Fabrication of nanocrystal forms of á´ -cycloserine and their application for transdermal and enteric drug delivery systems.

ᴅ-cycloserine (DCS), an FDA-approved medicine for the treatment of tuberculosis, is also a partial agonist at the glycine recognition site of N-methyl-ᴅ-aspartate (NMDA) receptor and has shown significant treatment efficacy for central nervous system (CNS) disorders including depression, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder. The physicochemical properties of DCS, however, limit the options of formulation and medicinal applications of DCS, and warrants further investigation for the development of CNS therapeutics. Nanocrystals play an important role in pharmaceutic design and development. The properties of nanocrystals are remarkably different from their bulk material counterpart, attributed to the large surface-area-to-volume ratio which can improve the bioavailability. In this study, for the first time, DCS, a highly water-soluble compound, has formed nanocrystals and this was confirmed by scanning electronic microscopy and X-ray powder diffraction. Furthermore, DCS nanocrystals were applied to several formulations to test their stability and then to the in vitro Franz diffusion test with reservoir patch formulation as well as in vivo pharmacokinetics study with enteric capsules. We tested these formulations regarding their nanocrystal physical properties, size effect, and dissolution rate, respectively. We found that DCS nanocrystals showed good performance in the Franz diffusion test and rodent pharmacokinetic studies due to the nanoparticle size and faster dissolution as compared with the commercial DCS powder. These DCS nanocrystal formulations could offer a new approach for the development of an advanced drug delivery system for the treatment of CNS disorders.

The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function.

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and ß-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

Suicide attempts in French Polynesia during the era of COVID-19: a prospective analysis over three years.

Background: Past studies in French Polynesia have identified suicide as a significant concern, with a measured annual incidence of 79.4 attempts per 100,000 population during 2008-2010. In response to the COVID-19 pandemic, a monitoring system was established to track and investigate suicide attempts (SA). Methods: A prospective study was conducted between April 2020 and March 2023, including all patients referred to the French Polynesia Hospital Center for SA. Demographic factors as well as clinical parameters were analyzed. Findings: During the study period, 895 SAs were registered and confirmed, with a crude annual rate of 106.7 events and the adjusted rate at 113.2 per 100,000 population. Substantial majority of SA happened in the island of Tahiti. Half of the subjects did not have psychiatric diagnosis. There was a significant increase in SA from year 1 to year 3, with young people (female more than male) particularly at risk, especially in Tahiti. The normalized incidence among females younger than 20-year-old was as high as 310.4 per 100,000 population. Interpretation: Our data revealed an overall 34.4% increase in SA in French Polynesia, with a striking 54.9% increase during the third year of pandemic. The last year's record high incidence, is confirmed by increased activity on suicide hotlines, notably in Tahiti. A correlation between COVID exposure and suicidal behaviors, both at the individual and social level, is suspected with young female in Tahiti being the most vulnerable. These findings highlight the need for reinforced prevention and an efficient suicide monitoring system even after the public health emergency was declared over. Funding: The study is investigator-initiated without funding.

Acidic Microenvironment-Sensitive Core-Shell Microcubes: The Self-assembled and the Therapeutic Effects for Caries Prevention.

OBJECTIVES: The aim of this study was to develop a new material with integrated interface design that could achieve the purpose of environmental-sensing controlled release against cariogenic bacteria. Furthermore, this material can rebalance oral flora and serve as a preventive and reparative measure of dental caries. MATERIALS AND METHODS: NaF@PAA@HA@polyelectrolytes@HA@PAA particles were synthesized using the method of two-solution phases precipitation followed by biocompatible polymers coating layer by layer. The structure of the particles was confirmed by transmission electron microscope. The fluoride release profile was measured by fluoride ion electrode. Antimicrobial activity against the cariogenic microorganisms was analyzed by scanning electron microscopy and energy dispersive spectrum. The efficacy experiments were conducted on tooth enamel slides to evaluated fluoride absorption and antibacterial activity of the prototype toothpaste containing microcube particles RESULTS: The structure of NaF@PAA@HA@polyelectrolytes@HA@PAA particles showed a core surrounded by tooth-adhesion polymer layers in thin fin or filament structure. The loaded concentration of fluoride in the particles' core was 148,996 ± 28,484 ppm. NaF@PAA@HA@polyelectrolytes@HA@PAA particles showed selective inhibition of cariogenic microorganisms over probiotic strains and stronger fluoride adhesion on tooth enamel. A burst release (over 80%) of fluoride from the particle-containing toothpaste was observed under cariogenic acidic environment (pH < 5), while it remained extremely low under neutral environment. Compared with the best results of commercial toothpastes, our prototype toothpaste increased enamel fluoride uptake by 8-fold in normal enamel slides and by 11-fold in the slides with induced white spot lesions after either 1- or 7-day treatment. The prototype toothpaste also showed better inhibition of cariogenic microorganisms than the commercial brands. The coverage area of cariogenic bacteria under our toothpaste treatment was 73% on normal enamel slides compared with the commercial brands, while it was 69% in the induced white spot lesions. CONCLUSIONS: In our study, an intelligent toothpaste was developed that selectively inhibits cariogenic bacteria by microenvironment proton-triggered fluoride release. Such novel design would accomplish a favorable flora balance for optimal long-term oral health.

