Duloxetine hydrochloride loaded film forming dermal gel enriched with methylcobalamin and geranium oil attenuates paclitaxel-induced peripheral neuropathy in rats

Abstract

Objective In attempt to conquer the major concerns of oral duloxetine hydrochloride (like low bioavailability, intolerable side-effects and no regeneration of demyelinated nerve fibres) for the management of chemotherapy-induced peripheral neuropathy (CIPN), an alternative delivery of duloxetine hydrochloride was aimed for in-vivo optimization. Methods A film forming dermal gel consisting of duloxetine hydrochloride was formulated and enriched with methylcobalamin and geranium oil. The formulated gel successfully qualified the various pharmaceutical characteristics of gel. Administration of paclitaxel (8 mg/kg/ i.p. in four divided doses) for 4 alternate days induced the symptoms of peripheral neuropathy in rats. On 14th day, the responses to noxious stimulus (mechanical hyperalgesia, cold allodynia, and heat hyperalgesia) were increased and reached to its maximum. Thereafter, drug treatment with formulated dermal gel and oral duloxetine hydrochloride (30 mg/kg, once daily) was initiated for 2 weeks in different group of animals. On the 28th day animals were sacrificed to isolate sciatic nerve, to assess biochemical changes (TBARS, reduced GSH, total protein, TNF-α, IL-6) and for histopathological examinations of nerve sections using Hematoxylin-Eosin and Toludine blue staining methods. Results Application of formulated dermal gel to paclitaxel-treated rats significantly improved paw-withdrawal latency responses during noxious stimulus testing, reduced the levels of TBARS, TNF-α, IL-6 and elevated the levels of reduced GSH as compared to paclitaxel treated rats. Histographs also indicated marked regeneration of the damaged nerve fibers. Topical delivery of duloxetine hydrochloride produced similar results in disparity to oral route. However, no significant disparity in responses was obtained with twice application of formulated dermal gel when compared to once daily application. Conclusion Tremendous recovery from nociception, oxidation and inflammation in addition to nerve degeneration was achieved through dermal application of duloxetine hydrochloride in peripheral neuropathy.

Development of a Eudragit-Chitosan Nanosystem for the pH-Dependent Transport of Duloxetine to the Brain: Synthesis, Characterization and In Silico Modeling Analysis

“…A similar result of a two-step degradation of Duloxetine, between 200 and 400 °C, was found in a study conducted by Mani et al (2014). The initial loss is associated with the melting point of Duloxetine HCL at 118-162 °C (Chahal et al, 2020). The inclusion of Duloxetine into the nanoparticulate structure thus showed enhancement in the thermal stability of Duloxetine, to a moderate extent (Akhtar et al, 2020).…”

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents

“…c&d: (PTX+5HT1AB+CBD or THCV): 5HT1A blocker (5HT1AB), 10 mg/kg/day, i.p., was given to mice for four weeks and three hours before administering CBD or THCV e&f: (PTX+CB2B+CBD or THCV): CB2 blocker (CB2B) 1 mg/kg/day, i.p., was given to mice for four weeks and three hours before administering CBD or THCV. The PTX, CBD, THCV, AM630, Rimonabant and WAY10065 dosages were determined using existing literature reports [16][17][18][19][20][21]. After the animals were euthanized using CO2 asphyxiation and dorsal root ganglions (L1-L5) were extracted, biochemical and molecular parameters were examined.…”

Neuro-immune interactions in paclitaxel-induced peripheral neuropathy

“…In addition to the dysfunction of mitochondria, inadequate endogenous antioxidant responses may contribute to enhanced ROS levels [49]. Indeed, expression of proteins of the endogenous antioxidant system such as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH) and malondialdehyde (MDA) [32,51,[53][54][55], and erythroid 2-related factor 2 (Nrf2) [56,57] in the DRG and/or peripheral sensory nerves of paclitaxeltreated rats is decreased. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, and gallic acid, a natural phenolic compound, reduce paclitaxel-induced neuropathic pain via promotion of the anti-oxidant cascade [54,58].…”