- Email: [email protected]
DOXANTRAZOLE, AN ANTIALLERGIC AGENT ORALLY EFFECTIVE IN MAN
1169 bronchoconstriction in the ratwas supmg. per kg. intravenously given 1 minute before intravenous antigen challenge. A concentration-dependent suppression of anaphylactic release of histamine was demonstrated using in-vitro preparations, previously described With suspensions of peritoneal cells (containing mast cells) from rats actively sensitised to egg albumin and injected also with Bordetella pertussis, suppression of release was seen at concentrations of 0-1-3 p,M (0-04-0-11 Ag. per ml.). Similar concentrations also depressed the release of histamine from ratperitoneal-cell suspensions when the release was induced by exposure to dextran in the presence of phosphatidylserine. Comparable effects were also observed using passively sensitised chopped human lung challenged with an extract of grass pollen. Higher concentrations (500 juM) were required to suppress anaphylactic release of histamine from actively sensitised guineapig lung, but this contrasts with the absence of effect with cromoglycate on this IgG mediated response, even at a concentration of 1 mM.
Anaphylactic
Preliminary
Communication
DOXANTRAZOLE, AN ANTIALLERGIC AGENT ORALLY EFFECTIVE IN MAN F. BATCHELOR M. J. FOLLENFANT L. G. GARLAND J. H. GORVIN H. F. HODSON A. F. GREEN D. T. D. HUGHES J. E. TATESON Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS
J.
Summary
In-vivo
studies
have
demonstrated
antiallergic properties in doxantrazole These properties were when given orally to rats. confirmed in work with in-vitro preparations. No significant animal toxicity has been detected. 200 mg. given by mouth inhibited the immediate-type asthmatic response in volunteer patients challenged with specific antigen. DISODIUM
,
cromoglycate represented an important pharmacological advance in the treatment of asthma. Its effects are attributable to suppression of the release of such anaphylactic mediators as histamine and slowreacting substance A that follows antigen reaction with reaginic antibody in conditions of hypersensitivity.1 However, it is ineffective in asthma except when inhaled 23 Several independent searches have been made for a similar but orally effective agent.4.s We describe here doxantrazole-i.e., 3-(5-tetrazolyl)thioxanthone 10,10-dioxide-which is very effective by the oral route in laboratory animals and man, persists in tissues for adequate time periods, and is free from demonstrable unwanted effects even at large multiples of the antiallergic dose. In our experiments the hydrated sodium salt (approximately 12% water) was used, but doses are expressed in terms of the weight of anhydrous salt. The compound has the following structural formula:
pressed by 1-30
The pharmacokinetic properties of the compound have been examined by our colleagues Dr R. H. Nimmo-Smith, Dr P. Johnson, and Dr A. Bye. They found that the concentrations of the compound required in vitro to suppress anaphylactic histamine release in rat and human tissues are readily achieved by oral administration to these species of well-tolerated dosages. For example, after an oral dose of 250 mg. in four human volunteers the mean plasma level rose to a peak of 17.6 //.g. per ml. ±4-1 (S.E.M.) in 1 hour and fell to about half this value (8’4± 1-3 ng. per ml.) in 5 hours. ‘
pharmacological examination revealed low toxicity (e.g., L.D’5o orally in mice and rats >2 g. per kg.) and no effect on any of a variety of physiological Extensive
test systems that would contraindicate its use in man. Three properties found are, however, worthy of mention. Firstly, the compound inhibited cyclic 3’,5’ adenosine monophosphate (CA.M.P.) phosphodiesterase, at concentrations of the order of 10-50 /M, using enzyme from bovine heart or guineapig or human lung, suggesting that the antiallergic effect may be related to an increase of intracellular CA.M.P. concentrations. This hypothesis has already been advanced to explain the antiallergic effect of disodium cromoglycate 12 which inhibits CA.M.P. phosphodiesterase from several tissues’3 Secondly, a relaxant action, perhaps
again
The oral activity of doxantrazole was shown in rats by inhibition of a reagin-mediated passive cutaneous anaphylaxis (P.C.A.) reaction using a high-titre reaginic antiserum.6,7 Using doses of 30 mg. per kg. orally, a maximum of 60% inhibition occurred when the interval between drug administration and antigen challenge was 8-30 minutes, and approximately 30% inhibition occurred when the interval was 7 hours. Using the 30-minute interval, the percent inhibition of the P.C.A. reaction increased linearly with log dose within the range 1-30 mg. per kg. Such dosages did not antagonise increases in capillary permeability caused by intradermal injection of histamine or 5-hydroxytryptamine, indicating that suppression of the P.C.A. reaction was due to inhibition of mediator release.
