Semi-mechanistic Modelling of the Analgesic Effect of Gabapentin in the Formalin-Induced Rat Model of Experimental Pain

Taneja, Amit; Trocóniz, Iñaki F.; Danhof, Meindert; Pasqua, Oscar Della

doi:10.1007/s11095-013-1183-4

Cited by 7 publications

(4 citation statements)

References 46 publications

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“…There are no data for cats that describe the optimum plasma drug concentrations for gabapentin. While previously reported data and modeling suggests a half maximal effective concentration (EC50) ranging from 1.4 and 16.7 μg/mL for treatment of hyperalgesia in the rat and 5.4 μg/mL for the treatment of neuropathic pain in man, we cannot determine if these values will apply to cats. Calculation of the average plasma concentration after multiple doses results in a value of 6.11 μg/mL, with median trough concentrations of 2.55 and 1.49 μg/mL for the second‐to‐last and last dose, respectively.…”

Section: Discussionmentioning

confidence: 82%

The pharmacokinetics of gabapentin in cats

Adrian

Papich

Baynes

et al. 2018

Veterinary Internal Medicne

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BackgroundGabapentin is the most commonly prescribed medication for the treatment of chronic musculoskeletal pain in cats. Despite this common and chronic usage, clinically relevant pharmacokinetic data is lacking.ObjectivesTo evaluate the pharmacokinetics of clinically relevant dosing regimens of gabapentin in cats.AnimalsEight research‐purpose mixed‐breed cats.MethodsCats were enrolled in a serial order, non‐randomized pharmacokinetic study. Gabapentin was administered as an IV bolus (5 mg/kg), orally (10 mg/kg) as a single dose or twice daily for 2 weeks, or as a transdermal gel (10 mg/kg) in serial order. Serial blood samples were collected up to 48 hours. Plasma concentrations were determined using Ultra Performance Liquid Chromatography‐Mass Spectrometry. Compartmental analysis was used to generate gabapentin time‐concentration models.ResultsAfter IV administration CL (median (range)) and terminal half‐life were 160.67 mL/kg*hr (119.63‐199.11) and 3.78 hours (3.12‐4.47), respectively. The oral terminal half‐life was 3.63 hours (2.96‐4.77), and 3.72 hours (3.12‐4.51) for single and repeated dosing. TMAX and CMAX, as predicted by the model were 1.05 hours (0.74‐2.11), and 12.42 μg/mL (8.31‐18.35) after single oral dosing, and 0.77 hours (0.58‐1.64), and 14.78 μg/mL (9.70‐18.41) after repeated oral dosing. Bioavailability after a single oral dose was 94.77% (82.46‐122.83).ImportanceRepeated oral dosing of gabapentin did not alter the drug's pharmacokinetics, making dose adjustments unnecessary with long‐term treatment. As prepared, the transdermal route is an inappropriate choice for drug administration. These relevant data are important for future studies evaluating potential efficacy of the medication for treating chronic pain states in cats.

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Section: Discussionmentioning

confidence: 82%

The pharmacokinetics of gabapentin in cats

Adrian

Papich

Baynes

et al. 2018

Veterinary Internal Medicne

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“…To identify the agonistic effect of 28 in vivo , we investigated the analgesic activity of 28 in formalin-induced inflammatory pain and thermal pain, and the classical anti-inflammatory drug ibuprofen (2 mg/kg) was used as a positive control. Formalin-treated mice exhibited persistent pain leading to a biphasic pattern nociceptive response (the acute and inflammatory phases) accompanied by typical repetitive withdrawal behavior. − Oral application of 28 showed significant analgesic effects in the two phases and dose-dependently relieved pain behavior in phase II, and 4 mg/kg 28 showed the best analgesic effect on the inflammatory pain induced by formalin (Figure A). Moreover, as shown in Figure B, subcutaneous injection (sc) of 28 (0.02, 0.2, and 2 μg/paw) also resulted in an excellent analgesic effect after administration in comparison with capsaicin (0.2 μg/paw) as a positive control .…”

Section: Resultsmentioning

confidence: 99%

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

Liang

Qiao

Zhou³

et al. 2022

J. Med. Chem.

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Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of N-indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure–activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively. The whole-cell clamp patch assay shows that 28 is a potent and selective TRPV1 agonist and it relieves inflammatory and thermal pain by desensitizing the native TRPV1 current in the dorsal root ganglion (DRG) in mice. Additionally, site-directed mutagenesis combined with molecular docking shows an important hydrogen interaction between Arg557 and the indazole of 28. Taken together, our findings provide insight into TRPV1 agonism–antagonism conversion based on the interaction between indazole and Arg557, which provides a strategy to obtain new TRPV1 agonists by structural modification of antagonists. Compound 28 may be used as a lead compound for further optimization.

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“…Analgesic effect in the second phase of the formalin test is predictive of antihyperalgesic activity of our extracts in neuropathic pain models. 11,29,30 It is possible that the mechanism of action of the solvent extracts could be peripherally similar to morphine by blocking substance P or bradykinin known to be involved in nociceptors sensitization or by inhibiting TRPA1 or TRPV1 receptors at the spinal site in phase 1. It could also be centrally by blocking pro-inflammatory pain mediators known to be involved in phase 2 or by inhibiting nociceptive effects of transmitters like glutamate which act as descending facilitators.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive activity of various solvent extracts of Maerua angolensis DC stem bark in rodents

Azi¹,

Eric²,

Donatus³

et al. 2014

J Phytopharmacol

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Various parts of Maerua angolensis notably the leaves, roots and stem barks are used to reduce pain and also in the management of psychosis, epilepsy, and arthritis in traditional medicine. In this study, a preliminary test was performed to determine the most active plant part on the hydroethanolic extracts in the abdominal writhing test in mice. Subsequently, the stem bark, the most active plant part, was extracted with petroleum ether, ethyl acetate or hydroethanol to obtain three extracts which were tested for analgesic activity in the formalin test in rats. Animals were grouped into groups of 5 and the extracts were administered orally. Diclofenac and morphine were used as reference analgesic agents while normal saline was used for control. The leaf, root and stem bark extracts (30, 100 and 300 mg/kg) significantly (P<0.0002) and dosedependently reduced abdominal writhes induced by acetic acid with the stem bark extract being more active. In the formalin test, all the extracts (3, 10 and 30 mg/kg) significantly (P<0.0006) and dose-dependently reduced the frequency and time spent in biting/licking of injected paws in both the neurogenic and inflammatory phases induced by formalin. The petroleum ether extract was most active in neurogenic while ethyl acetate was most active in inflammatory phase. Results justify the use of the plant parts in ethnomedicine for the management of various painful conditions.

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Semi-mechanistic Modelling of the Analgesic Effect of Gabapentin in the Formalin-Induced Rat Model of Experimental Pain

Cited by 7 publications

References 46 publications

The pharmacokinetics of gabapentin in cats

The pharmacokinetics of gabapentin in cats

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

Antinociceptive activity of various solvent extracts of Maerua angolensis DC stem bark in rodents

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