Journal of Clinical Pharmacology最新文献

{"title":"Cardiovascular effects of ketamine in sick patients: should physicians be concerned?","authors":"Maurice Lippmann, Abhishek Karnwal, Inderjeet S Julka","doi":"10.1177/0091270009352484","DOIUrl":"https://doi.org/10.1177/0091270009352484","url":null,"abstract":"W read with interest the article by Aroni et al with regard to the reevaluation of an old drug, ketamine, and its uses. The authors' article deals with ketamine in normal, healthy patients, in whom it is commonly used as an analgesic and anesthetic induction agent. We applaud the authors' insights, which appear to be positive in nature about the drug. What the authors did not portray is this drug's not uncommon negative effect, especially with regard to the cardiovascular system. Ketamine, a phencyclindine derivative, mediates its effects by acting on different sites. While the N-methyl-D-aspartate (NMDA)-receptor antagonism and opiate receptor effects contribute to the analgesic state, sympathomimetic properties are mediated by enhanced monoaminergic transmission, producing increases in heart rate, cardiac output, and blood pressure. Ketamine also causes increases in circulating catecholamine concentration by reducing its neuronal uptake. This leads to further stimulation of the sympathetic nervous system. In our experience, prolonged critical illness in patients results in catecholamine depletion, and the drug may cause hypotension resulting in inadequate tissue oxygenation. In a preliminary study by Waxman et al, a single intravenous dose of ketamine for anesthesia led to reduced left ventricular stroke work index in 6 of 12 severely ill patients. Based on that study, Lippmann et al carried out a detailed study and found that in critically ill patients (ie, patients in shock with sepsis who were hypovolemic and stressed preoperatively), ketamine did not always increase heart rate and blood pressure, as is often seen in the healthy young patients. These authors concluded that in patients with limited myocardial reserve and increased demand, ketamine may decrease cardiac output. Because ketamine is being suggested as the drug of choice to anesthetize patients in prehospital and disaster settings such as battlefield conflicts and earthquakes, surgeons and anesthesiologists should be made aware of ketamine's possible downside.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 4","pages":"482"},"PeriodicalIF":2.9,"publicationDate":"2010-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009352484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28660283","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":"Relationship between plasma protease inhibitor concentrations and lipid elevations in HIV patients on a double-boosted protease inhibitor regimen (saquinavir/lopinavir/ritonavir).","authors":"Martin S Rhee,&nbsp;James A Hellinger,&nbsp;Sandy Sheble-Hall,&nbsp;Calvin J Cohen,&nbsp;David J Greenblatt","doi":"10.1177/0091270009339739","DOIUrl":"https://doi.org/10.1177/0091270009339739","url":null,"abstract":"<p><p>The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased from 165 to 189 mg/dL (P = .0005) and the triglyceride increased from 113 to 159 mg/dL (P = .001). There were no associations between PI trough concentrations at week 12 and the percent total cholesterol change at week 12. No associations were found between PI trough concentrations and lipid changes in HIV patients on a double-boosted PI regimen (saquinavir/lopinavir/ritonavir). Factors other than systemic exposure to PIs (such as host or genetic factors) may modulate the hyperlipidemic effect of PIs.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 4","pages":"392-400"},"PeriodicalIF":2.9,"publicationDate":"2010-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009339739","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28666413","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":"Addition of cilostazol to aspirin and a thienopyridine for prevention of restenosis after coronary artery stenting: a meta-analysis.","authors":"Douglas L Jennings,&nbsp;James S Kalus","doi":"10.1177/0091270009338940","DOIUrl":"https://doi.org/10.1177/0091270009338940","url":null,"abstract":"<p><p>The purpose of this study is to evaluate the effect of adding cilostazol to dual antiplatelet therapy (aspirin and thienopyridine) on rates of restenosis after coronary artery stenting. A meta-analysis is conducted of randomized, controlled trials comparing 3 drug regimens (cilostazol, thienopyridine, aspirin [triple therapy]) with dual antiplatelet therapy to reduce restenosis after coronary stenting. A total of 5 studies are included for analysis. The analysis reveals