Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

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.

Hospitalization Due to Asthma Exacerbation: A China Asthma Research Network (CARN) Retrospective Study in 29 Provinces Across Mainland China

PURPOSE: Details of patients hospitalized for asthma exacerbation in mainland China are lacking. To improve disease control and reduce economic burden, a large sample survey among this patient population is indispensable. This study aimed to investigate the clinical characteristics and outcomes of such patients.METHODS: A retrospective study was conducted on patients hospitalized for asthma exacerbation in 29 hospitals of 29 regions in mainland China during the period 2013 to 2014. Demographic features, pre-admission conditions, exacerbation details, and outcomes were summarized. Risk factors for exacerbation severity were analyzed.RESULTS: There were 3,240 asthmatic patients included in this study (57.7% females, 42.3% males). Only 28.0% used daily controller medications; 1,287 (39.7%) patients were not currently on inhaled corticosteroids. Acute upper airway infection was the most common trigger of exacerbation (42.3%). Patients with severe to life-threatening exacerbation tended to have a longer disease course, a smoking history, and had comorbidities such as hypertension, chronic obstructive pulmonary disease (COPD), and food allergy. The multivariate analysis showed that smoking history, comorbidities of hypertension, COPD, and food allergy were independent risk factors for more severe exacerbation. The number of patients hospitalized for asthma exacerbation varied with seasons, peaking in March and September. Eight patients died during the study period (mortality 0.25%).CONCLUSIONS: Despite enhanced education on asthma self-management in China during recent years, few patients were using daily controller medications before the onset of their exacerbation, indicating that more educational efforts and considerations are needed. The findings of this study may improve our understanding of hospital admission for asthma exacerbation in mainland China and provide evidence for decision-making.

Seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China / 中华流行病学杂志

Objective To understand the seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China.Methods This was a retrospective study which involved patients hospitalized for asthma exacerbation in 29 hospitals throughout 7 geographic areas in the mainland of China (northeast,north,central,east,south,northwest and southwest).The numbers of asthmatic patients and total inpatients of the respiratory department of each hospital were recorded.The monthly ratio of asthmatic patients to the total inpatients in every area was calculated and compared.Results During the study period,6 480 patients were admitted for asthma exacerbation,accounting for 3.14％ of all the 206 135 patients admitted to the respiratory departments in the 29 hospitals.The ratio of asthmatic patients to total inpatients in the northeast area (5.61％) was highest,and the ratio in east area was lowest (1.97％).Statistical analysis showed that the difference among different areas was significant (P＜0.000 1).In most areas,both the number and proportion of hospitalized asthmatic patients peaked in spring (February-April) and autumn (September-October).In the northeast area,east area and south area,the peaks in spring were more obvious,while in the north area and southwest area,the peaks in autumn were more obvious.In the northwest area the peaks occurred in winter (December-January) and summer (June-August),respectively.The differences in hospitalization due to asthma among different months were significant in the northeast,north,and southwest areas (P＜0.005).Conclusion The number of patients hospitalized for asthma exacerbation fluctuated with season in different areas in China.In most areas,more asthmatic patients were admitted to hospitals in spring and autumn.

Seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China / 中华流行病学杂志

Objective To understand the seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China.Methods This was a retrospective study which involved patients hospitalized for asthma exacerbation in 29 hospitals throughout 7 geographic areas in the mainland of China (northeast,north,central,east,south,northwest and southwest).The numbers of asthmatic patients and total inpatients of the respiratory department of each hospital were recorded.The monthly ratio of asthmatic patients to the total inpatients in every area was calculated and compared.Results During the study period,6 480 patients were admitted for asthma exacerbation,accounting for 3.14％ of all the 206 135 patients admitted to the respiratory departments in the 29 hospitals.The ratio of asthmatic patients to total inpatients in the northeast area (5.61％) was highest,and the ratio in east area was lowest (1.97％).Statistical analysis showed that the difference among different areas was significant (P＜0.000 1).In most areas,both the number and proportion of hospitalized asthmatic patients peaked in spring (February-April) and autumn (September-October).In the northeast area,east area and south area,the peaks in spring were more obvious,while in the north area and southwest area,the peaks in autumn were more obvious.In the northwest area the peaks occurred in winter (December-January) and summer (June-August),respectively.The differences in hospitalization due to asthma among different months were significant in the northeast,north,and southwest areas (P＜0.005).Conclusion The number of patients hospitalized for asthma exacerbation fluctuated with season in different areas in China.In most areas,more asthmatic patients were admitted to hospitals in spring and autumn.

