Med. Sci. Law (1977) Vol. 17, No.3
Printed in Great Britain
193
A Case of Fatal Imipramine Poisoning in an Infant J. S. OLIVER,
SSe, PhD, CChem, MRIC
HAMILTON SMITH,
SSe, PhD, CChem, FRIC, MRCPath
Department of Forensic Medicine, University of Glasgow INTRODUCTION A number offatal cases of imipramine poisoning have been recorded in the literature. Curry (1964) reported seven, Dal Cortivo et al. (1963) reported one and Denton (1962) recorded two fatal cases and one non-fatal case. This paper presents the details of accidental poisoning in a child together with the analytical findings. The levels measured are compared with those found in adults and with values from the literature. CASE REPORT A l6-month-old child was left alone for a few minutes. When the mother returned she found the child sitting on the floor holding a bottle of pills, a few of which were scattered about the floor. A tablet was removed from the child's mouth. It was noticed that the tongue was red. An emetic of salt and water was given which made the child sick. Despite this, quick transference to hospital and subsequent treatment, the child died. From the beginning to the end of this episode 41 hours elapsed.
TOXICOLOGICAL ANALYSIS Samples of brain, liver and blood were received for analysis and produced the following results: Brain 2·8 mg imiprarninej l Of) g Liver 5·7 mg imipraminej l Ol) g Blood imipramine was present. No other drugs were present. METHOD The drug was isolated from biological materials using the extraction procedure described by Curry (1969). Thin-layer chromatography and ultraviolet spectrometry were used to establish the identity of the drug and ultraviolet spectrometry was used to measure the concentrations.
Ultraviolet Spectrometry The instrument used was a U nicam SP800 equipped with 1 em path length fused silica cells. Imipramine can be readily detected and estimated in a biological sample using the absorption curve obtained with the drug dissolved in O·lN sulphuric acid. The absorption maximum is at 251 nanometres. Thin-layer Chromatography The drug and extracts were chromatographed on Silica Gel G layers and revealed using acidified iodoplatinate reagent (Oliver and Smith, 1973). Two solvent systems can be used to identify imipramine. They are a 3 : 1 mixture of chloroform and methanol (imipramine R, 0,52) and a 200 : 3 mixture of methanol and ammonia (imipramine R, 0·57).
RESULTS AND DISCUSSION Both thin-layer chromatography systems showed the presence of imipramine in all the post-mortem materials and desmethylimipramine (R, 0·31 in chloroform/methanol and 0·25 in methanol/ammonia) in the liver. The levels of imipramine found are listed in Table 1. The analytical technique used produced a rapid and an easy confirmation that imipramine was present in the post-mortem material. The ultraviolet absorption spectrum obtained with the extracted drug was not influenced by co-extractable material, particularly . nicotinamide-like substances. This was further verified by thin-layer chromatography where no reaction was obtained with the spray reagent that did not correspond to either imipramine or its
194
Med. Sci. Law (1977) Vol. 17, No.3
Table I. Imipramine Levels from Fatal Poisoning Source Present study Present study Curry (1964) Dal Cortivo (1963)
Blood (mgt100 ml)
Liver (mgt1 00 g)
Brain (mg/100 g)
Present
5·7 2,0-9'5 0'5-25 5·4
2'8
0,033-1'2 0·8
metabolite, desmethylimipramine. However, the R, values found in both solvent systems for the extracted drugs had been influenced by co-extractable material. Addition of imipramine and desmethylimipramine to the liver extract produced two spots on the silica layer with both solvent systems. The added drugs were not separated from the extracted drugs. The results given in Table I show agreement between high liver levels and relatively low blood levels in adults with the findings in this case where the blood content of imipramine was not measurable though detectable. The spray reagent will readily detect I Ilg of imipramine; however the ultraviolet spectrometer reaches a limit of useful sensitivity with a blood imipramine level of about 0·25 mg!l 00 ml when a 10 ml blood sample is used for analysis. Thus the lower blood levels occasionally found may require the use of a colorimetric assay or gas-liquid chromatography. The metabolite, desmethylimipramine, appeared only in the liver extract. The measuring technique used does not differentiate the metabolite from imipramine since they have identical ultraviolet spectra. However, an examination of the thin-layer
3'08-7'2 None
Comment 1 infant 3 adults 7 cases 1 case
chromatography plates showed that there were approximately equal amounts of both drug and metabolite.
