Ying C Ou, Arthur Lo, Brian Lee, Phillip Liu, Karen Kimura, Charisse Eary, Alan Hopkins
{"title":"Integration of biostatistics and pharmacometrics computing platforms for efficient and reproducible PK/PD analysis: a case study.","authors":"Ying C Ou, Arthur Lo, Brian Lee, Phillip Liu, Karen Kimura, Charisse Eary, Alan Hopkins","doi":"10.1002/jcph.157","DOIUrl":"https://doi.org/10.1002/jcph.157","url":null,"abstract":"<p><p>Results of pharmacometric analyses influence high-level decisions such as clinical trial design, drug approval, and labeling. Key challenges for timely delivery of pharmacometric analyses are the data assembly process and tracking and documenting the modeling process and results. Since clinical efficacy and safety data typically reside in the biostatistics computing area, an integrated computing platform for pharmacometric and biostatistical analyses would be ideal. A case study is presented integrating a pharmacometric modeling platform into an existing statistical computing environment (SCE). The feasibility and specific configurations of running common PK/PD programs such as NONMEM and R inside of the SCE are provided. The case study provides an example of an integrated repository that facilitates efficient data assembly for pharmacometrics analyses. The proposed platform encourages a good pharmacometrics working practice to maintain transparency, traceability, and reproducibility of PK/PD models and associated data in supporting drug development and regulatory decisions. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1112-20"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31630583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Odin J Naderer, Lori S Jones, John Zhu, Milena Kurtinecz, Etienne Dumont
{"title":"Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor.","authors":"Odin J Naderer, Lori S Jones, John Zhu, Milena Kurtinecz, Etienne Dumont","doi":"10.1002/jcph.150","DOIUrl":"https://doi.org/10.1002/jcph.150","url":null,"abstract":"<p><p>GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double-blind, placebo-controlled, eight-cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time-invariant pharmacokinetics. A dose-proportional increase in area under concentration-time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice-daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild-to-moderate drug-related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first-in-class PDF inhibitor for clinical use. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 11","pages":"1168-76"},"PeriodicalIF":2.9,"publicationDate":"2013-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31625712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tae H Han, Ajay K Gopal, Radhakrishnan Ramchandren, Andre Goy, Robert Chen, Jeffrey V Matous, Maureen Cooper, Laurie E Grove, Stephen C Alley, Carmel M Lynch, Owen A O'Connor
{"title":"CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies.","authors":"Tae H Han, Ajay K Gopal, Radhakrishnan Ramchandren, Andre Goy, Robert Chen, Jeffrey V Matous, Maureen Cooper, Laurie E Grove, Stephen C Alley, Carmel M Lynch, Owen A O'Connor","doi":"10.1002/jcph.116","DOIUrl":"https://doi.org/10.1002/jcph.116","url":null,"abstract":"<p><p>Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ∼23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"866-77"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31496077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer cachexia raises the plasma concentration of oxymorphone through the reduction of CYP3A but not CYP2D6 in oxycodone-treated patients.","authors":"Takafumi Naito, Masaki Tashiro, Takuya Ishida, Kazunori Ohnishi, Junichi Kawakami","doi":"10.1002/jcph.112","DOIUrl":"https://doi.org/10.1002/jcph.112","url":null,"abstract":"<p><p>This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"812-8"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31480079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Herta M Crauwels, Rolf P G van Heeswijk, Annemie Buelens, Marita Stevens, Katia Boven, Richard M W Hoetelmans
{"title":"Impact of food and different meal types on the pharmacokinetics of rilpivirine.","authors":"Herta M Crauwels, Rolf P G van Heeswijk, Annemie Buelens, Marita Stevens, Katia Boven, Richard M W Hoetelmans","doi":"10.1002/jcph.107","DOIUrl":"https://doi.org/10.1002/jcph.107","url":null,"abstract":"<p><p>The objective of the study was to determine the impact of food and different meal types on the pharmacokinetics of rilpivirine, a nonnucleoside reverse transcriptase inhibitor. In this open-label, randomized, crossover study, healthy volunteers received a single, oral 75 mg dose of rilpivirine either with a normal-fat breakfast (reference), under fasting conditions, with a high-fat breakfast, or with a protein-rich nutritional drink. Pharmacokinetic parameters were determined by non-compartmental methods and analyzed using a linear mixed-effects model. Safety was assessed throughout. The least-squares mean ratio for area under the plasma concentration-time curve to last timepoint was 0.57 (90% confidence interval [CI]: 0.46-0.72) under fasting conditions compared to dosing with a normal-fat breakfast. With a high-fat breakfast or only a protein-rich nutritional drink, the corresponding values were 0.92 (90% CI: 0.80-1.07) and 0.50 (90% CI: 0.41-0.61), respectively, compared to dosing with a normal-fat breakfast. Under all conditions, rilpivirine was generally safe and well tolerated. Administration of rilpivirine under fasting conditions or with only a protein-rich nutritional drink substantially lowered the oral bioavailability when compared to administration with a normal-fat breakfast. Rilpivirine bioavailability was similar when administered with a high-fat or normal-fat breakfast. Rilpivirine should always be taken with a meal to ensure adequate bioavailability.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"834-40"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31467269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gomaa Mostafa-Hedeab, Maha M Saber-Ayad, Inas A Latif, Sahier O Elkashab, Tarek H Elshaboney, Magdy Ibrahim Mostafa, Sanaa Abd El-Shafy, Magda M Zaki
