Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

OBJECTIVE: To explore the effect of electrical stimulation at auricular points (EAS) combined with sound masking on the expression of cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in the auditory cortex of tinnitus rats. METHODS: A total of 27 adult male SD rats were randomly divided into a control group, a model group and an EAS group. The rats in the model group and the EAS group were intervened with intraperitoneal injection of sodium salicylate to induce tinnitus model, while the rats in the control group were intervened with injection of 0.9% NaCl solution. After the model was successfully established, the rats in the EAS group were treated with electrical stimulation at "Shenmen" (TF) and "Yidan" (CO), combined with sound masking; the treatment was given once a day for 15 days. The gap prepulse inhibition of acoustic startle (GPIAS) and prepulse inhibition (PPI) testing were performed using the acoustic startle reflex starter package for rats. The expression of BDNF, TrkB, CREB and p-CREB in the auditory cortex of each group were measured with Western Blot analysis. RESULTS: ① Compared with the control group, the GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly decreased in the model group (all <0.05); compared with the model group, GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly increased in the EAS group (all <0.05). ② Compared with the control group, the expression of BDNF and p-CREB in the model group was significantly increased (<0.01), and the expression of TrkB in the model group was significantly increased (<0.05); the differences of expression of BDNF, TrkB, CREB and p-CREB between the model group and the EAS group had no statistics significance (all >0.05). CONCLUSION EAS could improve the GPIAS values of high-frequency background sound in tinnitus rats, which may be related with the upregulation of the BDNF/TrkB/CREB signaling pathway in the auditory cortex, leading to the reversion of the maladaptive plasticity.
Acupuncture Points ; Animals ; Auditory Cortex ; Brain-Derived Neurotrophic Factor ; metabolism ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Electric Stimulation ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB ; metabolism ; Tinnitus ; metabolism ; therapy

Ellagic acid is ubiquitous in plants and is considered as a potential candidate for antioxidant and antineoplastic drugs. However, ellagic acid has poor solubility and precipitates easily even after initial solubilization. Improvement of its bioavailability has been a concern of pharmaceutical industry. It was found that storage in Sanlejiang oral liquid at low temperature keeps its stability. Ellagic acid is anomalous in a way that is easily soluble at low temperatures but precipitates at high temperatures. In order to reveal the mechanism of this phenomenon and develop precipitation prevention and control strategies, ellagic acid in Sanlejiang oral liquid was stored at high, medium and low temperatures for three months. The changes of composition and phase state of the whole system during storage were systematically tracked and studied by means of precipitation amount or morphology, HPLC chemical profile of supernatant versus precipitates, and comprehensive characterization of physical phase state. The results show that the amount of precipitation at low temperature is only 1/3 of that at normal room temperature. As the temperature rises, the sedimentation increases sharply. HPLC analyses of supernatant versus precipitates revealed that ellagic acid precipitation originated from two ways: chemical degradation and physical deposition. The chemical sedimentation is related to the hydrolysis of tannins under acidic condition, forming chebulagic acid and corilagin. Physical sedimentation is related to the decrease of the association degree and viscosity of polyphenol colloids when temperature rises. This study elucidated the stability mechanism of ellagic acid in liquid preparations of TCM, and provided the mechanistic basis for efficient utilization and solution prepartion of ellagic acid.

