查找:                      转第 显示法宝之窗 隐藏相关资料 下载下载 收藏收藏 打印打印 转发转发 小字 小字 大字 大字
【期刊名称】 《刑事技术》
GC-MS法测定急诊病人血液中的唑吡坦
【英文标题】 Determination of Zolpidem in Blood Samples from Emergency Patients Using GC-MS
【作者】 文汉泰洪荣基李骏熙高Ahra丁源俊郑熙仙
【作者单位】 忠南国立大学分析科学技术研究生院忠南国立大学分析科学技术研究生院忠南国立大学分析科学技术研究生院忠南国立大学分析科学技术研究生院忠南国立大学医院急救科忠南国立大学分析科学技术研究生院
【中文关键词】 法医毒物学;唑吡坦;急诊病人;GC-MS
【英文关键词】 forensic toxicology; zolpidem; emergency patients; GC-MS
【文章编码】 1008-3650(2019)01-0013-09【文献标识码】 A
【期刊年份】 2019年【期号】 1
【页码】 13
【摘要】 社会快速变化导致的压力和/或诱惑,使得药物中毒正愈发显著地逐年增多,因而成为急救医学的一个突出方面。故建立一个快速准确的筛选方法从而鉴定中毒物质就显得尤为必需。但在韩国急救室环境下这样的一种系统性毒物毒理学研究仍不充分。因此,本研究旨在通过使用GC-MS仪器系统建立一个快速准确的方法以鉴定所涉药物,并对药物浓度与临床症状之间的关系作评估,从而为病人的恰当治疗提供借鉴和依据。为此,我们收集了2015年2至7月入住忠南国立大学医院的80位病人的血样,并以GC-MS进行分析。结果发现,唑吡坦是检出率最高的药物,共有15例,病人中唑吡坦的浓度在19.63~3605.85ng/mL之间,病人年龄从20到88岁。其中有5例(33%)企图自杀的病人仅服用了唑吡坦,另外10例则还选择了其他药品(一种或几种)配合使用。这些药品中,酒精3例;但曲马多被选配得最多,有4例;接下来是醋氨酚(亦即对乙酰氨基酚)3例;曲唑酮和氯苯吡胺各2例。另外,阿普唑仑、氯氮平、苯海拉明、喹硫平分别检出1次。80岁以上年龄病人组的唑吡坦浓度最高,但这与格拉斯哥昏迷评分、心理变化、服药剂量以及药物中毒后已过时间等因素却没有关联性。这很可能与服药量和/或同其他药品一起使用的准确信息缺乏有关。应可推断,所观察到的个体表现差异更多地与病人的代谢状况而不是服药剂量具有相关性。全部15例病人包括唑吡坦浓度最高者都在几天之内大为好转并出院。故唑吡坦用药过量的症状是中度的,并不会造成进一步的伤害。本研究对于完善分析体系从急救室病人样品中检测毒品能起到补充作用,对指导合理用药剂量有借鉴意义,对毒代动力学研究建立一套快速恰当的治疗程序具有帮助价值。此外,本文相关信息和结论对于法医毒理学确定与检测涉及唑吡坦中毒的死亡也有助益。
【英文摘要】 In accordance with the tension and/or temptation from rapid changes in society, intoxication is significantly increasing year by year and becoming a remarkable presence in emergency medicine. It is necessary to establish a fast and accurate screening method to identify the toxicants, but research for such systematic toxicological analysis in emergency room setting is insufficient in Korea. Hence, the purpose of this study was to establish a fast and accurate method for identifying the drugs using GC-MS and to evaluate the correlation between the blood concentration of drugs and the clinical symptoms for proper treatment of patients. In order to set up the analytical method, blood specimens were collected from 80 patients who were admitted to Chungnam National University Hospital from February to July in 2015 and were analyzed by GC-MS. As a result, zolpidem was the most frequent drug, detected in 15 cases, showing its blood concentration ranging from 19.63 to 3605.85 ng/mL in the patients aging from 20 to 88 years old.5 of the cases were patients who ingested zolpidem for suicide attempt (33%). Ingestion of zolpidem alone was in 5 cases and ingestion with other drugs in 10 cases. Alcohol was detected in 3 cases. The most common drug taken together was tramadol, detected in 4 cases, followed by acetaminophen in 3 cases, and trazodone and chlorpheniramine in 2 cases, respectively. Alprazolam, clozapine, diphenhydramine and quetiapine were each detected once. The zolpidem concentration was the highest among the patients in their 80s (older than 80 years), but there was no correlation with GCS score, mental change, the ingested amount or elapsed time after intoxication. This is most likely due to the lack of accurate information on the ingested dose and other substances. It is supposed that the difference observed in each individual is associated with metabolism rather than ingested dose. All of 15 patients including those with high zolpidem concentrations improved within a few days and were discharged. Symptoms of intoxication by zolpidem overdose were moderate, no further damage observed. This study will supplement the analytical system for detecting toxicants from samples of emergency room patients, information of correct dosage, and toxicokinetics exploration to establish a procedure for fast and appropriate treatment. Besides, it will provide useful information for determining intoxication deaths related to zolpidem in forensic toxicology.
