Ivermectin

synthetic macrocyclic lactone pharmaceutical derived from avermectin B1 — itself a natural fermentation product of the soil actinomycete bacterium Streptomyces avermitilis, first isolated at the Kitasato Institute in Japan in 1967 by microbiologist Satoshi Ōmura.
Ōmura isolated and cultured a gram-positive bacterium sample NRRL 8165 (a then unknown species of Streptomyces) which was sent to William Campbell at Merck to test for antiparasitic effects.
NRRL 8165 cultures showed potent activity against Nematospiroides dubius infection in mice and the active components were purified revealing a family of macrocyclic lactones named avermectins.
Ōmura and Campbell jointly received the 2015 Nobel Prize in Physiology or Medicine for this discovery.
approved for human use in the late 1980s. ivermectin has a record of safety in human use with total distributed doses in one-third of the world population in the past 30 years. one of the most impactful pharmaceutical agents in modern medicine — responsible for the near-elimination of river blindness (onchocerciasis) and lymphatic filariasis in multiple African countries through mass drug administration programs.

ivermectin is a semi-synthetic derivative — avermectin B1 isolated from fermentation, then chemically modified to produce the more stable and potent ivermectin (22,23-dihydroavermectin B1). avermectins occur naturally as a fermentation product of Streptomyces avermitilis — eight different structures including ivermectin, abamectin, doramectin, eprinomectin, moxidectin, and selamectin isolated and divided into four major and four minor components.

ivermectin binds to glutamate-gated chloride channels in invertebrate nerve and muscle cell membranes resulting in membrane hyperpolarization which leads to paralysis and death. these chloride channels are specific to protostome invertebrate phyla. while closely related to mammalian glycine receptors, ivermectin has low affinity for mammalian ligand-gated chloride channels. ivermectin does not readily cross an intact blood-brain barrier.

documented antiparasitic activity: onchocerciasis (river blindness), lymphatic filariasis, strongyloidiasis, scabies, head lice, malaria, leishmaniasis, ascariasis, trichuriasis, cutaneous larva migrans, and gnathostomiasis.

ivermectin shields SARS-CoV-2 spike protein which binds to CD147 and ACE-2.

ivermectin is selectively concentrated in pulmonary tissue about 3 times more than plasma concentration and remains in pulmonary tissue for a long time.

ivermectin has antiviral activity in vitro against numerous RNA and DNA viruses including simian virus 40, pseudorabies virus, HIV, dengue virus, West Nile virus, Venezuelan equine encephalitis, influenza virus, and yellow fever virus. broad-spectrum antiviral activity results from inhibition of viral protein transport mediated through host importin α/β heterodimer — viral protein translocation into host nucleus through importin α/β is crucial for robust infection for many viruses.

in vitro studies consistently show ivermectin inhibiting SARS-CoV-2 replication — the 5,000-fold viral RNA reduction in the Caly et al. study was striking.
however the concentrations needed to achieve this in vitro are significantly higher than standard therapeutic doses achieve in human plasma. so just take larger doses.

may help treat inflammatory conditions, viral infections, and cancers. anticancer effects explored.

ivermectin's anticancer mechanisms include: MDM2-MDM4 inhibition (restoring p53 tumor suppressor function — p53 is mutated or suppressed in ~50% of all cancers), WNT-TCF pathway inhibition (relevant to colon, breast, and glioblastoma), PAK1 inhibition (breast cancer driver kinase), mitochondrial dysfunction induction in cancer cells through chloride channel disruption, and autophagy induction. preclinical evidence across breast, colorectal, glioblastoma, and leukemia cell lines.

side effects are usually mild and self-limited and include headache, dizziness, skin irritation, and nausea.