525 them were negative when tested with diluted solutions of the substance. The same reaction was seen in 10 controls tested. The skin symptoms were probably due to proteolytic effects of pancreozyme and not to delayed-type allergy. Exposure to airborne enzyme powder can induce immediate hypersensitivity reactions.1-4 Our experience illustrates, as others have found, that workers occupationally exposed to proteolytic enzymes are at great risk of sensitisation and that the utmost care must be taken to prevent contact with these substances especially the powder form. Non-allergic irritating skin reactions on exposed parts of the body such as wrists and forehead were very common. They were hard to prevent even if the workers used special overalls and when the level of airborne enzyme dust was reduced by evacuation. Of the twenty employees studied by us only two had had atopic symptoms before they started work with enzymes. We cannot conclude, therefore, atopics will be at greater risk of enzyme allergy than will non-atopics.
SCLEROSING PERITONITIS AND TIMOLOL
test
Departments of Dermatology Occupational Medicine, Södersjukhuset,
and
MARGIT FORSBECK LENA EKENVALL
S-100 64 Stockholm 38, Sweden
SUCCESSFUL CARDIAC TRANSPLANT AFTER MAINTENANCE WITH INTRA-AORTIC BALLOON PUMP
SiR,-Norman et al. described a patient assisted after openheart surgery with a mechanical cardiac support system and who had a heart transplant -but subsequently died. Our group has a patient with a surviving transplanted heart who was maintained on an intra-aortic balloon pump. A 48-year-old male, was transferred to the Columbia-Presbyterian Medical Center 11 days after acute anterior-wall myocardial infarction with an acute ventricular septal defect which had developed 2 days before admission. Intra-aortic balloonpump support6 was begun for hsemodynamic instability, and cardiac catheterisation showed a high muscular ventricular septal defect with a 4:1 shunt. Open-heart surgery was done the same day, and an extensive anterolateral and apical infarction The ventricular septal defect was repaired with a left ventriculotomy through the infarct with a limited infarctectomy. A teflon patch was attached to the left ventricular side of the normal septum with reinforced mattress sutures. Buttressed teflon strips coapted the ventricular muscle to the septal patch. Weaning from cardiopulmonary bypass with the intra-aortic balloon was satisfactory, but the patient remained dependent upon full ballon-pump support. Orthotopic cardiac transplantation was done 4 days after the initial surgery with complete recovery (balloon-pump removed in the operating room) and subsequent hospital discharge. He is now fully active. Our experience’ suggests that certain patients requiring mechanical circulatory support for acute ventricular failure superimposed on chronic end-stage heart disease may be suitable candidates for cardiac transplantation. As Norman et al. indicate, there is need for improved mechanical methods to support such patients who cannot be maintained on intra-aortic balloon support. DAVID BREGMAN RONALD DRUSIN RICHARD N. EDIE Department of Surgery, WILLIAM H. DOBELLE College of Physicians and Surgeons of Columbia University, New York 10032, U.S.A.
MARK A. HARDY KEITH REEMTSMA
Twarog, F. J., Weinstein, S. F., Kon Taik Khaw, Strieder, D. J., Colten, H. R. J. Allergy clin. Immun. 1977, 59, 35. 2. Göthe, C-J., Nilzén, A., Holmgren, A., Szamosi, A., Werner, M., Wide, L. Acta allergol. 1972, 27, 63. 3. Flindt, M. L. H. Lancet, 1978, 430. 4. Pauwels, R., Devos, M., Callens, L., van der Straeten, M. ibid. 1978, 669. 5. Norman, J. C., and others. Lancet, 1978, i, 1125. 6. Bregman, D. in Current Problems in Surgery. Chicago, 1976. 7. Reemtsma, K., Drusin, R., Edie, R., Bregman, D., Dobelle, W., Hardy, J. New Eng. J. Med. 1978, 238, 670. 1.
