General Theory of Drug-Receptor Interactions

Drug-Receptor Interaction Models. Calculation of Drug Parameters
  • F. G. van den Brink
Part of the Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology book series (HEP, volume 47)

Abstract

In the study of the interaction between pharmacologically active molecules and different types of receptor-effector systems (often designated as molecular pharmacology) an important role is played by theoretical mathematical models with which these interactions can be described (Clark, 1926, 1937; Gaddum, 1926, 1937; Ariëns, 1954; Ariëns et al., 1956a, b, c, 1964a, b, c; Stephenson, 1956; Van Rossum, 1958, 1966; Paton, 1961; Paton and Waud, 1964; Paton and Rang, 1966; Van den Brink, 1969 c, d, 1973 a, b). It should be stressed that these models do not pretend to be exact representations of the enormously complicated chain of events leading from the contact between the molecules of a pharmacologically active substance and a biological entity to the ensuing effect. This they cannot do and it is not their purpose. Even on a theoretical level the equations used only hold fully if quite a number of presuppositions are made (Van Rossum, 1966; Van den Brink, 1969 b). In practice the models cannot be expected to give more than a usable overall description of reality.

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References

  1. Åberg, B.: On the effects of weak auxins and antiauxins upon root growth. Physiol. Plantarum 5, 305–319 (1952).CrossRefGoogle Scholar
  2. Ahlquist, R.P.: A study of the adrenotropic receptors. Amer. J. Physiol. 153, 586–600 (1948).PubMedGoogle Scholar
  3. Ariëns, E.J.: Affinity and intrinsic activity in the theory of competitive inhibition. Part I. Problems and theory. Arch. int. Pharmacodyn. 99, 32–49 (1954).PubMedGoogle Scholar
  4. Ariëns, E.J.: Receptor theory and structure-action relationships. In: Harper, N.J., Simmonds, A.B. (Eds.) Advances in Drug Research, Vol. 3, pp. 235–285. London-New York: Academic Press 1966.Google Scholar
  5. Ariëns, E.J.: Reduction of drug action by drug combination. J. mond. Pharm. (La Haye) 12, 263–279 (1969).Google Scholar
  6. Ariëns, E.J., de Groot, W.M.: Affinity and intrinsic activity in the theory of competitive inhibition. Part III. Homologous decamethonium-derivatives and succinyl-choline-esters. Arch. int. Pharmacodyn. 99, 193–205 (1954).PubMedGoogle Scholar
  7. Ariëns, E.J., Simonis, A.M.: Affinity and intrinsic activity in the theory of competitive inhibition. Part II. Experiments with para-amino-benzoic acid derivatives. Arch. int. Pharmacodyn. 99, 175–187 (1954).PubMedGoogle Scholar
  8. Ariëns, E.J., Simonis, A.M.: Autonomic drugs and their receptors. Arch. int. Pharmacodyn. 127, 479–496 (1960).PubMedGoogle Scholar
  9. Ariëns, E.J., Simonis, A.M.: A molecular basis for drug action. J. Pharm. Pharmacol. 16, 137–157 (1964).CrossRefGoogle Scholar
  10. Ariëns, E.J., Simonis, A.M., de Groot, W.M.: Affinity and intrinsic activity in the theory of competitive and non-competitive inhibition and an analysis of some forms of dualism in action. Arch. int. Pharmacodyn. 100, 298–322 (1955).PubMedGoogle Scholar
  11. Ariëns, E.J., Simonis, A.M., van Rossum, J.M.: Drug receptor interaction: Interaction of one or more drugs with one receptor system. In: Ariëns, E.J. (Ed.): Molecular Pharmacology, Vol. I, pp. 119–286. New York-London: Academic Press 1964a.Google Scholar
  12. Ariëns, E.J., Simonis, A.M., van Rossum, J.M.: Drug receptor interaction: Interaction of one or more drugs with different receptor systems. In: Ariëns, E.J. (Ed.): Molecular Pharmacology, Vol. I, pp. 287–393. New York-London: Academic Press 1964b.Google Scholar
