Hypericin, February 1992

Hypericin is an antiviral found in small amounts in a plant (St.
John's wort, a medicinal herb) and also synthesized chemically. It has
shown activity against HIV in laboratory tests, and against other
retroviruses in animal tests; in addition, laboratory tests and some
human anecdotal reports have suggested broad-spectrum activity against a
number of other disease-causing viruses. But hypericin also has an
important side effect -- large doses cause phototoxicity, or abnormal
sensitivity to sunlight and other strong light, especially in people
with light skin. The key medical question at this time is whether it
will be possible to administer large enough doses of hypericin to be
useful for treating HIV and/or other viruses. There are also concerns
about whether enough resources are available to quickly determine the
best uses and ultimate value of this potentially important treatment.
AIDS TREATMENT NEWS has covered hypericin for over three years,
starting with issue #63, August 26, 1988; for technical background and
references, see AIDS TREATMENT NEWS #125, April 19, 1991. Last November
we reported the beginning of the first clinical trial of pure hypericin,
in three cities (issue #138, November 1, 1991).
The Current Clinical Trial
This trial, at New York University in New York City, Beth Israel
Hospital in Boston, and the University of Minnesota in Minneapolis, has
been stopped temporarily after significant phototoxicity developed at
the second dose being tested. This study had set out to enter eight
patients at each of four different doses, adjusted by body weight; the
doses were 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg, taken twice
per week. (Even the lowest dose is much higher than that from the St.
John's wort extracts which have previously been available in buyers'
clubs and health-food stores, which have contained little hypericin,
usually providing a fraction of a milligram per dose.) And the hypericin
in the trial was given intravenously, even though the drug is expected
to be used orally in practice; intravenous administration is preferred
in early trials in order to obtain better scientific data.
At the 0.5 mg dose, most if not all of the study volunteers with
white skin had phototoxicity which was severe enough that they had to
drop out of the trial. They had skin rashes and irritation, and some
were unable to go outdoors. But according to Fred Valentine, M. D.,
principal investigator of the study at New York University, there was no
sign of any systemic toxicity -- and all the problems which did occur
were temporary, going away after the drug was stopped. And one
volunteer, who is Black, had less severe problems; apparently the
pigment in his skin protected him against some of the phototoxicity by
preventing light from reaching deeper layers of the skin.
No information is yet available about whether the lowest dose
tested, which could be tolerated by most patients, showed any signs of
efficacy.
This early trial also collected information about hypericin's
pharmacokinetics (how long the drug lasted in the body). The half- life
of hypericin in the blood was found to be about 25 hours, which was less
than had been expected from studies in monkeys. Therefore it may be
necessary to give the drug more often than twice a week to maintain
blood levels. Also, more frequent but lower doses may reduce toxicity by
reducing peak blood levels.
At this time, the researchers have applied to the U. S. Food and
Drug Administration for permission to change the dosing of the drug, to
give lower amounts three times per week; they also want to recruit
volunteers with very dark skin, since they may be much less affected by
the phototoxicity. Also, the National Institute of Allergy and
Infectious Diseases (NIAID), which is supporting the current trial, has
contracted with the University of Iowa to produce an oral formulation of
the drug, perhaps a time-release version to avoid peak concentrations
and reduce possible toxicity.
The current status of hypericin, then, is that the drug could be
successful if any one or more of the following are true:
(1) The drug might be useful even in the 0.25 mg/kg dose (which can
usually be tolerated) -- either alone or in combination;
(2) If not, then it may be possible to administer higher doses by
reformulating the drug, changing the schedule of administration, or
providing better protection against sunlight;
(3) Even if hypericin turns out not to be useful for everybody, it
might still be effective for persons with dark skin; and
(4) In addition, hypericin may be effective against other viruses,
possibly in lower doses than would be required for treatment of HIV.
Other Viruses
At this time there is scientific and community interest in the
possible usefulness of hypericin for treating at least four other
viruses, listed below. But little information is available at this
time, so these possible applications of the drug must be considered
speculative.
(1) Hepatitis B. This possible use was noticed by accident during
an earlier hypericin trial, by the Community Research Initiative in New
York using low doses of the drug from a widely-available St. John's wort
plant extract. Because of an earlier report that hypericin might have
liver toxicity -- now believed to have been a false alarm -- liver
function tests were being watched very carefully. When apparent
improvements were seen in persons who had hepatitis, others who heard
about the result tried treating themselves for that condition. At this
time there seem to be about ten reports of apparent improvement. We are
checking further into this possibility.
(2) Cytomegalovirus (CMV). Laboratory tests have found antiviral
activity against murine CMV, which is related to but not identical to
human CMV. Now that hypericin is becoming available in larger doses than
before, it should be tested as a CMV treatment.
(3) Influenza. Both laboratory and anecdotal reports suggest the
possibility that hypericin might be useful in treating this infection.
(4) Human papillomavirus. One person in the current hypericin
trial had an unexpected improvement in warts caused by this virus.
