Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1992 Aug;34(2):106–114. doi: 10.1111/j.1365-2125.1992.tb04118.x

Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.

J McCulloch 1
PMCID: PMC1381526  PMID: 1419472

Abstract

1. A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2. The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3. The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4. NMDA receptor antagonists have marked effects on brain function in normal animals. The balance between these potential adverse effects and the anti-ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5. The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.

Full text

PDF
106

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andiné P., Lehmann A., Ellrén K., Wennberg E., Kjellmer I., Nielsen T., Hagberg H. The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection. Neurosci Lett. 1988 Jul 19;90(1-2):208–212. doi: 10.1016/0304-3940(88)90813-0. [DOI] [PubMed] [Google Scholar]
  2. Bielenberg G. W., Beck T. The effects of dizocilpine (MK-801), phencyclidine, and nimodipine on infarct size 48 h after middle cerebral artery occlusion in the rat. Brain Res. 1991 Jun 28;552(2):338–342. doi: 10.1016/0006-8993(91)90101-z. [DOI] [PubMed] [Google Scholar]
  3. Buchan A. M., Li H., Cho S., Pulsinelli W. A. Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats. Neurosci Lett. 1991 Nov 11;132(2):255–258. doi: 10.1016/0304-3940(91)90314-j. [DOI] [PubMed] [Google Scholar]
  4. Buchan A., Pulsinelli W. A. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci. 1990 Jan;10(1):311–316. doi: 10.1523/JNEUROSCI.10-01-00311.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bullock R., Butcher S. P., Chen M. H., Kendall L., McCulloch J. Correlation of the extracellular glutamate concentration with extent of blood flow reduction after subdural hematoma in the rat. J Neurosurg. 1991 May;74(5):794–802. doi: 10.3171/jns.1991.74.5.0794. [DOI] [PubMed] [Google Scholar]
  6. Bullock R., Graham D. I., Chen M. H., Lowe D., McCulloch J. Focal cerebral ischemia in the cat: pretreatment with a competitive NMDA receptor antagonist, D-CPP-ene. J Cereb Blood Flow Metab. 1990 Sep;10(5):668–674. doi: 10.1038/jcbfm.1990.120. [DOI] [PubMed] [Google Scholar]
  7. Busto R., Dietrich W. D., Globus M. Y., Valdés I., Scheinberg P., Ginsberg M. D. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987 Dec;7(6):729–738. doi: 10.1038/jcbfm.1987.127. [DOI] [PubMed] [Google Scholar]
  8. Butcher S. P., Bullock R., Graham D. I., McCulloch J. Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke. 1990 Dec;21(12):1727–1733. doi: 10.1161/01.str.21.12.1727. [DOI] [PubMed] [Google Scholar]
  9. Carter C., Rivy J. P., Scatton B. Ifenprodil and SL 82.0715 are antagonists at the polyamine site of the N-methyl-D-aspartate (NMDA) receptor. Eur J Pharmacol. 1989 May 30;164(3):611–612. doi: 10.1016/0014-2999(89)90275-6. [DOI] [PubMed] [Google Scholar]
  10. Chen M., Bullock R., Graham D. I., Frey P., Lowe D., McCulloch J. Evaluation of a competitive NMDA antagonist (D-CPPene) in feline focal cerebral ischemia. Ann Neurol. 1991 Jul;30(1):62–70. doi: 10.1002/ana.410300112. [DOI] [PubMed] [Google Scholar]
  11. Choi D. W., Koh J. Y., Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci. 1988 Jan;8(1):185–196. doi: 10.1523/JNEUROSCI.08-01-00185.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dawson V. L., Dawson T. M., London E. D., Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368–6371. doi: 10.1073/pnas.88.14.6368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dirnagl U., Tanabe J., Pulsinelli W. Pre- and post-treatment with MK-801 but not pretreatment alone reduces neocortical damage after focal cerebral ischemia in the rat. Brain Res. 1990 Sep 10;527(1):62–68. doi: 10.1016/0006-8993(90)91060-t. [DOI] [PubMed] [Google Scholar]
  14. Fleischer J. E., Tateishi A., Drummond J. C., Scheller M. S., Grafe M. R., Zornow M. H., Shearman G. T., Shapiro H. M. MK-801, an excitatory amino acid antagonist, does not improve neurologic outcome following cardiac arrest in cats. J Cereb Blood Flow Metab. 1989 Dec;9(6):795–804. doi: 10.1038/jcbfm.1989.113. [DOI] [PubMed] [Google Scholar]