  13. Ariëns, E.J., Simonis, A.M., van Rossum, J.M.: The relation between stimulus and effect. In: Ariëns, E.J. (Ed.): Molecular Pharmacology, Vol. I, pp. 394–466. New York-London: Academic Press 1964c.Google Scholar
  14. Ariëns, E.J., van Rossum, J.M.: pDx, pAx and pDx values in the analysis of pharmacodynamics. Arch. int. Pharmacodyn. 110, 275–299 (1957).PubMedGoogle Scholar
  15. Ariëns, E.J., van Rossum, J.M., Koopman, P.C.: Receptor reserve and threshold phenomena. I. Theory and experiments with autonomic drugs tested on isolated organs. Arch. int. Pharmacodyn. 127, 459–478 (1960).PubMedGoogle Scholar
  16. Ariëns, E.J., van Rossum, J.M., Simonis, A.M.: A theoretical basis of molecular pharmacology. Part I. Interaction of one or two compounds with one receptor system. Arzneimittel-Forsch. 6, 282–293 (1956a).Google Scholar
  17. Ariëns, E.J., van Rossum, J.M., Simonis, A.M.: A theoretical basis of molecular pharmacology. Part II. Interactions of one or two compounds with two interdependent receptor systems. Arzneimittel-Forsch. 6, 611–621 (1956b).Google Scholar
  18. Ariëns, E.J., van Rossum, J.M., Simonis, A.M.: A theoretical basis of molecular pharmacology. Part III. Interactions of one or two compounds with two independent receptor systems. Arzneimittel-Forsch. 6, 737–746 (1956c).Google Scholar
  19. Ariëns, E.J., van Rossum, J.M., Simonis, A.M.: Affinity, intrinsic activity and drug interactions. Pharmacol. Rev. 9, 218–236 (1957).PubMedGoogle Scholar
  20. Beidler, L.M.: Taste receptor stimulation. In: Progress in Biophysics and Biophysical Chemistry, Eds. Butler, J.A.V., Huxley, H.E., Zirkle, R.E., Vol. 12, pp. 107–151. New York: Pergamon Press 1962.Google Scholar
  21. Belleau, B.: A molecular theory of drug action based on induced conformational perturbations of receptors. J. med. Chem. 7, 776–784 (1964).PubMedCrossRefGoogle Scholar
  22. Belleau, B.: Conformational perturbation in relation to the regulation of enzyme and receptor behaviour. In: Harper, N.J., Simmonds, A.B., (Eds.): Advances in Drug Research, Vol. 2, pp. 89–126. London-New York: Academic Press 1965.Google Scholar
  23. Belleau, B.: Steric effects in catecholamine interactions with enzymes and receptors. Pharmacol. Rev. 18, 131–140 (1966).PubMedGoogle Scholar
  24. Belleau, B., Lavoie, J.L.: A biophysical basis of ligand-induced activation of excitable membranes and associated enzymes. A thermodynamic study using acetylcholinesterase as a model receptor. Canad. J. Biochem. 46, 1397–1409 (1968).CrossRefGoogle Scholar
  25. Bloom, B.M., Goldman, I.M.: The nature of catecholamine-adenine mononucleotide interactions in adrenergic mechanisms. In: Harper, N.J., Simmonds, A.B., (Eds.): Advances in Drug Research, Vol. 3, pp. 121–169. London-New York: Academic Press 1966.Google Scholar
  26. Bovet, D., Bovet-Nitti, F., Bettschart, A., Scognamiglio, W.: Mécanisme de la potentialisation par le chlorhydrate de diéthylamino-éthyldiphénylpropylacétate des effects de quelques agents curarisants. Helv. physiol. pharmacol. Acta 14, 430–440 (1956).PubMedGoogle Scholar
  27. Brandt, H.D.: The mechanisms by which Beta-Adrenergic Drugs antagonize Different Spasmogens, pp. 1–174. D. Sc. Thesis, University of Potchefstroom, 1971.Google Scholar
  28. Canepa, F.G.: Mechanism of ganglion blocking activity by methonium chains. Nature (Lond.) 195, 573–575 (1962).CrossRefGoogle Scholar
