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BROWN URINE—A CLUE TO PHENACETIN INTOXICATION
1253 an
ineffective service for ill children and anxious parents.
Surely the answer is that they should be required to provide the service for which they are being paid, rather than dumping these children on the hospital and then having to go and see them in hospital themselves. If the general practitioner has time to join a hospital and work in its accident and casualty department, surely he would have time to see the child properly at home or in his own surgery. Casualty departments are not the best places for ill children to be seen, full as they often are with badly injured people, drunks, &c., to say nothing of the increased chance of crossinfection and the likelihood of being seen by people unaware of their background and previous medical history. General Hospital,
Birmingham 4.
believed to be characteristic of phenacetin was not explicitly stated to be present in the chromatograms from any of their patients. Without this information, their paper is meaningless. Case 5, for example, who denied consumption of phenacetin, could well have taken only aspirin and paracetamol as judged by the chromatographic evidence presented in fig. 1. It is reasonable to assume that readily oxidisable drug metabolites are responsible both for the reducing properties of these urines and for the dark pigments, particularly at alkaline pH. Tollen’s reagent, however, is very non-specific and provides too sensitive a test. It will give a distinct reaction even with urine from normal individuals not orange spot
ingestion,
taking R. L. BATTEN.
was
but it
any
drugs.
University Departments of Therapeutics and Clinical Chemistry, EH3 9YW.
Royal Infirmary, Edinburgh BROWN URINE—A CLUE TO PHENACETIN INTOXICATION
HYPERALUMINÆMIA FROM
SIR,-Dr. Miller and his colleagues (Nov. 28, p. 1102) have not done their homework at all well. The excretion of dark urine following ingestion of phenacetin has been recognised since 1888.1 Thin-layer chromatography has been widely used for the separation of phenacetin metabolites after acid or enzymic hydrolysis of urine,2-8 and the " " " orange-brown or yellowish-orange spot was probably 3-amino-7-ethoxyphenoxaz-2-one, formed from 2hydroxy-4-ethoxyaniline.2-4 Furthermore, several workers have described the use of silver nitrate sprays.4.5.7.8 A solution of paracetamol in normal urine is not a valid standard for the chromatography of phenacetin metabolites, since it would not contain the phenoxazone. The detection of this compound is a much more significant clue2 to phenacetin abuse than the colour of the urine, its reducing properties, or the presence of p-aminophenol. Moreover, the indophenol assay used hardly provides strong supporting evidence for the ingestion of phenacetin since the reaction simply measures hydrolysable precursors of paminophenol which could equally well have been derived from ingested paracetamol. In the context of poisoning, it is quite misleading to imply that a dark urine with the " unusual property " of9 reducing cold ammon;acal silver nitrate (Tollen’s reagent) is seen only in phenacetin intoxication. The urine is usually dark after overdosage of paracetamol, and such specimens also rapidly reduce the reagent. It is important to distinguish between paracetamol and phenacetin since they have different toxic effects. Dark urine may also be voided in aspirin poisoning; of nine such specimens taken at random, we found that five rapidly reduced Tollen’s reagent. Paracetamol could not be detected in any of these by enzymic hydrolysis and gas-liquid chromatography. 10 This is pertinent since, in Britain, phenacetin is generally available in combination with aspirin. Dr. Miller and his colleagues gloss over the fact that salicylate was involved in three of their patients, and, in a fourth, a preparation containing "
aspirin was implicated. We would be obliged if they could define what they mean by " phenacetin metabolites ". The fast-moving yellowish1. 2.
3. 4. 5. 6.
7. 8. 9.
10.
Smith, P. K. Acetophenetidin; p. 13. London, 1958. Büch, H., Häuser, H., Pfleger, K., Rüdiger, W. Z. klin. Chem. 1966, 4, 288. Büch, H., Pfleger, K., Rummel, W., Ullrich, V., Hey, D., Staudinger, H. Biochem. Pharmac. 1967, 16, 2247. Prescott, L. F. Clin. Pharmac. Ther. 1969, 10, 383. Goenechea, S. Z. klin. Chem. klin. Biochem. 1969, 7, 346. Prescott, L. F., Sansur, M., Levin, W., Conney, A. H. Clin. Pharmac. Ther. 1968, 9, 605. Klutch, A., Bordun, M. J. pharm. Sci. 1968, 57, 524. Klutch, A., Harfenist, M., Conney, A. H. J. med. Chem. 1966, 9, 63. Smith, F. J., Jones, E. A Scheme of Qualitative Organic Analysis; p. 36. Glasgow, 1948. Prescott, L. F. J. Pharm. Pharmac. (in the press).