CONCLUSIONS The techniques of thin-layer chromatography and ultraviolet spectroscopy have been applied to a fatal case of imipramine poisoning in an infant. The results show a drug level within the range of values found for adults and showing the same trend of a high level in the liver and a low blood level. The techniques also allowed the rapid and easy identification of desmethylimipramine (desipramine). This was found to be present in the liver sample only. REFERENCES
Curry A. S. (1964) Seven fatal cases involving imipramine in man. ]. Pharm. Pharmac. 16,265-267. Curry A. S. (1969) Poison Detection in Human Organs. 2nd Ed. Springfield, Ill., Thomas. Dal Cortivo L. A., Giaquinta P. and Umberger C. J. (1963) The determination of imipramine in biological material.]. Forensic Sci. 8, 526-534. Denton S. (1962) Tofranil (imipramine) in toxicological analysis. AnalYst 87, 234-236. Oliver J. S. and Smith H. (1973) The interference of putrefactive bases in the analysis of biological materials for drugs. ]. Forensic Sci. Soc. 13, 47-54.
1977 World Congress on Mental Health The World Federation for Mental Health will hold its 1977 Congress in Vancouver BC, Canada from 21 to 26 August 1977. The theme will be 'Today's Priorities in Mental Health'. For further information and registration form, contact: The Secretariat, World Federation for Mental Health, 2255 Westbrook Hall, University of British Columbia, Vancouver BC, Canada V6T lW5. Telephone: (604) 228-2332. Cable address: MENSANTE.
Printed in Great Britain
193
A Case of Fatal Imipramine Poisoning in an Infant J. S. OLIVER,
SSe, PhD, CChem, MRIC
HAMILTON SMITH,
SSe, PhD, CChem, FRIC, MRCPath
Department of Forensic Medicine, University of Glasgow INTRODUCTION A number offatal cases of imipramine poisoning have been recorded in the literature. Curry (1964) reported seven, Dal Cortivo et al. (1963) reported one and Denton (1962) recorded two fatal cases and one non-fatal case. This paper presents the details of accidental poisoning in a child together with the analytical findings. The levels measured are compared with those found in adults and with values from the literature. CASE REPORT A l6-month-old child was left alone for a few minutes. When the mother returned she found the child sitting on the floor holding a bottle of pills, a few of which were scattered about the floor. A tablet was removed from the child's mouth. It was noticed that the tongue was red. An emetic of salt and water was given which made the child sick. Despite this, quick transference to hospital and subsequent treatment, the child died. From the beginning to the end of this episode 41 hours elapsed.
TOXICOLOGICAL ANALYSIS Samples of brain, liver and blood were received for analysis and produced the following results: Brain 2·8 mg imiprarninej l Of) g Liver 5·7 mg imipraminej l Ol) g Blood imipramine was present. No other drugs were present. METHOD The drug was isolated from biological materials using the extraction procedure described by Curry (1969). Thin-layer chromatography and ultraviolet spectrometry were used to establish the identity of the drug and ultraviolet spectrometry was used to measure the concentrations.
Ultraviolet Spectrometry The instrument used was a U nicam SP800 equipped with 1 em path length fused silica cells. Imipramine can be readily detected and estimated in a biological sample using the absorption curve obtained with the drug dissolved in O·lN sulphuric acid. The absorption maximum is at 251 nanometres. Thin-layer Chromatography The drug and extracts were chromatographed on Silica Gel G layers and revealed using acidified iodoplatinate reagent (Oliver and Smith, 1973). Two solvent systems can be used to identify imipramine. They are a 3 : 1 mixture of chloroform and methanol (imipramine R, 0,52) and a 200 : 3 mixture of methanol and ammonia (imipramine R, 0·57).