SiR,-Mr Baxter-Smith and colleagues (July 15, p. 149) de-
patient with a perforation of the jejunum and peritonitis who had been receiving timolol (’Blocadren’) for 18 months immediately before hospital admission scribe a fibrinous
and emergency surgery for acute small-bowel obstruction. In the opening paragraph they imply that timolol is more cardioselective than practolol. In fact, practolol is relatively cardioselective while timolol, like propranolol, is not. In my opinion, no objective evidence is presented which indicates that this is a case of sclerosing peritonitis of the type seen with practolol. In cases of sclerosing peritonitis associated with practolol the patients presenting with subacute or chronic small-bowel obstruction almost always had involvement of organs other than the peritoneum,’2 and in no case was bowel perforation present. Contrary to what Mr Baxter-Smith and his colleagues say, the parietal peritoneum and other abdominal viscera are not often spared from the sclerotic process.1-3 In their case only the visceral peritoneum was affected. I agree that the histology of the adhesions, as presented, is not like that seen in the practolol syndrome; it is more characteristic of secondary peritonitis. Absent in this case are the characteristic findings of the sclerosis associated with practolol (i.e., relatively avascular, dense, laminated fibrous tissue composed of collagen bundles and focal, perivascular, mononuclear cell infiltrates in the adipose tissue1 4. The 48 h duration of obstructive symptoms is probably too short for the development of organising fibrinous peritonitis; however, peritonitis can result from ischsemic and/or ulcerative lesions of the gut per se without perforation. S6 The duration of the ulcerative process in the jejunum was likely to have been longer than 48 h and could have been accompanied by a slow leak of jejunal contents producing chemical peritonitis. Certainly without this protective peritoneal reaction, the gut perforation would have presented as an acute surgical abdomen. There are similarities between this case and that reported by Kennedy and Ducrow.7 In their case, a patient with chronic gastric-ulcer disease and angina pectoris was treated with oxprenolol for only 4 months. 4 years later, during surgery for a rectal neoplasm, extensive fibrinous peritonitis was found which affected all the abdominal organs. The short treatment period with oxprenolol is not consistent with the practolol experience and suggests that this patient may have had a peritoneal reaction to her ulcer disease or rectal neoplasm and conceivably an undetected small perforation at either site. Meyboom9 has pointed out that idiopathic fibrosing peritonitis was described as early as 1942, long before any beta-adrenergic blocking agent was introduced. The lesion of the jejunum in Baxter-Smith’s case, the astiology of which is not apparent, raises questions concerning other medications the patient was receiving, such as enteric-coated potassium chloride tablets, one of the newer wax matrix formulations of this salt, or a diuretic with potassium included. Simple ulceration of the small bowel was a rare disease,9 until about 1963 when enteric-coated potassium-chloride tablets were introduced. 10 Furthermore, small-bowel ulcers with necrotising angiitis are usually multiple and associated with a collagen disease which may not be diagnosed until necropsy.11
1. Marshall, A. J., and others. Q. Il Med. 1977, 46, 135. 2. Thompson, R. P. H., Jackson, B. T. Br. med. J. 1977, i, 1393. 3. Kristensen, K., and others. Lancet, 1975, i, 741. 4. Nicholls, J. T. Ann. clin Res. 1976, 8, 229. 5. Horn, R. C. in Pathology (edited by W. A. D. Anderson); p. 1140, St. Louis, 1971. 6. Lee, F. D. in Muir’s Textbook of Pathology (edited by W. A. D. Anderson); 7. 8. 9. 10. 11.
p. 596, Chicago, 1976. Kennedy, S. C., Ducrow, M. Br. med. J. 1977, i, 1598. Meyboom, R. H. B. Lancet, 1975, i, 334. Watson, M. R. Archs Surg. 1963, 87, 600. Baker, D. R., and others. J. Am. med. Ass. 1964, 190, 586. Finkbiner, R. B., Decker, J. P. New Engl. J. Med. 1963, 268, 14.
526 Since the interior of the small bowel was not directly visualised in this case, the presence or absence of other non-perforating ulcerative lesions cannot be established. It is distinctly possible that, in this patient, hypertension, chronic proctitis, and necrotising angiitis indicate the presence of a collagen disorder. The concluding statement of Thompson and Jackson2-"All that is abdominal pain is not sclerosing peritonitis"--could be expanded to "All that is peritonitis in patients receiving beta blockers is not the practolol syndrome." Research Laboratories, Merck Sharp & Dohme, West Point, Pennsylvania
19486, U.S.A.
