Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.
Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Crown Ethers ; pharmacokinetics ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Dasatinib ; pharmacokinetics ; pharmacology ; Drug Interactions ; Erlotinib Hydrochloride ; pharmacokinetics ; pharmacology ; Glucuronosyltransferase ; metabolism ; Humans ; Imatinib Mesylate ; pharmacokinetics ; pharmacology ; Indoles ; pharmacokinetics ; pharmacology ; Niacinamide ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Phenylurea Compounds ; pharmacokinetics ; pharmacology ; Protein Kinase Inhibitors ; pharmacokinetics ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacokinetics ; pharmacology ; Pyrroles ; pharmacokinetics ; pharmacology ; Quinazolines ; pharmacokinetics ; pharmacology

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.
Administration, Oral ; Amlodipine ; administration & dosage ; blood ; Benzazepines ; administration & dosage ; blood ; Chromatography, Liquid ; Humans ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry

Objective:To observe the effects of warming triple needling plus Chinese medication on inflammatory responses and daily functioning ability in patients with knee osteoarthritis(KOA)due to wind-cold-dampness Bi-impediment. Methods:A total of 101 patients with KOA due to wind-cold-dampness Bi-impediment were divided into an acupuncture-medication group and a Chinese medication group using the random number table method.Fifty cases in the Chinese medication group took oral Fang Feng Xi Bi Tang for treatment,and 51 cases in the acupuncture-medication group received additional warming triple needling therapy.The symptom score of traditional Chinese medicine(TCM),inflammatory factor levels,and motor function of the knee joint were compared before and after treatment.The clinical efficacy was also compared between the two groups after treatment. Results:Three cases in the acupuncture-medication group and 2 cases in the Chinese medication group dropped out during the study,and the two groups each had 48 cases being included in statistical analysis ultimately.The total effective rate was 95.8%in the acupuncture-medication group,higher than 79.2%in the Chinese medication group,and the between-group difference was statistically significant(P<0.05).After treatment,the TCM symptom score dropped in both groups(P<0.05)and was lower in the acupuncture-medication group than in the Chinese medication group(P<0.05).The levels of interleukin(IL)-6,tumor necrosis factor(TNF)-α,and IL-1β dropped after the intervention in both groups(P<0.05)and were lower in the acupuncture-medication group than in the Chinese medication group(P<0.05).The scores of knee pain intensity,knee joint stiffness,and diurnal functioning decreased after treatment in the two groups(P<0.05)and were lower in the acupuncture-medication group than in the Chinese medication group(P<0.05). Conclusion:Warming triple needling plus Fang Feng Xi Bi Tang can reduce inflammatory responses,improve daily functioning ability,and enhance the quality of life in patients with KOA due to wind-cold-dampness Bi-impediment.

Firing patterns of injured nerve fibers were recorded using the single-fiber firing recording technique. Under the same background firing pattern, three types of bursting were induced separately by EGTA, veratridine or high [Ca(2+)](o) in the same type of nerve fibers. The results suggest that different firing patterns are related to different stimuli, which means that each firing pattern carries corresponding neural information.
Action Potentials ; Animals ; Calcium ; pharmacology ; Egtazic Acid ; pharmacology ; Nerve Fibers ; drug effects ; pathology ; Rats ; Veratridine ; pharmacology

OBJECTIVE: To explore the efficacy of blue light-emitting diodes(LEDs) as a novel light source for phototherapy. METHODS: Equimolar bilirubin standard albumin solutions were irradiated with two light sources; LEDs and single side conventional blue light( sCBL). Light intensity was measured with a light meter. The emission intensity of LEDs was the same as sCBL. To estimate the effects of the two light sources, the change in bilirubin isomer before and during phtotherapy was determined using high-performance liquid chromatography. RESULTS: The effects of different light sources on equimolar bilirubin standard albumin solutions, the lumirubin (LR) and 4Z, 15E-Bilirubin IX alpha(ZE) formation of LEDs was the same as sCBL(P>0.05). CONCLUSION: LEDs is equally effective as single sCBL for phototherapy in vitro.

BACKGROUND5-Hydroxytryptamine (5-HT) is a common neurotransmitter in the brain which plays an important role in the pathogenesis of sleep apnea. Dysfunction of 5-HT and 5-HT(2) receptors may lead to the collapse of the upper airway and the instability of respiratory control, which in turn produce apnea. Genioglossus (GG) is one of the most important oropharyngeal muscles maintaining the upper airway open. The present study aimed to investigate the effects of 5-HT and 5-HT(2) receptor on GG activity and the sleep apnea in Sprague-Dawley (SD) rats.