related
to
cA.M.p.-phosphodiesterase inhibition,
found with concentrations of 1-30 juM in guineapig tracheal-muscle preparations. However, as much as 30-100 mg. per kg. intravenously was required for a weak and short-lived bronchodilator effect in in-vivo preparations, using established techniques in dogs " and guineapigs 15 Thirdly, there is a brief hypotensive action, associated with bradycardia, after intravenous dosages of 1 mg. per kg. in dogs. This effect was abolished by vagotomy and reduced by atropine, and attributed to a reflex carried in afferent vagal fibres. Such effects were not seen with intravenous doses in guineapigs or cats or with oral dosing in dogs or man but are of some interest in relation to reports of similar effects with cromoglycate 16 Detailed investigation by Dr V. Udall and his colleagues of rats and monkeys given large multiples of the antiallergic dose daily for 1 or 2 months likewise revealed no adverse property. The compound was examined in several informed and consenting patients with allergic asthma by studywas
1170
its effect on the bronchoconstriction produced by bronchial challenge with specific antigen. Striking inhibition of the immediate-type asthmatic response was produced by single oral doses of 200 mg. Further work is required to demonstrate the value of this compound for long-term control of allergic asthma.
ing
Detailed reports of our findings will be published elsewhere. Requests for reprints should be addressed to D. T. D. H.
I
titioners in developing countries a guide which describes the traditional approaches to history-taking and clinical examination in neurology. The text is clear and the advice sound. There are some clinical photographs (not all satisfactory), radiographs, and many line diagrams (some a bit crude, as in fig. 1.2 on the " diagnostic drag-net "). There are some elementary spelling errors. Neurology is increasing in importance in tropical medicine, and this guide should prove useful to students, doctors, and nurses.I.
’I
I’
I
REFERENCES 1. 2.
3.
4. 5.
6. 7. 8.
9. 10. 11. 12. 13. 14.
15. 16.
Cox, J. S. G. Nature, 1967, 216, 1328. Benson, M. K., Curry, S. H., Mills, G. G. d’A, Hughes, D. T. D. Clin. Allergy, 1973, 3, 389. Walker, S. R., Evans, M. E., Richards, A. J., Patterson, J. W. J. Pharm. Pharmac. 1972, 24, 525. Assem, E. S. K., Evans, J. A., McAllen, M. Br. med. J. 1974, ii, 93. Broughton, B. J., Chaplen, P., Knowles, P., Lunt, E., Pain, D. L., Wooldridge, K. R. H., Ford, R., Marshall, S., Walker, J. L., Maxwell, D. R. Nature, 1974, 251, 650. Goose, J., Blair, A. M. J. N. Immunology, 1969, 16, 749. Orr, T. S. C., Blair, A. M. J. N. Life Sci. 1969, 8, 1073. Farmer, J. B., Richards, I. M., Sheard, P., Woods, A. M. NaunynSchmeidebergs Arch. exp. Path. Pharmak. 1973, 279, suppl. R35. Garland, L. G. Br. J. Pharmac. 1973, 49, 128. Garland, L. G., Mongar, J. L. ibid. 1974, 50, 137. Assem, E. S. K., Schild, H. O. Br. med. J. 1968, iii, 272. Taylor, W. A., Francis, D. H., Sheldon, D., Roitt, I. M. Int. Archs Allergy appl. Immun. 1974, 46, 104. Roy, A. C., Warren, B. T. Biochem. Pharmac. 1974, 23, 917. Konzett, H., Rössler, R. Naunyn-Schmeidebergs Arch. exp. Path. Pharmak. 1940, 195, 71. Dixon, W. E., Brodie, T. G. J. Physiol., Lond. 1903, 29, 97. Cox, J. S. G., Beach, J. E., Blair, A. M. J. N., Clarke, A. J., King, J., Lee, T. B., Loveday, D. E. E., Moss, G. F., Orr, T. S. C., Ritchie, J. T., Sheard, P. Adv. Drug Res. 1970, 115.