  29. Cavallito, C.J.: Some interrelationships of chemical structure, physical properties and curarimimetic action. In: Bovet, D., Bovet-Nitti, F., Martini-Bettolo, G.B., (Eds.): Curare and Curarelike Agents, pp. 288–303. Amsterdam-London-New York-Princeton: Elsevier Publ. Co. 1959.Google Scholar
  30. Chagas, C.: The fate of curare during curarization. In: de Reuck, A.V.S., (Ed.): Curare and Curare-like Agents, pp. 2–10. London: J. and A. Churchill Ltd. 1962.Google Scholar
  31. Changeux, J.P., Podleski, T.R.: On the excitability and cooperativity of the electroplax membrane. Proc. nat. Acad. Sci. (Wash.) 59, 944–950 (1968).CrossRefGoogle Scholar
  32. Changeux, J.P., Thiéry, J., Tung, Y., Kittel, C.: On the cooperativity of biological membranes. Proc. nat. Acad. Sci. (Wash.) 57, 335–341 (1967).CrossRefGoogle Scholar
  33. Chargaff, E., Olson, K.B.: Studies on the chemistry of blood coagulation. VI. Studies on the action of heparin and other anticoagulants. The influence of protamine on the anticoagulant effect in vivo. J. biol. Chem. 122, 153–167 (1937).Google Scholar
  34. Clark, A.J.: The reaction between acetyl choline and muscle cells. J. Physiol. (Lond.) 61, 530–546 (1926a).Google Scholar
  35. Clark, A.J.: The antagonism of acetyl choline by atropine. J. Physiol. (Lond.) 61, 547–556 (1926b).Google Scholar
  36. Clark, A.J.: The Mode of Action of Drugs on Cells, pp. 1–298. London: Edward Arnold and Co. 1933.Google Scholar
  37. Clark, A.J.: General pharmacology. In: Heubner, W., Schüller, J., (Eds.): Heffter’s Handbuch der experimentellen Pharmakologie, Vol. 4, pp. 1–228. Berlin: J. Springer 1937.Google Scholar
  38. Clark, A.J., Raventós, J.: The antagonism of acetylcholine and of quaternary ammonium salts. Quart. J. exp. Physiol. 26, 375–392 (1937).Google Scholar
  39. Croxatto, R., Huidobro, F.: Fundamental basis of specificity of pressor and depressor amines in their vascular effects; theoretical fundaments; drug receptor linkage. Arch. int. Pharmacodyn. 106, 207–243 (1956).PubMedGoogle Scholar
  40. Dagley, S., Freeman, L.O., Tatton, J.O’G.: The kinetics of growth of Bact. lactis aerogenes in the presence of phenol, alcohols, ketones and acetates. Biochem. J. 43, IV (1948).Google Scholar
  41. Dale, H.H.: The action of certain esters and ethers of choline, and their relation to muscarine. J. Pharmacol. (Lond.) 6, 147–190 (1914).Google Scholar
  42. Del Castillo, J., Katz, B.: Interaction at end-plate receptors between different choline derivatives. Proc. roy. Soc. B 146, 369–381 (1957).CrossRefGoogle Scholar
  43. Ehrlich, P.: Address in pathology: on chemiotherapy. Lancet 1913 II, 445–451Google Scholar
  44. Ehrlich, P.: Address in pathology: on chemiotherapy.Brit. med. J. 1913 II, 353–359.CrossRefGoogle Scholar
  45. Fastier, F.N.: Structure-activity relationships of amidine derivatives. Pharmacol. Rev. 14, 37–90 (1962).PubMedGoogle Scholar
  46. Fastier, F.N., Hawkins, J.: Inhibition of amine oxidase by isothiourea derivatives. Brit. J. Pharmacol. 6, 256–262 (1951).PubMedGoogle Scholar
  47. Fastier, F.N., Reid, C.S.W.: Circulatory properties of amine derivatives. II. Potentiation of the vasoconstrictor action of adrenaline. Brit. J. Pharmacol. 3, 205–210 (1948).PubMedGoogle Scholar
  48. Ferguson, J.: The use of chemical potentials as indices of toxicity. Proc. roy. Soc. B127, 387–404 (1939).Google Scholar
  49. Furchgott, R.F.: Dibenamide blockade in strips of rabbit aorta and its use in differentiating receptors. J. Pharmacol. exp. Ther. 111, 265–284 (1954).PubMedGoogle Scholar
  50. Furchgott, R.F.: The pharmacology of vascular smooth muscle. Pharmacol. Rev. 7, 183–265 (1955).PubMedGoogle Scholar
