.

A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method was established for the quantification of nifuratel in human plasma and applied to a study of its pharmacokinetics. A test and a reference formulation were investigated and compared, and the study group consisted of 24 healthy male volunteers. The analytical technique was based on a single extraction of the drug from the plasma with chloroform, using ornidazole as internal standard (IS). The chromatographic system consisted of a 5-microm 4.6 mmX250 mm C18 analytical column and the mobile phase consisted of methanol and purified water (45:55, v/v). Nifuratel and ornidazole concentrations were detected by ultraviolet (UV) absorbance at a wavelength of 254 nm. The lower limit of detection and quantification was 0.5 ng ml(-1), and the calibration curves were linear over a concentration range of 0.5-160 ng ml(-1) nifuratel in the plasma. The results showed that the area under the plasma concentration-time curve (AUC), time to maximum observed plasma concentration (Tmax), maximum concentration reached in the concentration profile (Cmax), and elimination half-life (t1/2) between the test tablets and the reference tablets demonstrated no significant difference (P>0.05). The relative bioavailability amounted to 103.13% +/-8.73%.

Aims: To assess the pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil (ADV) in healthy Chinese subjects., Methods: Forty-two healthy subjects were randomized into 5, 10, 20, 40 and 60-mg dose groups for safety assessment. Nine and 10 healthy males were enrolled for a single-dose pharmacokinetic profile and assessment of the effect of food on the pharmacokinetics of adefovir (PMEA), respectively. Another 10 healthy subjects were enrolled for a multiple-dose safety assessment and pharmacokinetic profile. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining PMEA concentrations with a validated LC-MS/MS method., Results: No serious adverse events occurred. The pharmacokinetic parameters of PMEA following ADV 10, 20 and 40 mg were: geometric mean [95% confidence interval (CI)] for AUC(0-24 h) 227 (205, 253), 423 (361, 506) and 686 (585, 828) microg l(-1) h, C(max) 23.0 (20.7, 27.3), 47.4 (42.8, 53.2) and 83.6 (72.6, 97.4) microg l(-1), arithmetic mean (95% CI) for t(1/2) 6.8 (6.3, 7.3), 7.4 (6.7, 8.1) and 7.7 (6.5, 8.9) h, median value (range) for t(max) 1.00 (1.00-2.00), 0.75 (0.75-2.50) and 1.00 (0.75-2.00) h, respectively. The steady-state pharmacokinetics parameters were similar to those following a single dose. The AUC of PMEA was unaffected by food., Conclusion: ADV is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PMEA is proportional to dose, but the linearity of AUC needs further study. There is no accumulation following multiple doses of ADV and the extent of absorption of PMEA is unaffected by food.

Background: To assess the safety and tolerance of adefovir dipivoxil tablet in Chinese healthy volunteers., Methods: Totally 42 healthy volunteers were enrolled in the study, 21 were female and 21 were male and their age ranged from 19 to 26 years. The subjects were randomly divided into 5, 10, 20, 40 and 60 mg dose-groups (6-10 subjects in each group) based on sex and weight, beginning with the 5 mg dose-group. Clinical symptoms, vital signs, electrocardiogram, routine blood test, routine urine test, prothrombin time and blood biochemical tests were recorded and evaluated., Results: No significant changes were found in clinical symptoms, vital signs and laboratory tests after dosing, except slight elevations of alanine aminotransferase in 2 subjects and bilirubin in 6 subjects observed and some gastrointestinal symptoms such as nausea and diarrhea found in 3 subjects, but the frequency and severity of all the adverse reactions were not found to be related to the dosages., Conclusion: The results showed that single oral dose of adefovir dipivoxil 60 mg or less was safe and tolerable.

Objective: To investigate the effect of hepatocyte growth factor (HGF) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) after allogeneic bone marrow transplantation (allo-BMT) and related mechanism in acute lymphoblastic leukemia (ALL) mice., Methods: Twenty nude mice were randomly divided into control (group A) and test (group B) groups for monitoring relapse, and 20 BALB/c mice into control (group C) and test (group D) groups for GVHD. HGF as injected from day 0 to day 7 after BMT for groups B and D, while PBS for A and C. CD4(+) and CD8(+) T cell were evaluated by flow cytometry. The survival of mice after BMT was recorded. The level of tumor necrosis factor-alpha (TNF-alpha) was evaluated by ELISA., Results: The median past-BMT survival were 7.00 +/- 1.58, 9.00 +/- 1.58, 11.00 +/- 3.95 and 24.00 +/- 13.44 days for groups A, B, C, D, respectively, being prolonged in group D. HGF could decrease the quantity of CD4(+) T cells [group D (10.39 +/- 1.15)% vs group C (13.50 +/- 1.80)%, P < 0.01] and increase CD8(+) T cell [group D (12.25 +/- 2.85)% vs group C (6.12 +/- 1.99)%, P < 0.01], decrease the level of TNF-alpha in transplanted ALL mice [group D (112.10 +/- 18.99) pg/ml vs group C (143.90 +/- 25.35) pg/ml, P < 0.01] and reduce the degree of GVHD., Conclusion: HGF could alleviate post-allo-BMT GVHD but retain GVL effect.

To observe the effects of hepatocyte growth factor (HGF) on graft-versus-host disease (GVHD) and Th1/Th2 related cytokines in mice with acute lymphoblastic leukemia (ALL) after allogenic bone marrow transplantation (allo-BMT), BALB/c mice were conditioned by total body irradiation with 11 Gy and then were transplanted with allogeneic bone marrow after establishing ALL model. BALB/c mice were divided into groups A and B. The mice of group A were injected subcutaneously with HGF from day 0 to 7 after allo-BMT, and the mice of group B were injected subcutaneously with PBS from day 0 to 7 after allo-BMT. The symptoms of GVHD and the GVHD pathological changes of liver and small intestine and skin were observed. The serum levels of both IFN-gamma and IL-4 were determined by ELISA. The results showed that the score of GVHD in group A was lower than that in group B (P < 0.05). The levels of IFN-gamma in both groups A and B were all higher than that in normal group (P < 0.05 and P < 0.001, respectively), However, the level of IFN-gamma in group A was lower than that in group B (P < 0.01). The levels of IL-4 in both group A and B were all lower than that in normal group (P < 0.05), but the level of IL-4 in group A was higher than that in group B (P < 0.05). It is concluded that HGF can alleviates the severity of GVHD, because of its balancing the Th1/Th2-related cytokines after allo-BMT.