Reviews of Books
Going
to
See the Doctor
GERRY STIMSON and BARBARA WEBB, Medical Sociology Research Centre, University College, Swansea. London: Routledge & Kegan Paul. 1975. Pp. 155. E4.95.
THIS little book, which one is tempted to call " the talk of surgery folk ", carries a radical message. Its material is based on a series of observations of, and interviews with, patients around the event of consulting a doctor. None of the anecdotes would startle a general practitioner, but the authors analyse and develop their findings in a It is often difficult to see where most challenging way. ends and reasoned argument begins, but the whole premise makes compelling reading for any health-care professional, being a serious attempt to investigate the patient’s view of consultations. Stimson and Webb see the consultation as a much more mechanical process than many doctors care to. From the premise that the patient is a participant in medicine rather than a recipient of medical care, they view patient behaviour as strategic in nature. Extending this to doctors’ behaviour, sacred cows are left, if not dying, looking a little sick. They suggest that the use of empathy amounts merely to the exercise of good manners and charge " amateur psychoanalysts " with seeking to extend the doctor’s power at the consultation, to the (implied) detriment of the patient. The whole idea of a doctor " knowing his patients is seen to support the notion of the patient as weak and vulnerable. For patient read consumer, for doctor, professional, and the ideas put forward go far beyond medicine. Clearly the surgery is a rich virgin territory for patient-liberation activities.
everyday
"
An Introduction to
Electrocardiography
F.R.C.P., St. Bartholomew’s Hospital, London. London: Pitman Medical. 1975. Pp. 125. 2.75.
JOHN HAMER,
THE need for an introductory text providing an understanding of electrocardiographic principles and of the main features of tracings is attested by the large number of slim volumes that have appeared lately. Most of these are unsuitable; their authors fail to distinguish between the important and the trivial. It is thus with pleasure that one welcomes Dr Hamer’s excellent little book. In this he compresses all the essential information in a readable fashion, with illustrations that are of high quality and well reproduced. For many, it will be all they need; there is enough in it for any undergraduate and most physicians with a peripheral interest in the subject, but it is particularly good for nurses who work in coronary-care units. There are sound explanations for all the arrhythmias, and only rarely can one cavil at the descriptions, and then only on minor grounds (e.g., in parasystole the ectopic focus does Comnot necessarily produce impulses at a slow rate). is need E.C.G. there mention of the to use mendably, machines with proper frequency responses and of the possibility of artefacts; and illustrations of some of the latter are desirable in future editions. Dr Hamer set himself an important target which he strikes with commendable success: the book answers the need of many doctors and nurses. With it, a sound professional fulfils the needs of the amateurs.
Methods in
Neurological Examination
T. 0. DADA, F.R.C.P.E., University of Lagos. Edinburgh: Churchill Livingstone. 1975. Pp. 227. E3.75.
THIS small book is one of a series entitled Medicine in the Tropics. The author is a British-t::ained neurologist working in Nigeria. He has written for students and prac-
Nuclear Medicine Edited by HENRY N. WAGNER, Jr., M.D., Johns Hopkins Medical Institution, Baltimore. New York : H.P. Publishing. Reading: Freeman. 1975. Pp.255.$21 ; E11.20.
THIS book contains 24 chapters on nuclear medicine which were first published in Hospital Practice betweer. 1968 and 1974 and are here updated. It is said to be written for " the practising physician as a guide to an important diagnostic resource, and for the medical student, the house officer, and the basic science student whose work is focused on medicine ". Detailed overlapping is rare, but many aspects of nuclear medicine have been left out. The technology sections tend to be bitty, and the clinical sections emphasise imaging rather than measurement. The chapter on the skeleton, for instance, consists of 13 pages containing 56 scans (some of animals), while there is only passing mention of any quantitative uptake studies and no mention at all of bone-turnover measurements. The list of references is selective. This book is rather superficial, and its best feature is its copious illustrations, many in colour.