  51. Gaddum, J.H.: The action of adrenalin and ergotamine on the uterus of the rabbit. J. Physiol. (Lond.) 61, 141–150 (1926).Google Scholar
  52. Gaddum, J.H.: The quantitative effects of antagonistic drugs. J. Physiol. (Lond.) 89, 7p—9p (1937).Google Scholar
  53. Gaddum, J.H.: Symposium on chemical constitution and pharmacological action. Trans. Faraday Soc. 39, 323–332 (1943).CrossRefGoogle Scholar
  54. Gaddum, J.H., Hameed, K.A., Hathway, D.E., Stephens, F.F.: Quantitative studies of antagonists for 5-hydroxytryptamine. Quart. J. exp. Physiol. 40, 49–74 (1955).PubMedGoogle Scholar
  55. Ginsborg, B.L., Stephenson, R.P.: On the simultaneous action of two competitive antagonists. Brit. J. Pharmacol. 51, 287–300 (1974).Google Scholar
  56. Goldstein, A.: The interaction of drugs and plasma proteins. Pharmacol. Rev. 1, 102–165 (1949).Google Scholar
  57. Hahn, F., Schmutzler, W., Seseke, G., Giertz, H., Bernauer, W.: Histaminasefreisetzung durch Heparin und Protamin beim Meerschweinchen. Biochem. Pharmacol. 15, 155–160 (1966).PubMedCrossRefGoogle Scholar
  58. Hamilton, W.: Discussion on Philosophy and Literature, Education and University Reform. New York: Harper and Brothers 1868.Google Scholar
  59. Higman, H.B., Bartels, E.: The competitive nature of the action of acetylcholine and local anesthetics. Biochim. biophys. Acta (Amst.) 54, 543–554 (1962).CrossRefGoogle Scholar
  60. Homer, L.D.: The receptor occupation theory of drug responses. J. theor. Biol. 17, 399–409 (1967).PubMedCrossRefGoogle Scholar
  61. Karlin, A.: On the application of “a plausible model” of allosteric proteins to the receptor for acetylcholine. J. theor. Biol. 16, 306–320 (1967).PubMedCrossRefGoogle Scholar
  62. Katz, B., Thesleff, S.: A study of the “desensitization” produced by acetylcholine at the motor end-plate. J. Physiol. (Lond.) 138, 63–80 (1957).Google Scholar
  63. Kimelberg, H., Moran, J.F., Triggle, D.J.: The mechanism of interaction of 2-halogenoethylamines at the noradrenaline receptor. J. theor. Biol. 9, 502–503 (1965).PubMedCrossRefGoogle Scholar
  64. Koshland, D.E.: The role of flexibility in enzyme action. Cold Spr. Harb. Symp. quant. Biol. 28, 473–482 (1963).Google Scholar
  65. Langley, J.N.: On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. J. Physiol. (Lond.) 33, 374–413 (1905).Google Scholar
  66. Lasareff, P.: Untersuchungen über die Ionentheorie der Reizung. III. Ionentheorie der Geschmacksreizung. Pflügers Arch. ges. Physiol. 194, 293–297 (1922).CrossRefGoogle Scholar
  67. Lucretius Carus, T.: In: De Rerum Natura, book IV, verse 615 et sqq.Google Scholar
  68. Mackay, D.: A flux-carrier hypothesis of drug action. Nature (Lond.) 197, 1171–1173 (1963).CrossRefGoogle Scholar
  69. Mackay, D.: The mathematics of drug-receptor interactions. J. Pharm. Pharmacol. 18, 201–222 (1966).PubMedCrossRefGoogle Scholar
  70. Miller, L.C., Becker, T.J., Tainter, M.L.: Quantitative evaluation of spasmolytic drugs in vitro. J. Pharmacol. exp. Ther. 92, 260–268 (1948).PubMedGoogle Scholar
  71. Monod, J., Wyman, J., Changeux, J.P.: On the nature of allosteric transitions: a plausible model. J. molec. Biol. 12, 88–118 (1965).PubMedCrossRefGoogle Scholar
  72. Nickerson, M.: Receptor occupancy and tissue response. Nature (Lond.) 178, 697–698 (1956).Google Scholar
  73. Nickerson, M.: Nonequilibrium drug antagonism. Pharmacol. Rev. 9, 246–259 (1957).PubMedGoogle Scholar
  74. Offermeier, J., van den Brink, F.G.: The antagonism between cholinomimetic agonists and β-adrenoceptor stimulants. The differentiation between functional and metaffinoid antagonism. Europ. J. Pharmacol. 27, 206–213 (1974).CrossRefGoogle Scholar