JOHN F. NANCARROW
HALOTHANE HEPATITIS
tious hepatitis from the ingestion of infected shellfish was present in the area." Third, they did not mention the fact that during the same epidemic 41 cases of jaundice had been reported after intravenous barbiturate anaesthesia for psychiatric procedures and 15 of them died from massive liver necrosis-a tragic example of the immunodepression of anxsthetic drugs." Finally, the two physicians did not appear to know that fever, rashes, myalgia, arthralgia, and so on are manifestations of the virxmic phase of infectious hepatitis.9 It is not improbable that the suggestion that halothane may cause allergic liver necrosis may come to be regarded as one of the silliest in the history of anaesthesia if not of medicine. In the meantime physicians would be well advised to stop meddling in anaesthetics and devote their attention to the search for reliable serological tests for all forms of viral hepatitis. Department of Anaesthetics,
SIR,-Professor Sherlock (Aug. 12, p. 364) gives the impression that she thinks that halothane confers immunity to all forms of viral hepatitis in people exposed to its vapour. She
Royal Infirmary, Manchester M13 9WL
MICHAEL
JOHNSTONE
may be
right, but I do not think she is because I am reasonably certain that the immunodepression of surgery and anaesthesia increases the severity of all infections. 12 Fatal liver necrosis from a herpes-type virus has occurred in a patient after surI gery under enflurane anaesthesia.3 in not a are Physicians position to prescribe anaesthetic that halothane should be Sherlock’s recommendation drugs. avoided in "minor" surgery is irresponsible. Halothane is usually the safest and best anaesthetic in these circumstances. If possible all anaesthetic drugs should be avoided in surgical patients with viral infections unrelated to the surgical pathology. A second anaesthetic should not be given until recovery from the immunodepression of the first operation is complete. Hepatitis B (serum hepatitis) is not an uncommon complication in patients after surgery and it may also afflict the surgical staff. The recognition and the control of the infection in these circumstances has been well described, and anaesthetists are advised to read carefully the published reports.4-6 Hepatitis A (infectious hepatitis) is a more difficult problem because there is no reliable serological test for it.’ In the early stages of the first clinical trial of halothane it was anticipated that sooner or later patients in the asymptomatic incubation phase of infectious hepatitis would be anaathetised with this agent, and anaesthetists were warned that the jaundice which subsequently appeared might be wrongly ascribed to the anoesthetic.8 With the cooperation of the Office of Morbidity Statistics for General Practice in the United Kingdom and the department of anaathetics in the University of Cardiff it was estimated that out of every million patients anaathetised with any anaesthetic agent jaundice might appear in about 100 of them some days or weeks postoperatively as the result of coincidental infectious hepatitis.9 This figure does not include transmitted hepatitis B. Despite the warning the hepatitis controversy was precipitated by two physicians who reported 8 cases of transient postoperative jaundice and suggested that the cause was an allergic reaction to halothane.’" In presenting their opinion they ignored four important facts. First, the fact that most of the cases occurred over a period of a few weeks should have alerted them to the possibility of an infectious origin. Second, they did not refer to the fact that a widely publicised epidemic of infec1. 2.
Munster, H. M. Lancet, 1976, i, 1329. Duncan, P. G., Cullen, B. F. Anesthesiology, 1976, 45, 522. 3. Douglas, H. J., Eger, E. I., Biava, C. G., Renzi, C. New Engl. J. Med. 1977, 296, 553. 4. Rimland, D., Parkin, W. E., Miller, G. B., Schrack, W. D. ibid. 1977, 296, 955.
5. 6.
Grady, G. F. ibid. 1977, 296, 996. Naulty, J. S., Reves, J. G., Tobey, R. E., Schultz, W. W. curr. Res. 1977, 56, 366. 7. Woolf, I., Williams, R. Br. J. Hosp. Med. 1977, 17, 117. 8. Johnstone, M. Anesthesiology, 1961, 22, 591. 9. Johnstone, M. Br.J. Anæsth. 1964, 36, 718. 10. Lindenbaum, J., Leifer, E. New Engl. J. Med. 1963, 268, 525.
