Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 32)

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Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 32)

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Introduction: Barbiturates are being widely used as antiepileptics, hypnotics and anaesthetics ( Figure 6.1 and Table 6.1). The incidence of barbiturate poisoning cases tends to increase in Japan ( Figure 6.2) [1]. A majority of the barbiturate drugs is being controlled by the Narcotics ⊡ Figure 6.1 Structures of barbiturates. © Springer-Verlag Berlin Heidelberg 2005 302 Barbiturates ⊡ Figure 6.2 Incidence of fatal barbiturate poisoning cases. Since fatal cases due to Vegetamin® tablets containing phenobarbital are many, its incidence rate is also shown in this figure. and Psychotropics Control Law in Japan; thus they are also important drugs in view of forensic toxicology. ...

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Nội dung Text: Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 32)

  1. 3.6 II.3.6 Barbiturates by Masaru Terada and Ritsuko Watanabe Introduction Barbiturates are being widely used as antiepileptics, hypnotics and anaesthetics ( > Figure 6.1 and > Table 6.1). The incidence of barbiturate poisoning cases tends to increase in Japan ( > Figure 6.2) [1]. A majority of the barbiturate drugs is being controlled by the Narcotics ⊡ Figure 6.1 Structures of barbiturates. © Springer-Verlag Berlin Heidelberg 2005
  2. 302 Barbiturates ⊡ Figure 6.2 Incidence of fatal barbiturate poisoning cases. Since fatal cases due to Vegetamin® tablets containing phenobarbital are many, its incidence rate is also shown in this figure. and Psychotropics Control Law in Japan; thus they are also important drugs in view of forensic toxicology. The analysis of barbiturates in human specimens is being made by GC [2–6], GC/ MS [3, 6, 7–9], HPLC [10–13], LC/MS/MS [14], capillary electrophoresis [15] and immu- noassays [16, 17]. In this chapter, usual methods for analysis of barbiturates by GC and HPLC are presented. ⊡ Table 6.1 Properties and doses of barbiturates Action type Compound Route Therapeutic Maximum dose (g) dose (g) long-acting barbital oral 0.3 0.5 phenobarbital oral 0.03–0.2 0.25 phenobarbital sodium suppository 0.015–0.03 0.2 metharbital oral 0.1 Intermediate amobarbital oral 0.1–0.3 0.5 acting amobarbital sodium i.v./i. m. 0.25–0.5 short-acting pentobarbital calcium oral 0.05–0.1 0.5 pentobarbital sodium i.v. 0.1 0.5 secobarbital sodium i.v. 0.1–0.2 hexobarbital oral 0.1–0.4 0.5 ultrashort-acting thiopental sodium i.v. 0.3–0.5 (anaesthetic) thiamylal sodium i.v. 0.3–0.5 1.0
  3. GC analysis 303 ⊡ Figure 6.3 Methylation reaction of phenobarbital with TMAH. GC analysis [3, 6] Reagents and their preparation • Barbital, phenobarbital sodium, amobarbital sodium, pentobarbital sodium, secobarbital sodium, hexobarbital, thiopental sodium and thiamylal can be purchased from Sigma (St. Louis, MO, USA); pure powder of metharbital was donated by Dainippon Pharmaceu- tical Co., Ltd., Osaka, Japan. • Each barbiturate is dissolved in methanol to prepare 1 mg/mL stock standard solution and stored at –20 °C. • An on-column methylation reagent, 0.2 M trimethylanilium hydroxide (TMAH) (Pierce, Rockford, IL, USA), is diluted with methanol to prepare 4 mM TMAH or 0.4 mM TMAH solution to be used as an on-column methylation reagent ( > Figure 6.3)a. • Diethyl ether b used is of a special grade as pure as that used for analysis of the autoxidation value (AV) and peroxide value (POV) (Dojin Laboratories, Kumamoto, Japan). Other organic solvents are of the highest purity commercially available. • For calibration curves, various concentrations (4–200 ng/mL) of each barbiturate are pre- pared by diluting each 1 mg/mL solution with methanol, and a 10-µL each is evaporated to dryness under a stream of nitrogen, followed by addition of 0.2 mL serum. GC conditions Instrument: a Shimadzu GC-14A gas chromatograph (Shimadzu Corp., Kyoto, Japan). Column: a methylsilicone fused silica wide-bore capillary columnc (DB-1, 15 m × 0.53 mm i. d., film thickness 1 µm, J & W Scientific, Folsom, CA, USA). Column temperature: 60 °C → 8 °C/min → 250 °C; injection temperature: 250 °C d; carrier gas (flow rate): He (15 mL/min); make-up gas (flow rate): He (30 mL/min); detectors: an FID and a nitrogen-phosphorus detector (NPD).