【全文】法宝引证码CLI.A.1253066    
  1 Introduction
  Rapid social changes cause a number of intoxication cases increasing annually, leaving acute intoxication becoming an important aspect of emergency medicine. It is very important to identify toxic drugs and chemicals in patients through a fast and accurate screening method.
  In this study, the screening method was established and applied to blood specimens collected from 80 patients who were admitted to Chungnam National University Hospital from February to July in 2015. Expectedly, zolpidem was the most commonly detected drug, being detected in 15 out of 80 cases.
  Zolpidem is structurally classified as an imidazopyri-dine, also chemically known as N, N-dimethyl-2-(6methyl-2-p-tolylimidazo[1, 2-α]pyridin-3-yl)acetamide {1}. Currently, zolpidem is the most prescribed sedative-hypnotic for treatment. It is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults {2-6}.
  Zolpidem has been marketed in Europe since 1987, and was approved by US Food and Drug Administration (FDA) in April 1992. It is the 15th most prescribed drug in the US {7}and as a result, a high number of acute intoxication has been reported about zolpidem.
  Acute intoxication related to zolpidem is often the stories from autopsy cases. According to Jones {8}, 357 cases of death related to zolpidem occurred from 2001 to 2010 in Sweden. Jonsson {9}found that in Sweden, 25 out of 3560 autopsy cases were death related to zolpidem alone. Also, Tominaga {10}reported that zolpidem was detected in 3 cases from 808 autopsy cases during 2010 to 2014 in Japan. Thus, it can be seen that zolpidem affects the cause of death alone or with other drugs.
  In Korea, zolpidem was detected in 16 autopsy cases conducted by National Forensic Service from 2006 to 2008, and discovered to be mainly used for suicide attempt as well as the cause of death due to acute intoxication {11}.
  The quantitation of zolpidem in 15 cases here showed a huge discrepancy between samples. Indeed, three cases revealed extremely high concentrations of zolpidem, over 1600 ng/mL, a concentration of comatose-fatality according to Schulz {12}. However, three patients in these cases were in neither comatose-fatal nor serious condition when admitted and fully recovered in a couple of days.
  Thus in this study, the relationship between blood concentrations and clinical symptoms was studied so as to explain how patients survived at such a high level of the drug. These are very observation-worthy non-fatal cases with extreme high zolpidem concentrations.
  2 Pertinent case reports
  Case 1: An 80 year-old male was admitted to the hospital after he failed to wake up. His mental state was stupor at the time of admission and GCS (Glasgow Coma Scale) was 7. Intubation was operated. There were no other unusual findings on brain MRI. Decreased con-sciousness was suspected due to drugs on the EEG (electroencephalogram) test. After consciousness was recovered, his CK (Creatine Kinase) was 1047 on the blood test. He was transferred to the division of pulmonology because aspiration pneumonia and rhabdomyolysis were suspected. Sample was collected 25 hours after intoxication.
  Case 8: An 81 year-old female, suffering with Parkinson’s and Alzheimer’s disease, was admitted after overdosing her prescription drug, zolpidem. Her mental state was alert and GCS was 14 at the time of admission. Chest X-ray suggested pneumonia, but no other unusual findings were observed. Sample was collected 13 hour after intoxication.
  Case 9: An 81 year-old female, suffering from depression, was admitted to the hospital after attempting suicide by ingesting zolpidem and half a bottle of alcohol, and then self-inflicting her right wrist. Her mental state was drowsy and GCS score was 8 at the time of admission. There were no other unusual findings. She was discharged next day. Sample was collected 9 hours after intoxication.
