Disclaimer: In light of the ongoing epidemic this post is intended to spark interest and invoke discussion about unconventional therapies.
Introduction
It is widely believed that there is no specific therapy for Ebolavirus. However, this is only partially true. Some experimental therapies exist, including convalescent serum and interferon, but the ability to deploy these to affected regions is severely limited by logistic constraints. Other experimental therapies have not yet been proven effective in humans. The current outbreak forces us to search for any drugs in our current armamentarium which could be potentially helpful.
Selective Estrogen Receptor Modulators (SERMs) for Ebola treatment
Johansen 2013 performed a high-throughput assay to screen approved drugs for activity against Ebolavirus. This assay identified two SERMs: clomiphene and toremifene. In-vitro assays subsequently demonstrated antiviral activity among several other drugs acting on the estrogen receptor including tamoxifen, raloxifene, diethylsilbestrol, quinestrol, and hydroxyprogesterone.
Further experiments were performed to characterize the activity of clomiphene and toremifene. Both drugs were active against a range of hemorrhagic fever viruses including Zaire Ebolavirus, Sudan Ebolavirus, and Marburg virus. Toremifene had a lower inhibitory concentration of 50% (IC-50) for Zaire Ebolavirus (1.73 uM for toremifene vs. 11.1 uM for clomiphene).
Toremifene and clomiphene were subsequently tested in a mouse model of Ebolavirus, using a dose of 60 mg/kg every other day. Survival increased from zero without treatment to 90% or 50% with clomiphene or toremifene respectively:
The mechanism of action of these drugs is independent of the estrogen receptor, but rather inhibition of viral entry into cells. They are effective in both male and female mice.
Pharmacokinetic challenges
Animal studies in this paper dosed both toremifene and clomiphene at 60 mg/kg. This dose is substantially higher than the dose used in humans, raising a question of whether it would be pharmacokinetically feasible to use these drugs.
Clomiphene dosing at 50 mg achieves a serum concentration of 8-9 ng/mL, which is equal to 0.014 uM and thus far below the IC-50 of clomiphene for Zaire Ebolavirus (11.1 uM). This suggests that it would not be feasible to treat Zaire Ebolavirus using clomiphene as currently formulated.
Toremifene seems to have better pharmacokinetics including oral bioavailability of 100% and a half-life of five days allowing intermittent dosing. The IC-50 of toremifine for Zaire Ebolavirus is 1.73 uM, which equals 1 ug/mL. Although this concentration is higher than levels required for management of breast cancer, concentrations well above 1 ug/mL were achieved in phase I trials. For example, Bishop 1992 found that toxicity emerged at a dose of 400 mg/m2/day and therefore recommended a dose of 300 mg/m2/day for subsequent trials (1). Of note, 300 mg/m2/day achieved an average trough level of 2.2 ug/mL and peak level of 4 ug/ml. Wiebe 1990 found that at a dose of 400 mg/day, the average steady state concentration was 3.4 ug/ml. In order to achieve steady-state levels rapidly it might be helpful to start with a loading dose perhaps equal to twice the maintenance dose.
In human trials, toremifene produces a series of metabolites which have biologic activity. For example, N-desmethyltoremifene has equivalent ability to bind to estrogen receptors, and accumulates to about three times higher concentrations than toremifene itself (Kohler 1990). Given the ability of multiple estrogen receptor antagonists to impair Ebolavirus, it is possible that these metabolites could also have antiviral activity.
Safety and tolerability
Toremifene is generally well tolerated, with side effects including hot flushes, nausea/vomiting, QT prolongation, dizziness, and increased risk of venous thromboembolic disease. At very high doses (400 mg/m2/day) severe vomiting, dizziness, and delirium may occur (Bishop 1992).
It must be noted that studies of toremifene have been performed in patients with breast cancer. The side-effect profile is not well characterized in men, although it would be expected to be mild given low estrogen levels. However, the side-effect profile in young women could be more severe given higher levels of estrogen in this population.