Objective To analyse the change of hepatic glycogen in the process of hepatocellular carcinoma development in N -nitrosodiethy-lamine(DEN) -induced mice, and investigate the relationship between the hepatic glycogen content and the different stage of liver cancer . Methods There were forty clean and healthy male mice .They were di-vided in two groups ,the normal group ( n=3 ) and the model group ( n=37).After adapting environment in one week ,the group of normal mice were sacrificed and all the model animals were administrated by solution of DEN (30 μg? mL-1 ) in the carcinoma-induced period.Every three mice were sacrificed in the this group induced by DEN in 4 , 8 , 12 , 16 , 20 ,24 weeks(n=21).The obtained liver tissues divided in seven groups and embedded by paraffin were cut at thick piece .After staining with pe-riodic acid-Schiff ( PAS) the hepatic glycogen were observed .In order to obtain the mean optical density , samples of each group were disposed by the software Motic Images Advanced 3.2.Lastly.Analysis of variance ( ANOVA) test was followed by individual comparison by Student -New-man-Keul test using SPSS V16.0.Result The contents of hepatic gly-cogen in normal group , 8-week and 12-week groups were decreased successively and significantly , and the 16-week were least .The con-tents of hepatic glycogen in 16-week compared with 20-week and 24-week groups were increased successively and significantly . Conclusion In the process of development of hepatic carcinoma induced by DEN , the regular of hepatic glycogen′s change was decreasing gradually at the prior period ,and then the level of hepatic glycogen increased later .

Objective To assess the effects of hypoxia combined with heavy physical workload on cardiac function of the military personnel who stationed at high altitude and to conclude the recovery effects as the personnel returning to normal altitude. Methods Ninety-six male military personnel,who rushed to plateau (3700 m) and undertaken heavy physical work for 50 days,were divided into severe,moderate, mild and no acute high altitude reaction (AHAR) group by their AHAR symptoms.Serum creatine kinase isoenzyme-MB (CK-MB) and lactic dehydrogenase isoenzyme-1(LDH-1),myocardial performance index (Tei index),left ventricular ejection fraction (LVEF),and left ventricular fractional shortening (LVFS) were respectively measured before they returned to,12 h and 15 d after they stationed at normal altitude (1500 m).Another 50 healthy volunteers who stationed at 1500 m were chosen as control group. Results The incidence of AHAR was 74.0％(71/96),including 32.5％ (25/71) mild,31.0％ (22/71) moderate and 33.8％ (24/71) severe cases.Level of serum CK-MB,LDH-1 and Tei index of severe group were significantly higher than those of moderate,mild and no AHAR group (P＜0.01),while LVEF,LVFS were significantly lower (P＜0.01).For stationed at 3700 m for 50 d,personnel's CK-MB and LDH-1 level was positively correlated with Tei index (r=0.625,0.598,P＜0.01),and negatively correlated with LVEF and LVFS (r=-0.716,-0.658,-0.639,-0.727,P＜0.01).The CK-MB and LDH-1 level and Tei index that gathered for 50-d stay were significantly higher than those of theirs stationed at 1500 m for 12 h and 15 d respectively,as well as higher than those of control group,but LVEF and LVFS were significantly lower in same comparison (t =7.146-28.613,P＜ 0.01).The self comparisons between 12 h and 15 d stationings respectively in AHAR and control group showed significant differences (t=8.677-17.852,P＜0.01).For staying 15 d at 1500 m,parameters showed no significant difference with control group's (t=0.612-1.558,P＞0.05). Conclnsions Hypoxia with heavy physical workload could obviously cause military personnel's cardiac function impairment and the harm is aggravated with the severity of AHAR.The cardiac function would obviously improve as returning to normal altitude for 12 h,and 15-d recovery would enable cardiac function normalized.