METHODSMicroinjection probes were placed within the fourth ventricle of sixteen SD rats. After recovery for a week, the electromyogram (EMG) of GG was recorded in the anesthetized and vagotomized rats. The changes of GG activity before and after the microinjection of 5-HT or 5-HT(2A/2C) agonist -2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were observed. Probes were also laid in another eight SD rats. Electroencephalogram (EEG), EMG of neck muscle and respiration were recorded at the same time a week later. The effects of DOI on the occurrence of sleep apnea were explored.

RESULTSBoth 5-HT and DOI significantly enhanced the activity of GG just 3 minutes after the completion of injection. The effect of 5-HT disappeared quickly and the effect of DOI lasted for more than 27 minutes. DOI also significantly decreased the post-sigh apnea index in non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep and decreased the spontaneous apnea index only in NREM sleep (P < 0.05, respectively).

CONCLUSION5-HT and 5-HT(2A/2C) system correlated closely with the pathogenesis of the sleep apnea syndrome and 5-HT receptors may become the target of the drug treatment.

Amphetamines ; pharmacology ; therapeutic use ; Animals ; Electroencephalography ; Male ; Rats ; Rats, Sprague-Dawley ; Serotonin ; pharmacology ; therapeutic use ; Serotonin Receptor Agonists ; pharmacology ; therapeutic use ; Sleep Apnea Syndromes ; drug therapy ; Sleep, REM ; drug effects

A simple, sensitive, selective, and reproducible liquid chromatography-tandem mass spectrometric method was developed for the simultaneous determination of repaglinide and metformin in human plasma using d5-repaglinide and d6-metformin as internal standards (ISs). After a simple protein precipitation using acetonitrile as the precipitation solvent, both analytes and ISs were separated on a Venusil ASB C 18 (150 mm x 4.6 mm, 5 microm) via gradient elution using acetonitrile--10 mmol x L(-1) ammonium acetate as the mobile phase. A chromatographic total run time of 7.5 min was achieved. Mass spectrometric detection was conducted with atmospheric pressure chemical ionization under positive-ion and multiple-reaction monitoring modes. The method was linear over the 0.2 to 60.0 ng x mL(-1) concentration range for repaglinide and over the 4 to 1 000 ng x mL(-1) range for metformin. For both analytes, the intra- and inter-accuracies and precisions were within the +/- 15% acceptable limit across all concentrations. The validated method was successfully applied to a clinical bioequivalence study.
Administration, Oral ; Adolescent ; Adult ; Area Under Curve ; Carbamates ; administration & dosage ; blood ; pharmacokinetics ; Chromatography, Liquid ; Drug Stability ; Female ; Humans ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Metformin ; administration & dosage ; blood ; pharmacokinetics ; Middle Aged ; Piperidines ; administration & dosage ; blood ; pharmacokinetics ; Tandem Mass Spectrometry ; Therapeutic Equivalency ; Young Adult

BACKGROUNDAmyloidosis is a collection of diseases in which different proteins are deposited. Amyloid deposits occur in systemic and organ-limited forms. In both systemic and localized forms of the disease, lung can be involved. The aim of this study was to explore the different respiratory manifestations of amyloidosis.

METHODSChest radiology, clinical presentations, bronchoscopic/laryngoscopic findings and lung function data of 59 patients with amyloidosis involving respiratory tract collected during January 1986 to March 2005, were analysed.

RESULTSOf the 16 cases with localized respiratory tract amyloidosis, 8 had the lesions in the trachea and the bronchi, 2 in the larynx and the trachea, 5 in the larynx and/or the pharynx, and 1 in the lung parenchyma. Of 43 systemic amyloidosis with respiratory tract involvement, 3 had the lesions in bronchi, 13 in lung parenchyma, 33 in pleura, 8 in mediastina, 1 in nose and 1 in pharynx. Chest X-rays were normal in most cases of tracheobronchial amyloidosis. CT, unlike chest X-rays, showed irregular luminal narrowing, airway wall thickening with calcifications and soft tissue shadows in airway lumen. Localized lung parenchymal amyloidosis presented as multiple nodules. Multiple nodular opacities, patch shadows and reticular opacities were the main radiological findings in systemic amyloidosis with lung parenchymal involvement. In pleural amyloidosis, pleural effusions and pleural thickening were detected. Mediastinal and/or hilar adenopathy were also a form of lung involvement in systemic amyloidosis. The major bronchoscopic findings of tracheobronchial amyloidosis were narrowing of airway lumen, while nodular, 'tumour like' or 'bubble like' masses, with missing or vague cartilaginous rings, were detected in about half of the patients.

CONCLUSIONSLocalized respiratory tract amyloidosis mostly affects the trachea and the bronchi. Chest X-rays are not sensitive to detect these lesions. Systemic amyloidosis often involves lung parenchyma and the pleura. Open lung biopsy or pleural biopsy should be performed for the diagnosis.