{"title":"Functional G1199A ABCB1 polymorphism may have an effect on cyclosporine blood concentration in renal transplanted patients.","authors":"Gomaa Mostafa-Hedeab, Maha M Saber-Ayad, Inas A Latif, Sahier O Elkashab, Tarek H Elshaboney, Magdy Ibrahim Mostafa, Sanaa Abd El-Shafy, Magda M Zaki","doi":"10.1002/jcph.105","DOIUrl":"https://doi.org/10.1002/jcph.105","url":null,"abstract":"<p><p>Cyclosporine A (CsA) shows significant inter-individual variability in its pharmacokinetics, which may be due to polymorphisms in ABCB-1 genes coding for P-glycoprotein. The aim of this study was to explore the role of genetic polymorphisms of ABCB-1 in affecting the CsA blood concentrations in renal transplanted patients over the first 3 months after transplantation. Renal transplanted patients receiving CsA (n = 40) were genotyped for ABCB -1 C3435T (I1145I) and G1199A (S400N) polymorphisms. CsA blood concentrations were measured on Day 7, 30, and 90 after transplantation. G1199A variant showed higher CsA blood concentrations in stable patients, that was significant for trough levels (198 vs. 136 ng/mL on Day 7, P = .004, 196 vs. 125 ng/mL on Day 30, P = .007, 194 vs. 121 ng/mL on Day 90, P = .005 for stable vs. unstable groups). Polymorphisms of ABCB-1 have only a minor effect on CsA blood concentrations. The functional G1199A polymorphism can affect the drug levels more than non-functional C3435T. This polymorphism might be of a potential prognostic value in renal transplanted patients. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"827-33"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31560157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.","authors":"Zhen Zhang, Tai-Ning Lam, Zhong Zuo","doi":"10.1002/jcph.96","DOIUrl":"https://doi.org/10.1002/jcph.96","url":null,"abstract":"<p><p>Radix Puerariae has been traditionally used for the treatment of diarrhea, acute dysentery, deafness and cardiovascular diseases. Yege (Gegen or Radix Puerariae lobatae), the dried root of Pueraria lobata (Wild.) Ohwi, has been widely used in China and, to a lesser extent, in Japan, Korea, and the United States. Although they have been classified into different categories in Chinese Pharmacopoeia, Yege is often used interchangeably in practice with Fenge (Radix Puerariae thomsonii), which is the dried root of Pueraria thomsonii Benth. Among various commercially available products of Radix Puerariae, injection of puerarin, the major isoflavone from Radix Puerariae, has been most widely used as a vasodilator for the treatment of angina and myocardial infarction. Considering the extensive clinical usage and recent alert of fatal herb-drug interaction of Radix Puerariae, the current review is proposed to cover its traditional applications, pharmacological activities, pharmacokinetics, clinical efficacy, and potential herb-drug interactions aiming to fill in the information gaps of this herb for frontline practitioners. Although various small, poorly designed clinical trials have demonstrated the safety, efficacy, and significant clinical benefits of Radix Puerariae, prospective randomized controlled clinical trials are needed to further establish its effective and safe use. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"787-811"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.96","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31433868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patrick R Mayo, Robert B Huizinga, Spencer Y Ling, Derrick G Freitag, Launa J Aspeslet, Robert T Foster
{"title":"Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects.","authors":"Patrick R Mayo, Robert B Huizinga, Spencer Y Ling, Derrick G Freitag, Launa J Aspeslet, Robert T Foster","doi":"10.1002/jcph.114","DOIUrl":"https://doi.org/10.1002/jcph.114","url":null,"abstract":"<p><p>Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"819-26"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31481756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Farzaneh Salem, Trevor N Johnson, Zoe E Barter, J Steven Leeder, Amin Rostami-Hodjegan
{"title":"Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.","authors":"Farzaneh Salem, Trevor N Johnson, Zoe E Barter, J Steven Leeder, Amin Rostami-Hodjegan","doi":"10.1002/jcph.100","DOIUrl":"https://doi.org/10.1002/jcph.100","url":null,"abstract":"<p><p>The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"857-65"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31559161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samir M Said, Hans D Esperer, Kathrin Kluba, Conrad Genz, Thomas Rauwolf, Alexander Schmeisser, Ruediger C Braun-Dullaeus
{"title":"Which patient is most likely to benefit from dronedarone? Analysis from the Magdeburg Dronedarone Registry (MADRE study).","authors":"Samir M Said, Hans D Esperer, Kathrin Kluba, Conrad Genz, Thomas Rauwolf, Alexander Schmeisser, Ruediger C Braun-Dullaeus","doi":"10.1002/jcph.103","DOIUrl":"https://doi.org/10.1002/jcph.103","url":null,"abstract":"<p><p>Based on an analysis of the Magdeburg Dronedarone Registry data we sought to determine which patients could benefit from dronedarone therapy regarding rhythm control. The study included 191 patients (85 women) aged 63 ± 10 years with a history of paroxysmal or persistent AF and a follow-up of 14 ± 5 months. The total AF recurrence rate was 67% and lone AF was significantly more often associated with AF recurrences than non-lone AF (84% vs. 62%, P = .01). Arterial hypertension, treated coronary artery disease, and diabetes mellitus were not significantly related to AF recurrences (64%, 67%, 58% resp. P = .3). Response rate to dronedarone in patients with slightly increased left atrial size was significantly greater than in patients with normal or markedly increased left atrial size (47%, 16%, 27% resp., P = .001). The rate of adverse effects was 32% in the study sample, and was significantly lower in patients with lone AF as compared to those with non-lone AF (11% vs. 37%, P = .002). The body mass index was a predictor neither of response rate nor adverse effects. The results suggest that dronedarone is more effective in patients with non-lone AF and slightly increased left atrial size. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"53 8","pages":"841-5"},"PeriodicalIF":2.9,"publicationDate":"2013-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31468554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}