  Case 12: An 88 year-old female, afflicting of anxiety disorder, was admitted after ingesting a large dose of hypnotics with alcohol. Her mental state was semi-coma and GCS score was 3 at the time of admission. Intubation was carried out. There were no other unusual findings. Sample was collected 11 hours after intoxication.
  Case 14: An 82 year-old male showing decreased consciousness was admitted to the hospital’s emergency room. According to the family, ingestion of hypnotics was suspected but no presence of clear evidence. His GCS score was 9 and mental state was stupor at the time of admission. Pulse rate (PR) was 125, respiratory rate (RR)40, with a fever of 39.7°C. Intubation and ventilator were applied. Lactic acid was 4.7, WBC (White blood cell)11800, and CRP (C-reactive protein)1.2, according to the blood test. Aspiration pneumonia was suspected based on chest X-ray and CT scan. He was transferred to a care facility as DNR (Do Not Resuscitate) state. Sample was collected 12 hours after intoxication.
  3 Experimental
  3.1 Patients samples
  In order to set up the analytical method, blood specimens were collected from 80 patients who were admitted to Chungnam National University Hospital from February to July in 2015. The collected specimens were respectively stored in EDTA solution at 4℃ until analysis. GCS score, mental change, elapsed time from intoxication and estimated dose of patients were recorded at the time of admission.
  3.2 Standards and reagents
  Blank human whole blood was purchased from the Korean Red Cross (Daejeon, Korea) and used for validation of the analytical procedure. Zolpidem standard and trimipramine-d3, taken as the internal standard (IS), were purchased from Cerilliant (Round Rock, TX, USA). All solvents were products from Burdick & Jackson (Muskegon, MI, USA), of HPLC grade.
  Stock solution of zolpidem was prepared at 1 and 10μg/mL in methanol, and trimipramine-d3 was prepared at 5μg/mL. Working solutions were prepared by diluting stock solution to appropriate concentrations. All solutions were stored at 4℃.
  Zolpidem metabolite, collected from patients in hospital.
  Solid-Phase Extraction (SPE) cartridges (Bond Elut Certify, 130 mg/3 mL, Agilent Technologies, Santa Clara, CA, USA) were used for sample preparation.
  3.3 Sample preparation
  3.3.1 Samplepreparation for screeningof patients samples
  For each sample, a 1.0 mL aliquot of blood sample and 3 mL of 0.1 mol/L phosphate buffer (pH 6.0) were added into a test tube. The mixture then followed to undergo:2 minutes of vortex, 10 minutes of sonification and 10 minutes of centrifugation at 3500 rpm.3 mL supernatant of the mixture was loaded into an SPE cartridge preconditioned with 2 mL methanol and 2 mL of 0.1 mol/L phosphate buffer. The cartridge was then washed with 1 mL water and 1 mL 0.2 mol/L acetic acid. Vacuum (15-in Hg) was applied for 4 minutes to dry.50μL of methanol was applied, and then dried for 1 minute (vacuum, 15-in Hg).
  The acidic analytes were eluted with 3 mL of chloroform/acetone (1:1, v/v)(Acidic fraction). The basic analytes were eluted with 3 mL of 2% ammoniated ethyl acetate (Basic fraction). The eluted substances were evaporated using nitrogen gas (50℃). The extract was reconstituted with 100μL of methanol, from which 1μL was injected into the GC-MS for analysis.
  3.3.2 Sample preparation for quantification of zolpidem
  A 1.0 mL aliquot of blood sample was added into a test tube, together with 30μL of IS (trimipramine-d3) and 3 mL of 0.1 mol/L phosphate buffer (pH 6.0). The following steps were same as those for patients samples in 3.3.1 above, with the exception of second dryness at vacuum of 1-in Hg.
  3.4 GC-MS condition
  3.4.1 GC-MS condition for screening of patients samples
  An Agilent 7890B GC system coupled with an Agilent 5977A MSD (Agilent Technologies, Santa Clara, CA, USA) was used in an assemblage of the HP-5MS fused silica capillary column (30 m ×0.25 mm i.d., 0.25μm film thickness, Agilent Technologies). Splitless mode was selected. Helium was chosen as the carrier gas at the flow rate of 1.0 mL/min. The oven temperature was set at 80℃initially for 1 min, and then programmed to increase to 300℃ by 20℃/min to hold for another 15 min. The temperatures at injection port and transfer line were 300℃and 250℃, respectively. The mass spectrometer was operated at 70 eV on electron impact mode.Analysis was performed in scan mode (m/z 45~550).
