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Disclaimer Regarding Recommendations:

RRP ISA is offering the following material as information for you to consider and not as medical advice. What follows should be reviewed with your personal physician.

These are guidelines for those who wish to replicate the treatment regimen that this writer has followed. He also happens to be RRP ISA's executive director.

He would be the first to say that the dosing guidelines presented here may not be optimal. This is simply because the research to determine optimal dosing has not been done. Much more study needs to be done to establish an optimal dosing schedule, which is why RRP ISA strongly encourages the otolaryngological community to begin clinical trials as soon as possible.

ART Sourcing:

Artemisinin itself may be acquired through Holley Pharmaceuticals at a 30% price reduction for RRP patients. This firm calls it "ArteMin." Please remind Michael Liu, who works with Holley, that you are an RRP patient. Holley claims its artemisinin has been tested by HPLC, and this is the source of Dr. Schlegel's artemisinin, as described in Learn>Novel Therapies.

Sourcing of artesunate has been through Hepalin/Wellcare (this firm calls it "Hepasunate" and describes it as artesunate). No price drop is offered. Additionally, Hepalin claims it tests by HPLC, melting point, etc. Spot testing of Hepalin's ART products for purity and dose has reportedly checked out in the past. It needs to be noted, however, that no one at the University of Washington serve as a quality assurance agent for Hepalin/Wellcare.

No physician's prescription is required for either of these products.

Artemisinin and its analogues (henceforth abbreviated ART) are imported, and much of it comes from mainland China. RRP ISA cannot vouch for product purity or quality, and we are not "recommending" these two sources over any other. There is a lot of counterfeit artemisinin being sold on the internet. Moreover, tens of thousands of malaria patients are dying each year because they are getting counterfeit artemisinin. After doing its own due diligence, these are the sources through whom staff at RRP ISA have ordered. If one wishes to follow the guidelines this writer has used, these are his two most reliable sources for ART.

Those patients or physicians who choose to order are advised to do their own due diligence. One strong recommendation is to put quality and reputation above price. Take care in your selection of source.

By way of a disclaimer, RRP ISA, its staff and its board does not assume responsibility with how you use the information provided here about dose and administration of ART, sourcing of this group of medications and/or how others have used this medication.

Initial use of ART (first three weeks):

Artemisinin can only be absorbed continuously for 6-7 days. In this initial phase, ART is given for a week on, a week off, and another week on. Note that this is the only time anyone will take ART for more than 3 days in a row, using the guidelines in this section.

Continuation Dosing:

Whether ART actually kills HPV-infected cells is open to doubt. Papillomas may still recur, though the overall virulence of the virus seems greatly reduced. As to how much it helps? Anecdotally, yhis writer had previously used cidofovir, MMR, PDT, retinoic acid(s), interferon(s), and even acyclovir and acupuncture. ART's effect seems to be many times greater than any of these.

This writer has used it monthly (artemisinin and artesunate) for nearly three years as of the writing of this section, based on his reasoning that ART's efficacy requires periodic refreshment (see below).

Following the loading dose phase, described above, he has used it for 3 days a month only, however, on this once-a-month basis.

For people wishing to replicate his approach, this once a month continuation dosing schedule will commence after the initial dosing is over (that's a week on, a week off and another week on). Thus we have (day 1) an initial dosing schedule lasting around three weeks. On day 21 (three weeks), the clock for the continuation schedule begins. A month from that day, it's appropriate to take artemisinin and artesunate together again, but this time only for about three days. Wait yet another month and you may take it again for three days. This cycle will continue indefinitely.

Summary (Initial and Continuation Dosing):

7 days on (artemisinin plus artesunate)
7 days off (no usage)
7 days on
21 days off
3 days on
27 days off
3 days on
27 days off
(Continue the "3 days on, 27 days off" as a maintenance regimen)

How Much To Take:

Dosing at about 7 mg/kg a day of body weight for the artemisinin from Holley and about 4 mg/kg a day for the artesunate from Hepalin/Wellcare seemed to work without any side-effects for this writer.