  4. 304 Barbiturates Procedure i. A 0.2-mL volume of serume, 1.3 mL distilled water, 1.0 mL of 0.2 M sodium acetate/acetic acid buffer solution (pH 6.0) and 6.0 mL of ethyl acetate/diethyl ether (1:1, v/v)f are placed in a glass centrifuge tube with a ground-in stopper. ii. The tube is shaken vigorously for 5 min. iii. It is centrifuged at 800 g for 5 min, and the organic layer is transferred to a glass vial with a conical bottom. iv. The organic extract is evaporated to dryness under a stream of nitrogen with warming at 40 °C; the residue is dissolved in 0.4 mL of 0.4 mM TMAH methanolic solution. v. A 1–2 µL aliquot of it is injected into GC; in this method, external calibration method is used. An external calibration curveg is constructed by spiking various concentrations of a barbiturate into serum. The peak area of a peak obtained from a test specimen is applied to the calibration curve to obtain its concentration in a specimen. For identification by GC/ MS, mass spectra are presented in > Table 6.2. ⊡ Table 6.2 Mass spectra of free forms and methyl derivatives of barbiturates Compound M. W. CI mode EI mode Other fragment ions (isobutane) base peak MH+ metharbital 198 155 170, 112, 169 methylmetharbital 212 213 169 184, 126, 112 allobarbital 208 167 124, 80, 141, 106, 53 methylallobarbital 236 237 195 138, 194, 110, 221 amobarbital 226 156 141, 157, 55, 98 methylamobarbital 254 255 169 184, 112, 126 pentobarbital 226 141 156, 157, 55, 98 methylpentobarbital 254 255 169 184, 112, 126 secobarbital 238 167 168, 97, 124, 55 methylsecobarbital 266 267 196 195, 181, 138, 223 hexobarbital 236 221 81, 157, 80, 79, 155, 108, 53 methylhexobarbital 250 251 235 81, 79, 169 mephobarbital 246 218 117,118,146,103 methylmephobarbital 260 261 232 117, 146, 175, 77 phenobarbital 232 204 117, 146, 161, 77, 115 methylphenobarbital 260 261 232 117, 146, 175, 77 cyclobarbital 236 207 141, 81, 79, 67 methylcyclobarbital 264 265 235 169, 79 thiamylal 254 184 168, 167 thiopental 242 172 157, 173, 97, 69 Instrument: a Shimadzu QP-1000EX GC/MS instrument: column: DB-1 (15 m × 0.25 mm i.d., film thickness 0.25 µm); column temperature: 60° C (3 min) → 8° C/min → 290° C; injection temperature: 250° C; carrier gas (flow rate): He (1 mL/min); electron energy: 70 eV (EI), 200 eV (CI); reagent gas: isobutane.
