“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

D-neuron, ligand neuron of trace amine-associated receptor 1 (TAAR1): Key of novel non-D2 receptor-binding antipsychotics

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron.

Ca2+ Participates in Programmed Cell Death by Modulating ROS During Pollen Cryopreservation

Programmed cell death (PCD) is one of the reasons for the decline in pollen viability after cryopreservation. However, the role of calcium ions (Ca2+) in PCD during pollen cryopreservation has not been revealed in the existing studies. In this study, Paeonia lactiflora 'Fen Yu Nu' pollen was used as the research material for investigating the effects of Ca2+ changes on PCD indices and reactive oxygen species (ROS) during pollen cryopreservation. The results showed that after cryopreservation, with the decrease of pollen viability, the Ca2+ content significantly increased. The regulation of Ca2+ content had a significant effect on PCD indices, which showed that the Ca2+ carrier A23187 accelerated the decrease of mitochondrial membrane potential level and increased the activity of caspase-3-like and caspase-9-like proteases and the apoptosis rate. The expression levels of partial pro-PCD genes were upregulated, the anti-PCD gene BI-1 was downregulated, and the addition of Ca2+ chelating agent EGTA had the opposite effect. The addition of the Ca2+ carrier A23187 after cryopreservation significantly increased the ROS content of pollen, the addition of the Ca2+ chelating agent EGTA had the opposite effect, and Ca2+ regulators also had significant effects on the contents of ROS production and clearance-related substances. Ca2+ affected intracellular ROS content by acting on the ROS production and clearance system during the cryopreservation of pollen and is thus involved in the occurrence of PCD.

Assessing the Structural and Functional Similarity of Insulin Glargine Biosimilars

Background: A biosimilar product is expected to exhibit similar safety, efficacy, and quality as that of the approved reference product. Only a few reports of thorough evaluation of the quality of insulin glargine biosimilars are available in literature. Here, we examine the structural and functional similarity of biosimilars of insulin glargine, the first basal long-acting insulin analogue with respect to its innovator product (Lantus® from Sanofi Aventis). Methods: Structural similarity was established using mass spectrometry, chromatographic, and spectroscopic techniques. Stability was compared by performing accelerated thermal stress studies. Functional similarity was established via in vitro assay. Results: Biosimilar 4 exhibited greater content of high molecular weight species (HMWs) (0.80%) and related substances (RS) (0.45±0.06%) vs others (HMWs of 0.04% and RS of 0.17%). Biosimilars 1 and 3 exhibited higher rate of impurity generation (0.78% and 0.73% per week, respectively), as compared with other drug products (0.02% to 0.43% per week). Furthermore, %aggregation at 14 days was found to statistically correlate ( R2= 0.99, root mean square error (RMSE) = 0.095) with %aggregation at 0 day (linearly) and the number of months from expiry (nonlinearly), highlighting the overpowering impact of the latter. Conclusions: While an overall structural and functional similarity was observed across insulin glargine biosimilars with respect to the innovator product, low amounts of product-related variants were seen in some biosimilars and these impact product stability. The %aggregation at 14 days exhibits statistical correlation with %aggregation at 0 day and the number of months from expiry. The order of biosimilarity was denoted as Lantus®>Biosimilar 2>Biosimilar 4>Biosimilar 1>Biosimilar 3.

Unsubstantiated health claims for COVID-19 infections are led by cannabidiol: return of snake oil medicine

Background The United States Food and Drug Administration (FDA) monitors, inspects, and enforces the promotion of products by companies that claim to mitigate, prevent, treat, diagnose, or cure COVID-19. The introduction of COVID-19-related diagnostics and therapeutics during the pandemic has highlighted the significance of rigorous clinical trials to ensure safety and efficacy of such interventions. The objective of this report is to provide a descriptive review of promotional violations of health products for COVID-19 infection. Methods Warning letters issued by the FDA’s Center for Drug Evaluation and Research were retrieved over an 18 month period (March 6, 2020, to August 30, 2021) to identify promotional violations. FDA violation letters categorized as “Unapproved and Misbranded Products Related to Coronavirus Disease 2019 (COVID-19)” were reviewed. A content analysis was performed for each letter to identify categories for product type, promotional venue, violation type, and country of origin. For cannabidiol-related violations, a content analysis was repeated within its own product category. Results A total of 130 letters were reported. Across all letters, cannabidiol products were the most frequent subject of violation (15/130; 11.5%). Of the cannabidiol letters, all reported the promotion of unapproved products (15/15; 100%), misbranding (15/15; 100%), and/or had claims that lacked scientific substantiation (14/15; 93.3%). All promotional violations were linked to websites (15/15; 100%), along with other mainstream venues: Facebook, Instagram, YouTube, Twitter, LinkedIn, and email. Lastly, the cannabidiol products were described to provide therapeutic benefit to COVID-19, by acting as an anti-viral (5; 33.3%), pro-inflammatory (1; 6.7%), anti-inflammatory (7; 46.7%), immune-booster (5; 40%), immune-suppressor (2; 13.3%), and/or other (2; 13.3%). Conclusion Despite the urgent need for COVID-19 treatments, promotional material by companies must comply with standard regulatory requirements, namely substantiation of claims. As the pandemic persists, the FDA must continue their efforts to monitor, inspect, and enforce violative companies. Cannabidiol-related substances led the spectrum of products with unsubstantiated claims to treat COVID-19 infection. Improving awareness among the public, healthcare providers, and stakeholders highlights the value of drug approval process, while protecting public safety.

Detection and Evaluation of process related impurities in Obeticholic Acid Drug material using HPLC Method

Obeticholic acid (OBE) is being used to treat primary biliary cirrhosis and cholangitis. An HPLC with refractive index detection method for eight process related substances of OBE was developed and verified for use in quality assurance laboratories for regular analysis. The separation and analysis were performed on YMC Triart C18 (3.0 µm particle size, 250 mm × 4.6 mm) column. Mobile phase employed consisted of 0.01N potassium phosphate buffer (3.0 ± 0.05 pH, set with 0.1% orthophosphoric acid) and acetonitrile at 45:55 (v/v) ratio. The method established for determination of eight impurities in OBE was validated and verified in keeping with International Council for Harmonisation guidelines. This method can be used for routine analysis of eight impurities in OBE bulk samples.