Anesth.
PHARMACOLOGY AND THE MOLE
SiR,—Your normally thoughtful columns developed a regrettable entrenched tone on June 17.’ While it must be accepted that we do not yet possess an understanding of the molecular action of drugs which demands that drug concentrations should be expressed in molar units, there are a number of other considerations which justify a change to these units. My experience over the past seven years of running a quality-control scheme for antiepileptic drugs, in which 200 laboratories in many countries participate, has led me to conclude that a major source of error stems from the inability of many laboratories to make up working standards. One important oversight is failure to correct for the fact that standards are usually made up by weighing in the salt, whereas it is the acid or base which is measured in serum. For example, phenytoin is usually added as the sodium salt, and failure to allow for the sodium atom will produce an approximately 10% error in the result. This oversight is not confined to the laboratory amateur-one of the leading producers of quality-control serum was guilty of this error when it introduced drug control sera. Some laboratories express their serum levels as the salt—e.g., lignocaine hydrochloride2-but this could cause confusion. In our not yet published study of the bioavailability of lignocaine hydrochloride and monohydrate, for example, it would be nonsensical if we expressed our results in anything but the base. In many publications it is, not made clear just what has been measured. How many disagreements in clinical pharmacology are due to simple confusions of this sort? Precision in medicine, often difficult, can be achieved in drug measurement. The use of molar units does not automatically overcome these problems, but when an analyst has to convert from gravimetric to molar units he has to think about what he is measuring.
Further problems arise when metabolites of drugs are being measured. Some drugs, for instance, have active metabolites, and in relating serum level to effect it is tempting to add the concentrations of parent compound and. metabolite together. But to do so on a gravimetric basis, as did Carr and Hobson did for tricyclic antidepressants3 is incorrect. On a molar basis, however, this makes more sense. Similarly, it is logical to use molar units in studies of the metabolic pattern of drugs, when it may be necessary to compare yields of metabolites through different pathways. You are right in saying that drugs are measured only occasionally, but it is reasonable to assume that as progress is made in clinical pharmacology, the indications for drug level moni-
Analg. 11. Dougherty, W. J., Altman, R. Am. J. Med. 1962, 32, 704. 1. Lancet, 1978, i, 1297. 2. Rowland, M., Thomson, P. D., Guichard, A., Melmon, K. L. Ann. N.Y. Acad. Sci. 1971, 179, 383. 3. Carr, A. C., Hobson, R. P. Br. med. J. 1977, ii, 1151.
SCLEROSING PERITONITIS AND TIMOLOL
test
Departments of Dermatology Occupational Medicine, Södersjukhuset,
and
MARGIT FORSBECK LENA EKENVALL
S-100 64 Stockholm 38, Sweden
SUCCESSFUL CARDIAC TRANSPLANT AFTER MAINTENANCE WITH INTRA-AORTIC BALLOON PUMP
SiR,-Norman et al. described a patient assisted after openheart surgery with a mechanical cardiac support system and who had a heart transplant -but subsequently died. Our group has a patient with a surviving transplanted heart who was maintained on an intra-aortic balloon pump. A 48-year-old male, was transferred to the Columbia-Presbyterian Medical Center 11 days after acute anterior-wall myocardial infarction with an acute ventricular septal defect which had developed 2 days before admission. Intra-aortic balloonpump support6 was begun for hsemodynamic instability, and cardiac catheterisation showed a high muscular ventricular septal defect with a 4:1 shunt. Open-heart surgery was done the same day, and an extensive anterolateral and apical infarction The ventricular septal defect was repaired with a left ventriculotomy through the infarct with a limited infarctectomy. A teflon patch was attached to the left ventricular side of the normal septum with reinforced mattress sutures. Buttressed teflon strips coapted the ventricular muscle to the septal patch. Weaning from cardiopulmonary bypass with the intra-aortic balloon was satisfactory, but the patient remained dependent upon full ballon-pump support. Orthotopic cardiac transplantation was done 4 days after the initial surgery with complete recovery (balloon-pump removed in the operating room) and subsequent hospital discharge. He is now fully active. Our experience’ suggests that certain patients requiring mechanical circulatory support for acute ventricular failure superimposed on chronic end-stage heart disease may be suitable candidates for cardiac transplantation. As Norman et al. indicate, there is need for improved mechanical methods to support such patients who cannot be maintained on intra-aortic balloon support. DAVID BREGMAN RONALD DRUSIN RICHARD N. EDIE Department of Surgery, WILLIAM H. DOBELLE College of Physicians and Surgeons of Columbia University, New York 10032, U.S.A.