  5. GC analysis 305 Assessment and some comments on the method The GC analysis of barbiturates without any derivatization gives very low sensitivities, even if a non-polar fused silica wide-bore capillary column (DB-1) is used, except for metharbital and hexobarbital. The sensitivities of most barbiturates are enhanced several-fold to several ten-fold by the methyl-derivatization ( > Figs. 6.4 and 6.5, and > Table 6.3). The on-column methylation is very rapid and simple. The detection limits of the methyl-derivatives of barbiturates were 60–90 pg on-column with an NPD and 14–19 ng on-column with an FID. Methylmephobarbital is identical with methylphenobarbital; this means that discrimination ⊡ Figure 6.4 Gas chromatograms of free forms (A) and methyl-derivatives (B) of barbiturates using an NPD. Amounts of barbiturates used for the free and derivatized forms were 2 and 1 ng on-column, respectively. 1: metharbital; 2: allobarbital; 3: amobarbital; 4: pentobarbital; 5: secobarbital; 6: hexobarbital; 7: phenobarbital.
  6. 306 Barbiturates ⊡ Figure 6.5 Gas chromatograms for methyl derivatives of barbiturates spiked into distilled water (A) and human serum (B), and for blank human serum (C) using an NPD. The amount of each barbiturate spiked into distilled water or 0.2 mL plasma was 0.5 µg. The peak numbers are the same as specified in > Figure 6.4. between mephobarbital and phenobarbital becomes impossible after methylation of these compounds. It should be cautioned that the peak of thiopental overlaps that of methylcyclo- barbital. HPLC analysis [10] Reagents and their preparation • Each barbiturate is dissolved in methanol to prepare 10 µg/mL standard solution and stored at –20 °C. • As internal standard (IS) solution, 5-(4-methylphenyl)-5-phenylhydantoin (Sigma) is dis- solved in methanol to prepare 10 µg/mL solution.
  7. HPLC analysis 307 ⊡ Table 6.3 Retention times and detection limits for main barbiturates and their methyl derivatives measured by GC-NPD Compound Retention time Detection limit (min) (pg/on-column) metharbital 6.86 139 methylmetharbital 6.30 52 allobarbital 9.13 667 methylallobarbital 7.61 46 amobarbital 10.7 667 methylamobarbital 9.27 61 pentobarbital 11.0 667 methylpentobarbital 9.61 60 secobarbital 11.6 435 methylsecobarbital 10.2 48 hexobarbital 12.3 169 methylhexobarbital 11.9 52 mephobarbital 12.8 306 methylmephobarbital 12.2 57 phenobarbital 13.5 1,670 methylphenobarbital 12.2 57 cyclobarbital 13.7 1,360 methylcyclobarbital 12.4 89 thiopental 12.4 80 • Calibration curves: 10, 25, 50, 100, 500 and 1,000 µL of the standard solution of each bar- biturate were separately placed in glass centrifuge tubes together with 50 µL of IS solution, and evaporated to dryness under a stream of nitrogen, followed by addition of 0.5 mL se- rum each. HPLC conditions Column: a reversed phase columnh (ODS-80 Ts, 10 cm × 4.6 mm i.d., particle diameter 2 µm, Toso, Tokyo, Japan). Mobile phase: 8 mM phosphoric acid solution/acetonitrile (3:7, v/v). Detection wavelength: 215 nm; flow rate: 0.4 mL/min; temperature: room temperature. Procedure i. A 0.5-mL volume of blood (urine)i, 50 µL IS solution, 0.5 mL distilled water, 0.1 mL of 0.2 acetic acid/sodium acetate buffer solution (pH 6.0) and 3 mL of ethyl acetate/diethyl ether (1:1, v/v) are placed in a 10-mL volume glass centrifuge tube with a ground-in stopper.