Lithium Benzoate Exerts Neuroprotective Effect by Improving Mitochondrial Function, Attenuating Reactive Oxygen Species, and Protecting Cognition and Memory in an Animal Model of Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disease affecting many cellular pathways, including protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation. Currently, no effective treatment for AD exists. Objective: We aim to determine the effect of lithium benzoate (LiBen) in protecting neurons from amyloid-ß (Aß) or other neurotoxin insults. Methods: Primary rat cortical neurons co-treated with neurotoxins and LiBen were used to examine its effect in cell viability, reactive oxygen species (ROS) clearance, and mitochondrial functions by MTT, CellRox fluorescence staining, and seahorse assay. Then, Barnes maze and prepulse inhibition test were performed in APP/PS1 mice that received chronic LiBen treatment to assess its effect on cognitive protection. Oral bioavailability of LiBen was also assessed by pharmacokinetic study in rat plasma. Results: In this study, we discovered that LiBen can attenuate cellular ROS level, improve mitochondrial function, increase cell viability against multiple different insults of mitochondrial dysfunction, Aß accumulation, and neuroinflammation, and promote neurogenesis. We demonstrated that LiBen has advantages over lithium or sodium benzoate alone as LiBen displays superior neuroprotective efficacy and oral bioavailability than the other two agents when being applied either alone or in combination. Furthermore, chronic administration of LiBen showed protection for cognition as well as spatial memory and reduced the senile plaque deposition in brains of AD animal models. Conclusion: LiBen stands as a promising therapeutic agent for improving cognition and delaying the progression of AD.

Pharmacokinetics and Safety of Sodium Benzoate, a d-Amino Acid Oxidase (DAAO) Inhibitor, in Healthy Subjects: A Phase I, Open-label Study.

PURPOSE: N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission plays a critical role in cognition and memory, and d-serine is a co-agonist of the receptor. d-serine is metabolized by d-amino acid oxidase (DAAO). Sodium benzoate is a DAAO inhibitor that leads to the elevation of d-serine levels and enhances NMDAR functions as a therapeutic for wide-spectrum central nervous system (CNS) disorders, including schizophrenia and dementia. For therapeutic application of sodium benzoate in CNS disorders, we conducted a Phase I study to evaluate its safety, tolerability, and pharmacokinetic profile after single-dose oral administration in healthy volunteers. In contrast to the accumulation in the CNS, sodium benzoate has a rapid pharmacokinetic profile when measured peripherally. METHODS: In this Phase I study, subjects were randomized into 4 different dose groups after a single oral administration. The pharmacokinetic parameters of sodium benzoate were assessed after exposure to 250, 500, 1000, and 2000 mg of sodium benzoate. All adverse events were investigated and recorded. FINDINGS: The Cmax and AUC of sodium benzoate exhibited a higher than dose-proportional increase within the dose range from 250 to 2000 mg under fasting conditions. The slopes were 1.78 and 2.61 and the 90% CIs were 1.41 to 2.15 and 2.20 to 3.03 for Cmax and AUC, respectively. Sodium benzoate was absorbed and converted to benzoic acid rapidly, reaching Cmax after ∼0.5 hour and elimination t1/2 after ∼0.3 hour. No subjects reported adverse events that were sodium benzoate related. IMPLICATIONS: The nonlinear pharmacokinetic response was observed within the dose range up to 2000 mg. Sodium benzoate treatment exhibited a favorable safety profile and was well tolerated at all dose levels. The study results serve as a foundation that should be useful for investigating efficacy and safety in the drug's subsequent clinical development. TRIAL REGISTRATION: TFDA-103607047.

Development of Ultrapure and Potent Tannic Acids as a Pan-coronal Antiviral Therapeutic.

The rampageous transmission of SARS-CoV-2 has been devastatingly impacting human life and public health since late 2019. The waves of pandemic events caused by distinct coronaviruses at present and over the past decades have prompted the need to develop broad-spectrum antiviral drugs against them. In this study, our Pentarlandir ultrapure and potent tannic acids (UPPTA) showed activities against two coronaviral strains, SARS-CoV-2 and HCoV-OC43, the earliest-known coronaviruses. The mode of inhibition of Pentarlandir UPPTA is likely to act on 3-chymotrypsin-like protease (3CLpro) to prevent viral replication, as supported by results of biochemical analysis, a 3CLpro assay, and a "gain-of-function" 3CLpro overexpressed cell-based method. Even in the 3CLpro overexpressed environment, Pentarlandir UPPTA remained its antiviral characteristic. Utilizing cell-based virucidal and cytotoxicity assays, the 50% effective concentrations (EC50) and 50% cytotoxicity concentration (CC50) of Pentarlandir UPPTA were determined to be ∼0.5 and 52.5 µM against SARS-CoV-2, while they were 1.3 and 205.9 µM against HCoV-OC43, respectively. In the pharmacokinetic studies, Pentarlandir UPPTA was distributable at a high level to the lung tissue with no accumulation in the body, although the distribution was affected by the food effect. With further investigation in toxicology, Pentarlandir UPPTA demonstrated an overall safe toxicology profile. Taking these findings together, Pentarlandir UPPTA is considered to be a safe and efficacious pancoronal antiviral drug candidate that has been advanced to clinical development.

Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression.

BACKGROUND: Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression. METHODS: We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared. RESULTS: Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects. CONCLUSIONS: Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.