that triple therapy is used in 796 patients, whereas dual therapy is used in 801 patients. Approximately 56% of patients receive a drug-eluting stent. The 6-month restenosis rates are significantly lower with triple versus dual antiplatelet therapy (12.7% vs 21.9%; odds ratio 0.5; 95% confidence interval, 0.38-0.66; P < .001). This benefit is seen regardless of whether a bare-metal or drug-eluting stent is used. Rates of major adverse cardiac events and bleeding are reported for 3 of the 5 studies (n = 1426); analysis of these outcomes shows no difference between treatment groups (P = .21 and .48, respectively). The addition of cilostazol to standard dual antiplatelet therapy reduces angiographic restenosis and increases MLD at 6 months without significantly affecting rates of major adverse cardiac events or bleeding.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 4","pages":"415-21"},"PeriodicalIF":2.9,"publicationDate":"2010-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009338940","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28652730","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":"Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.","authors":"Silvana Borges, Zeruesenay Desta, Yan Jin, Azzouz Faouzi, Jason D Robarge, Sanosh Philips, Santosh Philip, Anne Nguyen, Vered Stearns, Daniel Hayes, James M Rae, Todd C Skaar, David A Flockhart, Lang Li","doi":"10.1177/0091270009359182","DOIUrl":"10.1177/0091270009359182","url":null,"abstract":"<p><p>Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 4","pages":"450-8"},"PeriodicalIF":2.9,"publicationDate":"2010-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816977/pdf/nihms220544.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28652703","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":"PhRMA survey on the conduct of first-in-human clinical trials under exploratory investigational new drug applications.","authors":"Adel H Karara,&nbsp;Timi Edeki,&nbsp;James McLeod,&nbsp;Alfred P Tonelli,&nbsp;John A Wagner","doi":"10.1177/0091270009344987","DOIUrl":"https://doi.org/10.1177/0091270009344987","url":null,"abstract":"<p><p>The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are performed to determine whether the compound modulated its pharmacological target or to evaluate the degree of saturation of a target receptor. The present survey suggests that although the merits of exploratory INDs are still being debated, the diversity in the applications cited, the potential for early clinical guidance in decision making and the increasing pressure on containing drug development costs, suggest that the exploratory IND/CTA will be a valuable option with evolving and possibly more specific applications for the future.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 4","pages":"380-91"},"PeriodicalIF":2.9,"publicationDate":"2010-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009344987","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28666412","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":"Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants.","authors":"Ophelia Q P Yin,&nbsp;Neil Gallagher,&nbsp;Ai Li,&nbsp;Wei Zhou,&nbsp;Robert Harrell,&nbsp;Horst Schran","doi":"10.1177/0091270009336137","DOIUrl":"https://doi.org/10.1177/0091270009336137","url":null,"abstract":"<p><p>Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second-generation BCR-ABL tyrosine kinase inhibitor newly approved for the treatment of imatinib-resistant or imatinib-intolerant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia in chronic phase or accelerated phase. This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double-strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (C(max)) by 60% and the area under the serum concentration-time curve (AUC(0-infinity)) by 29% but did not affect the time to reach C(max) or the elimination half-life of nilotinib. The most common adverse events were headache and vomiting, which were mild or moderate in severity, and their frequency appeared to be similar between 2 treatments. Based on the currently available information about nilotinib and the observed extent of increase in nilotinib exposure, concurrent administration of nilotinib with grapefruit juice is not recommended.