Dextran Sulfate: New Promising Antiviral

this article, but were unable to get them a draft copy to review before press time. Any mistakes are our responsibility ot theirs. We must also emphasize that information is changing rapidly and this article may soon become obsolete--and in any case cannot be relied on for medical advice.

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Dextran sulfate, a drug used for 20 years in Japan and available there without a prescription, has become an important AIDS treatment possibility. While it is still too early to be sure the drug will be useful, preliminary experience is good and a number of people are already obtaining and using the substance, especially in Los Angeles, New York, and San Francisco.

Briefly the case for dextran sulfate is:

* In the laboratory it works about as well as AZT in inhibiting HIV, at concentrations which can be achieved in the
blood by oral use, yet it has very little toxicity (Ueno and Kuno, June 1987). In addition it seems to be synergistic with AZT; in the laboratory the combination works much better against the virus than either drug alone (Ueno and Kuno, June 1987; Ueno and Kuno, October 1987; disputed by Berenbaum, 1987). Besides inhibiting reverse transcriptase, dextran sulfate blocks the formation of giant syncytial cells in the laboratory-- important because healthy cells are trapped and destroyed when syncytial cells form. Dextran sulfate may be the first drug which can stop this cell-to-cell spread of the virus.
* Dextran sulfate is safe enough to be available without a prescription in Japan, where it is used for arteriosclerosis.
Because of its 20-year history of human use, much safety information is known.
Persons with AIDS or ARC are using doses two to three times larger than commonly used in Japan; however these larger doses have been tested in humans without problems. Persons with AIDS or ARC can show unexpected toxicities to drugs; but so far over fifty persons have used dextran sulfate under the close observation of private-practice physicians we have contacted, apparently without any serious problems. A common side effect is loss of appetite and a feeling of fullness; occasionally there is a minor rash.
Even persons allergic to sulfa drugs can apparently use dextran sulfate (Gingell, 1987).
* Dextran sulfate is being studied by Donald Abrams, M.D. at San Francisco General Hospital--the only official trial anywhere of dextran sulfate for persons with AIDS or ARC--and recently was put in the highest priority category for research by NIH. Abrams' study has not reported on efficacy, as it is a "phase I" dosage and toxicity trial, but it has not had any safety problems yet, even at doses higher than people are using for AIDS or ARC.
* The limited, anecdotal information we have on use of dextran sulfate for AIDS or ARC looks very good at this time.
* The drug is taken by mouth, and is not expensive.
* It is more or less available today. The case against dextran sulfate is:
* The fact that something works in the laboratory does not mean it works in humans.
* No formal clinical trial has yet been done to prove whether or not dextran sulfate works.
* We only have anecdotal information on a few people who have used the drug long enough to see results. The benefits found may have been coincidence; and even if they were real they might not be lasting.
* We do know that dextran sulfate is not the whole answer or the answer for everybody. We know of one person who died of AIDS complications despite having used the treatment for several weeks at least.