New Editions
Diagnosis of Bleeding Disorders. 2nd ed. By Charles A. Owen, Jr., E. J. Walter Bowie, and John H. Thompson. Boston, Mass.: Little, Brown. 1975. Pp. 398. S21.50. Topics in Gastroenterology 2. Edited by S. C. Truelove and Joan Trowell. Oxford: Blackwell. 1974. Pp. 373. £ 10.
I
I
IB I I ’
Anaphylactic
Preliminary
Communication
DOXANTRAZOLE, AN ANTIALLERGIC AGENT ORALLY EFFECTIVE IN MAN F. BATCHELOR M. J. FOLLENFANT L. G. GARLAND J. H. GORVIN H. F. HODSON A. F. GREEN D. T. D. HUGHES J. E. TATESON Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS
J.
Summary
In-vivo
studies
have
demonstrated
antiallergic properties in doxantrazole These properties were when given orally to rats. confirmed in work with in-vitro preparations. No significant animal toxicity has been detected. 200 mg. given by mouth inhibited the immediate-type asthmatic response in volunteer patients challenged with specific antigen. DISODIUM
,
cromoglycate represented an important pharmacological advance in the treatment of asthma. Its effects are attributable to suppression of the release of such anaphylactic mediators as histamine and slowreacting substance A that follows antigen reaction with reaginic antibody in conditions of hypersensitivity.1 However, it is ineffective in asthma except when inhaled 23 Several independent searches have been made for a similar but orally effective agent.4.s We describe here doxantrazole-i.e., 3-(5-tetrazolyl)thioxanthone 10,10-dioxide-which is very effective by the oral route in laboratory animals and man, persists in tissues for adequate time periods, and is free from demonstrable unwanted effects even at large multiples of the antiallergic dose. In our experiments the hydrated sodium salt (approximately 12% water) was used, but doses are expressed in terms of the weight of anhydrous salt. The compound has the following structural formula:
pressed by 1-30
The pharmacokinetic properties of the compound have been examined by our colleagues Dr R. H. Nimmo-Smith, Dr P. Johnson, and Dr A. Bye. They found that the concentrations of the compound required in vitro to suppress anaphylactic histamine release in rat and human tissues are readily achieved by oral administration to these species of well-tolerated dosages. For example, after an oral dose of 250 mg. in four human volunteers the mean plasma level rose to a peak of 17.6 //.g. per ml. ±4-1 (S.E.M.) in 1 hour and fell to about half this value (8’4± 1-3 ng. per ml.) in 5 hours. ‘
pharmacological examination revealed low toxicity (e.g., L.D’5o orally in mice and rats >2 g. per kg.) and no effect on any of a variety of physiological Extensive
test systems that would contraindicate its use in man. Three properties found are, however, worthy of mention. Firstly, the compound inhibited cyclic 3’,5’ adenosine monophosphate (CA.M.P.) phosphodiesterase, at concentrations of the order of 10-50 /M, using enzyme from bovine heart or guineapig or human lung, suggesting that the antiallergic effect may be related to an increase of intracellular CA.M.P. concentrations. This hypothesis has already been advanced to explain the antiallergic effect of disodium cromoglycate 12 which inhibits CA.M.P. phosphodiesterase from several tissues’3 Secondly, a relaxant action, perhaps
again
The oral activity of doxantrazole was shown in rats by inhibition of a reagin-mediated passive cutaneous anaphylaxis (P.C.A.) reaction using a high-titre reaginic antiserum.6,7 Using doses of 30 mg. per kg. orally, a maximum of 60% inhibition occurred when the interval between drug administration and antigen challenge was 8-30 minutes, and approximately 30% inhibition occurred when the interval was 7 hours. Using the 30-minute interval, the percent inhibition of the P.C.A. reaction increased linearly with log dose within the range 1-30 mg. per kg. Such dosages did not antagonise increases in capillary permeability caused by intradermal injection of histamine or 5-hydroxytryptamine, indicating that suppression of the P.C.A. reaction was due to inhibition of mediator release.
related
to
cA.M.p.-phosphodiesterase inhibition,
found with concentrations of 1-30 juM in guineapig tracheal-muscle preparations. However, as much as 30-100 mg. per kg. intravenously was required for a weak and short-lived bronchodilator effect in in-vivo preparations, using established techniques in dogs " and guineapigs 15 Thirdly, there is a brief hypotensive action, associated with bradycardia, after intravenous dosages of 1 mg. per kg. in dogs. This effect was abolished by vagotomy and reduced by atropine, and attributed to a reflex carried in afferent vagal fibres. Such effects were not seen with intravenous doses in guineapigs or cats or with oral dosing in dogs or man but are of some interest in relation to reports of similar effects with cromoglycate 16 Detailed investigation by Dr V. Udall and his colleagues of rats and monkeys given large multiples of the antiallergic dose daily for 1 or 2 months likewise revealed no adverse property. The compound was examined in several informed and consenting patients with allergic asthma by studywas
1170
its effect on the bronchoconstriction produced by bronchial challenge with specific antigen. Striking inhibition of the immediate-type asthmatic response was produced by single oral doses of 200 mg. Further work is required to demonstrate the value of this compound for long-term control of allergic asthma.
ing
Detailed reports of our findings will be published elsewhere. Requests for reprints should be addressed to D. T. D. H.
I
titioners in developing countries a guide which describes the traditional approaches to history-taking and clinical examination in neurology. The text is clear and the advice sound. There are some clinical photographs (not all satisfactory), radiographs, and many line diagrams (some a bit crude, as in fig. 1.2 on the " diagnostic drag-net "). There are some elementary spelling errors. Neurology is increasing in importance in tropical medicine, and this guide should prove useful to students, doctors, and nurses.I.
’I
I’
I
REFERENCES 1. 2.
3.
4. 5.
6. 7. 8.
9. 10. 11. 12. 13. 14.
15. 16.
Cox, J. S. G. Nature, 1967, 216, 1328. Benson, M. K., Curry, S. H., Mills, G. G. d’A, Hughes, D. T. D. Clin. Allergy, 1973, 3, 389. Walker, S. R., Evans, M. E., Richards, A. J., Patterson, J. W. J. Pharm. Pharmac. 1972, 24, 525. Assem, E. S. K., Evans, J. A., McAllen, M. Br. med. J. 1974, ii, 93. Broughton, B. J., Chaplen, P., Knowles, P., Lunt, E., Pain, D. L., Wooldridge, K. R. H., Ford, R., Marshall, S., Walker, J. L., Maxwell, D. R. Nature, 1974, 251, 650. Goose, J., Blair, A. M. J. N. Immunology, 1969, 16, 749. Orr, T. S. C., Blair, A. M. J. N. Life Sci. 1969, 8, 1073. Farmer, J. B., Richards, I. M., Sheard, P., Woods, A. M. NaunynSchmeidebergs Arch. exp. Path. Pharmak. 1973, 279, suppl. R35. Garland, L. G. Br. J. Pharmac. 1973, 49, 128. Garland, L. G., Mongar, J. L. ibid. 1974, 50, 137. Assem, E. S. K., Schild, H. O. Br. med. J. 1968, iii, 272. Taylor, W. A., Francis, D. H., Sheldon, D., Roitt, I. M. Int. Archs Allergy appl. Immun. 1974, 46, 104. Roy, A. C., Warren, B. T. Biochem. Pharmac. 1974, 23, 917. Konzett, H., Rössler, R. Naunyn-Schmeidebergs Arch. exp. Path. Pharmak. 1940, 195, 71. Dixon, W. E., Brodie, T. G. J. Physiol., Lond. 1903, 29, 97. Cox, J. S. G., Beach, J. E., Blair, A. M. J. N., Clarke, A. J., King, J., Lee, T. B., Loveday, D. E. E., Moss, G. F., Orr, T. S. C., Ritchie, J. T., Sheard, P. Adv. Drug Res. 1970, 115.
Reviews of Books
Going
to
See the Doctor
GERRY STIMSON and BARBARA WEBB, Medical Sociology Research Centre, University College, Swansea. London: Routledge & Kegan Paul. 1975. Pp. 155. E4.95.
