IVERMECTIN, A NEWELY RECOGNIZED “CHEMOTHERAPEUTIC” SUBSTANCE

An Overview of the Literature and a Discussion of Dose 20 December 2023

The following is a brief summary of the extensive literature that demonstrates the anti-cancer power of Ivermectin. This summary also includes an exploration of a possible dosing regimen for the treatment of patients with Ivermectin used either alone or in combination with a wide array of existing treatments for at least 11 different cancer types.

The U.S. Food and Drug Administration (FDA) approved anti-parasitic agent, Ivermectin has been used to effectively treat parasitic diseases since 1975. Since its approval by the FDA, at least one billion people world wide have used Ivermectin without significant or widespread adverse health effects. It is common practice for investigators to screen substances that have been approved by the FDA for human use to determine if they have the potential to treat conditions other than the one for which they were approved. Ivermectin has been subjected to such screening and has been found by numerous investigators to have negative effects on the survival, growth, and spread of cancer cells and tumors.

One of the more important studies of the use of Ivermectin to treat cancer is that of Draganov et al. (1) which is discussed in paragraph 4. below. The findings reported in the study by Draganov et al set the stage for the only clinical trial currently being undertaken in the United States. The trial is intended to explore the ability of Ivermectin to enhance the human immune system’s response to Triple Negative Breast Cancer by suppressing Treg cells thereby making the tumors more susceptible to infiltration by T cells.(7)

Other investigators have shown how Ivermectin alone has impaired the growth, replication, and spread of cancer cells and tumors. Still others have shown that Ivermectin works synergistically with a number of chemotherapeutic agents such as Vincristine and Cyclophosphamide which suggests that much lower doses of those highly toxic agents could be used for cancer treatment if administered with Ivermectin.

There is no doubt that Ivermectin has potent anti-cancer activity in the treatment of a broad spectrum of cancers as determined by in vivo laboratory studies. Several reviews of Ivermectin as a chemo therapeutic agent have been published. A particularly good review is that of Juarez et al. (2) which summarizes the work fo multiple investigators in which Ivermectin has been reported to interfere with the growth, spread, and viability of various cancer types. The Juarez review is notable in that it also explores the pharmacokinetics of Ivermectin which makes it useful for determining a therapeutic dose. The following is taken from the Juarez et al review.

Juarez et al (2) described how Ivermectin:

1. Inhibited the growth of Multi-Drug Resistant cancer phenotypes in mice by 50% using a dose of 1 mg/kg bw for 5 consecutive days (according to Juarez et al this is a Human Equivalent Dose of 81µg/Kg - e.g. 4mg/50 Kg person for 5 consecutive days). This finding also demonstrated a synergistic response in the presence of Vincristine [see refs 38-41 in Juarez et al (2)].

2. Increased activity of chloride channels which led to increased cancer cell death in cells from various leukemia lines and at a “low concentration” in cell lines derived from leukemia patients. Synergism with Ivermectin and Cytarabine and Daunorubicin were also noted [see Juarez et al (2) references 42-44].

3. Induced mitochondrial dysfunction and oxidative damage by inhibiting the mitochondrial O2 consumption rate which in turn decreased cancer cell enzyme activity.

4. Induced Immunogenic Cell Death (ICD) by stimulating an ATP dependent immune response which suggests that Ivermectin promotes and regulates ICD within the tumor microenvironment. Furthermore, during a screening of FDA approved drugs to determine if those drugs might have other uses, Draganov et al. (1) found that the ability of T-cells to infiltrate breast cancer tumors in mice that had been inoculated with various breast cancer cell lines was greatly enhanced. The ability of T-cells to infiltrate tumors which were once impervious to them was described as “turning a ‘cold tumor’ into a hot’ tumor”. Draganov et al also reported that Ivermectin neutralized the DNA transcriptional protein HMGB-1 (a PD-1 check point inhibitor which acts as a “brake” on T cells). Following treatment of mice infused with Triple Negative Breast Cancer cell lines using Ivermectin, Dragonov et al found that HMGB-1 was released into the intercellular space which indicated that Ivermectin induced Immunogenic Cell Death (ICD). The HMGB-1 protein is secreted by a variety of immune cells including dendritic cells. When the HMGB-1 protein is neutralized it appears to protect against damage caused by arthritis, colitis, ischemia, sepsis, and the autoimmune disease, Lupus. The implication of this work is that Ivermectin will enhance the effect of a dendritic cell vaccine.