  15. Foster A. C., Fagg G. E. Neurobiology. Taking apart NMDA receptors. Nature. 1987 Oct 1;329(6138):395–396. doi: 10.1038/329395a0. [DOI] [PubMed] [Google Scholar]
  16. France C. P., Woods J. H., Ornstein P. The competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 attenuates the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects. Eur J Pharmacol. 1989 Jan 10;159(2):133–139. doi: 10.1016/0014-2999(89)90697-3. [DOI] [PubMed] [Google Scholar]
  17. Frandsen A., Drejer J., Schousboe A. Direct evidence that excitotoxicity in cultured neurons is mediated via N-methyl-D-aspartate (NMDA) as well as non-NMDA receptors. J Neurochem. 1989 Jul;53(1):297–299. doi: 10.1111/j.1471-4159.1989.tb07327.x. [DOI] [PubMed] [Google Scholar]
  18. Gelmers H. J., Gorter K., de Weerdt C. J., Wiezer H. J. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988 Jan 28;318(4):203–207. doi: 10.1056/NEJM198801283180402. [DOI] [PubMed] [Google Scholar]
  19. George C. P., Goldberg M. P., Choi D. W., Steinberg G. K. Dextromethorphan reduces neocortical ischemic neuronal damage in vivo. Brain Res. 1988 Feb 9;440(2):375–379. doi: 10.1016/0006-8993(88)91011-6. [DOI] [PubMed] [Google Scholar]
  20. Gill R., Brazell C., Woodruff G. N., Kemp J. A. The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia. Br J Pharmacol. 1991 Aug;103(4):2030–2036. doi: 10.1111/j.1476-5381.1991.tb12371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gill R., Foster A. C., Woodruff G. N. Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci. 1987 Oct;7(10):3343–3349. doi: 10.1523/JNEUROSCI.07-10-03343.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gill R., Woodruff G. N. The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia. Eur J Pharmacol. 1990 Feb 6;176(2):143–149. doi: 10.1016/0014-2999(90)90522-8. [DOI] [PubMed] [Google Scholar]
  23. Gotti B., Benavides J., MacKenzie E. T., Scatton B. The pharmacotherapy of focal cortical ischaemia in the mouse. Brain Res. 1990 Jul 9;522(2):290–307. doi: 10.1016/0006-8993(90)91473-t. [DOI] [PubMed] [Google Scholar]
  24. Gotti B., Duverger D., Bertin J., Carter C., Dupont R., Frost J., Gaudilliere B., MacKenzie E. T., Rousseau J., Scatton B. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther. 1988 Dec;247(3):1211–1221. [PubMed] [Google Scholar]
  25. Hattori H., Morin A. M., Schwartz P. H., Fujikawa D. G., Wasterlain C. G. Posthypoxic treatment with MK-801 reduces hypoxic-ischemic damage in the neonatal rat. Neurology. 1989 May;39(5):713–718. doi: 10.1212/wnl.39.5.713. [DOI] [PubMed] [Google Scholar]
  26. Hossmann K. A. Treatment of experimental cerebral ischemia. J Cereb Blood Flow Metab. 1982 Sep;2(3):275–297. doi: 10.1038/jcbfm.1982.30. [DOI] [PubMed] [Google Scholar]
  27. Izumi Y., Roussel S., Pinard E., Seylaz J. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 1991 Nov;11(6):1025–1030. doi: 10.1038/jcbfm.1991.170. [DOI] [PubMed] [Google Scholar]
  28. Jones T. H., Morawetz R. B., Crowell R. M., Marcoux F. W., FitzGibbon S. J., DeGirolami U., Ojemann R. G. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981 Jun;54(6):773–782. doi: 10.3171/jns.1981.54.6.0773. [DOI] [PubMed] [Google Scholar]
  29. Kemp J. A., Foster A. C., Leeson P. D., Priestley T., Tridgett R., Iversen L. L., Woodruff G. N. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6547–6550. doi: 10.1073/pnas.85.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kochhar A., Zivin J. A., Lyden P. D., Mazzarella V. Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Arch Neurol. 1988 Feb;45(2):148–153. doi: 10.1001/archneur.1988.00520260034016. [DOI] [PubMed] [Google Scholar]
  31. Koek W., Colpaert F. C. Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther. 1990 Jan;252(1):349–357. [PubMed] [Google Scholar]
  32. Koek W., Woods J. H., Winger G. D. MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther. 1988 Jun;245(3):969–974. [PubMed] [Google Scholar]
