GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti‐depressant. However, it is well established that, in certain individuals, GABAA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β‐OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo‐induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABAA system.

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Background: Natamycin belongs to a large group of naturally occurring polyene antifungal antibiotics derived from Streptomyces natalensis. Natamycin has a restrictive pharmaceutical role because of its extremely low aqueous solubility, which severely reduces the bioavailability of the drug. To improve the absorption of the drug, nanocrystals of natamycin were prepared and incorporated into in situ gel. Aim: To improve the solubility and absorption of natamycin nanocrystals by preparing nanocrystal in situ gel of natamycin for ophthalmic delivery Methodology: Natamycin nanocrystal was prepared using Sono-Precipitation method. Box-Behnken approach was employed to assess the influence of independent variables, namely concentration of stabilizer, sonication time and amplitude on particle size and zeta potential of the prepared nanocrystal. Optimized natamycin nanocrystal in situ gel formulations was characterized for various parameters like pH, viscosity, drug content, in vitro drug release and ex vivo permeation studies. Results: The optimized formulation of natamycin nanocrystal with a particle size of  293.9nm and zeta potential -14.6mV was incorporated into in situ gels. The pH triggered in situ gel was prepared using Carbopol and Hydroxypropyl methylcellulose (HPMC)., which showed clear preparation, pH of the formulation was closed to the pH of tear fluid, i.e., 7.4, viscosity showed pseudoplastic behaviour with immediate gelation remained for an extended period, and the drug content was around 99.70%. From the characterizations given above, PF-4 was optimized and evaluated for In vitro drug release showing slow and sustained release when compared to the marketed formulation and followed first-order kinetics with the diffusion-controlled mechanism. Ex vivo permeation through goat's cornea of PF-4 showed better permeation than marketed formulation. The stability studies of PF-4 showed that formulation was stable at the appropriate condition. Conclusion: Nanocrystals formulations of natamycin was successfully formulated and incorporated into in situ gels. Further in vivo studies need to be carried out for confirmation of pharmacological activity

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA‐A receptor modulating stress and sex steroids (steroid‐PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA‐A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid‐PAMs and opportunities to treat these adverse effects of steroid‐PAMs with novel GAMSAs.