L. F. PRESCOTT S. S. BROWN.
ALUMINIUM RESINS
SIR,-Professor Wrong and Dr. Swales (Nov. 28, p. 1130) have missed the point of our article. Aluminium resins cause hyperaluminxmia in 30% of renal-failure patients. I do not know whether hyperaluminxmia is harmful, and, as the article said, it requires further work to determine the toxic effects of hyperaluminxmia. I am concerned about the use of aluminium hydroxide to lower serum-inorganic-phosphate levels, but I am not aware that an efficient trouble-free alternative to aluminium hydroxide seem to
has been found. The argument that aluminium must be safe because it is the third most abundant element in nature is a non-sequitur. Silicon is an abundant element in nature, but silicosis is a serious disease. The toxicity of hyperaluminsemia is a possibility, and if one could easily measure the level of serum-aluminium and exclude hyperaluminxmia I would agree with Professor Wrong and use the mixture of calcium and aluminium resins he advocates. Unfortunately, it is very difficult to measure aluminium specifically, and until it can be measured easily aluminium resin should be regarded with some suspicion, and its use limited to centres where serum-aluminium levels can be regularly monitored. Faculty of Life Sciences, University of the Negev, Israel.
G. M. BERLYNE.
ZINC AND HEALING SIR,-Dr. Greaves and Dr. Skillen (Oct. 31, p. 889) point out the need for closely controlled studies to evaluate the effect of oral zinc on the healing of chronic leg ulcers. Probably the only method of doing this would be to have all the patients on absolute bed rest. This would require admission to hospital and would present another difficulty in that most leg ulcers heal so rapidly on simple bed rest that it might be difficult to discern the difference between those which were treated and those which were not. In our series,2 healing-rates were calculated on patients who were treated as outpatients with simple wound care and elastic external support. Control healing-rates were established for each patient for at least 4 weeks and then oral zinc was added to the regimen. Almost all the patients showed significant healing on the control regimen. The addition of the zinc did not in a single instance accelerate the healing-rate. It should be mentioned that in Greaves and Skillen’s study no specific control period was used; Berlyne, G. M., Ben-Ati, J., Pest, D., Weinberger, J., Stern, M., Gilmore, G. R., Levine, R. Lancet, Sept. 5, 1970, p. 494. 2. Myers, M. B., Cherry, G. Am. J. Surg. 1970, 120, 77. 1.
ineffective service for ill children and anxious parents.
Surely the answer is that they should be required to provide the service for which they are being paid, rather than dumping these children on the hospital and then having to go and see them in hospital themselves. If the general practitioner has time to join a hospital and work in its accident and casualty department, surely he would have time to see the child properly at home or in his own surgery. Casualty departments are not the best places for ill children to be seen, full as they often are with badly injured people, drunks, &c., to say nothing of the increased chance of crossinfection and the likelihood of being seen by people unaware of their background and previous medical history. General Hospital,
Birmingham 4.
believed to be characteristic of phenacetin was not explicitly stated to be present in the chromatograms from any of their patients. Without this information, their paper is meaningless. Case 5, for example, who denied consumption of phenacetin, could well have taken only aspirin and paracetamol as judged by the chromatographic evidence presented in fig. 1. It is reasonable to assume that readily oxidisable drug metabolites are responsible both for the reducing properties of these urines and for the dark pigments, particularly at alkaline pH. Tollen’s reagent, however, is very non-specific and provides too sensitive a test. It will give a distinct reaction even with urine from normal individuals not orange spot
ingestion,
taking R. L. BATTEN.
was
but it
any
drugs.
University Departments of Therapeutics and Clinical Chemistry, EH3 9YW.