We want to emphasize that these possibilities are leads for future
research, and based on very little information at this time. On the
other hand, this list is not complete; over the years laboratory tests
have shown activity of hypericin against a number of viruses. The
chemical may have other uses which have not yet been considered or
tested. Future Development
There is widespread concern that the development of hypericin,
which has been seriously delayed in the past, may wait again -- this
time until the chemically synthesized drug is reformulated and tested
for oral use. The developer, VIMRx Pharmaceuticals Inc. of Stamford,
Connecticut, is a small company with limited resources; fortunately the
AIDS Clinical Trials Group (ACTG) of the U. S. National Institute of
Allergy and Infectious Diseases has been willing to help, but this
agency has little experience in most aspects of drug development, which
has usually been left to private corporations.
Meanwhile, more concentrated hypericin extracts from the St. John's
wort plant are becoming available. The plant extracts are not pure
hypericin, however; they also contain other chemicals from St. John's
wort, which might cause allergic reactions or other adverse effects.
Therefore, large doses should be approached cautiously.
An oral dose of 10 mg of hypericin, taken three times a week, would
approximate the total amount at which phototoxicity began to be seen in
the recent clinical trial with synthetic hypericin. But a number of
people (probably several dozen) have been using 10 mg per day or more of
hypericins extracted from the St. John's wort plant -- taken orally --
with very few adverse reports. According to Pacific BioLogic in
Oakland, California, which produces the concentrated extract, there has
been one case of severe sunburn, after half an hour exposure to the sun
without protection, and a few cases of diarrhea. It is possible that
these larger oral doses were tolerated because the hypericin is only
partly absorbed from the digestive system; in the clinical trial, by
contrast, the hypericin was given intravenously, so all of it reached
the bloodstream immediately. Keep in mind that anyone using
concentrated hypericin, no matter how it is taken, should avoid
sunlight, by using good sunscreen and a hat and other protective
clothing, or by staying indoors, until at least several days after the
last dose is used.
Comment
Instead of just waiting indefinitely for results of future trials,
the AIDS community is experimenting with more concentrated hypericin
extracts, to see what can be learned from practical experience with the
treatment. It is clear that scientific trials produce the most reliable
information; but the modern approach of controlled trials is a recent
innovation, which largely developed in the last three or four decades.
Until then, all drugs throughout history were developed through clinical
experience. When the mainstream drug-development system fails (for
whatever reason) to meet the needs of the current emergency, we should
not abandon clinical experience as a first step in drug development.
Modern viral-burden tests, data collection and analysis techniques,
and other scientific methods can work together with clinical experience
to make possible smaller, cleaner, faster, and more focused treatment
trials than we have usually seen in the past.
Recent Technical References
Our last major hypericin article, "Hypericin Update," in AIDS
TREATMENT NEWS #125, April 19, 1991, listed 18 technical references for
background on antiviral uses of hypericin. The following 1991 and 1992
references were not included in that list:
Anderson DO, Weber ND, Wood SG, Hughes BG, Murray BK, and North JA. In
vitro virucidal activity of selected anthraquinones and anthraquinone
derivatives. ANTIVIRAL RESEARCH 1991: volume 16, number 2, pages 185-
196.
Barnard DL, Huffman JH, Morris JLB, Wood SG, Hughes BG, and Sidwell RW.
Evaluation of the antiviral activity of anthraquinones, anthrones and
anthraquinone derivatives against human cytomegalovirus. ANTIVIRAL
RESEARCH 1992: volume 17, number 1, pages 63-77.
Davis C. HIV-specific treatment. DERMATOL. CLIN. (USA) 1991: volume 9
number 3, pages 585-596.
Dressler S. Alternative therapies in the treatment of HIV infections
[translation of German title]. THERAPIEWOCHE 1992: volume 42, number 1-
2, pages 34-37.
Dresser S. Antiretroviral therapy for AIDS infection [translation of
German title]. Zeitschrift fuer Klinische MEDIZINE 1991: volume 46,
number 20, pages 1405-1415.
Hudson JB, Lopez-Bazzocchi I, and Towers GHN. Antiviral activities of
hypericin. ANTIVIRAL RESEARCH 1991: volume 15, number 2, pages 101-
112.
Liebes L, Mazur Y, Freeman D and others. A method for the quantitation
of hypericin, an antiviral agent, in biological fluids by high-
performance liquid chromatography. ANALYTICAL BIOCHEMISTRY 1991:
volume 195, number 1, pages 77-85.
Meier B. The extraction strength of ethanol/water mixtures commonly used
for the processing of herbal drugs. PLANTA MEDICA 1991: volume 57,
supplement 2, pages A26-A27.
Mitsuya H, Yarchoan R, Kageyama S, and Broder S. Targeted therapy of
human immunodeficiency virus-related disease. FASEB JOURNAL 1991:
volume 5, number 10, pages 2369-2381.
Stock S. and Holzl J. Pharmacokinetic test of (14C)-labelled hypericin
and pseudohypericin from Hypericum perforatum and serum kinetics of
hypericin in man. PLANTA MEDICA 1991: volume 57, supplement 2, pages
A61-A62.
Vlietinck AJ and Vanden Berghe DA. Can ethnopharmacology contribute to
the development of antiviral drugs? JOURNAL OF ETHNOPHARMACOLOGY 1991:
volume 32, number 1-3, pages 141- 153.
Weiser D. Pharmacokinetics of hypericin after oral administration of St.
John's extract. [English translation of German title.] NERVENHEILKUNDE
1991: volume 10, number 7, pages A17-18.