  3.4.2 GC-MS condition for quantification of zolpidem
  Identical apparatus was applied as in 3.4.1. Split mode (20?1) was selected. The carrier gas and running were same as those in 3.4.1. The oven temperature was set at 120°C initially for 1 minute, and then programmed to increase to 300°C by 30°C/min to hold for another 3 min. Following the same temperature setup at injection port and transfer line as in 3.4.1 plus the mass spectrometer operating, the analysis was performed in selected ion monitoring (SIM) mode, with the parameters of m/z 235, 307 and 219 for zolpidem and m/z 61, 249 and 297 for trimipramine-d3.
  3.5 Analytical method validation
  The method for quantification was validated by mea-suring linearity, extraction efficiency, limit of detection (LOD), limit of quantification (LOQ), precision, and ac curacy {13}.
  Calibration curve was constructed for quantification by injecting 6 different concentrations (20, 50, 100, 200, 500 and 1000 ng/mL) of zolpidem into blank specimens. Extraction efficiency was estimated by comparing the injected solution with the extracted one. LOD and LOQ were determined through signal-to-noise (S/N) at 3:1 and 10:1. Precision and accuracy were tested by replicate analyses (n=3) of repeating 3 times for 3 days. Precision was calculated by the percentage of either relative standard deviation or accuracy.
  4 Results and Discussion
  4.1 Demographics
  Patients admitted to the emergency room of Chungnam National University Hospital from February to July in 2015 were examined.80 patients (46 males and 34 females) were intoxicated, and among them, 15 patients (18.7%, 12 males and 3 females) were intoxicated with zolpidem (Fig.1). The ages ranged from 20 to 88, with the average of 60.
  (图略)
  Fig.1 Demographics of patients intoxicated with zolpidem
  4.2 Status of detected drugs through screening method
  Through analysis of 80 patient`s samples from Chungnam National University Hospital, zolpidem was the most frequent drug, identified in 15 cases, followed by 9 cases of diphenhydramine, 8 cases of tramadol and acetaminophen, 6 cases of chlorpheniramine, 5 cases of quetiapine, and 4 cases of doxylamine. Imipramine, temazepam and trazodone were of 3, respectively. Diazepam, phenobarbital, dihydrocodeine and carbamazepine were of 2, individually.
  Most of the drugs such as benzodiazepine were analyzed through basic fraction, but acetaminophen and phenobarbital were analyzed in acid fraction.
  4.3 Analytical method validation
  The method was validated before analyzing zolpidem from actual samples. Linearity, LOD and LOQ, extraction efficiency, and precision and accuracy of zolpidem out from GC-MS were the tested parameters.
  The calibration curve was linear over the concentration range of 20-1000 ng/mL, with the correlation coefficient of r2=0.9997(Fig.2). The extraction efficiency ranged from 64.4% to 77.7%. LOD and LOQ values were 1 and 10 ng/mL, respectively (Table 1). The intra-and inter-day precision and accuracy were acceptable, ranging from 0.4%-1.85% and 86.82%-113.72%, respectively (Table 2).
