Topical medication cream. // Marco Verch, CC BY 2.0
In 1982, the FDA approved isotretinoin (Accutane), a Vitamin A derivative, for use in patients with acne. No new methods of acne medication had been approved from 1982 until the approval of topical clascoterone in August 2020, almost 40 years later.
Topical clascoterone is a cream that is applied directly to the skin of areas affected by acne. Clascoterone is an antiandrogen, which is a class of drug that blocks androgen receptors. The drug is the first antiandrogen to be approved by the FDA for acne medication, earning it the title of first-in-class medication. Androgens, which are male sex hormones present in males and lower levels in females, play an important role in the pathogenesis of acne.
During puberty, both males and females have increased levels of androgens like testosterone or dihydrotestosterone (DHT). Higher levels of testosterone can cause increased production of sebum, an oily substance secreted by sebaceous glands under the skin. Excessive amounts of sebum in a skin pore can cause a blockage (known as a comedo, blackhead, or whitehead) that may become infected.
Clascoterone was shown in vitro to have higher affinity for androgen receptors than DHT. This blockage of local androgen receptors by clascoterone was then shown by clinical trials to reduce the acne-causing effects of androgens.
The Investigator’s Global Assessment Scale (IGA) is a scale of acne severity that goes from 0 (clear) up to 4 (severe). Two clinical trials found that at least 18% of patients achieved a drop of at least 2 points on the IGA scale (resulting in a score of 0 or 1) at 12 weeks into treatment with topical clascoterone. One trial showed that patients, on average, saw a 39% decrease in total lesion count after 12 weeks of treatment.
The FDA listed the most common side effects of topical clascoterone as reddening, itching, and scaling or dryness of treated skin. The FDA-approved brand of topical clascoterone is Winlevi.
References
Piszczatoski, C. (2021, October 2). Topical Clascoterone: The First Novel Agent for Acne Vulgaris in 40 Years. https://doi.org/10.1016/j.clinthera.2021.08.007
U.S. Food and Drug Administration. (2020, September 3). Drug trial snapshot: Winlevi. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-winlevi
Researchers looking for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations published findings in Pathogens that showed that a combination of diphenhydramine (the active ingredient antihistamine in Benadryl) with lactoferrin (an immunologically active protein found in human and cow milk) reduced SARS-CoV-2 replication by 99% in human cells.
Background
The key to the researchers’ findings related to proteins called the sigma receptors. These receptor proteins are located in the endoplasmic reticulum (ER), an organelle responsible for protein folding and transportation. Sigma receptors have multiple functions, including regulation of the ER stress response.
The ER stress response occurs when the ER is overwhelmed with unfolded or misfolded proteins. This triggers the unfolded protein response (UPR), which seeks to return the cell to a normal state by increasing protein folding, autophagy (destruction of damaged proteins), and in the case of prolonged UPR, apoptosis (cell suicide).
ER stress usually occurs when the ER is overwhelmed with unfolded or misfolded proteins. Cells mitigate ER stress by provoking the unfolded protein response (UPR), which includes increased protein folding, autophagy (destruction of damaged proteins) and, in prolonged cases, apoptosis (cell suicide).
When the UPR causes autophagy, it does so by forming sites near the ER called autophagosomes. Coronaviruses (CoV) have been found to bind directly to the sigma-2 receptor to cause ER stress, enabling them to hijack autophagosomes for use as virus replication sites.
Implication
Researchers found that by binding a drug molecule to the sigma-2 receptor, SARS-CoV-2 would no longer be able to bind to it to cause ER stress (and ultimately virus replication). This is made even more effective by also binding to and activating the function of the sigma-1 receptor.
Results
The team identified a ligand called AZ66 as being able to bind to both sigma-1 and sigma-2 receptors. In experiments with human lung cells infected with SARS-CoV-2, AZ66 completely blocked virus production. However, the safety of AZ66 is unknown, as the drug candidate has not been tested in clinical trials.
Molecular docking model of human sigma-2 receptor (orange) bound to AZ66 (yellow).
Searching for common compounds with proven records of safety, the researchers analyzed electronic medical records to identify diphenhydramine (DPH), the active ingredient antihistamine in Benadryl, as being associated with higher survival rates for COVID-19 patients. This is due to DPH having effects on the sigma-1 receptor. DPH was found to reduce replication of SARS-CoV-2 in the infected human lung cells by about 30%.
Lactoferrin is an antimicrobial and immunostimulatory iron-sequestering protein found in human and cow milk that was brought to a researcher’s attention by the Global Virus Network’s COVID-19 task force due to its antiviral effects on SARS-CoV-2. When tested, it was also found to reduce virus replication by about 30%. The milk protein has a proven safety record as a supplement widely used to treat stomach ulcers.
When a diphenhydramine/lactoferrin combination was tested in human and monkey epithelial lung cells, they found that a synergistic effect occurred, reducing virus replication by 99%.
Commentary
The study’s first author, David A. Ostrov, Ph.D. of the University of Florida, hailed diphenhydramine and lactoferrin as “effective, economical,” and unlike AZ66, “[having] a long history of safety.” The combination could be used to prevent infection as well as decrease recovery time from COVID-19.
While the researchers await potential interest from pharmaceutical companies, Ostrov told the University of Florida Health Newsroom that he cautions against self-medicating with diphenhydramine or lactoferrin as a COVID-19 prevention or treatment. He said that any off-label use of medication should follow a consultation with a physician. Further, commercially available lactoferrin used for treatment of stomach ulcers is not exactly the same as the lactoferrin used in the study.
Lactovid™ is a combination of diphenhydramine and lactoferrin
Warning against off-label self-medication
This article does not offer medical advice. University of Florida researcher, David A. Ostrov, Ph.D., said that any off-label use of medication should follow a consultation with a physician. Off-label use is when a medication is used for anything other than its approved purpose.
This article is based on the following sources
– Bennett, D. (2020, December 3). Existing antihistamine drugs show effectiveness against COVID-19 virus in cell testing. University of Florida Health Newsroom. https://ufhealth.org/news/2020/existing-antihistamine-drugs-show-effectiveness-against-covid-19-virus-cell-testing – Bennett, D. (2021, November 22). Two common compounds show effectiveness against COVID-19 virus in early testing. University of Florida Health Newsroom. https://ufhealth.org/news/2021/two-common-compounds-show-effectiveness-against-covid-19-virus-early-testing – Ostrov, D. A., Bluhm, A. P., Li, D., Norris, M. H., et al. (2021, November 20). Highly specific sigma receptor ligands exhibit anti-viral properties in SARS-Cov-2 infected cells. Pathogens. https://doi.org/10.3390/pathogens10111514 – Vela, J. M. (2020). Repurposing sigma-1 receptor ligands for COVID-19 therapy? Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2020.582310
Example of molecular docking of a ligand in the main protease of SARS-CoV-2. Yellow: ligand position determined by computer simulation. Black: ligand position determined by experiment. Source: Joshua Vermaas/ORNL, US Department of Energy.
Using the University of Florida’s HiPerGator supercomputer with the University of California San Francisco’s DOCK software, researchers have identified two dipeptides as small molecule activators of the peptidase neurolysin enzyme.
Render of peptidase neurolysin enzyme.
Peptidase neurolysin is an enzyme that has been found to be “one of the brain’s potent, self-protective mechanisms promoting preservation and recovery of the brain after acute injury” (Karamyan). Karamyan’s research posited that in the case of these injuries, neurolysin is responsible for:
reducing fluid buildup around the brain (cerebral edema)
reducing neural cell death caused by excess neurotransmitters (excitotoxicity)
reducing inflammatory response in the brain (neuroinflammation)
Searching for ways to make neurolysin more effective, lead researcher Vardan Karamyan, PhD (Texas Tech University Health Sciences Center Department of Pharmaceutical Sciences) enlisted the help of David Ostrov, PhD (University of Florida College of Medicine Department of Pathology, Immunology and Laboratory Medicine).
Neurolysin is similar in structure to a molecule called ACE2 (angiotensin converting enzyme-2), the main receptor for the virus that causes COVID. Dr. Ostrov previously identified drugs that bind ACE2, and he used the same strategy to identify drug candidates that bind neurolysin.
Superposition of neurolysin (copper) on ACE2 (teal).
Ostrov used UF’s HiPerGator supercomputer to screen 139,725 compounds from a repository at the National Cancer Institute Developmental Therapeutics Program to identify candidates that could fit a site on neurolysin that would facilitate an increase in the enzyme’s function. This was achieved using the DOCK program package, developed by UCSF.
DOCK’s molecular docking simulations were used to identify if and how a ligand (drug-like small molecule) can bind to the active site of a macromolecule (in this case, neurolysin). This is usually done to find ways to promote or inhibit a macromolecule’s function, making molecular docking software a key component in the ever-expanding world of computational drug discovery.
According to the UFHealth Newsroom, UF’s HiPerGator supercomputer completed the query in 15 hours–only 1.4% of the time it would take a desktop computer to complete the same task.
In the lab, the researchers tested the function of DOCK’s best matches on rat neurolysin. They found that the dipeptides L-histidlyl-L-tyrosine and L-histidlyl-L-histidine enhanced the activity of neurolysin.
According to Ostrov, human clinical trials with the mentioned drug candidates could begin within 2 years if FDA approved drugs are found to enhance neurolysin activity. An approved drug could assist or facilitate recovery in stroke and traumatic brain injury (TBI) patients.
This article is based on the following sources
– Bennett, D. (2021, September 7). UF health researcher, collaborators discover compounds that might boost stroke recovery. University of Florida Health. https://ufhealth.org/news/2021/uf-health-researcher-collaborators-discover-compounds-might-boost-stroke-recovery – Karamyan, V. T. (2019, October). Peptidase neurolysin is an endogenous cerebroprotective mechanism in acute neurodegenerative disorders. https://doi.org/10.1016/j.mehy.2019.109309 – Statements from David A. Ostrov, PhD (University of Florida College of Medicine, Department of Pathology, Immunology and Laboratory Medicine)