  75. Paton, W.D.M.: A theory of drug action based on the rate of drug-receptor combination. Proc. roy. Soc. B 154, 21–69 (1961).CrossRefGoogle Scholar
  76. Paton, W.D.M., Rang, H.P.: A kinetic approach to the mechanism of drug action. In: Harper, N.J., Simmonds, A.B., (Eds.): Advances in Drug Research, Vol. 3, pp. 57–80. London-New York: Academic Press 1966.Google Scholar
  77. Paton, W.D.M., Waud, D.R.: Drug-receptor interactions at the neuromuscular junction. In: de Reuck, A.V.S., (Ed.): Curare and Curare-like Agents, pp. 34–54. London: J. and A. Churchill Ltd. 1962a.Google Scholar
  78. Paton, W.D.M., Waud, D.R.: Neuromuscular blocking agents. Brit. J. Anaesth. 34, 251–259 (1962b).PubMedCrossRefGoogle Scholar
  79. Paton, W.D.M., Waud, D.R.: A quantitative investigation of the relationship between rate of access of a drug to receptor and the rate of onset or offset of action. Naunyn-Schmiedebergs Arch. exp. Path. Pharmakol. 248, 124–143 (1964).CrossRefGoogle Scholar
  80. Pauling, L.: A molecular theory of general anesthesia. Science 134, 15–21 (1961).PubMedCrossRefGoogle Scholar
  81. Renqvist, Y.: Über den Geschmack. Skand. Arch. Physiol. 38, 97–201 (1919).Google Scholar
  82. Reuse, J.J.: Comparison of various histamine antagonists. Brit. J. Pharmacol. 3, 174–180 (1948).PubMedGoogle Scholar
  83. Rocha e Silva, M.: Kinetics of recovery from inhibition by antihistaminics, atropine and antispasmodics. Pharmacol. Rev. 9, 259–264 (1957).PubMedGoogle Scholar
  84. Rocha e Silva, M.: A thermodynamic approach to problems of drug antagonism. I. The “charnière theory”. Europ. J. Pharmacol. 6, 294–302 (1969).Google Scholar
  85. Rocha e Silva, M.: A thermodynamic approach to problems of drug antagonism. II. A microphysical model of the phenomenon of recovery. Physiol. chem. Phys. 2, 503–515 (1970).Google Scholar
  86. Schild, H.O.: pA, a new scale for measurement of drug antagonism. Brit. J. Pharmacol. 2, 189–206 (1947).PubMedGoogle Scholar
  87. Schild, H.O.: pAx and competitive drug antagonism. Brit. J. Pharmacol. 4, 277–280 (1949).PubMedGoogle Scholar
  88. Schild, H.O.: Drug antagonism and pAx. In: Symposium on Drug Antagonism. Pharmacol. Rev. 9, 242–246 (1957).PubMedGoogle Scholar
  89. Simonis, A.M.: Principi di farmacologia molecolare. Farmaco, Ed. sci. 20, 52–75 (1965).Google Scholar
  90. Stephenson, R.P.: A modification of receptor theory. Brit. J. Pharmacol. 11, 379–393 (1956).PubMedGoogle Scholar
  91. Stephenson, R.P., Ginsborg, B.L.: Potentiation by an antagonist. Nature (Lond.) 222, 790–791 (1969).CrossRefGoogle Scholar
  92. Storm van Leeuwen, W.: On sensitiveness to drugs in animals and men. J. Pharmacol. exp. Ther. 24, 13–19 (1925a).Google Scholar
  93. Storm van Leeuwen, W.: On antagonism of drugs. J. Pharmacol. exp. Ther. 24, 21–24 (1925b).Google Scholar
  94. Storm van Leeuwen, W.: A possible explanation for certain cases of hypersensitiveness to drugs in men. J. Pharmacol. exp. Ther. 24, 25–32 (1925c).Google Scholar
  95. Stubbins, J.F., Hudgins, P.M., Andrako, J., Beebe, A.J.: Anticholinergic agents based on Ariëns’ dual receptor site theory. J. pharm. Sci. 57, 534–535 (1968).PubMedCrossRefGoogle Scholar
  96. Taylor, D.B., Steinborn, J., Tzu-Chiau Lu: Ion exchange processes at the neuromuscular junction of voluntary muscle. J. Pharmacol. exp. Ther. 175, 213–227 (1970).PubMedGoogle Scholar
  97. Thron, C.D.: On the analysis of pharmacological experiments in terms of an allosteric receptor model. Molec. Pharmacol. 9, 1–9 (1973).Google Scholar
  98. Thron, C.D., Waud, D.R.: The rate of action of atropine. J. Pharmacol. exp. Ther. 160, 91–105 (1968).PubMedGoogle Scholar