Your first task, therefore, is to figure your weigh in kg. To do that, you divide your weight in pounds by the the number 2.2. EXAMPLE: If you weigh 165 pounds, your weight in kg is 75 kg (165 divided by 2.2=75).  ANOTHER EXAMPLE: A 40 pound patient weighs 18 kg (40 divided by 2.2=18).

Once you know the weight of the patient in kg, you're half-way there. If you follow the 7 mg per kg rule, a 165 patient would take 525 mg of artemisinin a day (7 X 75=525). The same patient would take 300 mg of artesunate (4 X 75=300). Rounding up or down is ok, as the capsules are offered in increments of 50 mg. Thus a 165 pound, 75 kg patient might wish to take 500 mg of artemisinin and 300 mg of artesunate.

The question of rounding up or down often arises. Following these guidelines, an 18 kg child, for example, would be taking 126 mg of artemisinin and 72 mg of artesunate, based on the 7/4 dosing ratio. These size capsules aren't made, however, so the patient's parents will need to decide whether to round up (150/100 mg) or down (100/50 mg). We can't advise on this, but we can say that while slightly exceeding the 7/4 level seems to be ok, greatly exceeding these 7/4 dosage schedule is probably not a good thing. What is small, what is great? This is a question each person must answer for him/herself, and RRP ISA wishes to steer clear of offering advice. If it's more than 10% to get a "round number in increments of 50 mg and this writer himself were doing it, he'd be inclined to round downwards. Otherwise, he might round up. If you feel like following what he did more to the letter, you may wish to consider breaking the capsules and dividing the ingredients by eye.

You will almost certainly need to do that anyway, since you will not be giving anyone a full day's dosing all at once. You will need to divide the daily dose, as described in the section below called When To Take It.

This amount will be the patient's standard daily dosing amount, although you will not take it every day. You will take it a week on, a week off (no ART whatsoever), and another week on. From that point, you will move to the continuation dosing schedule.

Use With Children:

Reports on safety in children deserve special mention.

ART is an anti-inflammatory and works through apoptosis, not necrosis. If that is true, some of the speculations below may be unwarranted. If inflammation were to result, however, could it not cause a potential airway obstruction in very young children? Anyone using ART with kids needs to be especially careful. There may indeed be no cause for concern, but we think that physician supervision and close monitoring is absolutely indicated and required in the case of toddlers and young children with small airways.

Artemisinin and artesunate generally appear safe for children, at least when used at the initial Guidelines dosing level, which Dr. N. Singh and others described as appearing quite safe. We cannot offer medical advice, but we can say that several sources, including the World Health Organization, have recommended ART for children with malaria.

But what about chronic use? Here, we have little or no data. This writer knows of no clinical trials for chronic use of ART, whether in children or adults. Are there hidden toxicities? We don't know. We would at the least suggest frequent blood chemistry panels, until more is known.

As in most things, you need to do your own due diligence. Having said that, we suggest reading from the material cited here (on all pages associated with Learn>Novel Therapies. That should allay most anxiety concerns for both prospective patients and health care professionals.

What To Take:

Note that these guidelines call for the taking of BOTH artemisinin AND artesunate. Not just artemisinin.

On the plus side, artemisinin has a longer half-life over artesunate. On the other side, Dr. Tomikazu Sasaki who is an expert on artemisinin at the University of Washington writes in an email (4/22/09): 

Again, more studies need to be done to determine the optimum combination and dosing.

When to Take It:

It's been reported that the artemisinin and artesunate have only about a 2-4 hour half-life, which is short. You may wish to divide the total dosage, spacing the smaller dosings at 4 hour intervals. You needn't be obsessive, however. This writer "fudged" during sleep and you may wish to do likewise, or during school hours.

