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

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

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

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.
Adolescent ; Adult ; Anticonvulsants ; blood ; pharmacokinetics ; therapeutic use ; Carbamazepine ; blood ; pharmacokinetics ; therapeutic use ; Drug Interactions ; Drug Therapy, Combination ; Epilepsy ; blood ; drug therapy ; Fatty Acids, Monounsaturated ; blood ; Female ; Humans ; Male ; Valproic Acid ; blood ; pharmacokinetics ; therapeutic use ; Young Adult

Objective: To study the adaptive response and time effect of A549 cell apoptosis induced by low-dose X-ray irradiation, and to preliminarily explore the possible mechanism of adaptive effect.  Methods: A549 cells were irradiated with X-ray of 50 mGy, 200 mGy and 500 mGy, respectively, and then irradiated with an effect dose of 20 Gy after intervals of 3 h, 6 h, 12 h, 24 h and 48 h, respectively, for cell apoptosis detection. The cell cycle distribution and DNA damage were detected after an interval of 6 h between the initial dose and the effect dose. 20 Gy and 0 Gy were set as the control. Results: After irradiation at 20 Gy at intervals of 3 h, 6 h, 12 h and 24 h from the low- dose irradiation, the apoptosis rates of the 50 mGy～20 Gy, 200 mGy～20 Gy, and 500 mGy~ 20 Gy groups were significantly lower than that of the 20 Gy group (P < 0.05); after an interval of 48 h, there was no significant difference in the apoptosis rate between the 50 mGy～20 Gy, 200 mGy～20 Gy, and 500 mGy～20 Gy groups and the 20 Gy group. After an interval of 6 h between the low-dose irradiation and the effect dose irradiation, the percentage of cells at G0/G1 phase in the 50 mGy～20 Gy and 200 mGy～20 Gy groups was significantly lower than that in the 20 Gy group (P < 0.05); the percentage of cells at G2/M phase in the 50 mGy～20 Gy and 200 mGy~20 Gy groups were significantly reduced compared with the 20 Gy group (P < 0.05). There was no significant difference in the percentage of cells at G0/G1 and G2/M phases between the 500 mGy～20 Gy and 20 Gy groups. Compared with the 20 Gy group, the cell DNA damage in the 50 mGy～20 Gy, 200 mGy～20 Gy and 500 mGy~20 Gy groups were decreased, but without significant difference.  Conclusion Low-dose X-ray irradiation can induce the adaptive response of A549 cells apoptosis, which is related to the time interval between the initial dose and the effect dose. The adaptive effect may be related to the changes in cell cycle induced by low-dose X-ray.

Objective: To evaluate the efficacy and safety of intravenous thrombolysis with recombinant tissue-plasminogen activator (rt-PA) in elderly patients with early-stage mild ischemic stroke (IS). Methods: This was a prospective, open-label, controlled study.Ninety-four elderly patients with mild IS admitted to our hospital from January 2014 to December 2017 were randomized into a thrombolysis arm (TA, n=46) and a control arm (CA, n=48). The short-term endpoints were the National Institutes of Health stroke scale (NIHSS) scores on 3^rd, 7^th, 14^thday after admission and the secondary endpoints were the modified Rankin Scale (mRS) score and the morbidity of recurrence IS within 90 days.Safety was evaluated by the incidence of intracranial hemorrhage (IH) and early neurological deterioration (END) during hospitalization. Results: The baseline NIHSS scores of patients in the TA and CA groups were similar [(4.1±0.7) vs.(4.1±0.7)]. However, there were significant differences in the NIHSS score on 3^rd [(3.4±1.2) vs.(4.2±1.4)], 7^th[(3.0±1.8) vs.(4.1±1.6)] and 14^thday [(2.5±2.0) vs.(3.4±1.6)], respectively, between the TA group and the CA group.Furthermore, the TA group was associated with a significantly higher proportion of patients with good prognosis (mRS, 0-2), compared with the CA group (71.7% vs.35.4%, P<0.01). Receiver operating characteristic curve analysis showed that patients with baseline NIHSS>3 could benefit from thrombolytic therapy.There were 1 case of symptomatic IH and 1 case of progressive stroke in the TA group, and 1 case of IH and 2 cases of progressive stroke in the control group.There were no significant differences in the rate of either END or IH between the two groups (P>0.05). Two patients in the TA group and three patients in the control group had recurrent IS within 90 days and the recurrence rate of IS was also similar within 90 days (P>0.05). Conclusions Intravenous thrombolytic therapy with rt-PA can improve the prognosis of elderly patients with mild stroke without increased risk of END, IH, or recurrence of IS.

Background The current increasing trend of new cases of occupational noise-induced deafness indicates that the hearing loss of occupational population has not been effectively controlled in China. It is of great significance to study the characteristics of hearing loss among noise-exposed workers and its related factors. Objective To investigate characteristics and influencing factors of hearing loss among occupational noise-exposed workers in a large machinery maintenance enterprise, and to provide a scientific basis to prevent and control noise-induced hearing loss. Methods A cross-sectional survey was conducted to investigate male Han occupational noise-exposed workers in a large mechanical maintenance enterprise. We acquired demographic characteristics, occupational exposure history, and individual life behavior characteristics of the workers through questionnaires, collected occupational exposure level data from annual occupational disease hazard factor surveillance reports, obtained pure tone hearing threshold test data through occupational health examinations, and estimated individual noise exposure levels using cumulative noise exposure (CNE). According to the results of pure tone air conduction hearing threshold test, the workers were divided into a hearing loss group and a normal hearing group. The chi-square test was employed to compare the occupational exposure characteristics and individual life behavior characteristics between the two groups. Additionally, the trend chi-square test was utilized to analyze the changing trends of age, length of service, CNE, and hearing loss rate within the two groups. The relationship between high-frequency hearing loss in both ears and its related influencing factors was assessed by a multiple logistic regression model. Results The M (P₂₅, P₇₅) of CNE for the 2531 occupational noise-exposed workers was 97.51 (95.39, 99.96) dB(A)·year. The incidence of hearing anomaly, binaural high-frequency hearing anomaly, random ear high-frequency hearing anomaly, binaural low-frequency hearing anomaly, and random ear low-frequency hearing anomaly were 22.48%, 16.59%, 22.13%, 2.77%, and 3.52%, respectively. High-frequency hearing threshold increase was the main reason for hearing anomaly (98.42%). In comparison to the CNE ≤ 97 dB(A)·year group, the 97 dB(A)·year100 dB(A)·year group experienced a 36.4% and 52.3% increase in the risk of bilateral high-frequency hearing loss, respectively. The smoking group exhibited a 43.5% elevated risk of bilateral high-frequency hearing loss when compared to the non-smoking group. Conversely, the group frequently wearing hearing protection equipment demonstrated a 23.6% lower risk of bilateral high-frequency hearing loss in comparison to the group occasionally wearing protective equipment. The data suggested that CNE＞97 dB(A)·year and smoking might be independent risk factors for bilateral high-frequency hearing loss, and frequently wearing hearing protection equipment might be an important protective factor. Conclusion Increased CNE and smoking can elevate the risk of high-frequency hearing loss, while personal hearing protection can effectively reduce the risk of hearing loss.

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.