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      An isobolographic analysis of the antinociceptive effect of xylopic acid in combination with morphine or diclofenac

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          Abstract

          Background:

          A common practice of managing pain globally is the combination of analgesics and this is aimed at facilitating patient compliance, simplifying prescription, and improving efficacy without increasing adverse effects. Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders and xylopic acid (XA) present in the fruit extract have been shown to possess analgesic properties in animals. There is the likelihood of concomitant use of XA and the commonly used analgesics in traditional settings. This study, therefore, evaluated the pharmacologic interaction between XA/morphine and xylopic/diclofenac combinations.

          Methods:

          The formalin test and acetic acid writhing test were used to study the antinociceptive activity of XA, morphine, and diclofenac. The isobolographic analysis was used to study the antinociceptive interactions between XA co-administered with morphine or diclofenac.

          Results:

          Results obtained revealed that XA (10–100 mg/kg), morphine (1–10 mg/kg), and diclofenac (1–10 mg/kg) produced dose-related antinociception with different potencies in the formalin and acetic acid writhing tests. Isobolographic analysis of XA/morphine and XA/diclofenac combinations revealed potentiation of their antinociceptive effects. The degree of potentiation calculated as interaction index showed synergism for both combinations in all the nociceptive tests.

          Conclusion:

          In conclusion, the present study demonstrated synergism for the co-administration of XA with morphine or diclofenac.

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          Most cited references28

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          The formalin test in mice: dissociation between inflammatory and non-inflammatory pain.

          The formalin test in mice is a valid and reliable model of nociception and is sensitive for various classes of analgesic drugs. The noxious stimulus is an injection of dilute formalin (1% in saline) under the skin of the dorsal surface of the right hindpaw. The response is the amount of time the animals spend licking the injected paw. Two distinct periods of high licking activity can be identified, an early phase lasting the first 5 min and a late phase lasting from 20 to 30 min after the injection of formalin. In order to elucidate the involvement of inflammatory processes in the two phases, we tested different classes of drugs in the two phases independently. Morphine, codeine, nefopam, and orphenadrine, as examples of centrally acting analgesics, were antinociceptive in both phases. In contrast, the non-steroid anti-inflammatory drugs indomethacin and naproxen and the steroids dexamethasone and hydrocortisone inhibited only the late phase, while acetylsalicylic acid (ASA) and paracetamol were antinociceptive in both phases. The results demonstrate that the two phases in the formalin test may have different nociceptive mechanisms. It is suggested that the early phase is due to a direct effect on nociceptors and that prostaglandins do not play an important role during this phase. The late phase seems to be an inflammatory response with inflammatory pain that can be inhibited by anti-inflammatory drugs. ASA and paracetamol seem to have actions independent of their inhibition of prostaglandin synthesis and they also have effects on non-inflammatory pain.
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            An overview of drug combination analysis with isobolograms.

            Drugs given in combination may produce effects that are greater than or less than the effect predicted from their individual potencies. The historical basis for predicting the effect of a combination is based on the concept of dose equivalence; i.e., an equally effective dose (a) of one will add to the dose (b) of the other in the combination situation. For drugs with a constant relative potency, this leads to linear additive isoboles (a-b curves of constant effect), whereas a varying potency ratio produces nonlinear additive isoboles. Determination of the additive isobole is a necessary procedure for assessing both synergistic and antagonistic interactions of the combination. This review discusses both variable and constant relative potency situations and provides the mathematical formulas needed to distinguish these cases.
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              Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic.

              The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels. We now better understand the roles of COX-1 and COX-2 in functions as disparate as the perception of pain and the progression of cancers. Clinical use of COX-2-selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure. This review will discuss how the latest studies help us understand the roles of COX-1 and COX-2 and what clinically proven benefits the newer generation of COX-2-selective inhibitors offer
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                Author and article information

                Journal
                J Basic Clin Pharm
                J Basic Clin Pharm
                JBCP
                Journal of Basic and Clinical Pharmacy
                Medknow Publications & Media Pvt Ltd (India )
                0976-0105
                0976-0113
                September 2015-November 2015
                : 6
                : 4
                : 103-108
                Affiliations
                [1] Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
                [1 ] Department of Biomedical and Forensic Sciences, School of Biological Science, University of Cape Coast, Cape Coast, Ghana
                Author notes
                Address for correspondence: Prof. Eric Woode, Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. E-mail: ewoode.pharm@ 123456knust.edu.gh
                Article
                JBCP-6-103
                10.4103/0976-0105.168055
                4660480
                26692735
                7823b9da-3f39-4c3a-b42d-a7122173cfd7
                Copyright: © Journal of Basic and Clinical Pharmacy

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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                Categories
                Original Article

                isobologram,mice,nociception,potentiation,synergism
                isobologram, mice, nociception, potentiation, synergism

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