5. Induced autophagy (an essential part of apoptosis) by blocking autophagy repressors in breast, ovarian, colon, melanoma, and glioblastoma cancers. Those repressors play an important role in regulating cancer stem cell growth. Ivermectin promotes the degradation of the autophagy repressor PAK-1, an oncogene kinase necessary for cellular organization and for promoting tumor growth in more than 70% of human cancers which includes the inhibition of cancer stem cell development.

6. Inhibited stem cell development in the breast cancer cell line MDA-MB-231 by 80% at doses that resulted in an internal concentration of 0.5 µMolar Ivermectin. This occurred by inhibiting the WNT-T Cell Factor signaling pathway which regulates multiple cellular functions during Cancer Stem Cell development including: cell fate determination, cell migration, and cell polarity.

7. Inhibited double stranded RNA helicase. RNA helicase is a group of enzymes that are essential for cellular replication and other functions. The inhibition was observed in glioma cells both in vitro and in vivo and resulted in what was described as an “anti-tumor effect” (2).

8. Selectively inhibited Cancer Stem Cell (CSC) growth and reproduction. Based on the work of Gupta et al (3) which demonstrated that the veterinary use anti-parasitic drug Salinomycin reduced the proportion of CSCs by more than 100 fold compared to Paclitaxel, Dominguez-Gomez et al (4) examined the effect of Ivermectin on CSCs in the breast cancer cell line MDA-MB-231 and found that Ivermectin inhibited CSC growth and reproduction at intracellular concentrations of 0.2-8 µM.

9. Ying Ying et al (5) reported that Ivermectin inhibited the proliferation of two glioblastoma cell lines. The inhibition was dose dependent. Though the range of doses was not specified the effective dose at which a 50% reduction in cell proliferation (ED50) was observed was stated to be “about 5 µM”. These investigators also reported that Ivermectin induced apoptosis and inhibited angiogenesis by “suppressing capillary network formation”.

Juarez et al (6) treated twenty-eight malignant cell lines with 5 μM Ivermectin and reported that Ivermectin worked synergistically with cyclophosphamide. Cell viability, clonogenicity, cell cycle, cell death and pharmacological interaction with common cytotoxic drugs were assessed as was the anti-tumor effects of Ivermectin in vivo. The breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7, and the ovarian SKOV-3, were found to be the most sensitive cancers to the effects of ivermectin. Conversely, the prostate cancer cell line DU145 was the most resistant to its use. In the sensitive cells, ivermectin induced cell cycle arrest at G0–G1 phase and modulated the proteins associated with cell cycle control. In addition to working synergistically with cyclophosphamide, Ivermectin also acted synergistically with Docetaxel, and Tamoxifen in reducing both cell viability and colony formation. Ivermectin also reduced both tumor size and weight in tumor-bearing mice.

In summary, Ivermectin adversely affects tumor development, growth, and metastasis in a variety of cancer cell lines and it dose so in a variety of ways at least one of which is by enhancing the adaptive immune system. Ivermectin has also been shown to act synergistically with vincristine, docetaxel, tamoxifen, and cyclophosphamide.

There is no doubt that Ivermectin administered either alone or in combination with a number of different cancer chemotherapeutic agents has an adverse effect on cancer growth, development, and metals. What is missing from our current knowledge is information on an appropriate dose amount and regimen for treating cancer patients alone or in concert with another component.