AIDS/ARC Experience So Far

Michael J. Scolaro, M.D., a Los Angeles physician very experienced in treating AIDS and ARC, has been following over 30 patients who have obtained dextran sulfate. About 15 of them have used it for at least two months, long enough for results to be seen.
These patients have also used other antivirals, especially low-dose AZT, acyclovir, and AL 721 substitutes. None of the patients on dextran sulfate is using the full dose of AZT. A handful are using only dextran sulfate and acyclovir, because they cannot afford AL 721 and cannot tolerate AZT; they are also doing well.
Dr. Scolaro has found that at least 60 percent of the patients who have used dextran sulfate for at least two months
have shown dramatic improvement in laboratory tests and clinical well being. Often T-helper cells have doubled, from 300 to 700 or more, from 400 or 450 to 900.
For patients with less than 100 T-helper cells, however, he has not seen increases in the numbers, so he counsels these persons not to look only at numbers but also look at clinical effectiveness. Are they feeling well, avoiding new opportunistic infections, and responding well to treatment for pre-existing ones?
Dr. Scolaro's first patient who used dextran sulfate, seen in August of 1987, "was literally preterminal, with advanced
neuropathy, mycobacterium avium, CMV retinitis, and he was semicomatose". He was on a number of drugs, including large doses of acyclovir, glucocorticoids, and several anti-MAI treatments, but not including AZT. "He is now not only alive and walking and talking, he walks with a walker, he had almost a complete regression of his peripheral neuropathy, a magnificent return of cerebral function, has gained about 65 pounds." Dr. Scolaro explained that he could not necessarily attribute the improvement to dextran sulfate, but that he and another physician on the case were impressed and felt that this drug may have been the key element that made a difference, in combination with the
other drugs.
Recently Dr. Scolaro had another case much like this one. But despite great improvement so far it is still too early to be sure the second person will survive.
Dr. Scolaro does not see dextran sulfate as proven. "It's exciting, I think it's promising, I think it's premature to be
able to say that it's going to be the answer. I don't know that it works in vivo by itself; the in vitro studies showed that
Ueno's compound did not suppress HIV by 100 percent; the exciting thing was the synergistic effect...
"I have to say that from my perspective and my observation now over the last four to five years, that I have not found a
compound that seems to thus far be doing things so quickly. Not even AZT did that. I had very few patients who had a dramatic rise in T-4 counts. And even when there was a rise it was not sustained. In fairness to what we're doing now, I don't know that the rises in cell counts are going to be sustained with dextran."
We talked to Fred Ponder, a partner and business manager of Dr. Alan Levin's Positive Action Healthcare in San Francisco (see Sentinel January 1, 1988); Mr. Ponder has computerized the patient data. About 20 patients at the clinic are using dextran sulfate now, five of them for two months. These five are also using transfer factor; four of them are asymptomatic seropositive, one has AIDS. Only one of the five is on AZT.
All five who have used dextran sulfate for at least two months have improved. One went from 500 T-helper cells and
falling to over 800; he was negative for P-24 antigen all along. Another went negative on the P-24 antigen, after being a high positive for several months. Two others had improved T-cell counts. The person with AIDS went to over 400 T-helper cells for the first time in a year.
Another clinical researcher, however, failed to get results with dextran sulfate. He tested only three patients, one with
ARC and two asymptomatic seropositive. He found no change in the P-24 antigen or in reverse transcriptase levels. But he used less than the usual dose--1600 mg per day vs the more common 2100 mg for a person of average weight. And he had to stop the study after only a month, apparently because of pressure from his institution.
Our impression from interviews so far is that most of the people who are getting good results are using frequent doses of dextran sulfate--usually every four hours. Some do and some do not include the middle of the night dose. Almost all are combining dextran sulfate with other antivirals, especially acyclovir, and often low-dose AZT and/or AL 721 in addition.

Precautions and Safety

The usual anti-AIDS dose is two to three times higher than the standard clinical dose in Japan. But animal studies suggest that there is a large safety range, with the lethal dose over one hundred times the AIDS dose (see below). And long-term studies have found no harm in human use of the doses commonly used for AIDS (Gingell, 1987).
Dextran sulfate has an anticoagulant effect so theoretically it could cause bleeding problems; we have not heard of any problems, however, and some studies have failed to find any effect on coagulation. But to be safe, the literature for
physicians recommends coagulation tests. (See other precautions below.)
The clinical trial at San Francisco General Hospital requires subjects to have acceptable values on various blood,
kidney, liver, and other tests, and to avoid aspirin during the trial, presumably to help guard against any bleeding problems. There are many exclusion criteria and restrictions; some may be for safety, others to make it easier to interpret the results of the trial.
An anonymous "underground" instruction sheet has the following safety section:
"Cautions/Side Effects: Before starting dextran sulfate, make sure from your doctor that your kidneys and platelets are
okay. Otherwise there could be some very extreme problems with bleeding.
"There are two nuisance side effects which can occur with dextran sulfate. One is a mild loss of appetite, the other is
mild diarrhea..." ("Dear Dextran User", unsigned.) The Appendix, below, includes a translation of portions of
the Japanese equivalent of the Physician's Desk Reference. It gives recommended safety precautions, but it was written for other uses, not treatment for AIDS or ARC.
Note that this article (including the Appendix) does NOT contain complete safety precautions, nor instructions for use.
The dextran sulfate situation is moving so rapidly that any detailed instructions could be obsolete very quickly. Instructions for use, including safety precautions, will continue to evolve as more information becomes available. Check with treatment organizations such as buyers' clubs or Project Inform (see below), or with any source from which you obtain dextran sulfate, to get the latest information. And let your physician know about any treatment you plan to use, in case he or she knows about any new dangers or precautions.