  8. 308 Barbiturates ii. The tube is well voltex-mixed or shaken for 2 min. iii. It is centrifuged at 800 g for 5 min, and the organic layer is transferred to a glass vial with a conical bottom. iv. The organic extract is evaporated to dryness under a stream of nitrogen with warming at 40 °C. The residue is dissolved in 100 µL of the mobile phase. v. A 10-µL aliquot of the above solution is injected into HPLC. The peak area ratio obtained from a test specimen is applied to the calibration curvej to calculate its concentration, which had been constructed with the spiked serum according to the above procedure. Assessment and some comments on the method In this method, the authors used an HPLC column with a particle diameter of 2 µm in place of 5 µm; the smaller diameter gives various advantages, such as higher sensitivity, rapid analysis and a smaller amount of the flow of mobile phase. The detection limit for most barbiturates ⊡ Figure 6.6 HPLC chromatograms for blood extracts in the presence (b) and absence (a) of barbiturates. The concentration of each barbiturate spiked into blood was 0.1 µg/mL. 1: barbital; 2: allobarbital; 3: metharbital; 4: phenobarbital; 5: cyclobarbital; 6: pentobarbital; 7: hexobarbital; 8: amobarbital; 9: secobarbital; 10: thiopental; 11: IS [5-(4-methylphenyl)-5-phenylhydantoin].
  9. Toxic and fatal concentrations 309 ⊡ Table 6.4 Retention times and detection limits for main barbiturates measured by HPLC Compound Retention time (min) Detection limit (µg/mL) barbital 3.8 0.05 allobarbital 5.1 0.05 metharbital 5.9 0.05 phenobarbital 6.1 0.05 cyclobarbital 7.1 0.05 pentobarbital 10.6 0.05 hexobarbital 10.6 0.05 amobarbital 10.9 0.05 secobarbital 14.2 0.05 thiopental 21.8 0.5 was about 0.05 µg/mL except for thiopental (0.5 µg/mL) ( > Table 6.4). The peak of pentobar- bital overlaps that of hexobarbital; the peak of amobarbital appears very close to these peaks ( > Figure 6.6). Toxic and fatal concentrations Therapeutic, toxic and fatal blood concentrations of some barbiturates are shown in > Table 6.5 [18, 19]. Every concentration shows a wide variation according to individuals. By single admin- istration, the dose (route), peak blood concentration and its time are: phenobarbital 50 mg (oral), 1.9 µg/mL after 3 h [6]; amobarbital 120 mg (oral), 1.8 µg/mL after 2 h [20]; pentobarbital 100 mg (oral), 1.2–3.1 µg/mL after 0.5–2 h [21]; thiopental 400 mg (intravenous), 28 µg/mL after 2 min, 7 µg/mL after 15 min, and 3 µg/mL after 90 min [22]. The minimum fatal doses are: amobarbital, about 1.5 g; pentobarbital, about 1 g; phenobarbital, about 1.5 g; and thiopental, about 1 g [19]. ⊡ Table 6.5 Blood concentrations of main barbiturates (µg/mL) Compound Therapeutic Toxic conc. Fatal conc. Reference conc. amobarbital 1–5 10–30 13–96 [18] 2–12 >9 9–72 [19] pentobarbital 1–3 >5 10–169 [18] 1–10 >8 8–73 [19] phenobarbital 10–40 40 – 60 >80 [18] 2–30 4–90 4–120 [19] thiopental 1–42 >7 10–400 [18] 4.2–134 6–392 [19]
  10. 310 Barbiturates Survived and fatal poisoning cases Survived phenobarbital poisoning case [23] A 26-year-old male ingested 2–3 g of phenobarbital plus phenytoin. Upon arrival at a hospital, blood phenobarbital concentration was as high as 107 µg/mL. As emergency treatments, 30 g of activated charcoal and 30 g of sodium sulfate were administered orally. The concentration of blood phenobarbital decreased to 72 µg/mL after 24 h; he thereafter recovered without any complication. Fatal thiopental poisoning cases Case 1 [24]: a 21-year-old female received intravenous administration of 17 mL of Thiobal (thiopental sodium solution) for artificial abortion at a women’s clinic, and fell into a shock state 20 min after. Although various emergency treatments were made, she died 2 h after. The blood concentration of thiopental of this victim was 8.2 µg/mL. Case 2 [25]: a 26-year-old male (son) and a 54-year-old female (mother). At their wit’s end due to domestic violence by the son, his father intended to commit triple-suicide. He injected about 12 mL (about 1.75 g thiopental) and about 15 mL (about 1.5 g thiopental) of thiopental solution into his son and wife intravenously, respectively; both of them were killed. He intro- duced car exhaust into his car room and also tried to inject the same solution intravenously by himself to commit suicide, but his trials were abortive. The blood thiopental concentrations of his son and wife were 6.9 and 4.4 µg/mL, respectively. Case 3 [25]: a 25-year-old female