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 2","pages":"188-94"},"PeriodicalIF":2.9,"publicationDate":"2010-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009336137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28537901","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":"Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers.","authors":"Andrej Skerjanec,&nbsp;Jixian Wang,&nbsp;Kelly Maren,&nbsp;Lisa Rojkjaer","doi":"10.1177/0091270009340418","DOIUrl":"https://doi.org/10.1177/0091270009340418","url":null,"abstract":"<p><p>Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 2","pages":"205-13"},"PeriodicalIF":2.9,"publicationDate":"2010-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009340418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28529874","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":"Toward optimal treatment in women: the effect of sex on metoprolol-diphenhydramine interaction.","authors":"Ashish Sharma,&nbsp;Philippe Pibarot,&nbsp;Sylvie Pilote,&nbsp;Jean G Dumesnil,&nbsp;Marie Arsenault,&nbsp;Pierre Maxime Bélanger,&nbsp;Bernd Meibohm,&nbsp;Bettina A Hamelin","doi":"10.1177/0091270009340417","DOIUrl":"https://doi.org/10.1177/0091270009340417","url":null,"abstract":"<p><p>The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 2","pages":"214-25"},"PeriodicalIF":2.9,"publicationDate":"2010-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009340417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28537900","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":"Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers.","authors":"Daniel A Spyker,&nbsp;Patrik Munzar,&nbsp;James V Cassella","doi":"10.1177/0091270009347866","DOIUrl":"https://doi.org/10.1177/0091270009347866","url":null,"abstract":"<p><p>The objective of this randomized, double-blind, placebo-controlled, dose escalation study was to determine the pharmacokinetic characteristics, safety, and tolerability of single doses of inhaled loxapine aerosol in healthy volunteers. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Fifty participants were randomized to receive 0.625, 1.25, 2.5, 5.0, or 10 mg of loxapine aerosol or placebo. Following inhalation, the t(max) median (25%, 75%) was 2 (1, 3) minutes. The loxapine AUC(infinity) was dose proportional across all doses with slope (90% confidence interval) of log AUC(infinity) versus log dose = 0.909 (0.832, 0.987). No clinically meaningful changes were noted in hematology results, blood chemistry, vital signs, or respiratory function. The most common adverse events were dizziness, somnolence, and bad taste. The inhalation of Staccato loxapine represents a safe, well-tolerated means for rapidly achieving therapeutic plasma concentrations of loxapine.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"50 2","pages":"169-79"},"PeriodicalIF":2.9,"publicationDate":"2010-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270009347866","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28510644","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":"Pharmacokinetic profiles of controlled-release hydrogel polymer vaginal inserts containing misoprostol.","authors":"Barbara L Powers,&nbsp;Deborah A Wing,&nbsp;Denis Carr,&nbsp;Karine Ewert,&nbsp;Mike Di Spirito","doi":"10.1177/0091270007309707","DOIUrl":"https://doi.org/10.1177/0091270007309707","url":null,"abstract":"<p><p>Misoprostol, a prostaglandin E1 analogue, is commonly administered intravaginally for cervical ripening and induction of labor. There is uncertainty regarding the correct dose because of the need to divide the tablets, and there is difficulty in removing the product when there is an adverse event. A proprietary hydrogel polymer containing a removable controlled-release reservoir dose of misoprostol is being developed for vaginal administration (misoprostol vaginal insert) to address these drawbacks while maintaining efficacy. This study investigated the pharmacokinetic profiles of these vaginal inserts and orally administered misoprostol. Twelve nonpregnant women received 100-, 200-, and 400-microg misoprostol vaginal inserts and separately received an oral dose of 200 microg of misoprostol. Values for area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, were dose proportional with 481, 1026, and 2191 pg.h/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, respectively. Maximum plasma concentrations were 33.1, 73.4, and 144 pg/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, compared with 609 pg/mL for the 200 microg of oral misoprostol. After administration of the insert, plasma misoprostol acid levels increased gradually with time of the maximum measured plasma concentration at 5 to 9 hours. Following removal of the insert, misoprostol acid was eliminated rapidly from the systemic circulation with a mean half-life <1 hour.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"48 1","pages":"26-34"},"PeriodicalIF":2.9,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/0091270007309707","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27110370","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}