A retrospective study of the inducing factors and clinical characteristics of patients hospitalized for asthma exacerbation in China in 2013-2014 / 中华内科杂志

Objective To study the inducing factors and clinical characteristics of patients hospitalized for asthma exacerbation in China. Methods Patients hospitalized for asthma exacerbation at 29 hospitals in China were retrospectively recruited during 2013-2014. Results Clinical data of 3 240 asthmatic patients were collected and analyzed including 1 369(42.3%) males and 1 871(57.7%)females. The patients hospitalized for asthma exacerbation counted for 2.95% (6 375/215 955) of all patients hospitalized during the same period. The leading six inducing factors, in sequence, were acute upper respiratory tract infection[42.3%(1 370/3 240)],changes of weather[22.8%(738/3 240)],noxious gas[(4.3% (140/3 240), allergy challenges [3.5%(115/3 240)], strenuous exercise [1.8%(57/3 240)], and air pollution [1.5%(49/3 240)].In older patients,more exacerbations were induced by weather changes,yet less sensitive to allergy challenges. As to middle-aged patients, they were less sensitive to upper respiratory tract infections,however the difference was not statistically significant(P>0.05).In winter more asthma patients were induced by upper respiratory tract infections,while in autumn more patients were induced by weather changes,strenuous exercise and air pollution.In spring and summer more patients were induced by allergy challenges, but the differences failed to achieve statistical significance (P>0.05). In northern cities more patients were induced by upper respiratory infections, whereas in southern cities more by noxious gases. Allergy challenges and air pollution tended to affect more patients in northern cities,but the difference was of no significance (P>0.05). The differences of inducing factors among patients of different gender, with or without a smoking history, and with different exacerbation severity didn't show any statistical significance. The patients with severe and life-threatening exacerbations counted for 20.1%(652/3 240).The percentage of patients older than 60 years was higher in patients with severe or life-threatening exacerbations than in whose with mild or moderate exacerbations,so did the percentage of male patients,of patients with disease duration longer than 10 years, with smoking history, and with a history of hospitalization or emergency department visits due to asthma exacerbation during the last year.Conclusion The acute upper respiratory tract infection ranks top among all the inducing factors. Senility, male gender, long duration of disease, smoking history, and a history of frequent hospital visits might be the risk factors for severe or life-threatening asthma exacerbations.

The effect of N-acetylcysteine on the airway inflammation and remodeling of obese asthma mice / 中国医师杂志

Objectives To evaluate the effect of N-Acetylcysteine on the airway inflammation and remodeling of obese asthma mice with high-fat diets. Methods Forty female C57BL/6J mice were randomly divided into 4 groups, asthma group (A), obese asthma group (B), treatment group (C) and normal control group (D). Group A were sensitized and challenged by ovalbum (OVA) and normal diets. Group B were sensitized and challenged as group A but fed with high-fat diets, while group C were sensitized, challenged and fed as group B, but administrated N-Acetylcysteine 200 mg/kg. d from the third week after challenge. The cells in BALF were counted and classified after staining, IL-6 and 8-iso-PGF2α(8-iso-PGF2α) in lung tissues were detected by ELISA. WAt, WAm, Pbm, as the remodeling indices, measured in lung pathological section. All parameters were compared among 4 groups. Results In comparison with group D, the leukocytes and EOS in BALF, WAt/Pbm, WAm/Pbm in lung section were increased as well as IL-6 and 8-iso-PGF2α in lung tissue elevated in group A and group B, while the maximum changes were observed in group B (P ＜0. 05). After NAC treatment, the IL-6, 8-iso-PGF2α and WAt/ Pbm were decreased significantly (P ＜0. 05). Pearson correlation analysis showed that WAt/Pbm and IL-6 were in positive correlation with 8-iso-PGF2α (r =0. 817, 0. 737, P ＜0. 01). Conclusions N-Acetylcysteine can alleviate the airway inflammation and remodel reaction of asthma by a substantial inhibition of the oxidative stress reaction in lung.