Availability

So far most people have obtained dextran sulfate by going to Japan, or knowing someone who lives there or travels there. But more convenient sources are developing.
The interest in this treatment is so new and growing so rapidly that we can give few specifics, as information changes as soon as it is written. To find out about getting dextran sulfate, we suggest the following:
* You physician might be able to help--although few are familiar with dextran sulfate at this time.
* Check with friends, support groups, or buyers clubs.
* If you cannot find information locally, check with Project Inform in San Francisco; see phone numbers below.
In Canada, dextran sulfate is available from Dextran Products Limited (a subsidiary of Polydex Pharmaceuticals), near Toronto. It is sold for investigational use. Persons must pick it up in Toronto, as the company cannot ship it to the U.S.; the minimum order is $500. For more information call George Usher or Mr. Patel, (416) 755-2231.
Dextran sulfate may also be available from a Mexican company, Medicina Del Futuro, which can be reached in the U.S. at (619) 229-3019. This number is an answering service, so someone will have to call you back. It is our understanding that the company was unable to arrange purchase from Japan, and may have the product manufactured in Mexico instead.
Nutricology Inc. in San Leandro, CA may carry the Polydex product; for more information call (800) 545-9960.

Quality Control

There are many different forms of the chemical "dextran sulfate". The right kind has a molecular weight of 7000-8000 and a sulfur content of 17-20 percent (Ueno and Kuno, June 1987). For use by mouth, dextran sulfate must be "enteric coated", prepared so that it will pass through the stomach and dissolve in the intestines, because the stomach acidity would destroy it. Most dextran sulfate for human use comes as coated tablets; but some has been enteric coated as individual granules, which can be placed in ordinary capsules for use.
Japan appears to be the only country where dextran sulfate has been used as a drug. Because it has been available there without a prescription for 20 years, companies have much experience in manufacturing it for human use. Fifteen different Japanese suppliers are listed below. As far as we know, all of them supply the right kind of dextran sulfate, with good quality control. So far, most people have been using the Kowa tablets.
The Canadian company has much experience in making dextran sulfate, but has not provided enteric coating until now. On the Mexican product, we do not yet have information on quality because we do not know who is doing the manufacturing.
All the knowledgeable people we have talked to trust the Japanese products. But most think there should be independent testing of any others before they come into widespread use. The HIV-positive buyers clubs have experience in testing other products, such as AL 721 substitutes, and some of them are investigating how to test dextran sulfate properly.

Price

The retail price is about $1. per gram or a little more. Therefore the cost of using this treatment will be in the range
of $2. to $3. per day for a person of average weight.