Virtually every investigator has called for clinical trials to further elucidate the efficacy and mechanism of Ivermectin in treating cancer either alone or as an adjunct to a wide range of existing chemotherapeutic agents, including anti-check point inhibitors. The fact that Ivermectin has been demonstrated to act synergistically with a number of commonly used and highly toxic chemotherapeutic agents may allow those agents to be used with good outcomes at much lower sub-toxic concentrations.

Despite the many calls for clinical trials of Ivermectin in the treatment of cancer, as noted above, at the present time there is only one clinical trial being conducted in the United States. That trial is currently in its recruitment phase. [Yuan, Y. et al. (7) ] That trial is designed to explore the use of Ivermectin in concert with the immune check point inhibitor, Balstilimab as a treatment for Triple Negative Breast Cancer. The study by Draganov (1) which formed the basis

for this clinical trail (described below) demonstrated how Ivermectin turned “cold tumors” into “hot tumors” eg tumors rich in T cells . In their study, Draganov et al inoculated female BALB/c mice with 4T1 breast cancer cells. Following tumor development the mice were given 5mg Ivermectin/Kg BW by oral gavage for 6 days. Using a Human Dose Equivalent of 0.404 mg/kg the daily dose for a 50 kg human would be about 20.2 mg.

The information supporting the clinical trail by Yuan Yuan at Cedars-Sinai Medical Center in Los Angeles, CA provides scant insight regarding dose. Though they state that dosing will occur on an intermittent 21 day cycle for “up to 35 cycles” they provide no information regarding the dose(s) that will be administered to study participants. In this study a “21 day cycle” is defined as Ivermectin dosing on days 1,2, & 3 - 8, 9, & 10 - 15,16, & 17. No Ivermectin will be given on days 4, 5, 6, 7, 11, 12, 13, 14, or 18, 19, & 20.

Because Ivermectin is not rapidly transformed into metabolites it remains in circulation for a relatively long time with a half life about 19 hours. And because it enters into enterohepatic circulation it exhibits two peak plasma concentrations; one at about 4 hours and the second between 6 and 12 hours following an oral dose (2) this may explain the relatively long half life of 19 hours. Therefore, an oral dose twice a day will ensure that the concentration of Ivermectin in the body will remain at a relatively constant but increasing body burden over multiple days.

Based on the information from Juarez et al (2) concerning the biphasic maximum concentration of Ivermectin and it relatively long half-life it seems likely that on the four days during which no Ivermectin is administered that the participants circulating concentration may remain at therapeutic levels. (See Figure 1.)

Juarez et al (2) provided pharmacokinetic data on the maximum plasma concentration of Ivermectin following oral doses of 0.35-0.6 mg/kg, 0.7- 1.1 mg/kg, and 1.4 - 2.0 mg/kg. At the lowest dose, 0.35 mg/kg (17.5 mg/50 Kg person) the maximum plasma concentration achieved at 4 hours post dose was 87 ngm/ml. Using a distribution volume of 49.7 L the total amount of Ivermectin present in the plasma of that 50 kg person will be about 4 hours post dose (Cmax) will be about 4 mg. The doses used by Juarez et al are consistent with the doses used any Gupta (3), Ying Ying (5), and Juarez (6) in which doses of 5 µM were used to treat tumor bearing mice.

While the information which describes the conduct of the the clinical trial is not particularly informative regarding the precise dose planned for use in the clinical trial described above (7) it does suggest that intermittent dosing with Ivermectin may be an appropriate regimen.

Figure 1 depicts the uptake and accumulation of Ivermectin in plasma over 4 consecutive days using that data.

Peter P. Lee (8) the corresponding author on the paper by Draganov et al (1) and the person who is leading the team that is conducting the clinical trial at Cedars-Sinai Medical Center (7) provided some insight into the importance of their trial and the work of Dranganov et al. wrote in Oncology Times (8):

“This is the first time that a research team has demonstrated that checkpoint inhibitors can be used to successfully treat breast cancer— when combined with Ivermectin, an inexpensive and existing safe drug.