We would emphatically warn against taking all the capsules at once. That would almost certainly constitute an overdose. This writer spaced the usage of ART throughout the day. He never took all the artesunate in the morning, for example, and the artemisinin in the evening. Every few hours, he would take a prorated amount of artemisinin and artesunate. In following these guidelines, you would want to do likewise.

Because of the short half-life, you would do well to think of taking ART the last thing before retiring for sleep and early in the morning as well. This writer took it (both artemisinin and artesunate) no less than four times a day.

Storage of ART:

Both artemisinin and artesunate are light sensitive, yet they come bottled in white plastic bottle that, while semi-opaque, still allow light to get in. You may want to wrap the bottles with tin foil so as to prevent light from entering, or else you will want to ensure that they are kept in a dark closet. You can reasonably carry a daily dose of capsules around with you, but you should be cautious about keeping the bottle unprotected in an open cupboard, etc.

Antioxidants And Other Medications:

ART works by superoxidizing the iron (the ferrous form) inside diseased cells. This writer strongly suggests not taking any supplemental antioxidants within 12 hours of dosing with artemisinin or artesunate. This includes vitamins C, E, A, etc. That includes multivitamins.

It also includes powerful food-based antioxidants like blueberries, though most other foods are ok. Please educate yourself on your food-sources and use your common sense, however.

Because of the pro-oxidant mechanism of action for the ART, antioxidants tend to defeat the ART. This admonition is as significant as the one on the importance of taking the artemisinin with fat-contaioning food and the artesunate with water. If you take ART and get no measurable results but also take antioxidants at the same time, please do not blame the ART. 

The problem is that you have taken the ART on one hand and unknowingly worked to defeat it on the other. While there's no success like failure, this is absolutely not an approach that is likely to result in positive results.

If taking statins or other medications, we again emphasize the need to coordinate our usage guidelines with your physician who may have also asked you to take Co-Q. I myself take no stains and no Co-Q during my period of ART dosing.

How Does It Work On HPV Tumors and RRP?

The form of the iron that freely circulates in the blood (a ferric form) is converted into the ferrous form, used inside cells. The HPV virus needs that particular form of iron to replicate and create papillomas. Transferrin receptors appear to play a role here, as discussed elsewhere. ART enters the cell and superoxidizes the ferrous form of iron--it doesn't affect the form of  iron in the blood or the stomach. It creates apoptotic intracellular conditions that Dr. Tom Broker described as "spectacular." Even if it doesn't appear to kill all of the virus, it seems to down-regulate it radically.

Should I Take It With Iron Supplements:

That could cause problems, especially if the supplement contains the ferrous form of iron that ART reacts with. If ART reacted to the form of ferrous iron in the supplement, it may cause nausea and, mpore ominously, it could be expected to eliminate or greatly reduce the ability of ART to work on RRP. This writer used no form of iron supplementation whatsoever, not even in "vitamin pills," during the dosing days.

Cooking Utensils:

Same precautions apply here as with iron supplements. Cast iron utensils may (?) leach ferrous-based iron into one's food. That could be expected to eliminate or severely reduce the ability of the ART to work on RRP. Take great care to note these concerns. ART works by selectively "attacking" certain forms of iron. If you ingest ferrous-based forms of iron during your dosing days, you will probably get little or no benefit from ART.

Whether To Take It With Or Without Food:

Dr. Sasaki, a expert in artemisinin and chemistry at the University of Washington confirms that artemisinin is partially fat soluble, not water soluble. Artemisinin is not very bioavailable, however, because it is only partially soluble.

Dr. Singh at the Univ. of Washington recommended that the stomach contents be emptied of food when taking ART. He suggests waiting 3-4 hours after a meal. He affirmed the importance of fat in  the absorption process, so he suggested taking ART with a glass of whole milk (milk contains no iron) + some water as well.

Other ART experts at the Univ. of Washington initially disputed the need for the fasting part of this ritual in verbal communication, contending that the iron in food is well-chelated and does not react to the ART in any event, even when iron (ferric form) is floating free in the bloodstream.

