Tozinameran (BNT162b2) Vaccine: The Journey from Preclinical Research to Clinical Trials and Authorization.

Vaccination development and production was an essential question for the prevention and global control of COVID-19. The strong support from governing authorities such as Operation Warp Speed and robust funding has led to the development and authorization of the tozinameran (BNT162b2) vaccine. The BNT162b2 vaccine is a lipid nanoparticle-encapsulated mRNA that encodes for SARS-CoV-2 spike protein, the main site for neutralizing antibodies. Once it binds with the host cells, the lipid nanoparticles enable the transfer of the RNA, causing S antigens' expression of the SARS-CoV-2, conferring immunity. The vaccine is administered as a 2-dose regime 21 days apart for individuals 16 years and older. Pfizer-BioNTech's BNT162b2 vaccine was the first candidate to receive FDA-Emergency Use Authorization (EUA) on December 11, 2020. During phase 2/3 clinical trials, 95% efficacy was reported among 37,706 participants over the age of 16 who received the BNT162b2 vaccination; additionally, 52% efficacy was noted 12 days following the administration of the first dose of BNT162b2, reflecting early protection of COVID-19. The BNT162b2 vaccine has exhibited 100% efficacy in clinical trials of adolescents between the ages of 12 and 15. Clinical trials in pregnant women and children under the age of 12 are expected to also exhibit promising results. This review article encompasses tozinameran (BNT162b2) vaccine journey, summarizing the BNT162b1 and BNT162b2 vaccines from preclinical studies, clinical trial phases, dosages, immune response, adverse effects, and FDA-EUA.

International policies and challenges on the legalization of traditional medicine/herbal medicines in the fight against COVID-19.

The coronavirus disease 2019 (COVID-19) has now rapidly spread around the world, causing an outbreak of acute infectious pneumonia. To develop effective and safe therapies for the prevention and treatment of COVID-19 has become the major global public health concern. Traditional medicine (TM)/herbal medicines (HMs) have been used to treat multiple epidemics in human history, which brings hope for the fight against COVID-19 in some areas. For example, in China, India, and South Korea with traditional medication history and theory, the governments issued a series of guidelines to support TM/HMs in the medication of COVID-19. In contrast, other countries e.g. North American and European governments are typically silent on these practices, unless to warn of possible harm and overselling. Such difference is due to the discrepancy in culture, history and philosophical views of health care and medication, as well as unharmonized policies and standards in the regulation and legalization of TM/HMs among different areas. Herein, we reviewed the responses and scientific researches from seven selected countries on the policies and legalization of TM/HMs to treat COVID-19, and also analyzed the major challenges and concerns to utilize the traditional knowledge and resource.

Cannabidiol - therapeutic and legal aspects.

Cannabidiol (CBD) is an alkaloid present in Cannabis sativa, along with tetrahydrocannabinol (THC) and more than 100 other substances belonging to a group of compounds called cannabinoids. Whereas the legal status and medical use of Cannabis is a controversial issue in many countries, inconsistent legislation makes CBD status even more complicated. Some CBD products are legal in some countries, while banned in other countries, further compounding the confusion. In 2018, the Food and Drug Administration (FDA) approved the first CBD containing medical product, Epidiolex®, for the treatment of paediatric seizures. Currently, several clinical trials are in progress for the potential treatment of neurologic and behavioural disorders. CBD's current legal and regulatory status is a continuously evolving issue; the current review is presenting historical and present information regarding the use of CBD products worldwide.

Reality and Legality: Disentangling What Is Actual from What Is Tolerated in Comparisons of Hemp Extracts with Pure CBD.

Manufacturers of hemp-based cannabidiol products have argued that their products should be federally regulated as dietary supplements in the U.S. The justifications offered for this suggestion often focus on a variety of assumptions that either are commonly invoked in marketing strategies of the cannabis/hemp industry or are codified in the 1994 Dietary Supplement Health Education Act. Three such assumptions are addressed herein and are characterized as: 1) the false dichotomy of herbs vs drugs, 2) the entourage fallacy, and 3) the false equivalence of incomparable evidence. An argument is presented which is intended to persuade that the legality or mere composition of phytochemical products do not speak to the reality of their pharmacological effects. It is further argued that non-prescription cannabidiol and hemp extracts should not be afforded regulatory protection by designation as dietary supplements.

Differentiating Full-Spectrum Hemp Extracts from CBD Isolates: Implications for Policy, Safety and Science.

The passage of the 2018 United States Agriculture Improvement Act removed industrial hemp, defined as Cannabis sativa L. containing less than 0.3% THC content by dry weight, from Schedule I of the Controlled Substances Act and made it an agricultural commodity. Following these changes, the popularity of hemp-derived cannabidiol (CBD) dietary supplements by consumers has greatly exceeded the scientific understanding of purported benefits, safety and composition of these botanical extracts. Further complicating CBD hemp supplement regulation, Food and Drug Administration (FDA) considers CBD to be an approved drug (Epidiolex) in the treatment of severe epilepsy disorders, Dravet and Lennox-Gastaut syndromes. At the same time, hemp-derived CBD supplements can contain a complex phytochemical matrix from the hemp plant, distinguishing the composition of these products from isolated CBD preparations. This work aims to provide clarity on differentiating botanical full-spectrum hemp extracts containing CBD from isolates, from a phytochemical, toxicological and regulatory perspective.

Nutraceuticals: A Comparative Analysis of Regulatory Framework in Different Countries of the World.

BACKGROUND: Nutraceutical is a term that is a combination of nutrition and pharmaceutical. They are believed to improve physical and mental health and provide therapeutic benefit in disease conditions. Nutraceuticals are claimed to be beneficial in several disease conditions which include cardiovascular disorder, neurodegenerative disorders, metabolic disorders and cancer prevention. OBJECTIVE: In the current review, we will study the current regulatory framework in some of the major countries of the world by comparing different parameters of these regulations. FINDINGS: Global nutraceutical market is currently expanding at a rapid pace but there are some restraints to the market growth which include poor quality manufacturing and unharmonized regulations leading to trade barriers across the globe. Although there are laws and regulations in place which govern nutraceutical products in different countries, these regulations lack harmonization and differ from country to country. Some of the countries follow stringent regulations, whereas, in some of the countries, well-structured and stern regulations for nutraceuticals are lacking. CONCLUSION: The development of a well regulated, harmonized and research-driven approach can help boost the confidence of consumers in nutraceutical products in the world thereby driving the nutraceutical market.

Medical cannabis: Risks related to its indication prior to approval. / Cannabis medicinal: riesgos relacionados con la indicación previa a su aprobación.

In recent years, the interest in medical cannabis prescription has increased significantly. This article provides information about the little scientific basis supporting the prescription of these products for a wide and diverse range of medical conditions. It is critical for any substance to be used in human beings to follow a strict scientific approval protocol, detached from any trend or individual outcome. Before prescribing any drug to human beings, it is necessary to have a clear picture of its uses, especially its safety, which is practically unknown in the case of medical cannabis.

En los últimos años, se ha observado un incremento significativo en el interés por la prescripción del cannabis medicinal. En el siguiente artículo, se informa acerca de la escasa base científica que avala la prescripción de estos compuestos en un listado amplio y diverso de patologías médicas. Se considera fundamental que cualquier sustancia que vaya a ser utilizada en humanos siga un protocolo de aprobación estricto y científico, que pueda desligarse de modas o de resultados individuales. Es necesario que, antes de la prescripción de una droga en personas, deba tenerse un panorama claro de cuáles son los usos del compuesto en cuestión, pero, sobre todo, de su seguridad, que es prácticamente desconocida en el cannabis medicinal.

On healthcare by popular appeal: critical assessment of benefit and risk in cannabidiol based dietary supplements.

Introduction: In recent decades, federal legislation in the U.S. has recognized a new paradigm of pharmacotherapy in which ideology and popular demand, as opposed to sound clinical evidence, drives the marketing of ostensible herbal therapeutics as 'dietary supplements'. This vogue of democratizing medicine has more recently manifested in the ongoing legalization of cannabis products at the state level, where an arbitrary variety of definitions, restrictions, and assumed therapeutic uses are applied to a family of phytochemicals with no definitive evidence of efficacy or safety. With the recent publication of clinical trials submitted to the FDA in efforts to gain approval of the cannabidiol based therapeutic Epidiolex, a rare opportunity exists to examine high-quality data for a drug which has in recent years been marketed as a greatly unregulated dietary supplement. Areas covered: A critical analysis is offered of data regarding efficacy, dosing, exposure, adverse events, drug-drug interactions, and non-specific effects associated with CBD - all of which raise questions regarding the wisdom of assuming the safety and efficacy of cannabinoids in particular and dietary supplements in general. Expert opinion: Ongoing lack of meaningful regulation of cannabinoid supplements continues to put consumers at undue risk without clear evidence of therapeutic value.

The Surprising Reach of FDA Regulation of Cannabis, Even After Descheduling.

As more states legalize cannabis, the push to "deschedule" it from the Controlled Substances Act is gaining momentum. At the same time, the Food and Drug Administration (FDA) recently approved the first conventional drug containing a cannabinoid derived from cannabis­cannabidiol (CBD) for two rare seizure disorders. This would all seem to bode well for proponents of full federal legalization of medical cannabis. But some traditional providers are wary of drug companies pulling medical cannabis into the regular small molecule drug development system. The FDA's focus on precise analytical characterization and on individual active and inactive ingredients may be fundamentally inconsistent with the "entourage effects" theory of medical cannabis. Traditional providers may believe that descheduling cannabis would free them to promote and distribute their products free of federal intervention, both locally and nationally. Other producers appear to assume that descheduling would facilitate a robust market in cannabis-based edibles and dietary supplements. In fact, neither of these things is true. If cannabis were descheduled, the FDA's complex and comprehensive regulatory framework governing foods, drugs, and dietary supplements would preclude much of this anticipated commerce. For example, any medical claims about cannabis would require the seller to complete the rigorous new drug approval process, the cost of which will be prohibitive for most current traditional providers. Likely also unexpected to some, there is no pathway forward for conventional foods containing cannabis constituents, with the (probably exclusive) exception of certain hemp seed ingredients, if those foods cross state lines. And it will certainly come as a shock to many that federal law already prohibits the sale of dietary supplements containing CBD--including those already on the market as well as those made from "hemp," which has recently been descheduled under the 2018 Farm Bill. This Article describes in detail the surprising reach of the FDA and then outlines three modest, but legal, pathways forward for cannabis-based products in a world where cannabis has been descheduled.

Analysis on Composition Rules of Chinese Patent Drugs Treating Pain-Related Diseases Based on Data Mining Method.

OBJECTIVE: To analyze the composition rules of oral prescriptions in the treatment of headache, stomachache and dysmenorrhea recorded in National Standard for Chinese Patent Drugs (NSCPD) enacted by Ministry of Public Health of China and then make comparison between them to better understand pain treatment in different regions of human body. METHODS: Constructed NSCPD database had been constructed in 2014. Prescriptions treating the three pain-related diseases were searched and screened from the database. Then data mining method such as association rules analysis and complex system entropy method integrated in the data mining software Traditional Chinese Medicine Inheritance Support System (TCMISS) were applied to process the data. RESULTS: Top 25 drugs with high frequency in the treatment of each disease were selected, and 51, 33 and 22 core combinations treating headache, stomachache and dysmenorrhea respectively were mined out as well. CONCLUSIONS: The composition rules of the oral prescriptions for treating headache, stomachache and dysmenorrhea recorded in NSCPD has been summarized. Although there were similarities between them, formula varied according to different locations of pain. It can serve as an evidence and reference for clinical treatment and new drug development.

Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration-approved drugs.

BACKGROUND AND PURPOSE: Macropinocytosis is involved in many pathologies, including cardiovascular disorders, cancer, allergic diseases, viral and bacterial infections. Unfortunately, the currently available pharmacological inhibitors of macropinocytosis interrupt other endocytic processes and have non-specific endocytosis-independent effects. Here we have sought to identify new, clinically relevant inhibitors of macropinocytosis, using an FDA-approved drug library. EXPERIMENTAL APPROACH: In the present study, 640 FDA-approved compounds were tested for their ability to inhibit macropinocytosis. A series of secondary assays were performed to confirm inhibitory activity, determine IC50 values and investigate cell toxicity. The ability of identified hits to inhibit phagocytosis and clathrin-mediated and caveolin-mediated endocytosis was also investigated. Scanning electron microscopy and molecular biology techniques were utilized to examine the mechanisms by which selected compounds inhibit macropinocytosis. KEY RESULTS: The primary screen identified 14 compounds that at ~10 µM concentration inhibit >95% of macropinocytotic solute internalization. Three compounds - imipramine, phenoxybenzamine and vinblastine - potently inhibited (IC50  ≤ 131 nM) macropinocytosis without exerting cytotoxic effects or inhibiting other endocytic pathways. Scanning electron microscopy imaging indicated that imipramine inhibits membrane ruffle formation, a critical early step leading to initiation of macropinocytosis. Finally, imipramine has been shown to inhibit macropinocytosis in several cell types, including cancer cells, dendritic cells and macrophages. CONCLUSIONS AND IMPLICATIONS: Our results identify imipramine as a new pharmacological tool to study macropinocytosis in cellular and biological systems. This study also suggests that imipramine could be a good candidate for repurposing as a therapeutic agent in pathological processes involving macropinocytosis.

The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies.

BACKGROUND: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. METHODS: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. RESULTS AND CONCLUSION: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance.

Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice.

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P = 0.0083) or zanamivir monotherapy (88% versus 26%, P = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1ß, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.