was found dead in her room; she had committed suicide by injecting an alate needle into a vein of the right dorsum pedis for drop infusion of thiopen- tal (its amount infused not clear). The concentration of thiopental in her heart blood was 6.3 µg/mL; the amount administered was estimated to be about 1.5 g. Fatal pentobarbital poisoning case [26] A 3.2-year-old male. A doctor directed a nurse to inject 50 mg pentobarbital into the child intramuscularly; but the nurse misunderstood the direction. She began intravenous injection of 50 mL pentobarbital solution to the child. After injection of the 15 mL solution, he fell into a shock state. In spite of efforts with various emergency treatments, he died 22 h later. The pentobarbital concentration in his blood was 17.5 µg/mL (total amount injected estimated about 500 mg). Fatal poisoning cases due to a combined drug or multiple drugs including a barbiturate Case 1 [27]: a 40–45 year-old (estimated) female was found dead on a bed of a hotel. In her room, 2 tablets of Vegetamin (a combined drug containing, phenobarbital, promethazine and
  11. Survived and fatal poisoning cases 311 chlorpromazine) and one capsule of Insumin (flurazepam) were found. From the stomach con- tents, phenobarbital, promethazine and chlorpromazine were detected. Drug concentrations in blood, the liver and kidney were: phenobarbital, 98.0, 106 and 105 µg/g; promethazine, 5.05, 38.2 and 6.92 µg/g; chlorpromazine, 1.68, 22.1 and 3.03 µg/g, respectively. Case 2 [28]: A 30-year-old female was found dead by a passer-by at an open-air parking lot close to her home almost in the nude with her clothes being scattered around her body. In the previous night, the victim had drunk and eaten with her friends and left them. Twenty four empty packages of Isomytal (amobarbital) were discovered at her home. From her blood, amo- barbital at 10.6 µg/mL, phenobarbital at 28.6 µg/mL, promethazine at 2.8 µg/mL and chlor- promazine at 0.9 µg/mL were detected. Case 3 [29]: A 44-year-old male was found dead by his wife in his bedroom with smoke from the right side of his mattress. She called an ambulance, but he had been dead. COHb concentration in his blood was 1 %; burning wounds found in his whole body were negative for vital reaction. From his stomach contents, amobarbital, bromisovalum and levomepromazine were detected. The drug concentrations in blood, the liver, brain and urine were: amobarbital, 25, 47, 30 and 7 µg/mL (g); bromisovalum, 37, 70, 57 and 6 µg/mL (g); levomepromazine, 1.5, 19, 2.0 and not detectable µg/mL (g), respectively. Notes a) By the on-column methylation with TMAH, many compounds are methyl-derivatized immediately ( > Figure 6.3). Except for barbiturate drugs, this method is applicable to glutethimide, primidone and oxazolo-benzodiazepines. For thiopental, the derivatization reaction causes some decomposition products together with the methylated product; the analysis of the underivatized form of thiopental gives better results. The 4 mM and 0.4 mM concentrations of TMAH are used for the FID and NPD, respectively. b) It should be cautioned that thiopental is desulfurized and decomposed by a peroxide in- cluded in diethyl ether. c) Similar types of columns from other manufacturers, such as SPB-1, Ultra#1, CBP-1 and CP-Sil5, can be used. d) When the injection temperature is not high enough (not higher than 200 °C), the efficiency of the on-column methylation is low. e) Blood plasma and whole blood can be also used. f) As extraction solvents, diethyl ether, ethyl acetate, chloroform and dichloromethane can be used; however, the present ethyl acetate/diethyl ether (1:1, v/v) gave the cleanest back- grounds with few impurity peaks for human specimens. For metharbital, diethyl ether, ethyl acetate and dichloromethane give low extraction efficiencies (46–63 %). g) Each calibration curve showed good linearity in the range of 0.2–10 ng on-column (0.2– 10 µg/mL). The detection limits of this method were 60–90 µg/mL in serum. The recovery rates of 0.1–5.0 µg of barbiturates spiked into 0.2 mL serum were 83–111 %. Mass spectra, retention times, detection limits and each GC chromatograms for underivatized and meth- ylated barbiturates are shown in > Tables 6.2 and 6.3, and > Figure 6.5. h) Similar types of ODS (octadecylsilane type silica gel) columns from other manufacturers, such as Zorbax ODS and Hypersil, can be also used. However, the retention times may be longer, because of 5 µm of particle diameter.