  (图略)
  Fig.2 Calibration curve of zolpidem
  Table 1 Method validation for zolpidem

┌────┬───┬─────┬────┬───┬─────┬─────┬──────┐
│Compound│RT/min│Quantifier│Qualifie│R2  │LOD/(ng/mL│LOQ/(ng/mL│Efficiency/%│
│    │   │ Ion/(m/z)│r Ion/(m│   │)     │)     │      │
│    │   │     │/z)   │   │     │     │      │
├────┼───┼─────┼────┼───┼─────┼─────┼──────┤
│Zolpidem│9.47 │235    │219, 307│0.9997│1     │10    │71.80    │
│    │   │     │    │   │     │     │      │
└────┴───┴─────┴────┴───┴─────┴─────┴──────┘

  Table 2 Intra- and inter-day precision and accuracy

┌─────┬─────────┬────────────┬──────────┐
│     │Concentration   │Precision/(RSD, %)   │Accuracy/%     │
│     ├─────────┼─────┬──────┼─────┬────┤
│     │/(ng/mL)     │Intraday │Interday  │Intraday │Interday│
│     │         │     │      │     │    │
├─────┼─────────┼─────┼──────┼─────┼────┤
│Zolpidem │50        │1.85   │0.71    │113.72  │113.33 │
│     ├─────────┼─────┼──────┼─────┼────┤
│     │500        │0.44   │0.72    │86.82   │87.39  │
│     ├─────────┼─────┼──────┼─────┼────┤
│     │1000       │0.4    │0.42    │104.92  │105.09 │
└─────┴─────────┴─────┴──────┴─────┴────┘

  4.4 Blood concentration of zolpidem
  The blood concentration of zolpidem in 15 patients ranged from 19.63-3605.85 ng/mL (Table 3). In cases of ingesting zolpidem alone (n=5), the blood concentration was spanning from 20.04-3605.85 ng/mL, while bestriding across 19.63-2195.85 ng/mL in the cases involving multiple drugs (n=10). According to Schulz{12}, the blood concentration of zolpidem amid 80-200 ng/mL is therapeutic concentration, toxic for 120-700 ng/mL, and comatose-fatal across 1600-7700 ng/mL. Th

  ······

法宝用户,请登录后查看全部内容。
还不是用户?点击单篇购买;单位用户可在线填写“申请试用表”申请试用或直接致电400-810-8266成为法宝付费用户。
【注释】                                                                                                     
【参考文献】 {1}SALVA P, COSTA J. Clinical pharmacokinetics and pharmacodynamics of zolpidem - therapeutic implications[J]. Clinical Pharmacokinetics, 1995, 29(3):142-153.
  {2}MERLOTTI L, ROEHRS T, KOSHOREK G, et al. The dose effects of zolpidem on the sleep of healthy normals[J]. Journal of Clinical Psychopharmacology, 1989, 9(1):9-14.
  {3}NICHOLSON A, PASCOE P A. Hypnotic activity of an imid-azo-pyridine (zolpidem)[J]. British Journal of Clinical Pharmacology, 1986, 21(2):205-211.
  {4}LUND R, RüTHER E, WOBER W, et al. Effects of zolpidem (10 and 20 mg), lormetazepam, triazolam and placebo on night sleep and residual effects during the day. In: Imidazopyridines in Sleep Disorders[M]. New York: Raven Press, 1988:193203.
  {5}OSWALD I, ADAM K. A new look at short-acting hypnotics, Imidazopyridines in sleep disorders[J]. LERS Monograph Series, 1988, 6:253-260.
  {6}BLOIS R, GAILLARD J. The effects of zolpidem on charac-teristics of normal human sleep. In: Imidazopyridines in Sleep Disorders[M]. New York: Raven Press, 1988:375-376.
  {7}AITKEN M. Declining medicine use and costs: for better or worse? A review of the use of medicine in the United States in 2012[R]. IMS Institute for Healthcare Informatics, 2013:1-50.
  {8}JONES A W, HOLMGREN A. Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies[J]. Forensic Science International, 2012, 222(1-3):118-123.
  {9}J?NSSON A K, S?DERBERG C, ESPNES K A, et al. Sedative and hypnotic drugs—fatal and non-fatal reference blood concentrations[J]. Forensic Science International, 2014, 236:138145.
  {10}TOMINAGA M, MICHIUE T, ISHIKAWA T, et al. Evaluation of postmortem drug concentrations in cerebrospinal fluid com-pared with blood and pericardial fluid[J]. Forensic Science International, 2015, 254:118-125.
  {11}CHUNG H S. Therapeutic and toxic concentrations of chemi-cals. In: National Forensic Service, 2010: pp.3.
  {12}SCHULZ M, SCHMOLDT A. Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics[J].Pharmazie, 2003, 58:447-474.
  {13}PETERS F T, DRUMMER O H, MUSSHOFF F. Validation of new methods[J]. Forensic Science International, 2007, 165(23):216-224.
  {14}BASELT R, CRAVEY R. Disposition of toxic drugs and chem-icals in man[M].4th ed. Chemical Toxicology Institute, 1995.
  {15}GOCK S BWONG S H Y, NUWAYHID N, et al. Acute zolpi-dem overdose - Report of two cases[J]. Journal of Analytical Toxicology, 1999, 23(6):559-562.
  {16}SASAKI C, SHINOZUKA T, MURAKAMI C, et al. Simulta-neous determination of 5 psychotropic drugs of various types in an autopsy case of acute multiple drug poisoning[J]. Forensic Science International, 2013, 227(1-3):90-94.
