QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.067264v1 310/3/981    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grabovsky, Y. Articles by Tallarida, R. J. Search for Related Content PubMed PubMed Citation Articles by Grabovsky, Y. Articles by Tallarida, R. J.

NEUROPHARMACOLOGY

Isobolographic Analysis for Combinations of a Full and Partial Agonist: Curved Isoboles

College of Science and Technology and School of Medicine, Temple University, Philadelphia, Pennsylvania

Combinations of drugs are frequently used therapeutically to achieve an enhanced effect without using an excess quantity of either agent. If the drugs exert overtly similar action, e.g., two analgesics, the effect of the combination may be tested for additivity, i.e., an effect level that is achieved based on the individual drug potencies. But combinations of agonists will sometimes display either superadditive (synergistic) or subadditive responses. Whether the two agonists are both drugs, or a combination of a drug and an endogenous chemical, there is interest in characterizing the interaction to determine whether it departs from additivity because quantitative information of this kind, aside from its therapeutic importance, may also illuminate mechanism. A common method for this characterization uses the isobologram. This is a plot in rectangular coordinates of dose combinations (a,b) that produce the same effect level (often taken to be 50% of the maximum). In its usual form, this plot is constructed as a straight line (of additivity) connecting intercepts that represent the individually effective doses, e.g., ED₅₀ values of each. This line is the reference for distinguishing additive from nonadditive interactions accordingly as the tested combination is on or off this line. Discussed here are the assumptions that underlie this linear plot. Specifically we show that a combination of drugs with a variable potency ratio, exemplified by a full and a partial agonist, lead to curvilinear isoboles of additivity that may erroneously be attributed to either synergism or subadditivity.

Address correspondence to: Dr. Ronald J. Tallarida, Dept. of Pharmacology, Temple University School of Medicine, 3420 N. Broad St, Philadelphia, PA 19140. E-mail: ronald.tallarida{at}temple.edu

This article has been cited by other articles:

				A. S. Braverman, R. J. Tallarida, and M. R. Ruggieri Sr. The Use of Occupation Isoboles for Analysis of a Response Mediated by Two Receptors: M2 and M3 Muscarinic Receptor Subtype-Induced Mouse Stomach Contractions J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 954 - 960. [Abstract] [Full Text] [PDF]

				B. D. Fischer, E. I. Zimmerman, M. J. Picker, and L. A. Dykstra Morphine in Combination with Metabotropic Glutamate Receptor Antagonists on Schedule-Controlled Responding and Thermal Nociception J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 732 - 739. [Abstract] [Full Text] [PDF]

				R. J. Tallarida An Overview of Drug Combination Analysis with Isobolograms J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 1 - 7. [Abstract] [Full Text] [PDF]

				J. I. Lorenzo and P. Sanchez-Marin Comments on "Isobolographic Analysis for Combinations of a Full and Partial Agonist: Curved Isoboles" J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 476 - 478. [Full Text] [PDF]

				R. J. Tallarida Response to Comments on "Isobolographic Analysis for Combinations of a Full and Partial Agonist: Curved Isoboles" J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 479 - 479. [Full Text] [PDF]