MARK A. HARDY KEITH REEMTSMA
Twarog, F. J., Weinstein, S. F., Kon Taik Khaw, Strieder, D. J., Colten, H. R. J. Allergy clin. Immun. 1977, 59, 35. 2. Göthe, C-J., Nilzén, A., Holmgren, A., Szamosi, A., Werner, M., Wide, L. Acta allergol. 1972, 27, 63. 3. Flindt, M. L. H. Lancet, 1978, 430. 4. Pauwels, R., Devos, M., Callens, L., van der Straeten, M. ibid. 1978, 669. 5. Norman, J. C., and others. Lancet, 1978, i, 1125. 6. Bregman, D. in Current Problems in Surgery. Chicago, 1976. 7. Reemtsma, K., Drusin, R., Edie, R., Bregman, D., Dobelle, W., Hardy, J. New Eng. J. Med. 1978, 238, 670. 1.
SiR,-Mr Baxter-Smith and colleagues (July 15, p. 149) de-
patient with a perforation of the jejunum and peritonitis who had been receiving timolol (’Blocadren’) for 18 months immediately before hospital admission scribe a fibrinous
and emergency surgery for acute small-bowel obstruction. In the opening paragraph they imply that timolol is more cardioselective than practolol. In fact, practolol is relatively cardioselective while timolol, like propranolol, is not. In my opinion, no objective evidence is presented which indicates that this is a case of sclerosing peritonitis of the type seen with practolol. In cases of sclerosing peritonitis associated with practolol the patients presenting with subacute or chronic small-bowel obstruction almost always had involvement of organs other than the peritoneum,’2 and in no case was bowel perforation present. Contrary to what Mr Baxter-Smith and his colleagues say, the parietal peritoneum and other abdominal viscera are not often spared from the sclerotic process.1-3 In their case only the visceral peritoneum was affected. I agree that the histology of the adhesions, as presented, is not like that seen in the practolol syndrome; it is more characteristic of secondary peritonitis. Absent in this case are the characteristic findings of the sclerosis associated with practolol (i.e., relatively avascular, dense, laminated fibrous tissue composed of collagen bundles and focal, perivascular, mononuclear cell infiltrates in the adipose tissue1 4. The 48 h duration of obstructive symptoms is probably too short for the development of organising fibrinous peritonitis; however, peritonitis can result from ischsemic and/or ulcerative lesions of the gut per se without perforation. S6 The duration of the ulcerative process in the jejunum was likely to have been longer than 48 h and could have been accompanied by a slow leak of jejunal contents producing chemical peritonitis. Certainly without this protective peritoneal reaction, the gut perforation would have presented as an acute surgical abdomen. There are similarities between this case and that reported by Kennedy and Ducrow.7 In their case, a patient with chronic gastric-ulcer disease and angina pectoris was treated with oxprenolol for only 4 months. 4 years later, during surgery for a rectal neoplasm, extensive fibrinous peritonitis was found which affected all the abdominal organs. The short treatment period with oxprenolol is not consistent with the practolol experience and suggests that this patient may have had a peritoneal reaction to her ulcer disease or rectal neoplasm and conceivably an undetected small perforation at either site. Meyboom9 has pointed out that idiopathic fibrosing peritonitis was described as early as 1942, long before any beta-adrenergic blocking agent was introduced. The lesion of the jejunum in Baxter-Smith’s case, the astiology of which is not apparent, raises questions concerning other medications the patient was receiving, such as enteric-coated potassium chloride tablets, one of the newer wax matrix formulations of this salt, or a diuretic with potassium included. Simple ulceration of the small bowel was a rare disease,9 until about 1963 when enteric-coated potassium-chloride tablets were introduced. 10 Furthermore, small-bowel ulcers with necrotising angiitis are usually multiple and associated with a collagen disease which may not be diagnosed until necropsy.11
1. Marshall, A. J., and others. Q. Il Med. 1977, 46, 135. 2. Thompson, R. P. H., Jackson, B. T. Br. med. J. 1977, i, 1393. 3. Kristensen, K., and others. Lancet, 1975, i, 741. 4. Nicholls, J. T. Ann. clin Res. 1976, 8, 229. 5. Horn, R. C. in Pathology (edited by W. A. D. Anderson); p. 1140, St. Louis, 1971. 6. Lee, F. D. in Muir’s Textbook of Pathology (edited by W. A. D. Anderson); 7. 8. 9. 10. 11.