RESULTS AND DISCUSSION Both thin-layer chromatography systems showed the presence of imipramine in all the post-mortem materials and desmethylimipramine (R, 0·31 in chloroform/methanol and 0·25 in methanol/ammonia) in the liver. The levels of imipramine found are listed in Table 1. The analytical technique used produced a rapid and an easy confirmation that imipramine was present in the post-mortem material. The ultraviolet absorption spectrum obtained with the extracted drug was not influenced by co-extractable material, particularly . nicotinamide-like substances. This was further verified by thin-layer chromatography where no reaction was obtained with the spray reagent that did not correspond to either imipramine or its
194
Med. Sci. Law (1977) Vol. 17, No.3
Table I. Imipramine Levels from Fatal Poisoning Source Present study Present study Curry (1964) Dal Cortivo (1963)
Blood (mgt100 ml)
Liver (mgt1 00 g)
Brain (mg/100 g)
Present
5·7 2,0-9'5 0'5-25 5·4
2'8
0,033-1'2 0·8
metabolite, desmethylimipramine. However, the R, values found in both solvent systems for the extracted drugs had been influenced by co-extractable material. Addition of imipramine and desmethylimipramine to the liver extract produced two spots on the silica layer with both solvent systems. The added drugs were not separated from the extracted drugs. The results given in Table I show agreement between high liver levels and relatively low blood levels in adults with the findings in this case where the blood content of imipramine was not measurable though detectable. The spray reagent will readily detect I Ilg of imipramine; however the ultraviolet spectrometer reaches a limit of useful sensitivity with a blood imipramine level of about 0·25 mg!l 00 ml when a 10 ml blood sample is used for analysis. Thus the lower blood levels occasionally found may require the use of a colorimetric assay or gas-liquid chromatography. The metabolite, desmethylimipramine, appeared only in the liver extract. The measuring technique used does not differentiate the metabolite from imipramine since they have identical ultraviolet spectra. However, an examination of the thin-layer
3'08-7'2 None
Comment 1 infant 3 adults 7 cases 1 case
chromatography plates showed that there were approximately equal amounts of both drug and metabolite.
CONCLUSIONS The techniques of thin-layer chromatography and ultraviolet spectroscopy have been applied to a fatal case of imipramine poisoning in an infant. The results show a drug level within the range of values found for adults and showing the same trend of a high level in the liver and a low blood level. The techniques also allowed the rapid and easy identification of desmethylimipramine (desipramine). This was found to be present in the liver sample only. REFERENCES
Curry A. S. (1964) Seven fatal cases involving imipramine in man. ]. Pharm. Pharmac. 16,265-267. Curry A. S. (1969) Poison Detection in Human Organs. 2nd Ed. Springfield, Ill., Thomas. Dal Cortivo L. A., Giaquinta P. and Umberger C. J. (1963) The determination of imipramine in biological material.]. Forensic Sci. 8, 526-534. Denton S. (1962) Tofranil (imipramine) in toxicological analysis. AnalYst 87, 234-236. Oliver J. S. and Smith H. (1973) The interference of putrefactive bases in the analysis of biological materials for drugs. ]. Forensic Sci. Soc. 13, 47-54.
1977 World Congress on Mental Health The World Federation for Mental Health will hold its 1977 Congress in Vancouver BC, Canada from 21 to 26 August 1977. The theme will be 'Today's Priorities in Mental Health'. For further information and registration form, contact: The Secretariat, World Federation for Mental Health, 2255 Westbrook Hall, University of British Columbia, Vancouver BC, Canada V6T lW5. Telephone: (604) 228-2332. Cable address: MENSANTE.