  33. Kurumaji A., Nehls D. G., Park C. K., McCulloch J. Effects of NMDA antagonists, MK-801 and CPP, upon local cerebral glucose use. Brain Res. 1989 Sep 4;496(1-2):268–284. doi: 10.1016/0006-8993(89)91074-3. [DOI] [PubMed] [Google Scholar]
  34. LUCAS D. R., NEWHOUSE J. P. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol. 1957 Aug;58(2):193–201. doi: 10.1001/archopht.1957.00940010205006. [DOI] [PubMed] [Google Scholar]
  35. Lanier W. L., Perkins W. J., Karlsson B. R., Milde J. H., Scheithauer B. W., Shearman G. T., Michenfelder J. D. The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates. J Cereb Blood Flow Metab. 1990 Mar;10(2):252–261. doi: 10.1038/jcbfm.1990.42. [DOI] [PubMed] [Google Scholar]
  36. Lehmann J., Hutchison A. J., McPherson S. E., Mondadori C., Schmutz M., Sinton C. M., Tsai C., Murphy D. E., Steel D. J., Williams M. CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist. J Pharmacol Exp Ther. 1988 Jul;246(1):65–75. [PubMed] [Google Scholar]
  37. Lodge D., Collingridge G. Les agents provocateurs: a series on the pharmacology of excitatory amino acids. Trends Pharmacol Sci. 1990 Jan;11(1):22–24. doi: 10.1016/0165-6147(90)90037-9. [DOI] [PubMed] [Google Scholar]
  38. McCulloch J., Iversen L. L. Autoradiographic assessment of the effects of N-methyl-D-aspartate (NMDA) receptor antagonists in vivo. Neurochem Res. 1991 Sep;16(9):951–963. doi: 10.1007/BF00965838. [DOI] [PubMed] [Google Scholar]
  39. McDonald J. W., Silverstein F. S., Johnston M. V. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol. 1987 Aug 21;140(3):359–361. doi: 10.1016/0014-2999(87)90295-0. [DOI] [PubMed] [Google Scholar]
  40. McDonald J. W., Silverstein F. S., Johnston M. V. Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model. Brain Res. 1989 Jun 19;490(1):33–40. doi: 10.1016/0006-8993(89)90427-7. [DOI] [PubMed] [Google Scholar]
  41. Meldrum B. Protection against ischaemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovasc Brain Metab Rev. 1990 Spring;2(1):27–57. [PubMed] [Google Scholar]
  42. Michaels R. L., Rothman S. M. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci. 1990 Jan;10(1):283–292. doi: 10.1523/JNEUROSCI.10-01-00283.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Michenfelder J. D., Lanier W. L., Scheithauer B. W., Perkins W. J., Shearman G. T., Milde J. H. Evaluation of the glutamate antagonist dizocilipine maleate (MK-801) on neurologic outcome in a canine model of complete cerebral ischemia: correlation with hippocampal histopathology. Brain Res. 1989 Mar 6;481(2):228–234. doi: 10.1016/0006-8993(89)90798-1. [DOI] [PubMed] [Google Scholar]
  44. Minamisawa H., Nordström C. H., Smith M. L., Siesjö B. K. The influence of mild body and brain hypothermia on ischemic brain damage. J Cereb Blood Flow Metab. 1990 May;10(3):365–374. doi: 10.1038/jcbfm.1990.66. [DOI] [PubMed] [Google Scholar]
  45. Nehls D. G., Kurumaji A., Park C. K., McCulloch J. Differential effects of competitive and non-competitive N-methyl-D-aspartate antagonists on glucose use in the limbic system. Neurosci Lett. 1988 Aug 31;91(2):204–210. doi: 10.1016/0304-3940(88)90769-0. [DOI] [PubMed] [Google Scholar]
  46. Nellgård B., Wieloch T. Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J Cereb Blood Flow Metab. 1992 Jan;12(1):2–11. doi: 10.1038/jcbfm.1992.2. [DOI] [PubMed] [Google Scholar]
  47. Nicholls D., Attwell D. The release and uptake of excitatory amino acids. Trends Pharmacol Sci. 1990 Nov;11(11):462–468. doi: 10.1016/0165-6147(90)90129-v. [DOI] [PubMed] [Google Scholar]
  48. Olney J. W., Labruyere J., Price M. T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science. 1989 Jun 16;244(4910):1360–1362. doi: 10.1126/science.2660263. [DOI] [PubMed] [Google Scholar]