In these studies, 40-60 percent of animals treated with the ivermectin plus anti-PD1 antibody combination completely eradicated their tumors. They were able to fight off the cancer again after it was reintroduced. It is the two drugs together that is the magic. Either drug alone has almost zero effect, but together they have a powerful synergist effect”

Lee also wrote:“We found that the therapeutic combination also worked in neo-adjuvant models (before surgery) and adjuvant models (after surgery). Most importantly, the combination worked against metastatic breast cancer, potentially curing 50 percent of animals.”

Lee made several extraordinary statements.

— First, Ivermectin works synergistically with the anti-PD1 antibody, Balstilimab to eradicate TNBCs in up to 60% of treated mice.

— Second, according to Lee the combination of Ivermectin and Balstitlimab “worked against metastatic breast cancer” as well.

— Third and perhaps more importantly, the combination of Ivermectin and Balsistimab worked to fend off cancer development in about 50% of mice that were re-instilled with TNBC cells. In other words the combination of Ivermectin and Balstilimab appears to have conferred a long lasting immunity against cancer in the test animals in the Draganov et al (1) study.

— Fourth, Lee offered that these results were obtained “with roughly $30/dose of Ivermectin”.

A final word about clinical trials and Ivermectin. It has been estimated that at least one billion people have taken Ivermectin without experiencing substantial or widespread adverse effects. Further, there are no reports of adverse effects during any of the in vivo studies using mice given Ivermectin at doses that mimic human doses used to treat COVID (about 0.4 mg/kg body weight) nor are any severe adverse effects expected from the clinical trial being conducted by Ying Ying (7). From a public health policy prospective, if informed consent is obtained and if administration of this “over the counter” substance is conducted consistent with prevailing national regulations there should be no barrier to the use of Ivermectin in clinical settings to treat cancer patients under the protection of FDA guidance for the Off Label use of drugs.

Figure 1. Is based on the pharmacokinetic information provided by Juarez et al (2) and it provides a a visual presentation of the results of a 17.5 mg dose (based on a 50 kg patient) given every 12 hours for 4 consecutive days.

The solid lines at the bottom show a maximum amount of Ivermectin in blood of about 4mg at about 6 hours following oral administration. The dashed lines show how total amount of Ivermectin will increase in the patient with each subsequent dose based on the reported Cmax and the 19 hour T-1/2 of elimination. The very last curve shows that at the end of Day 4 the amount of Ivermectin in the plasma will be about 13 mg. Based on the T-1/2 of 19 hours there will still be about 4 mg present at the end of Day 5 and about 2 mg at the end of day 6.

This provides some insight into the planned dosing regimen of Yuan et al in the Cedars-Sinai clinical trial. However, with a weekly cycle of 3 days on and 4 days off Ivermectin it appears that the test subjects will be essentially depleted of Ivermectin by day 6 of the dosing regimen. The impact of that is unknown.

Figure 1. Plasma Concentration as a Function of Dose Over Multiple Days

References

(1) Droganov, D. et al.: npj Breast Cancer (2021); 22

(2) Jaurez, M. et al. Amer J Cancer Res. 2018; 8(2): 317-331

(3) Gupta et al. Identification of selective inhibitors of cancer stem cells by high-throughput

screening. Cell (2009)138: 645-659

(4) Domingo-Gomez, et al (2018) Mol .Med. Rep. 17: 3397 -3403

(5) Yinying Liu et al (2016) BBRC 480 (3) : 18 Nov. 2016: 415-421

(6) Juarez, M. Et al. 2020 Cancer Chemotherapy and Pharmacology 85: 1153-1163

(7) https://classic.clinicaltrials.gov/ct2/show/NCT05318469?term=ivermectin&cond=cancer&cntry=US&draw=2&rank=1

(8) Lee, Peter P. 2021 Oncology times 43 (9): 10-12


Union, Kentucky

20 December 2023