Thus it is that we have some friendly contradiction going. One published study showed that the presence of food didn't seem to interfere with ART absorption,l but absorption isn't the same as effect. Moreovewr, we don't fully know what will happen to the ART after a multitude of chemical operations on the food in the stomach.

It may well-be that Dr. Singh, who urged patients to take ART with milk but no food, was in fact ahead of the curve.

While this writer himself got results taking ART with a full meal, and he also got great results using the "glass of milk" approach. About half the time, he is now taking it with fat-containing meals once again. Half the time, he takes it with milk only. His otolaryngologist told him recently he's never seen his larynx looking better (after using ART for three years).

The most important thing is to take both the artemisinin and artesunate with whole milk or yogurt (not low fat or non-fat) or food that has some sort of fat content (e.g., eggs, oils, toast and peanut butter or regular butter, cheese, meat,etc.). One must remember to also drink a few ounces of water at the same time. If you want to hedge your bets until more is known about iron metabolism in the gut, you would do only milk 50% of the time, with food 50% of the time.

In an earlier version of these Guidelines, we mentioned how Dr. Singh initially mentioned that a teaspoonful of ice-cream might also do the trick. It does not contain an amount of fat commensurate with a glassful of milk, however.  A teaspoonful of ice cream contains much less fat, suggesting to this writer that it does not seem very suitable for use with ART. Ice cream itself is ok, but make sure that the amount of fat in it is at least proportionate to what you'd be getting in a glassful of whole milk.

If you are using just water or just food, you are not properly absorbing the artesunate and artemisinin together. In that case, your trial with ART clearly diverges from these Guidelines.

What Not To Do (Mixing Treatment Modalities):

Please pay close attention to what is said here.

ART is not a vitamin. While is may not be regulated by the FDA in America, it is considered a potent medicine elsewhere in the world. It saves lives. You want to treat it with respect.

People have taken ART with DIM (though not taken at the same exact time) with no apparent problems but no studies on this have been reported. We would discourage the use of I3C and ART, partly because I3C is an old technology that doesn't work as well as DIM, partly because it's very unstable and leads to several very toxic condensation byproducts.

Likewise, we don't know if there are any interactions with other medications such as cidofovir, RRP, interferon or other medications you may be taking.

You may still wish to limit the use of unnecessary medications while using ART in that the use of several medications at once makes assigning credit in case of a good response impossible. Was it the ART? Or something else you were doing at the same time?

There should be no problem taking Gardasil (three systemic injections) with ART assuming they were dosed according to Merck's timelines (the third dose being at six months).

Unless you know how another drug will interact with it, however, we think that it would be prudent to avoid adding a lot of unknown variables unless your physician says otherwise.

Treatment Effects (Writer's Story):

For more than two years, since implementing these guidelines, this writer experienced no need for surgery (previously required up to four times a year previously, and an average of twice per year).

On followup examinations, there was no discernible regrowth of the RRP, which previously regrew with in a matter of a few months to the point where it was always visible on indirect laryngoscopy .

After >two years of remission, this writer was diagnosed with one very small papilloma on his left vocal cord. The papilloma on the true cord surface hardly grew in several months, and his voice was still very strong. He had a surgery in summer 2008, although it really wasn't needed or recommended due to the small size of the lesion. His voice was strong both before and after the surgery.

The reappearance of ANY papilloma, however, seems to confirm that ART doesn't cure RRP, and that ongoing treatment is necessary. Hence the need for the Continuation Dosing section described above.

Following his first use of ART in Winter of 2006, this writer's voice became dramatically stronger and clearer than it had been in nearly 30 years. This effect appears to have been replicated for a number of RRP patients who have taken ART  and have reported their responses to this website (Learn>Novel Therapies>Patient Reports).

In those patients reporting in, the use of ART appears to have profoundly altered the course not just of laryngeal papillomatosis but also of tracheal/bronchial RRP and in at least one case, even pulmonary cancer). This has been objectively confirmed, of course, through CT scans, laryngoscopy photographs, etc.