  49. Osborne K. A., Shigeno T., Balarsky A. M., Ford I., McCulloch J., Teasdale G. M., Graham D. I. Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1987 Apr;50(4):402–410. doi: 10.1136/jnnp.50.4.402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ozyurt E., Graham D. I., Woodruff G. N., McCulloch J. Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat. J Cereb Blood Flow Metab. 1988 Feb;8(1):138–143. doi: 10.1038/jcbfm.1988.18. [DOI] [PubMed] [Google Scholar]
  51. Park C. K., Nehls D. G., Graham D. I., Teasdale G. M., McCulloch J. Focal cerebral ischaemia in the cat: treatment with the glutamate antagonist MK-801 after induction of ischaemia. J Cereb Blood Flow Metab. 1988 Oct;8(5):757–762. doi: 10.1038/jcbfm.1988.124. [DOI] [PubMed] [Google Scholar]
  52. Park C. K., Nehls D. G., Graham D. I., Teasdale G. M., McCulloch J. The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol. 1988 Oct;24(4):543–551. doi: 10.1002/ana.410240411. [DOI] [PubMed] [Google Scholar]
  53. Pickard J. D., Murray G. D., Illingworth R., Shaw M. D., Teasdale G. M., Foy P. M., Humphrey P. R., Lang D. A., Nelson R., Richards P. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989 Mar 11;298(6674):636–642. doi: 10.1136/bmj.298.6674.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Prince D. A., Feeser H. R. Dextromethorphan protects against cerebral infarction in a rat model of hypoxia-ischemia. Neurosci Lett. 1988 Mar 10;85(3):291–296. doi: 10.1016/0304-3940(88)90581-2. [DOI] [PubMed] [Google Scholar]
  55. Rothman S. M., Olney J. W. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol. 1986 Feb;19(2):105–111. doi: 10.1002/ana.410190202. [DOI] [PubMed] [Google Scholar]
  56. Roussel S., Pinard E., Seylaz J. Kynurenate does not reduce infarct size after middle cerebral artery occlusion in spontaneously hypertensive rats. Brain Res. 1990 Jun 4;518(1-2):353–355. doi: 10.1016/0006-8993(90)90997-p. [DOI] [PubMed] [Google Scholar]
  57. Shimada N., Graf R., Rosner G., Wakayama A., George C. P., Heiss W. D. Ischemic flow threshold for extracellular glutamate increase in cat cortex. J Cereb Blood Flow Metab. 1989 Oct;9(5):603–606. doi: 10.1038/jcbfm.1989.86. [DOI] [PubMed] [Google Scholar]
  58. Siesjö B. K., Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab. 1989 Apr;9(2):127–140. doi: 10.1038/jcbfm.1989.20. [DOI] [PubMed] [Google Scholar]
  59. Simon R., Shiraishi K. N-methyl-D-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol. 1990 Jun;27(6):606–611. doi: 10.1002/ana.410270604. [DOI] [PubMed] [Google Scholar]
  60. Singh L., Donald A. E., Foster A. C., Hutson P. H., Iversen L. L., Iversen S. D., Kemp J. A., Leeson P. D., Marshall G. R., Oles R. J. Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative. Proc Natl Acad Sci U S A. 1990 Jan;87(1):347–351. doi: 10.1073/pnas.87.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Steinberg G. K., George C. P., DeLaPaz R., Shibata D. K., Gross T. Dextromethorphan protects against cerebral injury following transient focal ischemia in rabbits. Stroke. 1988 Sep;19(9):1112–1118. doi: 10.1161/01.str.19.9.1112. [DOI] [PubMed] [Google Scholar]
  62. Steinberg G. K., Kunis D., Saleh J., DeLaPaz R. Protection after transient focal cerebral ischemia by the N-methyl-D-aspartate antagonist dextrorphan is dependent upon plasma and brain levels. J Cereb Blood Flow Metab. 1991 Nov;11(6):1015–1024. doi: 10.1038/jcbfm.1991.169. [DOI] [PubMed] [Google Scholar]
  63. Sterz F., Leonov Y., Safar P., Radovsky A., Stezoski S. W., Reich H., Shearman G. T., Greber T. F. Effect of excitatory amino acid receptor blocker MK-801 on overall, neurologic, and morphologic outcome after prolonged cardiac arrest in dogs. Anesthesiology. 1989 Dec;71(6):907–918. doi: 10.1097/00000542-198912000-00014. [DOI] [PubMed] [Google Scholar]
  64. Uematsu D., Araki N., Greenberg J. H., Sladky J., Reivich M. Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology. 1991 Jan;41(1):88–94. doi: 10.1212/wnl.41.1.88. [DOI] [PubMed] [Google Scholar]
  65. Wallace M. C., Teasdale G. M., McCulloch J. Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat. J Neurosurg. 1992 Jan;76(1):127–133. doi: 10.3171/jns.1992.76.1.0127. [DOI] [PubMed] [Google Scholar]
  66. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES