On the occurrence of antipyrine in opium
Author: H. S. K. HERTZ and BIEMANN
Pages: 67 to 70
Creation Date: 1976/01/01
Department of Chemistry, Massachusetts Institute of Technology, cambridge, Massachusetts 02139
Relatively little is known about the non-alkaloidal constituents of opium. Furthermore, research on methods for the determination of the geographic origin of opium has been hampered by the lack of opium samples of known origin. In an attempt to study these two problems and to possibly arrive at a joint solution to them, a study of the non-alkaloidal constituents of opium was undertaken. The most interesting and totally unexpected result of this investigation was the discovery of large amounts of the synthetic drug, antipyrine (I), in various samples of opium seized in Iran. The drug was identified with the use of a gas chromatograph-mass spectrometer-computer system. A brief description of the application of this system to the investigation of opium extracts, as well as a discussion of some of the implications of the presence of antipyrine in the opium is presented below.
Sample handling procedure
Approximately 2.0 gms of opium were used for most extractions. The sample was stirred overnight with 50 ml of distilled methylene chloride. The extract was filtered and the residue stirred for several more hours with a fresh 50-ml portion of methylene chloride. The extract was filtered and the combined filtrates were dried over anhydrous Na 2SO 4 and reduced to dryness to yield an average of 0.55 to 0.60 gms of material. These crude extracts from seventeen opium samples were then investigated by use of a combined gas chromatograph-low resolution mass spectrometer-computer (GC-MS-Computer) system (1).
The GC-MS-computer system employed consists of a Perkin-Elmer Model 990 gas chromatograph, an Hitachi Perkin-Elmer RMU 6L mass spectrometer and an IBM 1800 data acquisition and control system. The gas chromatograph is coupled to the mass spectrometer by a porous fritted glass tube pressure reduction unit linked to a low volume splitter. This arrangement allows one to continuously obtain mass spectra of the individual components of a mixture as they emerge from the gas chromatograph. Furthermore, since the mass spectrometer is operated on-line with the computer, the mass spectrometric data taken over the complete gas chromatogram in 4-sec intervals are accumulated by the computer, which subsequently processes, normalizes, and, to a varying degree, evaluates the mass spectra. In addition, the mass spectrometer can be used as the detector for the gas chromatograph. Thus, the computer also stores and plots a computer-generated gas chromatogram. Such a chromatogram for one of the opium extracts is shown in the figure. The numbers along the abscissa correspond to the spectrum index numbers of the individual spectra taken during the course of the gas chromatogram. The identification of the various components of the mixture are listed in the legend for the figure.
TOTAL IONIZATION PLOT RUN No. 574 Spectrum index number
Computer-generated gas chromatogram for a sample of opium confiscated in Iran. Identifications are as follows:
M = meconine, H = hydrocotarnine, A = antipyrine, MeC 18 = methyl oleate and linoleate, C = codeine, Th = thebaine, La = laudanosine, MeC 24 = methyl tetracosanoate, P = papaverine, Cr=cryptopine, T=α-tocopherol (Vitamin E), N=narcotine, S=β-sitosterol, Ca=cycloartenol, Cl = cyclolaudenol.
As can be seen from the figure, one of the most abundant compounds in this sample of opium is represented by the fraction labelled A. Surprisingly, the mass spectra (scans 75-85) recorded during the emergence of this peak showed no relationship to those of the other components. Its detailed interpretation finally suggested that it was possibly that of 1-phenyl-2,3-dimethylpyrazolone (antipyrine) and this was then confirmed by comparison with an authentic sample. It should be noted that the gas chromatogram shown in the figure is typical of opium samples that had been seized in Iran, but in those from other areas of the Near East peak A was entirely absent. Since antipyrine is a synthetic compound and obviously not of natural origin, its addition is an obvious attempt at cutting the crude opium in the early stages of the handling procedure. The final fate of such a large amount of antipyrine in the processed opium or heroin is unknown. However, due to the possibly harmful effects of antipyrine on humans the presence of this compound in samples of contraband opium should be borne in mind.
Antipyrine was introduced for medicinal use in 1884, the year in which it was synthesized by Knorr (2). The name for the drug was derived from its antipyretic effect. It received its first large scale test in 1888 against a severe influenza epidemic in Germany. Later the analgesic power of antipyrine was discovered and it was then prescribed mainly for that purpose.
However, for numerous reasons antipyrine has fallen out of favour and is rarely used in the United States today. The decline of its use can be attributed not only to various toxic effects, real or suspected, but also to the great popularity of the salicylates which exhibit the same pharmacological properties (3-5).
There have been several reports (3-5) that antipyrine may have the same toxic effects, which a closely related pyrazolone derivative, aminopyrine (II) exhibits. The latter affects white blood cells and may cause serious, and often fatal, agranulocytosis. Lastly, there are reports of the action of antipyrine on the motor nerves of the central nervous system (5).
In view of the toxicity of antipyrine when administered alone, its combination with opium may cause further side effects. The rationale for cutting opium with antipyrine can probably be found in some early reports on the combination of antipyrine and the opium alkaloid and analgesic, morphine. Sixty years ago Burgi (6) and Lomonosoff (7) reported that the action of morphine is greatly enhanced by the addition of antipyrine. Peters (8) and Snow (9) reported on the increased analgesic properties of a morphine-antipyrine combination in the treatment of cancer. However, these papers also showed that the relative ratio of these two drugs is important to achieve the proper effect of their combination, while other proportions can have a detrimental effect.
Due to these many and varied effects of antipyrine on humans, the occurrence of antipyrine in contraband opium could be a serious problem. The presence of antipyrine in opium and concomitant toxic effects should be kept in mind when treating drug users. In conjunction with this, one should note that antipyrine can give a positive colour test for heroin (10).
The authors are indebted to Dr. Ralph Zirkind, former Director of ARPA, Washington, D.C. who made the opium available to them. This work was supported by a Research Grant (RR00317) and a Training Grant (GM01523) from the National Institutes of Health.
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