  {17}COLUCCI A P, GAGLIANO-CANDELA R, AVENTAGGIA-TO L, et al. Suicide by self-administration of a drug mixture (Propofol, Midazolam, and Zolpidem) in an anesthesiologist: the first case report in Italy[J]. Journal of Forensic Sciences, 2013, 58(3):837-841.
  {18}KELLER T, SCHNEIDER A, TUTSCH-BAUER E. GC/MS determination of zolpidem in postmortem specimens in a voluntary intoxication[J]. Forensic Science International, 1999, 106(2):103-108.
  {19}GREENBLATT D J, VON MOLTKE L L, HARMATZ J S, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole*[J]. Clinical Pharmacology & Therapeutics, 1998, 64(6):661-671.
  {20}LANGTRY H D, BENFIELD P. Zolpidem[J]. Drugs, 1990, 40(2):291-313.
  {21}PRIEST R. Ambieu (zolpidem 5 mg &10 mg), UK product license application[Z]. Paris: Registretion department (LERS), 1993.
  {22}PATAT A, TROCHERIE S, THEBAULT J, et al. EEG profile of intravenous zolpidem in healthy volunteers[J]. Psychopharmacology, 1994, 114(1):138-146.
  {23}VANDEL S, VANDEL B, JOANNE C, et al. Influence of eth-nic origin on the clinical pharmacology of zolpidem. In: Imidazopyridines in Sleep Disorders[M]. New York: Raven Press, 1988:390.
  {24}COLLE M, ROSENZWEIG P, BIANCHETTI G, et al. Noctur-nal profile of growth hormone secretion during sleep induced by zolpidem: a double-blind study in young adults and children[J]. Hormone Research in Paediatrics, 1991, 35(1):3034.
  {25}THENOT J, HERMANN P, DURAND A, et al. Pharmacokinetics and metabolism of zolpidem in various animal species and in humans. In: Imidazopyridines in Sleep Disorders[M].New York: Raven Press, 1988:139-153.
  {26}DESAGER J P, HULHOVEN R, HARVENGT C, et al. Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic[J]. Psychopharmacology, 1988, 96(1):63-66.
  {27}ALBIN H, VINCON G, VINCON J, et al. Study of the pharmacokinetics of zolpidem in healthy volunteers after repeated administration: effects on antipyrine clearance. In: Imidazopyridines in Sleep disorders[M]. New York: Raven Press, 1988:369-370.
  {28}DEBAILLEUL G, KHALIL F A, LHEUREUX P. HPLC quantification of zolpidem and prothipendyl in a voluntary intoxi-cation[J]. Journal of Analytical Toxicology, 1991, 15(1):3537.
  {29}WILKINSON C J. The abuse potential of zolpidem administered alone and with alcohol[J]. Pharmacology Biochemistry and Behavior, 1998, 60(1):193-202.
  {30}WILKINSON C J. The acute effects of zolpidem, administered alone and with alcohol, on cognitive and psychomotor function[J]. Journal of Clinical Psychiatry, 1995, 56(7):309-318.
  {31}GUSTAVSEN I, AL-SAMMURRAIE M, M?RLAND J, et al.Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers[J].Accident Analysis & Prevention, 2009, 41(3):462-466.
  {32}SUH J H, ROH H K, EO E K, et al. Clinical characteristics of acute zolpidem intoxication[J]. Journal of the Korean Society of Clinical Toxicology, 2008, 6(2):91-98.
  {33}GARNIER R, GUERAULT E, MUZARD D, et al. Acute zolp-idem poisoning analysis of 344 cases[J]. Clinical Toxicology, 1994, 32(4):391-404.
  {34}WYSS P, RADOVANOVIC D, MEIER-ABT P. Acute over-dose of zolpidem (stilnox)[J]. Schweizerische Medizinische Wochenschrift, 1996, 126(18):750-756.
©北大法宝:(www.pkulaw.cn)专业提供法律信息、法学知识和法律软件领域各类解决方案。北大法宝为您提供丰富的参考资料,正式引用法规条文时请与标准文本核对
欢迎查看所有产品和服务。法宝快讯:如何快速找到您需要的检索结果?    法宝V5有何新特色?
本篇【法宝引证码CLI.A.1253066      关注法宝动态: