Responses by Australian pharmacologists to respiratory depression caused by opiates and barbiturates
Ian D. Rae
A
+ Author Affiliations
- Author Affiliations
A School of Chemistry, University of Melbourne, Vic. 3010, Australia. Email: iandrae@bigpond.com
Historical Records of Australian Science 33(1) 1-11 https://doi.org/10.1071/HR21005
Published: 17 January 2022
Abstract
In the middle of the last century, pharmacologists at the University of Melbourne led by Professor Frank Shaw inadvertently discovered that an amino-acridine they were using in other experiments reversed the respiratory depressive effects of morphine. They widened their search for such activity, experimenting with a range of heterocyclic substances and achieving success with a thiazole derivative, provided to them by the Professor of Organic Chemistry at the university, that countered the effects of morphine. Working with chemists and pharmacologists at a company with which Shaw had close links, Nicholas Pty Ltd, they discovered a glutarimide that offered the same benefit in cases of barbiturate intoxication. While this collaboration between pharmacologists and chemists, in industry and university, promised much, neither of these drugs survived into modern medical practice. The reasons for this include the development of better drugs or more appropriate patient care, Shaw’s withdrawal from the work because of illness, and decisions in the company that might have been influenced by increasingly stringent requirements for the registration of new drugs. Nonetheless this was important research that drew on the depth of expertise in pharmacology and chemistry among university researchers and a major Australian company with whom they collaborated and exchanged personnel.
References
Adams, E. (1958) Barbiturates, Scientific American, 198, 60–64.| BarbituratesCrossref | GoogleScholarGoogle Scholar |
Albert, A., Rubbo, S., Goldacre, R., Davey, M., and Stone, J. (1945) The influence of chemical structure on antibacterial activity, part II: a general survey of the Acridine Series, British Journal of Experimental Pathology, 26, 160–192.
Anderson, K. W. (1958) The determination of Beta-Substituted Glutarimides in blood: time-concentration curves after intravenous administration of two barbiturate antagonists, The Journal of Pharmacy and Pharmacology, 10, 242–248.
| The determination of Beta-Substituted Glutarimides in blood: time-concentration curves after intravenous administration of two barbiturate antagonistsCrossref | GoogleScholarGoogle Scholar | 13539799PubMed |
Anonymous (1938) E. Merck Darmstadt: a History of Chemical Achievement 1827–1937, Darmstadt.
Anonymous, (1944) Brief history of the Drugs Subcommittee, Australian Journal of Science, 7, 75–80.
Anonymous, (1949a) Drug addiction: heroin and the barbiturates, The Medical Journal of Australia, , 289–290.
Anonymous (1949b) Australia’s high drug consumption, Age (Melbourne), 26 August, 2.
Anonymous, (1951) Antimorphine drug promotes breathing newborn infants, Chemical and Engineering News, 29, 5058.
Anonymous, (1953) Treatment of barbiturate poisoning, Lancet, 261, 81.
| Treatment of barbiturate poisoningCrossref | GoogleScholarGoogle Scholar |
Anonymous (1954a) New drug helps relieve all pain, The Argus (Melbourne), 21 October, 7.
Anonymous (1954b) Doctors find drug antidotes, Sydney Morning Herald, 16 January, 3.
Anonymous (1956) We discover a new drug, The Argus (Melbourne), 7 May, 7.
Backer, H. J., and deJonge, J. (1943) Dérivés de la Sulfanilamide Renferant l’Anneaux 1,2,4-triazol, Recueil des Travaux Chimiques des Pays-Bas (Leiden, Netherlands), 62, 158–162.
| Dérivés de la Sulfanilamide Renferant l’Anneaux 1,2,4-triazolCrossref | GoogleScholarGoogle Scholar |
Baeyer, A. (1863) Untersuchungen über die Harnsäuregruppe, Justus Liebigs Annalen der Chemie, 127, 1–27 and 199–236.
Benica, W. S., and Wilson, C. O. (1950) Glutarimides I. 3-Alkyl-3-methylglutarimides, Journal of the American Pharmaceutical Association, 39, 451–454.
| Glutarimides I. 3-Alkyl-3-methylglutarimidesCrossref | GoogleScholarGoogle Scholar | 14774275PubMed |
Bentley, G. A. (1949) ‘Some aspects of the pharmacology of Aminicrin [i.e. Aminacrin] and related substances’, unpublished MSc thesis, University of Melbourne.
Bentley, G. A. (1952) ‘Aspects of the pharmacology of morphine’, unpublished PhD thesis, University of Melbourne.
Blumberg, H., and Dayton, H. B. (1972) ‘Naloxone and related compounds’, in Agonist and Antagonist Actions of Narcotic Analgesic Drugs, eds H. W. Kosterlitz, H. O. J. Collier and J. E. Villarreal, London.
Brooke, E. M. (1956) Too much barbiturate?, Lancet, 267, 150–152.
| Too much barbiturate?Crossref | GoogleScholarGoogle Scholar |
Cade, J. F. J. (1949) Lithium salts in the treatment of psychotic excitement, The Medical Journal of Australia, 2, 349–352.
| Lithium salts in the treatment of psychotic excitementCrossref | GoogleScholarGoogle Scholar |
Campbell, J. N., and Rooney, S. M. (2018) A Time-Release History of the Opioid Epidemic, Cham.
Cass, N., Nelson, E. R., and Shaw, F. H. (1955) ‘The synthesis of a series of imides and pharmacological experience one of the members’, in Report of the Thirtieth Meeting of the Australian and New Zealand Association for the Advancement of Science, ed. C. S. Daley, Sydney, p. 276.
Christie, G., Gerson, S., Gray, R., Shaw, F. H., McCance, I., and Bruce, D. W. (1958) Treatment of certain side-effects of morphine, British Medical Journal, 1, 675–680.
| Treatment of certain side-effects of morphineCrossref | GoogleScholarGoogle Scholar | 13510767PubMed |
Collins, D. J., Culvenor, C. C. J., Lamberton, J. A., Loder, J. W., and Price, J. R. (1990) Plants for Medicines: a Chemical and Pharmacological Survey of Plants in the Australian Region, Melbourne.
Courtwright, D. T. (2001) Forces of habit: drugs and the making of the modern world, Cambridge, MA.
Davies, W., Maclaren, J. A., and Wilkinson, L. R. (1950) The synthesis and properties of 2:4-diaminothiazoles, Journal of the Chemical Society, , 3491–3494.
| The synthesis and properties of 2:4-diaminothiazolesCrossref | GoogleScholarGoogle Scholar |
Deichmann, W. B., Kitzmiller, K. V., Heyroth, F. F., and Witherup, S. (1948) The Physiological response of experimental animals following absorption of 2-aminothiazole, The Journal of Industrial Hygiene and Toxicology, 30, 71–78.
| 18905196PubMed |
Eckenhoff, J. E., and Dam, W. (1956) The treatment of barbiturate poisoning with or without analeptics, The American Journal of Medicine, 20, 912–918.
| The treatment of barbiturate poisoning with or without analepticsCrossref | GoogleScholarGoogle Scholar | 13326905PubMed |
Eckenhoff, J. E., and Norton, M. L. (1958) The treatment of intractable pain with large doses of morphine and Amiphenazole (Daptazole®), Acta Anaesthesiologica Scandinavica, 2, 45–51.
| The treatment of intractable pain with large doses of morphine and Amiphenazole (Daptazole®)Crossref | GoogleScholarGoogle Scholar | 13532232PubMed |
Eckenhoff, J. E., Schmidt, C. F., Dripps, R. D., and Kety, S. S. (1949) A status report on analeptics, Journal of the American Medical Association, 139, 780–788.
| A status report on analepticsCrossref | GoogleScholarGoogle Scholar | 18112556PubMed |
Eckenhoff, J. E., Elder, J. D., and King, B. D. (1952) N-Allyl-normorphine in the treatment of morphine or Demerol narcosis, The American Journal of the Medical Sciences, 223, 191–197.
| N-Allyl-normorphine in the treatment of morphine or Demerol narcosisCrossref | GoogleScholarGoogle Scholar | 14902806PubMed |
Eckenhoff, J. E., Hoffman, G. L., and Funderburg, L. W. (1953) N-Allylnormorphine: an antagonist to neonatal narcosis produced by sedation of the parturient, American Journal of Obstetrics and Gynecology, 65, 1269–1275.
| N-Allylnormorphine: an antagonist to neonatal narcosis produced by sedation of the parturientCrossref | GoogleScholarGoogle Scholar | 13057957PubMed |
Fischer, E., and von Mering, J. (1903) Über eine neue Klasse von Schlafmitteln, Therapie der Gegenwart, 44, 97–101.
Fitzgerald, M. (1955) £1 million wanted, The Argus (Melbourne), 22 March, 4.
Flesch, J. (2012) Life’s Logic: 150 years of Physiology at the University of Melbourne, North Melbourne.
Gawler, O. (1954) Victorian Year Book 1950–51, Melbourne.
Golder, F. J., Gruber, R. B., Puskovic, V., Peng, S., Dax, S. L., MacIntyre, D. E., and Mannion, J. C. (2012) Reversal of opioid-induced respiratory depression by the (+)-enantiomer, DAL-054, but not the (-)-enantiomer, GAL-053, of Doxapram, The FASEB Journal, 26, 704–726.
| Reversal of opioid-induced respiratory depression by the (+)-enantiomer, DAL-054, but not the (-)-enantiomer, GAL-053, of DoxapramCrossref | GoogleScholarGoogle Scholar |
Goldstein, S. W. (1947) Barbiturates: a blessing and a menace, Journal of the American Pharmaceutical Association, 36, 5–14.
| Barbiturates: a blessing and a menaceCrossref | GoogleScholarGoogle Scholar | 20285819PubMed |
Gscheidlen, S. (1869) Über die physiologischen Wirkung des essigsauren Morphiums, Untersuchungen aus dem physiologischen Laboratorium in Würzburg, Zweiter Theil, 1–66. Abstracted (1869), The American Journal of the Medical Sciences, 56, 238.
Gussow, L., and Carlson, A. (2018) ‘Sedative hypnotics’, in Rosens Emergency Medicine: Concepts and Clinical Practice, eds R. M. Walls, R. S. Hockberger and M. Gauschee-Hil, 9th edn, Philadelphia, pp. 1974–1981.
Handley, G. J., Nelson, E. R., and Somers, T. C. (1960) Compounds derived from β-substituted glutaric acids: glutarimides, glutaramic acids, 1,5-pentane diols, Australian Journal of Chemistry, 13, 129–144.
| Compounds derived from β-substituted glutaric acids: glutarimides, glutaramic acids, 1,5-pentane diolsCrossref | GoogleScholarGoogle Scholar |
Harris, T. A. B. (1955) A barbiturate antagonist, Lancet, 265, 181.
| A barbiturate antagonistCrossref | GoogleScholarGoogle Scholar |
Hart, E. R., and McCawley, E. L. (1944) The pharmacology of N-allyl normorphine as compared with morphine, The Journal of Pharmacology and Experimental Therapeutics, 82, 339–348.
Hatt, H. H. (1967) William Davies 1895–1966, Chemistry in Britain, 3, 265.
ICD (1948) International classification of diseases, revision 6 (1948), www.wolfbane.com/icd/icd6h.htm, viewed June 2021.
Jarrott, B. (2017) Tacrine: in vivo veritas, Pharmacological Research, 116, 29–31.
| Tacrine: in vivo veritasCrossref | GoogleScholarGoogle Scholar | 28040533PubMed |
Jasinski, D. R., Martin, W. R., and Hoertzen, C. A. (1967) The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone), The Journal of Pharmacology and Experimental Therapeutics, 157, 420–426.
| 6039832PubMed |
Keefe, P. R. (2021) Empire of Pain: the Secret History of the Sackler Family, London.
Keogh, P. P. (1946) ‘Report on the determination of the alkaloids of Cinchona’, unpublished MSC thesis, University of Melbourne.
Keogh, P. P., and Bentley, G. A. (1948) The pharmacology of monacrine, Australian Journal of Science, 11, 98–99.
Kolm, J. E. (1988) ‘The Chemical Industry—Australian Contributions to Chemical Technology’, in Technology in Australia, 1788–1988, ed. J. Woodcock, Melbourne, pp. 656–658.
Koppanyi, T., and Fazekas, J. F. (1950) Acute barbiturate poisoning: analysis and evaluation of current therapy, The American Journal of the Medical Sciences, 220, 559–576.
| Acute barbiturate poisoning: analysis and evaluation of current therapyCrossref | GoogleScholarGoogle Scholar | 14783127PubMed |
Korszniak, N. (1996) The Department of Pharmacology at the University of Melbourne 1953–1995, Melbourne.
Kreuger, H. (1941) ‘Morphine: action on respiration’, in The Pharmacology of the Opium Alkaloids, eds. H. Kreuger, Nathan B. Eddy and Margaret Sumwalt, vol. 1, Washington, D.C., pp. 77–246.
Laycock, G. M. (1962) ‘A study of hypnotic-analeptic interaction with special reference to Bemegride’, unpublished MSc thesis, University of Melbourne.
Laycock, G. M., and Shulman, A. (1963) Partial agonists in the central nervous system, Nature, 200, 849–851.
| Partial agonists in the central nervous systemCrossref | GoogleScholarGoogle Scholar | 14096054PubMed |
Liddy, M. J. (1978) Epidemiology of Fatalities Related to the Abuse of Narcotic Drugs in N.S.W. and A.C.T. 1974–1977, Lidcombe, NSW.
Loewy, A. (1890) Zur kentniss der Erregbarkeit des Atherncentrums, Archiv für die gesamte Physiologie des Menschen und der Tiere, 47, 601–621.
Lunsford, C. D., Cale, A. D., Ward, J. W., Franko, B. V., and Jenkins, H. (1964) 4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones: a new series of CNS stimulants, Journal of Medicinal Chemistry, 7, 302–310.
| 4-(β-Substituted ethyl)-3,3-diphenyl-2-pyrrolidinones: a new series of CNS stimulantsCrossref | GoogleScholarGoogle Scholar | 14204965PubMed |
McCance, I. (c. 1960) ‘[No title]’, Thesis submitted for the degree of Master of Science, unpublished MSc thesis, University of Melbourne.
McEwan, J. (2007) A History of Therapeutic Goods Regulation in Australia, https://www.tga.gov.au/sites/default/files/history-tg-regulation.pdf, viewed September 2021.
McPhee, P. (1999) ‘Pansy’: a Life of Roy Douglas Wright, Carlton South.
Patel, V. K., Jindal, M. N., Patel, N. B., and Venkatakrishna-Bhatt, H. (1980) Reduction of barbiturate anaesthesia by new glutarimide compounds in mice, Psychopharmacology, 71, 101–103.
| Reduction of barbiturate anaesthesia by new glutarimide compounds in miceCrossref | GoogleScholarGoogle Scholar | 6779318PubMed |
Pohl, J. (1915) Ueber der N-Allylnorcodein, einer Antagonisten des Morphins, Zeitschrift für die experimentelle Pathologie, 17, 370–382.
| Ueber der N-Allylnorcodein, einer Antagonisten des MorphinsCrossref | GoogleScholarGoogle Scholar |
Porter, Q. N. (1993) Davies, William (1895–1966), Australian Dictionary of Biography, 13, 585–586. http://adb.anu.edu.au/biography/davies-william-bill-9918, viewed May 2021.
Rasmussen, C. (2002) Rubbo, Sydney Dattilo (1911–1969), Australian Dictionary of Biography, 16, 143–144. https://adb.anu.edu.au/biography/rubbo-sydney-dattilo-11578, viewed May 2021.
Roberts, C. (1953) The pills are tiny, but … death waits in the cupboard, The Argus (Melbourne), 27 July, 4.