  99. Van den Brink, F.G.: Eine Molekulargrundlage für die Wirkung von Pharmaka. 3. Teil: Substanzen mit mehrfacher Wirkung. Arzneimittel-Forsch. 16, 1403–1412 (1966).Google Scholar
  100. Van den Brink, F.G.: Different kinds of antagonism. In: Histamine and Antihistamines. Molecular Pharmacology, Structure-Activity Relations, Gastric Acid Secretion, pp. 25–28. Nijmegen: Drukkerij Gebr. Janssen N.V. 1969a.Google Scholar
  101. Van den Brink, F.G.: Discussion of the presuppositions in the agonistic model. In: Histamine and Antihistamines. Molecular Pharmacology, Structure-Activity Relations, Gastric Acid Secretion, pp. 43–45. Nijmegen: Drukkerij Gebr. Janssen N.V. 1969b.Google Scholar
  102. Van den Brink, F.G.: The model of metactoid interaction. In: Histamine and Antihistamines. Molecular Pharmacology, Structure-Activity Relations, Gastric Acid Secretion, pp. 49–56. Nijmegen: Drukkerij Gebr. Janssen N.V. 1969c.Google Scholar
  103. Van den Brink, F.G.: The model of metaffinoid interaction. In: Histamine and Antihistamines. Molecular Pharmacology, Structure-Activity Relations, Gastric Acid Secretion, pp. 56–62. Nijmegen: Drukkerij Gebr. Janssen N.V. 1969d.Google Scholar
  104. Van den Brink, F.G.: The interaction of histaminomimetic compounds and of competitive antagonists of histamine with the histamine receptor; the concept additional receptor area. In: Histamine and Antihistamines. Molecular Pharmacology, Structure-Activity Relations, Gastric Acid Secretion, pp. 107–111. Nijmegen: Drukkerij Gebr. Janssen N.V. 1969e.Google Scholar
  105. Van den Brink, F.G.: A new theoretical model of functional interaction. Naunyn-Schmiedebergs Arch. Pharmak. 269, 385 (1971).CrossRefGoogle Scholar
  106. Van den Brink, F.G.: The model of functional interaction. I. Development and first check of a new model of functional synergism and antagonism. Europ. J. Pharmacol. 22, 270–278 (1973a).CrossRefGoogle Scholar
  107. Van den Brink, F.G.: The model of functional interaction. II. Experimental verification of a new model: The antagonism of β-adrenoceptor stimulants and other agonists. Europ. J. Pharmacol. 22, 279–286 (1973b).CrossRefGoogle Scholar
  108. Van Rossum, J.M.: Pharmacodynamics of Cholinomimetic and Cholinolytic Drugs, pp. 9–160. Bruges: St. Catherine Press Ltd. 1958.Google Scholar
  109. Van Rossum, J.M.: Cumulative dose-response curves. II. Technique for the making of doseresponse curves in isolated organs and the evaluation of drug parameters. Arch. int. Pharmacodyn. 143, 299–330 (1963).Google Scholar
  110. Van Rossum, J.M.: Limitations of molecular pharmacology. In: Harper, N.J., Simmonds, A.B., (Eds.): Advances in Drug Research, Vol. 3, pp. 189–234, London-New York: Academic Press 1966a.Google Scholar
  111. Van Rossum, J.M.: Die Pharmakon-Rezeptor-Theorie als Grundlage der Wirkung von Arzneimitteln. Möglichkeiten und Beschränkungen. Arzneimittel-Forsch. 16, 1412–1426, 1966b.Google Scholar
  112. Van Rossum, J.M., van den Brink, F.G.: Cumulative dose-response curves. I. Introduction to the technique. Arch. int. Pharmacodyn. 143, 240–246 (1963).PubMedGoogle Scholar
  113. Veldstra, H.: Synergism and potentiation with special reference to the combination of structural analogues. Pharmacol. Rev. 8, 339–387, (1956).PubMedGoogle Scholar
  114. Watkins, J.C.: Pharmacological receptors and general permeability phenomena of cell membranes. J. theor. Biol. 9, 37–50 (1965).PubMedCrossRefGoogle Scholar

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  • F. G. van den Brink

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