Ivermectin is a medication used to treat a number of parasite infections. Chemically, this compound and derivatives are macrocyclic lactones originally isolated from a Steromyces bacterium.( Figure 1)
Figure 1. Chemical structure of Ivermectin
Pharmacologically this drug is a glutamate-gated chloride channel activator and so used as a broad-spectrum antiparasitic drug. Ivermectin also has potent antiviral activity towards both HIV-1 and dengue virus. Ivermectin induces autophagy through the AKT/mTOR signaling pathway and mitophagy. 
Ivermectin was introduced in therapy in 1981 and the two discoverers, Drs Omura and Campbell were awarded jointly the Nobel-prize in Physiology or Medicine in 2015. (see the 2016 April issue of the Cyclodextrin News) The discovery and application of Ivermectins have radically lowered the incidence of river blindness and other parasitic infections.
In the drug repurpusing campaign, Ivermectin was also included in the antiviral testing process against COVID-19.
Promising human clinical results on the antiparasitic drug Ivermectin
There are two major studies to mention here on the encouraging therapeutic potential of this antiparasitic drug against coronavirus.
1. The Argentina Study: Argentina’s largest newspaper, Clarin, reported on September 23 about promising results in an ivermectin study, as Clarin reports “this is the first scientific evidence available in the world, which manages to verify the effect of this drug on the coronavirus under in vivo conditions in infected patients.”
The results were reported by the Ministry of Science and Technology, and followed a four-month effort; the work was conducted by a public-private consortium led by Alejandro Krolewiecki of the Tropical Diseases Research Institute. Scientists explained that the elevated dose 0.6 mg/kg of Ivermectin was three times the amount “usually used.” This dose produces the fastest and most profound elimination of the corona virus when treatment is started in the early stages of infection (up to 5 days from the onset of symptoms).”
Testing was done with 45 patients with moderate or mild COVID-19. 30 got the high-dose ivermectin, and the remainder were controls.
High Ivermectin Dose, Rapid Virus Elimination: Adrián Lifchitz, professor of Pharmacology at Unicen, was the lead for the study of ivermectin concentrations in plasma samples of the trial subjects. “We found that the medication produced a rapid viral elimination from the body and this helps to reduce the probability of infection. The effect that ivermectin causes on the rate of disappearance of the virus depends on the amount of the drug that is absorbed (amount that enters the organism), after taking it orally. The design, development, and analysis of this study was a public-private cooperation formed by the Veterinary Research Center of Tandil (CIVETAN), UNCPBA-CICPBA-CONICET; the Biotechnological Services Platform-COMTra-National University of Quilmes; the EleaPhoenix SA Laboratory (co-financed the project); the Tropical Diseases Research Institute – National University of Salta – CONICET and the Virology Laboratory of the Garrahan Hospital.
2. Japanese and Bangladeshi study
Another human Ivermectin study was conducted by Japanese and Bangladeshi research team. They completed a retrospective study involving 325 consecutive patients infected with SARS-CoV-2 at the COVID-19 treatment unit at Mymensingh Medical College hospital (MMCH), Mymensingh, Bangladesh from April to June 2020. Results were published online on Sept. 24 in a peer-reviewed periodical. 
With a total of 248 adult patients infected with SARS-CoV2 free of any pathological conditions, 115 of them received ivermectin plus standard of care, while 133 of the subjects only received standard of care. The ivermectin treatment produced no adverse events.
While none of the ivermectin-treated patients showed progressive pathology (e.g. pneumonia or cardiovascular complications), 9.8% of the standard of care group developed pneumonia and 1.5% had ischemic stroke. While only 9.6% of the ivermectin-treated group ultimately required oxygen inhalation, 45.9% of the standard of care group fell in this category.
This observation held up for the development of respiratory distress as well (2.6% ivermectin vs. 15.8% standard of care group). Moreover, of those patients needing antibiotic treatment, superiority of ivermectin was clear with 15.7% of the ivermectin groups vs. 60.2% of the standard of care group. Finally, those patients in the ivermectin arm got better faster.
The ivermectin-treated group became COVID-19 negative in a median of 4 days vs. 15 days for the standard of care group. Although the researchers acknowledge randomized, multicenter study could strengthen the evidence, they’re clear that ivermectin should be considered as a first-line therapy as part of a COVID-19 containment strategy.
Ivermectin and cyclodextrins
The formulation of ivermectin by using cyclodextrins has been subject of a number of papers and patents. (for more details see Cyclodextrin News, 2016 April issue) The primary aim of using CDs was to improve aqueous solubility and absorption rate of Invermectin upon oral administration. This compound is insoluble in water but soluble in methanol and 95% ethanol. It is sensitive to light and oxygen as well as to hydrolysis. The molecular encaspsulation by CDs improves the solubility and stability of Ivermectin. Two major Chinese formulation patents disclose the cyclodextrin-ivermectin compositions. 
Dos Santos Moreira et al reported on improved solubility and biological efficacy for the beta-CD-entrapped ivermectin nano-precipitates on Aedes aegypti larvae. 
An interesting application of cyclodextrin-enabled ivermectin and its derivatives (abamectin, doramectin) was published for the treatment of metabolic diseases, such as hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesteremia, diabetes or obesity. The ivermectin and its derivatives are also used in medicine for treating farnesoid X receptor-mediated cholestasis, gall stone, non-alcoholic fatty liver disease, atherosclerosis, inflammation and cancer. 
Not only inclusion complexes, but also chemically-tagged conjugates of cyclodextrins with ivermectin were synthesized and investigated. The intraperitoneal injection of covalently linked ivermectin to beta-CD was found effective in the inhibition of transcription factor (TCF)-dependent human colon cancer xenograft in vivo. 
 Zachari, M. et al Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform, Developmental Cell 50, 627–643, 2019. https://doi.org/10.1016/j.devcel.2019.06.016
 Khan MSI, et al., Ivermectin treatment may improve the prognosis of patients with COVID-19, Archivos de Bronconeumologia (2020), doi: https://doi.org/10.1016/j.arbres.2020.08.007
 Yu, S.; Li, G.: Cyclodextrin-clathrated insecticidal avermectins solution. Chinese Patent Appl. CN 101933508, 2011, and Zhang, X.; Liu, X.; Zhang, X. beta-Cyclodextrin inclusion compound as veterinary drug, its preparation process and application. Chinese Patent Appl. CN 101954089, 2011
 Dos Santos Moreira et al.Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts. Journal of Agricultural and Food Chemistry 66(28):7275-7285, 2018. https://doi.org/10.1021/acs.jafc.8b01300
 Li et al. Ivermectin and application of derivative thereof . CN102872066, 2013
 Melotti, A. et al The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 6(10), 1263–1278, 2014. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287931/