Side-Effects (General):

Some patients report a sense of malaise, slight temporary mental fogging, minor digestive issues or a strange taste in their mouths. The latter two reports are possibly connected with idiosyncratic dosing patterns (e.g., taking ART with I3C after we suggested not to do that), etc. Side effects reportedly resolve when the the dosing peri

Experts discourage taking ART within six weeks of radiation. Both modalities can kill affected cells, and you probably do not want to create an additive effect, since that hasn't been well-studied, at least not to the best of our knowledge. 

RRP ISA strongly suggests that everyone wishing to use ART obtain a baseline blood test (e.g, the usual liver enzymes, renal function, etc.). The writer has been taking ART for several years with no discernable ART-related abnormalities.

Neurotoxicities, including irreversible hearing loss, have been reported to be associated with very high doses of artemether (a different drug from artemisinin or artesunate) that was administered systemically (not orally) into animal models. Note that these side effects exist only in animal models and only with very high doses of artemether, not with artemisinin or artesunate.

Artemisinin has been used VERY widely for malaria. Many consider it and artesunate to be the treatment of choice, although multiple agents are usually used in order to prevent malaria resistance to artemisinin.

It is widely regarded as extremely safe even in children but that is for malaria dosing, not for chronic dosing (once or more monthly). There have been virtually no clinical trials of ART for chronic use, therefore we have little to no hard data. That said, we've been informed that the dosing levels are still very low, even lower on a per day basis than for malaria.

For chronic dosing, we suggest definitely coordinating with your physician and regular liver chemistry panels, etc. Used with anemia and certain other diseases affecting blood iron levels may be counter-indicated although we know of one patient with borderline-anemia who has used it without any adverse tipping toward anemia. Again, ART does not react with the form of iron in the bloodstream. This should be your doctor's call, however.

The writer has not experienced significant side-effects at the dosing levels mentioned here. You or your child could be different, however, and you should not take any medications, including ART, without your physician's knowledge.

For more on side-effects, see Learn>Novel Therapies>Artemisinin Safety and Pharmacokinetics. Also see Learn>Novel Therapies>Guidelines II.

Cautionary Comments for Pregnant Women

Taking ART when one is pregant may not be such a good thing. No negative data exists, but we know artemisinin crosses the blood-brain barrier. Small amounts of ferrous exist in all cells, though in the target cells (cancers or RRP) that artemisinin selects, it exists in huge amounts. The question is whether superoxidation of even small amounts of ferrous in embryonic brains might be damaging. No one knows, but I did find an interesting article on ferrous and brains relating to a drug called deprenyl at http://www3.interscience.wiley.com/journal/104543109/abstract?CRETRY=1&SRETRY=0 and also at http://www.benbest.com/lifeext/deprenyl.html.

From the latter: 

"The breakdown products of dopamine resulting from MAO-B degradation are hydrogen peroxide, ammonia and an aldehyde. Aldehydes are highly reactive compounds that can modify proteins. Ammonia is also toxic, particularly to glia (non-neuron brain cells). Hydrogen peroxide in the presence of ferrous iron ion can lead to hydroxyl radicals, the most toxic of all free radicals. Hydrogen peroxide can easily pass into the cell nucleus where it can encounter iron ions to produce hydroxyl radicals that damage and mutate DNA. The combination of deprenyl and melatonin has been shown to counteract hydroxyl radical production due to dopamine autoxidation in the brain significantly more than either agent alone [JOURNAL OF PINEAL RESEARCH; Khaldy,H; 29(2):100-107 (2000)]. (Carnosine, which has been shown to reduce cellular senescence, also inhibits MAO-B free radical generation.)"

 Butyric Acid (Butyrate)

One person at the University of Washington says that butyric acid (butyrate) potentiates the ART up to tenfold--allegedly without any toxic side-effects. Two other ART expert at the University of Washington, however, have said that they do not believe butyric acid has been properly tested with ART, and they do not think it's needed.