Adolescent ; Adult ; Aged ; Amyloidosis ; complications ; Bronchoscopy ; Female ; Humans ; Laryngoscopy ; Male ; Middle Aged ; Radiography, Thoracic ; Respiratory Tract Diseases ; diagnosis ; etiology ; therapy ; Tomography, X-Ray Computed

OBJECTIVETo investigate the in vitro effects and the primary mechanisms of Changweiqing (, CWQ) on antimetastasis and antiinvasion of hypoxic colon carcinoma cells. In addition, to provide experimental evidence for the Chinese medicinal theory of "strengthening the body's resistance to eliminate pathogenic factors" in the treatment of colorectal cancer, including its invasion and metastasis.

METHODSFirst, CWQ sera were prepared with serum-pharmacology methods. Then, the modified hypoxic chamber was designed and flushed with 5% CO(2) and 95% N(2) at 37 °C to induce a hypoxic environment. The effect of CWQ serum on the viability of LoVo cells was tested with MTT cytotoxicity assay. The wound model and chamber model were established to estimate the effects of CWQ serum on migration and invasion of LoVo cells. The model for cell adhesion was established to evaluate the effect of CWQ serum on LoVo cells' adhesion. The gelatin zymography model was performed to determine the effects of CWQ serum on the activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The effects of CWQ serum on the hypoxia-inducible factor 1 α (HIF-1α) nuclear translocation and the mRNA level of vascular endothelial growth factor (VEGF) in LoVo cells were determined by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses, respectively.

RESULTSCWQ inhibited LoVo cells' migration based on wound healing assay. The inhibitive effect could reach about 68.00% under hypoxic culture and about 29.87% under normoxic culture when cells were treated with 10% CWQ serum for 24 h. The results from both cell invasion and adhesion assays showed that CWQ serum could dose-dependently repress the invasion of LoVo cells and inhibit cells from adhering to extra cellular matrix (ECM). Under the hypoxic culture condition, RT-PCR analysis showed that 10% CWQ serum had down-regulated the expression of VEGF by 45.87%, and the result of Western blot analysis provided further evidence. The HIF-1α amount in the nucleus of the LoVo cells was also diminished in a dose-dependent manner, as shown by the Western blot. Gel zymogram assay revealed that CWQ serum could suppress the activities of MMP-2 and MMP-9.

CONCLUSIONSCWQ could effectively inhibit tumor metastasis in vitro The antimetastatic effects of CWQ were associated with the inhibition of cell motility, which was evidenced by inhibition of cell invasion and adhesion. The molecular mechanisms of the inhibition of tumor invasion by CWQ were due to the reduced expression of both HIF-1α and VEGF and the suppression of MMP-2 and MMP-9 expression.

Animals ; Cell Adhesion ; drug effects ; Cell Hypoxia ; drug effects ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cell Nucleus ; drug effects ; metabolism ; Colorectal Neoplasms ; enzymology ; genetics ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Extracellular Matrix ; drug effects ; metabolism ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase 9 ; metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Protein Transport ; drug effects ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

Objective:To observe the therapeutic efficacy of acupuncture plus Tai Ji Quan (Tai Chi) in recovering the neurological function and treating depression state in post-stroke depression patients,together with a 12-month follow-up.Methods:A total of 105 eligible post-stroke depression patients were randomized into an acupuncture plus Tai Ji group (53 cases) and a control group (52 cases) based on their visiting sequence.The patients all received routine treatment and rehabilitation training for stroke.In addition,the control group was given oral administration of citalopram hydrobromide tablets,1 month as a course of treatment,for 3 courses in total.Meanwhile,the acupuncture plus Tai Ji group received acupuncture and practiced Tai Ji Quan,for 1 month and 12 months respectively.Before the intervention,after 1-month intervention and 12 months later,the National Institute of Health stroke scale (NIHSS),Barthel index (BI) and Hamilton depression rating scale (HAMD) were adopted for efficacy evaluation.Results:Prior to the intervention,there were no significant differences in HAMD,NIHSS and BI scores between the two groups (all P＞0.05);after 1-month intervention,there were significant between-group differences in NIHSS,BI and HAMD scores (P＜0.05 or P＜0.01);the 12-month follow-up revealed significant between-group differences in NIHSS,BI and HAMD scores (all P＜0.01).In the treatment of stroke,the total effective rate was 84.4％ in the acupuncture plus Tai Ji group,significantly higher than 68.9％ in the control group (P＜0.05);in the treatment of depression,the total effective rate was 86.7％ in the acupuncture plus Tai Ji group,significantly higher than 77.8％ in the control group (P＜0.05).Conclusion:Acupuncture plus Tai Ji Quan can produce a significant efficacy in improving the limb motor function and depression in post-stroke depression patients.