p. 596, Chicago, 1976. Kennedy, S. C., Ducrow, M. Br. med. J. 1977, i, 1598. Meyboom, R. H. B. Lancet, 1975, i, 334. Watson, M. R. Archs Surg. 1963, 87, 600. Baker, D. R., and others. J. Am. med. Ass. 1964, 190, 586. Finkbiner, R. B., Decker, J. P. New Engl. J. Med. 1963, 268, 14.
526 Since the interior of the small bowel was not directly visualised in this case, the presence or absence of other non-perforating ulcerative lesions cannot be established. It is distinctly possible that, in this patient, hypertension, chronic proctitis, and necrotising angiitis indicate the presence of a collagen disorder. The concluding statement of Thompson and Jackson2-"All that is abdominal pain is not sclerosing peritonitis"--could be expanded to "All that is peritonitis in patients receiving beta blockers is not the practolol syndrome." Research Laboratories, Merck Sharp & Dohme, West Point, Pennsylvania
19486, U.S.A.
JOHN F. NANCARROW
HALOTHANE HEPATITIS
tious hepatitis from the ingestion of infected shellfish was present in the area." Third, they did not mention the fact that during the same epidemic 41 cases of jaundice had been reported after intravenous barbiturate anaesthesia for psychiatric procedures and 15 of them died from massive liver necrosis-a tragic example of the immunodepression of anxsthetic drugs." Finally, the two physicians did not appear to know that fever, rashes, myalgia, arthralgia, and so on are manifestations of the virxmic phase of infectious hepatitis.9 It is not improbable that the suggestion that halothane may cause allergic liver necrosis may come to be regarded as one of the silliest in the history of anaesthesia if not of medicine. In the meantime physicians would be well advised to stop meddling in anaesthetics and devote their attention to the search for reliable serological tests for all forms of viral hepatitis. Department of Anaesthetics,
SIR,-Professor Sherlock (Aug. 12, p. 364) gives the impression that she thinks that halothane confers immunity to all forms of viral hepatitis in people exposed to its vapour. She
Royal Infirmary, Manchester M13 9WL
MICHAEL
JOHNSTONE
may be
right, but I do not think she is because I am reasonably certain that the immunodepression of surgery and anaesthesia increases the severity of all infections. 12 Fatal liver necrosis from a herpes-type virus has occurred in a patient after surI gery under enflurane anaesthesia.3 in not a are Physicians position to prescribe anaesthetic that halothane should be Sherlock’s recommendation drugs. avoided in "minor" surgery is irresponsible. Halothane is usually the safest and best anaesthetic in these circumstances. If possible all anaesthetic drugs should be avoided in surgical patients with viral infections unrelated to the surgical pathology. A second anaesthetic should not be given until recovery from the immunodepression of the first operation is complete. Hepatitis B (serum hepatitis) is not an uncommon complication in patients after surgery and it may also afflict the surgical staff. The recognition and the control of the infection in these circumstances has been well described, and anaesthetists are advised to read carefully the published reports.4-6 Hepatitis A (infectious hepatitis) is a more difficult problem because there is no reliable serological test for it.’ In the early stages of the first clinical trial of halothane it was anticipated that sooner or later patients in the asymptomatic incubation phase of infectious hepatitis would be anaathetised with this agent, and anaesthetists were warned that the jaundice which subsequently appeared might be wrongly ascribed to the anoesthetic.8 With the cooperation of the Office of Morbidity Statistics for General Practice in the United Kingdom and the department of anaathetics in the University of Cardiff it was estimated that out of every million patients anaathetised with any anaesthetic agent jaundice might appear in about 100 of them some days or weeks postoperatively as the result of coincidental infectious hepatitis.9 This figure does not include transmitted hepatitis B. Despite the warning the hepatitis controversy was precipitated by two physicians who reported 8 cases of transient postoperative jaundice and suggested that the cause was an allergic reaction to halothane.’" In presenting their opinion they ignored four important facts. First, the fact that most of the cases occurred over a period of a few weeks should have alerted them to the possibility of an infectious origin. Second, they did not refer to the fact that a widely publicised epidemic of infec1. 2.