THIS little book, which one is tempted to call " the talk of surgery folk ", carries a radical message. Its material is based on a series of observations of, and interviews with, patients around the event of consulting a doctor. None of the anecdotes would startle a general practitioner, but the authors analyse and develop their findings in a It is often difficult to see where most challenging way. ends and reasoned argument begins, but the whole premise makes compelling reading for any health-care professional, being a serious attempt to investigate the patient’s view of consultations. Stimson and Webb see the consultation as a much more mechanical process than many doctors care to. From the premise that the patient is a participant in medicine rather than a recipient of medical care, they view patient behaviour as strategic in nature. Extending this to doctors’ behaviour, sacred cows are left, if not dying, looking a little sick. They suggest that the use of empathy amounts merely to the exercise of good manners and charge " amateur psychoanalysts " with seeking to extend the doctor’s power at the consultation, to the (implied) detriment of the patient. The whole idea of a doctor " knowing his patients is seen to support the notion of the patient as weak and vulnerable. For patient read consumer, for doctor, professional, and the ideas put forward go far beyond medicine. Clearly the surgery is a rich virgin territory for patient-liberation activities.
everyday
"
An Introduction to
Electrocardiography
F.R.C.P., St. Bartholomew’s Hospital, London. London: Pitman Medical. 1975. Pp. 125. 2.75.
JOHN HAMER,
THE need for an introductory text providing an understanding of electrocardiographic principles and of the main features of tracings is attested by the large number of slim volumes that have appeared lately. Most of these are unsuitable; their authors fail to distinguish between the important and the trivial. It is thus with pleasure that one welcomes Dr Hamer’s excellent little book. In this he compresses all the essential information in a readable fashion, with illustrations that are of high quality and well reproduced. For many, it will be all they need; there is enough in it for any undergraduate and most physicians with a peripheral interest in the subject, but it is particularly good for nurses who work in coronary-care units. There are sound explanations for all the arrhythmias, and only rarely can one cavil at the descriptions, and then only on minor grounds (e.g., in parasystole the ectopic focus does Comnot necessarily produce impulses at a slow rate). is need E.C.G. there mention of the to use mendably, machines with proper frequency responses and of the possibility of artefacts; and illustrations of some of the latter are desirable in future editions. Dr Hamer set himself an important target which he strikes with commendable success: the book answers the need of many doctors and nurses. With it, a sound professional fulfils the needs of the amateurs.
Methods in
Neurological Examination
T. 0. DADA, F.R.C.P.E., University of Lagos. Edinburgh: Churchill Livingstone. 1975. Pp. 227. E3.75.
THIS small book is one of a series entitled Medicine in the Tropics. The author is a British-t::ained neurologist working in Nigeria. He has written for students and prac-
Nuclear Medicine Edited by HENRY N. WAGNER, Jr., M.D., Johns Hopkins Medical Institution, Baltimore. New York : H.P. Publishing. Reading: Freeman. 1975. Pp.255.$21 ; E11.20.
THIS book contains 24 chapters on nuclear medicine which were first published in Hospital Practice betweer. 1968 and 1974 and are here updated. It is said to be written for " the practising physician as a guide to an important diagnostic resource, and for the medical student, the house officer, and the basic science student whose work is focused on medicine ". Detailed overlapping is rare, but many aspects of nuclear medicine have been left out. The technology sections tend to be bitty, and the clinical sections emphasise imaging rather than measurement. The chapter on the skeleton, for instance, consists of 13 pages containing 56 scans (some of animals), while there is only passing mention of any quantitative uptake studies and no mention at all of bone-turnover measurements. The list of references is selective. This book is rather superficial, and its best feature is its copious illustrations, many in colour.
New Editions
Diagnosis of Bleeding Disorders. 2nd ed. By Charles A. Owen, Jr., E. J. Walter Bowie, and John H. Thompson. Boston, Mass.: Little, Brown. 1975. Pp. 398. S21.50. Topics in Gastroenterology 2. Edited by S. C. Truelove and Joan Trowell. Oxford: Blackwell. 1974. Pp. 373. £ 10.
I
I
IB I I ’