Sackville, R., Hackett, E., and Nies, R. (1979) Royal Commission into the Non-medical Use of Drugs in South Australia, Final Report, Adelaide.
Sertürner, F. W. (1817) Über das Morphium, ein neue salzfähiger Grundlage, und der Mekonsäure, als Hauptbestandteile des Opiums, Annalen der Physik, 55, 56–89.
| Über das Morphium, ein neue salzfähiger Grundlage, und der Mekonsäure, als Hauptbestandteile des OpiumsCrossref | GoogleScholarGoogle Scholar |
Shaw, F. H. (1955) Further experience with ‘Megimide’—a barbiturate antagonist, The Medical Journal of Australia, 42, 889–891.
| Further experience with ‘Megimide’—a barbiturate antagonistCrossref | GoogleScholarGoogle Scholar | 13287449PubMed |
Shaw, F. H. (1957) Bemegride, Amiphenaxole and barbiturate poisoning—the present position, The Medical Journal of Australia, 44, 712–714.
| Bemegride, Amiphenaxole and barbiturate poisoning—the present positionCrossref | GoogleScholarGoogle Scholar | 13430077PubMed |
Shaw, F. H. (1958) Design and chance in the development of new drugs, Proceedings of the Royal Australian Chemical Institute, 25, 247–252.
Shaw, F. H. (1960) Morphine fallacies, The Australasian Journal of Pharmacy, 41, 344–349.
Shaw, F., and Bentley, G. A. (1949) Some aspects of the pharmacology of morphine, with special reference to its antagonism by 5-amino-acridine and other chemically related compounds, The Medical Journal of Australia, 2, 868–874.
| Some aspects of the pharmacology of morphine, with special reference to its antagonism by 5-amino-acridine and other chemically related compoundsCrossref | GoogleScholarGoogle Scholar | 15401512PubMed |
Shaw, F. H., and Bentley, G. A. (1952) Morphine antagonism, Nature, 169, 712–713.
| Morphine antagonismCrossref | GoogleScholarGoogle Scholar | 14956997PubMed |
Shaw, F. H., and Bentley, G. A. (1953) The pharmacology of some new anti-cholinesterases, The Australian Journal of Experimental Biology and Medical Science, 31, 573–576.
| The pharmacology of some new anti-cholinesterasesCrossref | GoogleScholarGoogle Scholar | 13149558PubMed |
Shaw, F. H., and Bentley, G. A. (1955) Morphine antagonism, The Australian Journal of Experimental Biology and Medical Science, 33, 143–151.
| Morphine antagonismCrossref | GoogleScholarGoogle Scholar | 13239534PubMed |
Shaw, F. H., and Schulman, A. (1955a) Morphine antagonists, Nature, 175, 388–389.
| Morphine antagonistsCrossref | GoogleScholarGoogle Scholar | 14356188PubMed |
Shaw, F. H., and Schulman, A. (1955b) Treatment of intractable pain with large doses of morphine and diamino-phenylthiazole, British Medical Journal, 1, 1367–1369.
| Treatment of intractable pain with large doses of morphine and diamino-phenylthiazoleCrossref | GoogleScholarGoogle Scholar | 14363900PubMed |
Shaw, F. H., Simon, S. E., Cass, N., Schulman, A., Anstee, J. R., and Nelson, E. R. (1954) Barbiturate antagonism, Nature, 174, 402–403.
| Barbiturate antagonismCrossref | GoogleScholarGoogle Scholar | 13194004PubMed |
Shulman, A., and Laycock, G. M. (1967) Dual action of 5-ethyl-5-(1,3-dimethylbutyl)barbiturate, dilantin and β-methyl-β-2-propylglutarimide, European Journal of Pharmacology, 2, 17–25.
| Dual action of 5-ethyl-5-(1,3-dimethylbutyl)barbiturate, dilantin and β-methyl-β-2-propylglutarimideCrossref | GoogleScholarGoogle Scholar | 4384752PubMed |
Shulman, A., Shaw, F. H., Cass, N. M., and Whyte, H. M. (1955) A new treatment of barbiturate intoxication, British Medical Journal, 1, 1238–1244.
