In recent years, psychoactive drugs such as benzodiazepines (BZDs) have been frequently detected in water environments, however, there is still limited understanding regarding their potential impact on neurological health and underlying mechanisms. This study evaluated the neurotoxicity of the typical BZD drug flunitrazepam (FLZ, 0.2 and 5 μg/L) in zebrafish embryos and adults, and investigated the relationship between ferroptosis and FLZ-induced neurotoxicity. The results indicated that acute exposure to FLZ significantly inhibited zebrafish embryo hatching and promotes death, induced larval deformities, and led to abnormal neurobehavioral responses in larvae, likely due to ferroptosis induction. Results from a 30-day subacute exposure to FLZ showed that it decreased motor function and induced cognitive impairment in adult zebrafish. Immunofluorescence of brain tissues revealed a reduction in neurons in the telencephalon and an increase in microglia in the mesencephalon of the zebrafish exposed to FLZ. The ultrastructure of brain mitochondria showed serious damage. Besides, FLZ exposure increased iron levels, reduced GSH/GSSG and increased LPO in brain tissue, which is related to the abnormal expression of genes associated with ferroptosis. In the rescue experiments with co-exposure to deferoxamine (DFO), the motor-related parameters and biochemical indexes related to ferroptosis were restored, suggesting that FLZ can induce ferroptosis. The molecular docking results indicated that FLZ had a higher affinity with transferrin. This study elucidates the close relationship between ferroptosis and FLZ-induced neurotoxicity, which is significant for understanding the physiological damage caused by psychoactive substances and assessing environmental risks.

01 Sep 2024·Biomedicine & Pharmacotherapy

Enhancing the efficacy of fluconazole against Leishmania major: Formulation and evaluation of FLZ-nanoemulsions for topical delivery

Article

Author: Nourian, Alireza ; Fallah, Mohammad ; Nahanji, Manizheh Kashi ; Maghsood, Amir Hossein ; Mahboobian, Mohammad Mehdi ; Mohebali, Mehdi ; Motavallihaghi, Seyedmousa ; Harchegani, Amir Larki

BACKGROUNDCutaneous Leishmaniasis (CL) remains a significant public health concern, particularly in the tropical and subtropical regions. Present treatment options for CL such as Fluconazole (FLZ) face limitations, including low solubility and bioavailability. This study aimed to address these challenges by investigating the use of nano-emulsions (NEs) to enhance the efficacy of FLZ against Leishmania major(L.major).MATERIALS AND METHODSFLZ-NEs were formulated with oleic acid, Tween-20, and ethanol using low-energy emulsification at various surfactant/co-surfactant ratios. Subsequently, a comprehensive analysis was conducted to assess the physicochemical characteristics of the samples. This analysis encompassed stability, zeta potential, pH, viscosity, refractive index, and droplet size. We then studied the anti-parasitic properties of these optimized FLZ-NEs both in vitro and in vivo.RESULTSThe selected nano-emulsion (NE) formulation (2 % oleic acid, 20 % Tween 20, 10 % ethyl alcohol) showcased desirable properties like small droplet size (10.51 ± 0.24 nm), low dispersity (0.19 ± 0.03), and zeta potential value (- 0.41 ± 0.17 mV), key for stability and targeted drug delivery. This optimal formulation translated into remarkable efficacy. In vitro, FLZ-NEs demonstrated a threefold increase in their ability to combat promastigotes and a remarkable thirtyfold increase in their ability to combat amastigotes. Additionally, they demonstrated a ninefold advantage in their ability to specifically target parasites within infected macrophages, thereby attacking the infection site. These promising in vitro results translated into improved outcomes in vivo. Compared to other chemicals studied, FLZ-NE-treated mice showed decreased disease severity, weight growth, and quicker ulcer healing. It was further supported by histopathological research, which showed reduced tissue damage linked to Leishmania infection.CONCLUSIONThese findings show the potential of nanotechnology-based drug delivery in improving anti-leishmanial treatment.

01 Jul 2024·Saudi Pharmaceutical Journal

Formulation and evaluation of Fluconazole Nanosuspensions: In vitro characterization and transcorneal permeability studies

Article

Author: Abou El Ela, Amal El Sayeh F ; Alqahtani, Yara ; Aldosari, Basmah N ; Ibrahim, Mohamed Abbas

The aim in this study was to develop and evaluate a nanofluconazole (FLZ) formulation with increased solubility and permeation rate using nanosuspensions. The FLZ nanosuspensions were stabilized using a variety of stabilizing agents and surfactants in various concentrations. The FLZ nanosuspension was characterized in vitro using particle size, zeta potential, X-ray powder diffraction (XRPD), and solubility. In addition, the ex vivo ocular permeation of FLZ through a goat cornea was analyzed. The results showed that the particle size of all nanosuspension formulations was in the nanometer range from 174.5 ± 1.9 to 720.2 ± 4.77 nm; that of the untreated drug was 18.34 μm. The zeta potential values were acceptable, which indicated suitable stability for formulations. The solubility of the nanosuspensions was up to 5.7-fold higher compared with that of the untreated drug. The results of the ex vivo ocular diffusion of the FLZ nanosuspensions showed the percentage of FLZ penetrating via the goat cornea increased after using Kollicoat to stabilize the nanosuspension formulation. Consequently, when using a nanosuspension formulation of Kollicoat, the antifungal activity of the drug strengthens.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Preclinical	CN	Peking Union Medical College	-
Parkinson Disease	Preclinical	CN	Institute of Materia Medica	-

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