The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. In vitro cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.

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Chronic urticaria (CU) is a condition characterized by intensely pruritic, edematous, erythematous papules lasting for more than 6 weeks. Over half of the cases have concomitant swelling of deeper tissues, known as angioedema. The socio-economic burden of the disease is significant. Unfortunately, patients with severe CU, refractory to conventional treatment, have limited and expensive therapeutic options. The pathogenesis of CU is not yet completely understood. Therefore, elucidating the pathophysiological mechanisms involved would potentially identify new therapeutic targets. It has been accepted in recent years that mast cells and their activation, followed by excessive degranulation represent the key pathophysiological events in chronic spontaneous urticaria (CSU). The triggering events and the complexity of the effector mechanisms, however, remain intensely debated topics with conflicting studies. One pathogenetic mechanism incriminated in chronic spontaneous urticaria is the response mediated by the high-affinity receptor for IgE (FcεRI) expressed on mast cells. Increasing recognition of chronic spontaneous urticaria as an autoimmune disease linked to the cytokine-chemokine network imbalance resulting from alteration of innate immune response is another pathogenetic explanation. It is likely that these different pathological mechanisms are more interconnected, both acting synergistically, rather than separately, to produce the clinical expression of CU. The discovery and understanding of pathogenic mechanisms represent the premise for the development of safe and effective immunomodulators and targeted biological treatment for severe, refractory CU.

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Bisphenol A (BPA) exposure can be associated with neurodevelopmental disorders due to impairment of cell proliferation and synaptic development. Our study evaluated the effects of melatonin (MEL) on ambulatory activity, lipid peroxidation, cytokines, ERK/NF-kB signaling pathway in hippocampus and frontal lobe, and histopathological changes in the hippocampus of the BPA-treated rats. The animals were divided in 4 groups: control, BPA, BPA + MEL I, BPA + MEL II. MEL I (20 mg/kg b.w), and MEL II (40 mg/kg b.w.) were orally administered for 28 days. In the 29th day, BPA (1 mg/kg b.w) was intraperitoneally administered and, after 24 h, Open Field Test (OFT) and Elevated Plus Maze (EPM), were conducted. The results showed that MEL II group made signi cantly more entries in the open arms of EPM, travelled signi cantly greater distance and spent more time in the central part of OFT. Malondialdehyde levels were diminished by MEL II in the hippocampus and by MEL I in the frontal lobe. In the hippocampus, MAPK level was signi cantly lowered by both doses of MEL (p < 0.05) while in frontal lobe, only MEL II reduced the MAPK activation. MEL I and II signi cantly decreased the γH2AX and upregulated the NFkB and pNFkB expressions in the hippocampus while MEL II downregulated the MCP1 expression. Both doses of MEL attenuated the BPA-evoked histopathological alterations in the hippocampus. These data indicate that MEL can mediate the neuroprotection against BPA-induced neurotoxicity and improves the behavioral changes suggesting a real potential as protective agent in brain toxicity.Additionally, BPA exposure increases the expression of proin ammatory cytokines such as IL-6, IL-1 b and TNF-a, reduces the expression of anti-in ammatory IL-10, and induces the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), some other mitogen-activated protein kinase (MAPK) and nuclear factor (NF -kB) pathway (Inadera 2015; Rebolledo-Solleiro 2021).Several in vivo and in vitro models reported that natural compounds (vitamin A, C and E, Quercetin, Lycopene, Gallic acid, Ginseng, Tualang honey) may alleviate BPA -induced -toxicity (Amjad, 2020). Melatonin (MEL), secreted by the pineal gland in the brain, known for its antioxidant and antiapoptotic effects (Lee 2019; Rehman 2019).Considering that oxidative stress appears to be an important contributor to the neurotoxicity induced by BPA, and the antioxidants, with remarkable neuroprotective effects, could play a valuable protective role, our study aimed to evaluate the effects of MEL preadministration on ambulatory activity, lipid peroxidation, in ammatory cytokines, ERK/NF-kB signaling pathway in hippocampus and frontal lobe and histopathological changes in hippocampus of the BPA -treated rats. The BPA was administered in a single dose in rats treated orally with two doses of MEL for 28 days.÷ ersefunctions, suchas, ∘ adianrhythm, e ≠ rgymηbolism and imμ ≠ systemrega --→ r, hasbeenrep or ted → exert ≠ uroprotect has been identi ed as an important factor to neu...