| A new treatment of barbiturate intoxicationCrossref | GoogleScholarGoogle Scholar | 14363849PubMed |
Shulman, A., Laycock, G. M., and Henry, J. A. (1965) Titration curves depicting central stimulant, depressant and dual stimulant-depressant action of glutarimide homologues in mice, Nature, 208, 568–571.
| Titration curves depicting central stimulant, depressant and dual stimulant-depressant action of glutarimide homologues in miceCrossref | GoogleScholarGoogle Scholar |
Smith, R. G. (1958) Nicholas Institute for Medical and Veterinary Research, Proceedings of the Royal Australian Chemical Institute, 25, 72–78.
Smith, R. G., and Barrie, A. (1976) Aspro—How a Family Business Grew up, Melbourne.
Somers, P. C. (1955) The barbiturate antagonist ‘N.P. 13’ and the morphine antagonist ‘D.A.P.T.’, The Australasian Journal of Pharmacy, 36, 864–865.
Somers, T. C. (1956) New analeptics and hypnotics related to the barbiturate antagonist, ‘Bemegride’, Nature, 178, 996–997.
| New analeptics and hypnotics related to the barbiturate antagonist, ‘Bemegride’Crossref | GoogleScholarGoogle Scholar | 13378509PubMed |
Thole, F. B., and Thorpe, J. F. (1911) The formation and reactions of imino-compounds, part XV: the production of imino-derivatives of piperidine leading to the formation of β,β-disubstituted glutaric acids, Journal of the Chemical Society, , 422–448.
| The formation and reactions of imino-compounds, part XV: the production of imino-derivatives of piperidine leading to the formation of β,β-disubstituted glutaric acidsCrossref | GoogleScholarGoogle Scholar |
Turner, A. W., and Hodgetts, V. E. (1956) Barbiturate antagonism: the use of ‘Megimide’ and of ‘Daptazole’ in curtailing ‘Nembutal’ anaesthesia, and in treating apnoeio ‘Nembutal’ intoxication in sheep, Australian Veterinary Journal, 32, 49–54.
| Barbiturate antagonism: the use of ‘Megimide’ and of ‘Daptazole’ in curtailing ‘Nembutal’ anaesthesia, and in treating apnoeio ‘Nembutal’ intoxication in sheepCrossref | GoogleScholarGoogle Scholar |
Unna, K. (1943) Antagonistic effect of N-allyl-normorphine upon morphine, The Journal of Pharmacology and Experimental Therapeutics, 79, 27–31.
van der Schier, R., Roozekrans, M., van Velzen, M., Daha, A., and Niesters, M. (2014) Opioid-induced respiratory depression: reversal by non-opioid drugs, Prime Reports, 6, 79, 1–8. http://f1000.com/prime/reports/m/6/79, viewed August 2021.
Ward, J. W., and Franko, B. V. (1962) A new centrally acting agent (AHR-619) with marked of respiratory stimulating, pressor and ‘awakening’ effects, Federation Proceedings, 21, 325.
Wasserman, A. J., and Richardson, D. W. (1962) Human cardio-pulmonary effects of AHR-619, a respiratory stimulant, Federation Proceedings, 21, 342.
(b) Wesson, D. R. (1977) Barbiturates, Their Use, Misuse and Abuse, New York.
Wiedling, S. (1948) A simple method of direct comparison of the depressant effect of the barbiturates on the respiration and circulation, Nature, 162, 1003.
| A simple method of direct comparison of the depressant effect of the barbiturates on the respiration and circulationCrossref | GoogleScholarGoogle Scholar | 18106138PubMed |
Wilkinson, L. R. (1949) 4-Aminothiazoles and related compounds, unpublished MSc thesis, University of Melbourne.
Williams, G. (1955) They have disease on the run, The Argus (Melbourne), 15 February, 23.
Yost, C. S. (2006) A new look at the respiratory stimulant doxapram, CNS Drug Reviews, 12, 236–249.
| A new look at the respiratory stimulant doxapramCrossref | GoogleScholarGoogle Scholar | 17227289PubMed |
