Revisiting the Isobole and Related Quantitative Methods for Assessing Drug Synergism

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2012 Apr 19

PMID 22511201

Citations 57

Authors

Ronald J Tallarida

Affiliations

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Abstract

The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called "Bliss independence," is inconsistent with the isobolar approach and also has a less clear conceptual basis. In its simplest application the isobole is the familiar linear plot in cartesian coordinates with intercepts representing the individual drug potencies. It is also shown that the isobole can be nonlinear, a fact recognized by its founder (Loewe) but neglected or rejected by virtually all other users. Whether its shape is linear or nonlinear the isobole is equally useful in detecting synergism and antagonism for drug combinations, and its theoretical basis leads to calculations of the expected effect of a drug combination. Numerous applications of isoboles in preclinical testing have shown that synergism or antagonism is not only a property of the two agonist drugs; the dose ratio is also important, a fact of potential importance to the design and testing of drug combinations in clinical trials.

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References

Woolverton W, Wang Z, Vasterling T, Carroll F, Tallarida R . Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action. Psychopharmacology (Berl). 2007; 196(4):575-82. PMC: 3109501. DOI: 10.1007/s00213-007-0991-9. View

Tallarida R . An overview of drug combination analysis with isobolograms. J Pharmacol Exp Ther. 2006; 319(1):1-7. DOI: 10.1124/jpet.106.104117. View

Tallarida R, Raffa R . The application of drug dose equivalence in the quantitative analysis of receptor occupation and drug combinations. Pharmacol Ther. 2010; 127(2):165-74. PMC: 4036078. DOI: 10.1016/j.pharmthera.2010.04.011. View

Tallarida R, Stone Jr D, McCary J, Raffa R . Response surface analysis of synergism between morphine and clonidine. J Pharmacol Exp Ther. 1999; 289(1):8-13. View

Tallarida R . The interaction index: a measure of drug synergism. Pain. 2002; 98(1-2):163-8. DOI: 10.1016/s0304-3959(02)00041-6. View

Podolsky S, Greene J . Combination drugs--hype, harm, and hope. N Engl J Med. 2011; 365(6):488-91. DOI: 10.1056/NEJMp1106161. View

Schroder W, Tzschentke T, Terlinden R, De Vry J, Jahnel U, Christoph T . Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther. 2011; 337(1):312-20. PMC: 3364495. DOI: 10.1124/jpet.110.175042. View

Tallarida R . Interactions between drugs and occupied receptors. Pharmacol Ther. 2006; 113(1):197-209. PMC: 2045509. DOI: 10.1016/j.pharmthera.2006.08.002. View

Adams J, Tallarida R, Geller E, Adler M . Isobolographic superadditivity between delta and mu opioid agonists in the rat depends on the ratio of compounds, the mu agonist and the analgesic assay used. J Pharmacol Exp Ther. 1993; 266(3):1261-7. View

10.

Tallarida R, Cowan A, Raffa R . Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice. J Pharmacol Exp Ther. 2003; 307(2):699-704. DOI: 10.1124/jpet.103.054320. View

11.

Boehm C, Carney E, Tallarida R, Wilson R . Midazolam enhances the analgesic properties of dexmedetomidine in the rat. Vet Anaesth Analg. 2010; 37(6):550-6. PMC: 4003565. DOI: 10.1111/j.1467-2995.2010.00565.x. View

12.

Lamarre N, Parry T, Tallarida R . On the quantitation of an agonist with dual but opposing components of action: application to vascular endothelial relaxation. Eur J Pharmacol. 2011; 670(1):204-7. PMC: 4010114. DOI: 10.1016/j.ejphar.2011.08.007. View

13.

Rawls S, Cowan A, Tallarida R, Geller E, Adler M . N-methyl-D-aspartate antagonists and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a cannabinoid agonist, interact to produce synergistic hypothermia. J Pharmacol Exp Ther. 2002; 303(1):395-402. DOI: 10.1124/jpet.102.037473. View

14.

Grabovsky Y, Tallarida R . Isobolographic analysis for combinations of a full and partial agonist: curved isoboles. J Pharmacol Exp Ther. 2004; 310(3):981-6. DOI: 10.1124/jpet.104.067264. View

15.

Woolverton W, Wang Z, Vasterling T, Tallarida R . Self-administration of cocaine-remifentanil mixtures by monkeys: an isobolographic analysis. Psychopharmacology (Berl). 2008; 198(3):387-94. PMC: 2667245. DOI: 10.1007/s00213-008-1152-5. View

16.

Kimmel H, Tallarida R, Holtzman S . Synergism between buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat. Psychopharmacology (Berl). 1998; 133(4):372-7. DOI: 10.1007/s002130050416. View

17.

Codd E, Martinez R, Molino L, Rogers K, Stone D, Tallarida R . Tramadol and several anticonvulsants synergize in attenuating nerve injury-induced allodynia. Pain. 2007; 134(3):254-262. DOI: 10.1016/j.pain.2007.04.019. View

18.

BERENBAUM M . What is synergy?. Pharmacol Rev. 1989; 41(2):93-141. View

19.

Porreca F, Jiang Q, Tallarida R . Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction. Eur J Pharmacol. 1990; 179(3):463-8. DOI: 10.1016/0014-2999(90)90190-h. View

20.

Lamarre N, Tallarida R . A quantitative study to assess synergistic interactions between urotensin II and angiotensin II. Eur J Pharmacol. 2008; 586(1-3):350-1. DOI: 10.1016/j.ejphar.2008.02.071. View