Role of peripheral and central sensitization in the anti-hyperalgesic effect of hecogenin acetate, an acetylated sapogenin, complexed with ß-cyclodextrin: Involvement of NFκB and p38 MAPK pathways.

Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's quality of life. In view of the ineffectiveness of the current pharmacotherapy, substances obtained from natural products (NPs) are a promising alternative. One NP that has been discussed in the literature is hecogenin acetate (HA), a steroidal sapogenin with anti-inflammatory and antinociceptive activity. However, HA has low water solubility, which affects its bioavailability. Thus, the objective of this study was to evaluate the anti-hyperalgesic activity of pure and complexed hecogenin acetate (HA/ßCD) in an animal model of chronic neuropathic and inflammatory pain. The inclusion complex was prepared at a molar ratio of 1:2 (HA:ßCD) by the lyophilization method. For the induction of chronic inflammatory pain, the mice received an intraplantar injection of CFA (complete Freund's adjuvant), and were evaluated for mechanical hyperalgesia and for the levels of myeloperoxidase (MPO) in the skin of the paw after eight days of treatment. HA and HA/ßCD reduced mechanical hyperalgesia in relation to the vehicle group until the fourth and fifth hours, respectively, in the acute evaluation, with a superior effect of the complexed form over the pure form in the second and third hour after treatment (p < 0.001). In the chronic evaluation, HA and HA/ßCD reduced hyperalgesia in relation to the vehicle in the eight days of treatment (p < 0.001). Both pure (p < 0.01) and complexed (p < 0.001) forms reduced myeloperoxidase activity in the skin of the animals' paw. Groups of animals subjected to the same pharmacological protocol were submitted to the partial sciatic nerve ligation (PSNL) model and evaluated for mechanical and thermal hyperalgesia, and cold allodynia. HA and HA/ßCD reduced mechanical hyperalgesia until the fourth and sixth hours, respectively, and both reduced hyperalgesia in relation to the vehicle in the chronic evaluation (p < 0.001). HA and HA/ßCD also reduced thermal hyperalgesia and cold allodynia (p < 0.05 and p < 0.001, respectively). The analysis of the spinal cord of these animals showed a decrease in the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and a reduction in the phosphorylation of NFκB and p38MAPK, as well as a decrease in microglioses compared to the vehicle group. In addition, HA/ßCD reduced the nociception induced by intraplantar injection of agonist TRPA1 (p < 0.01) and TRPM8 (p < 0.05). Treatment for eight days with HA and HA/ßCD showed no signs of gastric or liver damage. HA and HA/ßCD were, therefore, shown to have antinociceptive effects in chronic pain models. Based on our exploration of the mechanisms of the action of HA, these effects are likely to be related to inhibited leukocyte migration, interaction with the TRPA1 and TRPM8 receptors, reduced pro-inflammatory cytokines levels, microglial expression and suppression of NF-κB p65 and p38 MAPK pathway signaling. Therefore, HA/ßCD has great potential for use in the treatment of chronic pain.

Pharmaceutical agents for treatment of leishmaniasis: a patent landscape.

INTRODUCTION: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Worldwide, approximately 1.5-2 million new cases of leishmaniasis and 20,000-30,000 deaths occurs each year. Effective treatment for all forms of leishmaniasis have numerous adverse effects contributing to poor adherence and/or treatment interruption by the patient. Development of novel therapies, as multitarget drugs, for example, can contribute to accelerate discover safer, more active, and patient-compliant drugs for leishmaniasis treatment. AREAS COVERED: In this review, authors summarize pharmaceutical agents for treatment of leishmaniasis developed between 2014 and 2019, which includes synthetic and natural drugs for specific treatments, as well as considering new approaches and strategies using drug delivery system. EXPERT OPINION: Universities or public research institutes produced most of the patents related to pharmaceutical agents for treatment of leishmaniasis in this review, and the majority of the inventions disclosed did not conduct clinical trials. In other words, there is still a lot of investment to be done for the identification of new drugs.

Anti-hyperalgesic effect of (-)-α-bisabolol and (-)-α-bisabolol/ß-Cyclodextrin complex in a chronic inflammatory pain model is associated with reduced reactive gliosis and cytokine modulation.

Chronic pain is a continuous or recurring pain which exceeds the normal course of recovery to an injury or disease. According to the origin of the chronic pain, it can be classified as inflammatory or neuropathic. This study aimed to evaluate the antinociceptive and anti-inflammatory effect of (-)-α-bisabolol (BIS) alone and complexed with ß-cyclodextrin (ßCD) in preclinical models of chronic pain. Chronic pain was induced by Freund's Complete Adjuvant (FCA) or partial lesion of the sciatic nerve (PLSN). Swiss mice were treated with BIS, BIS-ßCD (50 mg/kg, p.o) or vehicle (control) and mechanical hyperalgesia, thermal hyperalgesia, muscle strength and motor coordination were evaluated. In addition, levels of TNF-α and IL-10 and expression of the ionized calcium-binding adapter protein (IBA-1) were assessed in the spinal cord of the mice. The complexation efficiency of BIS in ßCD was evaluated by High-Performance Liquid Chromatography. BIS and BIS-ßCD reduced (p < 0.001) mechanical and thermal hyperalgesia. No alterations were found in force and motor coordination. In addition, BIS and BIS-ßCD inhibited (p < 0.05) TNF-α production in the spinal cord and stimulated (p < 0.05) the release of IL-10 in the spinal cord in PLSN-mice. Further, BIS and BIS-ßCD reduced IBA-1 immunostaining. Therefore, BIS and BIS-ßCD attenuated hyperalgesia, deregulated cytokine release and inhibited IBA-1 expression in the spinal cord in the PLSN model. Moreover, our results show that the complexation of BIS in ßCD reduced the therapeutic dose of BIS. We conclude that BIS is a promising molecule for the treatment of chronic pain.