Hospital initiative management or patients self management in asthma control and pulmonary function:a study in contrast / 中国医师进修杂志

ObjectiveTo compare the effect of hospital initiative management or patients self management in asthma control and pulmonary function, and improve the control level of asthma. Methods Forty moderate asthma patients enrolled successfully from July to December in 2009 were divided into 2 groups by random digits table:hospital initiative management group (group A) and patient self management group (group B) with 20 cases each, and received the asthma treatment with hospital initiative management or patient self management for 1 year. The acute attack time, emergency visit time, hospitalization time,pulmonary function and Saint George respiratory questionnaire (SGRQ) were compared between two groups.ResultsAfter 1 year management, there were 19 patients in good compliance, satisfaction score was (9.300 ± 0.801 ) scores, 13 total control, 6 partial control and 1 uncontrol in group A, while there were 11 patients in good compliance, satisfaction score was (7.800 ± 1.542) scores, 6 total control, 8 partial control and 6 uncontrol in group B. The compliance, satisfaction and control in group A were much better than those in group B (P＜0.01 or ＜0.05). The forced expiratory volume in 1 second (FEV1)[(2.56 ±0.30) L]and peak expiratory flow (PEF)[(6.26±0.39) t/s]were elevated while SGRQ[(21.55 ±6.35) scores]in group A were better than those in group B[(2.38 + 0.31 ) L, (5.83 ± 0.52 ) L/s,(29.80 ± 12.04) scores](P ＜ 0.05 or ＜ 0.01 ). ConclusionThe compliance, asthma control, pulmonary function and respiratory quality are improved by hospital initiative management, so it is helpful to promote this management model in China via a close cooperation between general hospital and community hospital.

Prevalence and management of asthma in downtown of Qingdao city / 中国医师进修杂志

Objective To explore the prevalence and management status of asthma in downtown of Qingdao City.Method A stratified-cluster-disproportional random sampling survey was conducted with uniform procedure and questionnaire.Results The overall incidence of asthma in Qingdao City was 3.12％ (188/6026).The 2 most frequently risk factors of asthma were the allergic history and the asthma heredity (OR =3.562,2.381,P ＜ 0.05 ).In 188 diagnosed asthma patients,only 65 (34.5％)asthma patients accepted the guideline therapy,and 51 (27.1％)of them achieved well-controlled or total control.The 2 common reasons for the poor compliance were fear of adverse drug reaciion and feeling of ineffectiveness of inhaled corticosteroids.Conclusion The population in urban area of Qingdao City is suffered with high prevalence of asthma,poor compliance of guideline treatment and terrible management status.

Study of SCTPA and V/Q scan in diagnosis of pulmonary thromboembolism / 中国实用内科杂志

Objective To evaluate the clinical value of SCTPA and pulmonary V/Q scan in the diagnosis of pulmonary thromboembolism(PTE).Methods Ninety-two patients suspected of having PTE received SCTPA,pulmonary V/Q scan,and other related examinations.Results Thirty-five patients were diagnosed as having PTE in 92 patients investigated,30 cases were revealed by SCTPA,and 20 cases revealed by pulmonary V/Q scan.The area under ROC curve of SCTPA by V/Q scan and combination examination was 0.922,0.824,and 0.933,respectively(P