Logistics and cost
Unfortunately toremifene is a fairly expensive agent. The cost per treatment would likely be several hundred dollars. However, this cost is quite reasonable considering the potential lives saved. Furthermore, if toremifene could decrease the duration of illness and viral shedding, it could help contain the outbreak.
One major advantage of toremifene is that it could be easily transported and deployed to rural areas in Africa. Many other potential treatments for Ebolavirus (i.e., antiserum or interferon) require refrigeration and parenteral administration, which are major barriers to therapy in these areas.
Conclusion
Selective estrogen receptor modulators (SERMs) including toremifene show activity against Zaire Ebolavirus in vitro and in mouse models. Toremifene is FDA-approved with a fairly benign side-effect profile. Given that there are few other treatment options for Zaire Ebolavirus, it may be reasonable to trial these drugs among victims of this epidemic.
Notes
(1) mg/m2/day refers to mg per meter squared body surface area per day. The typical body surface area of a woman is 1.7 m2, so 300 mg/m2/day is roughly equivalent to ~500 mg/day.
Acknowledgements: Thanks very much to Timothy Lahey, infectious disease specialist, and Jeffrey Endicott, ICU Pharmacist, for thoughtful input on this post.
Image credits: https://en.wikipedia.org/wiki/Toremifene#/media/File:Toremifene.svg
Image credits: https://en.wikipedia.org/wiki/Toremifene#/media/File:Toremifene.svg
Latest posts by Josh Farkas (see all)
- PulmCrit Blogitorial – Use of ECGs for management of (sub)massive PE - March 24, 2024
- PulmCrit Wee: Propofol induced eyelid opening apraxia – the struggle is real - March 20, 2024
- PulmCrit wee: Why I like central lines for GI bleed resuscitation - March 13, 2024
Ebola or even Ebola Trojan Condition (EVD) is undoubtedly an issue that establishes a critical trigger with regard to matter. Herpes can spread swiftly which enable it to demonstrate perilous. See more http://survival-mastery.com/med/health/the-ebola-virus.html
In the U.S. Army/NIH study you cited, over 2000 approved drugs were screened for activity against Ebola. Only the two estrogen receptor modulators, clomiphene and toremiphene, were selected by the investigators for in vivo testing. The WHO passed over toremiphene last week, citing safety concerns. Clomiphene might be worth another look. Clomiphene has been prescribed for decades. It is generic and cheap. Manufacturing capacity is already in place. Clomiphene in pill form as you pointed out probably cannot treat Ebola. Its approvals may or may not cover IV injection. We know from this paper (see link) that clomiphene was used… Read more »
Are you sure your math is correct for the dosing for the clomid?
From wikipedia, clomid had molar mass of 406 and bioavailability of 90%, 1/2 life of 5 days
4uM looks like the best target dose. If the clomid were distributed evenly over the entire 65 kg (or 65 L) for the average human the required dose would be:
Dose = 4e-6 * 65 * 406 = 0.105 grams and typical dose is 50mg.
Or using the mouse data (60mg/kg) and area based scaling the dose should be 60/12.3*65 = 317mg
These seem like reasonable doses for short term treatment.
I just noticed they did mention that Tamoxifen showed anti-viral properties, I wonder if an aromatase inhibitor like anastrozole (Arimidex) or Letrozole (Femara) would prove similar results?
I wonder what the results would be if they administered the SERM with an immune system booster such as GcMAF? Would the SERM Tamoxifin also produce similar results?
Interesting question. The concept isn't that the drug would stop all virus from infecting any cell, and therefore avoid infection entirely. More likely, I think it would just slow down the virus enough (on the whole) to give the immune system a better chance at controlling the infection. Ultimately, I think if the patient survived they would develop immunity and eliminate the virus entirely. This is, however, unknown.
If I read the original report right (I have forgotten most of my cell biology and it was late at night) these drugs did not stop the virus entering the cells but prevented fusion with one of the organnelles which had to happen before the virus replicates. Could this leave intact virus in the cells to cause a later relapse or carrier state?
Thanks for bringing this possibility up. It seems like things are spiraling out of control in Liberia and it would be a godsend if one of these treatments proved feasible.