APPENDIX:
Dextran Sulfate Information From the Japanese Equivalent of Physician's Desk Reference

(NOTE: We have translated the main points, not the full text. Our comments are in parentheses.)
Indication: Hyperlipidemia
Caution:
* While using, administer coagulation tests.
* Don't use on anyone with a tendency to hemorrhage.
* Don't use if severe renal problems.
* Note synergistic effect with mitomycin, a cancer drug. Interactions with other drugs:
* Administer very carefully when other anticoagulants used.
* Note caution on mitomycin, above.
Side effects:
* Loss of appetite or feeling of bloating (most common side effect, found in 3.5 percent of patients in one study).
* Diarrhea.
* Occasional skin rash.
* In IV injections, dizziness can occur.
* In IV injections, shock can occur; stop therapy.
Dose (antilipemic) 450-900 mg per day in 3-4 doses. (Note that HIV doses are higher, about 30 mg per kilogram per day -- somewhat more than 2000 mg for a person of average weight.)
The IV form is available from Kowa for when the oral form cannot be administered or is not effective.
Store at room temperature below 25 degrees C, in low humidity, away from light.
Actions:
* Antilipemic
* Anticoagulant
* Antiplatelet activity
* Effective for arteriosclerosis in humans
Toxicity tests:
* Lethal dose in animals, about 4300 mg/Kg--(about 140 times the AIDS/ARC dose).
* Long-term toxicity test in rats at 1019-1209 mg/Kg found higher rate of growths in mucosal lining of lower intestines and
rectum than controls.
Absorption, distribution, and elimination:
* Short half life, 25 minutes when injected in marmots. (Presumably the medicine would last longer in oral use, due to
time taken for absorption.)
* Studies with radioactive markers showed distribution primarily in the liver, lungs, bone marrow, muscles, and brain.
The Japanese PDR includes technical details on many of the points listed above.

Brand Names and Suppliers

The Kowa product comes in two forms: "MDS Kowa T" and "MDS Kowa A". The "T" form is correct; the "A" form (ampules prepared for intravenous use) has the wrong sulfur content, three to six percent.)

BRAND NAME TABLET SIZE, mg PHARMACEUTICAL COMPANY

Asuro 150 Nippon Kayaku
Emstlan 300 Towa Yakuhin
MDS 150, 300 Kowa
Colyonal 300 Mochida
Shanbird 150 Tsuruhara
Smedon 150 Meiji
DSS 150 Fujimoto
Dexpepe 150, 300 Toho
Dexul 150, 300 Sawai
Destromyde 150, 300 Kanebo
Tokistornin 150 Mekuto
Dolomezan 150, 300 Taiyo Yakuhin
Bicibon 150, 300 Toyama Kagaku
Maleton 150 Takeza
Ripoferol 300 Nichii

(Usually the brand name, above, appears once in Roman letters on the box or in the package insert which comes with it. The molecular weight and sulfur content should also be legible to those who do not read Japanese.)
ACKNOWLEDGEMENT: Jim Palazzolo, a professional Japanese translator in San Francisco, obtained the Japanese PDR section on dextran sulfate and translated this information for us.

References

Berenbaum, Morris C. Anti-HIV Synergy between Dextran Sulphate and Zidovudine. The Lancet p. 461, August 22, 1987.
Gingell, Barry. Dextran Sulfate -- an Exciting New Drug. Treatment Issues (GMHC, New York) p. 5, December 31, 1987.
Ito, M and others. Inhibitory Effect of Dextran Sulfate and Heparin On the Replication Of Human Immunodeficiency Virus (HIV)
In Vitro. Antiviral Research p 361-367, July 1987. Ueno, R and Kuno, S. Dextran Sulphate, a Potent Anti-HIV
Agent In Vitro Having Synergism With Zidovudine. The Lancet p. 1379, June 13, 1987.
Ueno, R and Kuno, S. Anti-HIV Synergism Between Dextran Sulphate and Zidovudine. The Lancet p. 796-797, October 3, 1987.

For More Information

For an information sheet about dextran sulfate, persons can call Project Inform at (800) 334-7422 in California, (800) 822- 7422 from other states, or (415) 928-0293 from anywhere. Also, check with local buyers' clubs, such as Healing Alternatives in San Francisco at (415) 626-2316, or the PWA Health Group in New York at (212) 995-5846.