  12. 312 Barbiturates i) For organ specimens, a 1-g aliquot of a tissue is minced and homogenized with 4 mL dis- tilled water, followed by centrifugation at 12,000 g for 10 min. A 1-mL volume of the super- natant fraction is processed like the blood (urine). j) Linear relationship was observed in the range of 0.1–5 µg/mL for most barbiturates. The recovery rates from blood were 95–104 %. In this method using urine as a test specimen, interfering impurity peaks derived from urine appear until 10 min of retention time. The retention times, detection limits, and HPLC chromatograms for barbiturates are shown in > Table 6.4 and > Figure 6.6. References 1) National Research Institute of Police Science (ed) (1994–2001) Annual Case Reports of Drug and Toxic Poiso- ning in Japan, Nos. 37–49. National Research Institute of Police Science, Chiba (in Japanese) 2) Terada M, Yamamoto T, Kuroiwa Y et al. (1992) Gel permeation chromatographic clean-up prior to determina- tion of barbiturates in blood extract by gas chromatography. Jpn J Forensic Toxicol 10:31–37 3) Terada M, Shinozuka T, Yasuda M et al. (1992) Simultaneous determination of acidic and neutral drugs by wide bore column gas chromatography with nitrogen-phosphorus detection. In: Nagata T (ed) TIAFT, Proceedings of the 30th International Meeting. Fukuoka, pp 479–482 4) Hattori H, Hoshino N, Seno H et al. (1992) Capillary gas chromatography of underivatized barbiturates in hu- man blood with a nitrogen-phosphorus detector and with splitless injection. Jpn J Forensic Toxicol 10:16–22 5) Coudore F, Alazard JM, Paire M et al. (1993) Rapid toxicological screening of barbiturates in plasma by wide- bore capillary gas chromatography and nitrogen-phosphorus detection. J Anal Toxicol 17:109–113 6) Terada M, Shinozuka T, Bai H et al. (1995) Simultaneous determination of barbiturate drugs in human serum by wide-bore capillary gas chromatography with nitrogen-phosphorus detection. Jpn J Forensic Toxicol 13:223– 231 7) Meatherall R (1997) GC/MS confirmation of barbiturates in blood and urine. J Forensic Sci 42:1160–1170 8) Hall BJ, Brodbelt JS (1997) Determination of barbiturates by solid-phase microextraction (SPME) and ion trap gas chromatography-mass spectrometry. J Chromatogr A 777:275–282 9) Kudo K, Nagata T, Kimura K et al. (1988) Toxicological analysis of thiamylal in biological materials by gas chro- matography/mass spectrometry. Forensic Sci Int 37:193–200 10) Tanaka E, Terada M, Tanno K et al. (1997) Forensic analysis of 10 barbiturates in human biological samples using a new reversed-phase chromatographic column packed with 2-micrometre porous microspherical silica-gel. Forensic Sci Int 85:73–82 11) Hart AP, Mazarr Proo S, Blackwell W et al. (1997) A rapid cost-effective high-performance liquid chromatogra- phic (HPLC) assay of serum lamotrigine after liquid-liquid extraction and using HPLC conditions routinely used for analysis of barbiturates. Ther Drug Monit 19:431–435 12) Biosca YM, Sagrado S, Camanas RMV et al. (1999) Determination of barbiturates in urine by micellar liquid chromatography