Objective To assess the effects of hypoxia combined with heavy physical workload on cardiac function of the military personnel who stationed at high altitude and to conclude the recovery effects as the personnel returning to normal altitude. Methods Ninety-six male military personnel,who rushed to plateau (3700 m) and undertaken heavy physical work for 50 days,were divided into severe,moderate, mild and no acute high altitude reaction (AHAR) group by their AHAR symptoms.Serum creatine kinase isoenzyme-MB (CK-MB) and lactic dehydrogenase isoenzyme-1(LDH-1),myocardial performance index (Tei index),left ventricular ejection fraction (LVEF),and left ventricular fractional shortening (LVFS) were respectively measured before they returned to,12 h and 15 d after they stationed at normal altitude (1500 m).Another 50 healthy volunteers who stationed at 1500 m were chosen as control group. Results The incidence of AHAR was 74.0％(71/96),including 32.5％ (25/71) mild,31.0％ (22/71) moderate and 33.8％ (24/71) severe cases.Level of serum CK-MB,LDH-1 and Tei index of severe group were significantly higher than those of moderate,mild and no AHAR group (P＜0.01),while LVEF,LVFS were significantly lower (P＜0.01).For stationed at 3700 m for 50 d,personnel's CK-MB and LDH-1 level was positively correlated with Tei index (r=0.625,0.598,P＜0.01),and negatively correlated with LVEF and LVFS (r=-0.716,-0.658,-0.639,-0.727,P＜0.01).The CK-MB and LDH-1 level and Tei index that gathered for 50-d stay were significantly higher than those of theirs stationed at 1500 m for 12 h and 15 d respectively,as well as higher than those of control group,but LVEF and LVFS were significantly lower in same comparison (t =7.146-28.613,P＜ 0.01).The self comparisons between 12 h and 15 d stationings respectively in AHAR and control group showed significant differences (t=8.677-17.852,P＜0.01).For staying 15 d at 1500 m,parameters showed no significant difference with control group's (t=0.612-1.558,P＞0.05). Conclnsions Hypoxia with heavy physical workload could obviously cause military personnel's cardiac function impairment and the harm is aggravated with the severity of AHAR.The cardiac function would obviously improve as returning to normal altitude for 12 h,and 15-d recovery would enable cardiac function normalized.

OBJECTIVETo explore the relationship between the depression symptoms and occupational stress in occupational populations.

METHODSDepression symptoms were measured by using the center for epidemiological survey-depression scale. The occupational stress instrument were employed to investigate the stressors, personalities, social support, and coping strategies as well as the subject's age, length of service, sex, educational level and marriage status. Chi(2) test was used for analyzing the difference of depression. The multiple covariance analysis was used for testing the difference of stressors, personalities, social support, and coping strategies among the groups with different scores of depression. The variables obtained in the optional prediction equation were identified by multiple stepwise regression analysis.

RESULTSThe incidence rate of definite depression symptoms was 40.2%. The total average score was 21.74 +/- 8.99. Henan province had the highest incidence rate of depression symptoms, 43.8%, Hebei 39.4%, and Beijing the lowest, 23.4%. The male workers had the higher incidence rate of depression symptoms, 43. 0% than female, 35.4% (P < 0.01). The older group had the lower incidence rates of depression symptoms, compared with the younger group (P < 0.01). The workers divorced or with the bereft spouse had the higher incidence rate of depression symptoms than the workers married and unmarried (P < 0.05). The workers with middle school education had the higher incidence rates of depression symptoms than those with master degree. Incidence rates in the most occupational groups were more than 30%. The significant difference was shown between the different jobs (P < 0.01). The difference of the adjusted means among three groups of different depression score were analyzed. The results showed the workers with definite depression symptoms had the higher scores than the other two groups in physical factors, role ambiguity, role conflict, job monotony, mental load, responsibility for persons, job future ambiguity, job hazards, type A behavior and work locus of control, and social support (P < 0.05, P < 0.01). The former had the lower scores than the other two groups in the scores of promotion, participation, autonomy, task identity, feedback, friendship opportunity, speed control, training adequacy, challenge, self-esteem, organizational commitment, and coping strategies. Fifteen variables entered the predictive equation of depression score explaining 33.1% of variance.

CONCLUSIONThere are serious mental health problems in the occupational population in our country. Stressors and personalities affect the mental health.

Adolescent ; Adult ; Aged ; China ; epidemiology ; Depression ; epidemiology ; Female ; Humans ; Incidence ; Male ; Mental Health ; Middle Aged ; Multivariate Analysis ; Occupational Diseases ; epidemiology ; Stress, Psychological ; epidemiology