This question is interesting, but until more is known, this writer will not use it, and RRP ISA has explicitly asked Holley management and staff NOT to steer RRP patients and doctors toward butyrate, assuming the person(s) calling in have identified themselves RRP patients/physicians in order to get the 30% discount.

We are emphatic at this juncture in suggesting that until more is known, patients do not add it to their regimen.

Concluding Remarks:

Again, what is written here is offered only for its informational value, not as medical advice. The specific course any patient follows should be at the advice of his or her personal physician. Your following this approach may complement, but emphatically must not take the place of, regular medical care by a qualified physician. If you need surgery, get it. Same with anything else that is medically recommended, etc.

If you try this approach, please read this material several times over, so you thoroughly understand what is said here. Please also let us know how it works. You are encouraged to use the RRP Forum to post your report.

We wish you the very best of luck.

Gardasil As A Therapeutic Agent:

In addition to the ART, we have also discussed in website and RRP Forum why it might be prudent to consider taking the three-shot series of Gardasil injections (not interlesional, but using the standard prophylactic protocol).

While we are in no way proposing that Gardasil can cure existing cases of HPV disease such as RRP--this was thought unlikely by many experts, based on genital studies of Gardasil and also based on the adjuvant and VLP (viral like particle) composition of the vaccine--many unanswered questions do exist about Gardasil that cannot completely rule out a therapeutic effect in the respiratory tract (see Dr. Steinberg's remarks on Learn>Novel Therapies).

There is evidence that VLP vaccines like Gardasil can be used successfully in laryngeal RRP treatment (Schlegel, Frazer). Moreover, genital HPV is arguably not the same as respiratory HPV. This has been thoroughly discussed elsewhere [e.g., Learn>RRP Focus Sessions>2007 RRP Focus Session>RRP ISA presentation, etc.]

RRP ISA has suggested that the effect of ART might be (???) enhanced if the Gardasil vaccine somehow "turned on the lights," allowing patient's immune system to "see" those infected cells. Here, we must be more specific. Could it mobilize the local immune system? RRP ISA believes that cannot be ruled out, and Merck's own medical director in charge of Gardasil (Dr. Haupt) himself has concurred.

It is understood that the metaphor of "turning on the lights” is very simplistic, especially in describing early and chronic infections, but a synergistic effect between Gardasil and ART simply cannot be ruled out (or verified) until more data is collected.

What we can say is that the conclusions resulting from Merck's genital studies seem flawed in that they are based on the notion that the respiratory tract functions similarly to the genital tract.

That assumption, as proven by HIV/AIDS epidemiological data, is almost certainly untrue [for more, see this writer's argument in the 2007 RRP Focus Session and also see Dr. Steinberg's remarks under Learn>Novel Therapies].

If patients do decide to use Gardasil, however, two things must be said.

First, do not rely on your physician to know the proper timing of the doses. Just two days ago, we talked to a young patient whose immune system was inappropriately flooded with "viral-like particles" from Gardasil at the four month mark, when the physician should have waited six months before giving him the third injection. No surprise that his RRP, which had responded just fine to artemisinin till then, suddenly turned acute and flared precisely after that occurred. Patients and parents need to adhere to Merck's recommended injection schedule and make sure their physicians are aware of it. As with many things connected to RRP, waiting for your physician to educate you is a road that is often paved with peril.

Second, do not ask for Gardasil for treatment. Gardasil was not designed to treat, but to prevent. You'll do much better getting your physician to offer you Gardasil if you tell him or her that you're sexually active (assuming you're an adult) and wish to prevent getting yet another strain of RRP through oral sex. Or if you are a parent, you might tell your child's physician that you're hoping that Gardasil will prevent any further manifestation of RRP in their lungs or trachea. These reasons would probably be convincing; saying you want it for treatment is only likely to elicit a refusal and/or a raised eyebrow.

                                                             Also see Guidelines II