and direct injection of sample. J Pharm Biomed Anal 21:331–338 13) Borregon PFG, Lores M, Cela R (2000) Analysis of barbiturates by micro-high-performance liquid chromatogra- phy with post-column photo-chemical derivatization. J Chromatogr A 870:39–44 14) Spell JC, Srinivasan K, Stewart JT et al. (1998) Supercritical fluid extraction and negative ion electrospray liquid chromatography tandem mass spectrometry analysis of phenobarbital, butalbital, pentobarbital and thio- pental in human serum. Rapid Commun Mass Spectrom 12:890–894 15) Ferslew KE, Hagardorn AN, McCormick WF (1995) Application of micellar electrokinetic capillary chromatography to forensic analysis of barbiturates in biological fluids. J Forensic Sci 40:245–249 16) Schwenzer KS, Pearlman R, Tsilimidos M et al. (2000) New fluorescence polarization immunoassays for analysis of barbiturates and benzodiazepines in serum and urine: performance characteristics. J Anal Toxicol 24:726–732 17) Charlier CJ, Plomteux GJ (2000) Evaluation of Emit Tox benzodiazepine and barbiturate assays on the Vitalab Viva analyser and FPIA on the Abbott ADx analyser. Clin Chem Lab Med 38:615–618 18) Winek CL (1994) Drug & chemical blood-level data 19) Moffat AC, Jackson JV, Moss MS et al. (eds) (1986) Clarke’s Isolation and Identification of Drugs. The Pharmaceu- tical Press, London
  13. Survived and fatal poisoning cases 313 20) Inaba T, Tang BK, Endrenyi L et al. (1976) Amobarbitala probe of hepatic drug oxidation in man. Clin Pharm Ther 20:439–444 21) Sun S, Chum AHC (1977) Determination of pentobarbital in serum by electron-capture GLC. J Pharm Sci 66:477–480 22) Brodie BB, Mark LC, Papper EM et al. (1950) The fate of thiopental in man and a method for its estimation in biological materials. J Pharm Exp Ther 98:85–96 23) Goldberg MJ, Berlinger WG (1982) Treatment of phenobarbital overdose with activated charcoal. JAMA 247:2400–2401 24) Furuno J, Sugawara N (1972) On a fatal case of thiopental shock and the metabolism. Jpn J Legal Med 26:71–77 (in Japanese with an English abstract) 25) Tadano Y, Yamakawa M, Miura K et al. (1989) Cases of homicide and suicide using thiopental sodium. Res Pract Forensic Med 32:117–121 (in Japanese with an English abstract) 26) Fukumoto H, Fukumoto K (1970) A case of fatal pentobarbital poisoning – Estimation of pentobarbital dosage from the blood concentration –. Jpn J Legal Med 24:68–72 (in Japanese with an English abstract) 27) Kageura M, Hara K, Hieda Y et al. (1987) Forensic toxicological study on a combined drug (phenobarbital, pro- methazine and chlorpromazine). Res Pract Forensic Med 30:83–87 (in Japanese with an English abstract) 28) Terada M, Yasuda M, Wakasugi C (1993) A case report on the detection of antipsychotic drugs. Jpn J Legal Med 47:285–286 (in Japanese) 29) Terada M, Yoshimura S, Yamamoto T et al. (1981) A case report on the detection of amobarbital, bromvalery- lurea and levomepromazine from the postmortally burnt body. Jpn J Legal Med 35:456–461 (in Japanese with an English abstract)

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