Royal Infirmary, Edinburgh BROWN URINE—A CLUE TO PHENACETIN INTOXICATION
HYPERALUMINÆMIA FROM
SIR,-Dr. Miller and his colleagues (Nov. 28, p. 1102) have not done their homework at all well. The excretion of dark urine following ingestion of phenacetin has been recognised since 1888.1 Thin-layer chromatography has been widely used for the separation of phenacetin metabolites after acid or enzymic hydrolysis of urine,2-8 and the " " " orange-brown or yellowish-orange spot was probably 3-amino-7-ethoxyphenoxaz-2-one, formed from 2hydroxy-4-ethoxyaniline.2-4 Furthermore, several workers have described the use of silver nitrate sprays.4.5.7.8 A solution of paracetamol in normal urine is not a valid standard for the chromatography of phenacetin metabolites, since it would not contain the phenoxazone. The detection of this compound is a much more significant clue2 to phenacetin abuse than the colour of the urine, its reducing properties, or the presence of p-aminophenol. Moreover, the indophenol assay used hardly provides strong supporting evidence for the ingestion of phenacetin since the reaction simply measures hydrolysable precursors of paminophenol which could equally well have been derived from ingested paracetamol. In the context of poisoning, it is quite misleading to imply that a dark urine with the " unusual property " of9 reducing cold ammon;acal silver nitrate (Tollen’s reagent) is seen only in phenacetin intoxication. The urine is usually dark after overdosage of paracetamol, and such specimens also rapidly reduce the reagent. It is important to distinguish between paracetamol and phenacetin since they have different toxic effects. Dark urine may also be voided in aspirin poisoning; of nine such specimens taken at random, we found that five rapidly reduced Tollen’s reagent. Paracetamol could not be detected in any of these by enzymic hydrolysis and gas-liquid chromatography. 10 This is pertinent since, in Britain, phenacetin is generally available in combination with aspirin. Dr. Miller and his colleagues gloss over the fact that salicylate was involved in three of their patients, and, in a fourth, a preparation containing "
aspirin was implicated. We would be obliged if they could define what they mean by " phenacetin metabolites ". The fast-moving yellowish1. 2.
3. 4. 5. 6.
7. 8. 9.
10.
Smith, P. K. Acetophenetidin; p. 13. London, 1958. Büch, H., Häuser, H., Pfleger, K., Rüdiger, W. Z. klin. Chem. 1966, 4, 288. Büch, H., Pfleger, K., Rummel, W., Ullrich, V., Hey, D., Staudinger, H. Biochem. Pharmac. 1967, 16, 2247. Prescott, L. F. Clin. Pharmac. Ther. 1969, 10, 383. Goenechea, S. Z. klin. Chem. klin. Biochem. 1969, 7, 346. Prescott, L. F., Sansur, M., Levin, W., Conney, A. H. Clin. Pharmac. Ther. 1968, 9, 605. Klutch, A., Bordun, M. J. pharm. Sci. 1968, 57, 524. Klutch, A., Harfenist, M., Conney, A. H. J. med. Chem. 1966, 9, 63. Smith, F. J., Jones, E. A Scheme of Qualitative Organic Analysis; p. 36. Glasgow, 1948. Prescott, L. F. J. Pharm. Pharmac. (in the press).
L. F. PRESCOTT S. S. BROWN.
ALUMINIUM RESINS
SIR,-Professor Wrong and Dr. Swales (Nov. 28, p. 1130) have missed the point of our article. Aluminium resins cause hyperaluminxmia in 30% of renal-failure patients. I do not know whether hyperaluminxmia is harmful, and, as the article said, it requires further work to determine the toxic effects of hyperaluminxmia. I am concerned about the use of aluminium hydroxide to lower serum-inorganic-phosphate levels, but I am not aware that an efficient trouble-free alternative to aluminium hydroxide seem to
has been found. The argument that aluminium must be safe because it is the third most abundant element in nature is a non-sequitur. Silicon is an abundant element in nature, but silicosis is a serious disease. The toxicity of hyperaluminsemia is a possibility, and if one could easily measure the level of serum-aluminium and exclude hyperaluminxmia I would agree with Professor Wrong and use the mixture of calcium and aluminium resins he advocates. Unfortunately, it is very difficult to measure aluminium specifically, and until it can be measured easily aluminium resin should be regarded with some suspicion, and its use limited to centres where serum-aluminium levels can be regularly monitored. Faculty of Life Sciences, University of the Negev, Israel.
G. M. BERLYNE.
ZINC AND HEALING SIR,-Dr. Greaves and Dr. Skillen (Oct. 31, p. 889) point out the need for closely controlled studies to evaluate the effect of oral zinc on the healing of chronic leg ulcers. Probably the only method of doing this would be to have all the patients on absolute bed rest. This would require admission to hospital and would present another difficulty in that most leg ulcers heal so rapidly on simple bed rest that it might be difficult to discern the difference between those which were treated and those which were not. In our series,2 healing-rates were calculated on patients who were treated as outpatients with simple wound care and elastic external support. Control healing-rates were established for each patient for at least 4 weeks and then oral zinc was added to the regimen. Almost all the patients showed significant healing on the control regimen. The addition of the zinc did not in a single instance accelerate the healing-rate. It should be mentioned that in Greaves and Skillen’s study no specific control period was used; Berlyne, G. M., Ben-Ati, J., Pest, D., Weinberger, J., Stern, M., Gilmore, G. R., Levine, R. Lancet, Sept. 5, 1970, p. 494. 2. Myers, M. B., Cherry, G. Am. J. Surg. 1970, 120, 77. 1.