Munster, H. M. Lancet, 1976, i, 1329. Duncan, P. G., Cullen, B. F. Anesthesiology, 1976, 45, 522. 3. Douglas, H. J., Eger, E. I., Biava, C. G., Renzi, C. New Engl. J. Med. 1977, 296, 553. 4. Rimland, D., Parkin, W. E., Miller, G. B., Schrack, W. D. ibid. 1977, 296, 955.
5. 6.
Grady, G. F. ibid. 1977, 296, 996. Naulty, J. S., Reves, J. G., Tobey, R. E., Schultz, W. W. curr. Res. 1977, 56, 366. 7. Woolf, I., Williams, R. Br. J. Hosp. Med. 1977, 17, 117. 8. Johnstone, M. Anesthesiology, 1961, 22, 591. 9. Johnstone, M. Br.J. Anæsth. 1964, 36, 718. 10. Lindenbaum, J., Leifer, E. New Engl. J. Med. 1963, 268, 525.
Anesth.
PHARMACOLOGY AND THE MOLE
SiR,—Your normally thoughtful columns developed a regrettable entrenched tone on June 17.’ While it must be accepted that we do not yet possess an understanding of the molecular action of drugs which demands that drug concentrations should be expressed in molar units, there are a number of other considerations which justify a change to these units. My experience over the past seven years of running a quality-control scheme for antiepileptic drugs, in which 200 laboratories in many countries participate, has led me to conclude that a major source of error stems from the inability of many laboratories to make up working standards. One important oversight is failure to correct for the fact that standards are usually made up by weighing in the salt, whereas it is the acid or base which is measured in serum. For example, phenytoin is usually added as the sodium salt, and failure to allow for the sodium atom will produce an approximately 10% error in the result. This oversight is not confined to the laboratory amateur-one of the leading producers of quality-control serum was guilty of this error when it introduced drug control sera. Some laboratories express their serum levels as the salt—e.g., lignocaine hydrochloride2-but this could cause confusion. In our not yet published study of the bioavailability of lignocaine hydrochloride and monohydrate, for example, it would be nonsensical if we expressed our results in anything but the base. In many publications it is, not made clear just what has been measured. How many disagreements in clinical pharmacology are due to simple confusions of this sort? Precision in medicine, often difficult, can be achieved in drug measurement. The use of molar units does not automatically overcome these problems, but when an analyst has to convert from gravimetric to molar units he has to think about what he is measuring.
Further problems arise when metabolites of drugs are being measured. Some drugs, for instance, have active metabolites, and in relating serum level to effect it is tempting to add the concentrations of parent compound and. metabolite together. But to do so on a gravimetric basis, as did Carr and Hobson did for tricyclic antidepressants3 is incorrect. On a molar basis, however, this makes more sense. Similarly, it is logical to use molar units in studies of the metabolic pattern of drugs, when it may be necessary to compare yields of metabolites through different pathways. You are right in saying that drugs are measured only occasionally, but it is reasonable to assume that as progress is made in clinical pharmacology, the indications for drug level moni-
Analg. 11. Dougherty, W. J., Altman, R. Am. J. Med. 1962, 32, 704. 1. Lancet, 1978, i, 1297. 2. Rowland, M., Thomson, P. D., Guichard, A., Melmon, K. L. Ann. N.Y. Acad. Sci. 1971, 179, 383. 3. Carr, A. C., Hobson, R. P. Br. med. J. 1977, ii, 1151.
