- Quinacrine and Chlorpromazine May Be Active against vCJD
Prions
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- Scientists in America have given details of the drugs
that have been used to treat a young English woman thought to have variant
Creutzfeldt-Jakob disease [abbreviated as vCJD or CJD (new var.) in ProMED-mail].
The young woman from Merseyside was given just a year to live when she
was diagnosed with suspected [variant] CJD in June, but after treatment
in America she showed significant improvement. However, the US scientists
said that a second patient given the drugs showed no signs of improvement
[and treatment was discontinued].
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- A Department of Health spokesman said that the UK government
had been in touch with the American team and would consider funding research
and setting up a clinical trial. He added that the families of 6 other
living British sufferers of the disease would be informed of the American
treatment. But he sounded a note of caution about the drugs involved, which
are currently used to treat patients with malaria and psychosis. The drugs
are quinacrine, used to treat malaria, and chlorpromazine, which is given
to patients with schizophrenia and other psychotic conditions. Tests on
mice found that both prevented prion molecules from changing into the form
linked with vCJD, which destroys the brain. Critically, both are able to
penetrate the blood-brain barrier - a natural "wall" put up by
the body to stop toxic substances entering the brain.
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- The US team is led by Professor Stanley Prusiner, who
won the 1997 Nobel prize for medicine for his work on prions -- the infectious
protein agents thought to cause brain diseases such as BSE and CJD. A paper
describing this research will be published in the Proceedings of the National
Academy of Sciences.
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- -- ProMED-mail <promed@promedmail.org
-
- [Later news bulletins from the BBC have emphasized caution
in interpretation of these initial reports. Nonetheless, rapid progress
is being made in this field of research. Recently Ebari, Flechsig and Weissmann
(Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 16, 9295-9299, July 31, 2001)
reported another significant observation relevant to the treatment of prion-related
disease. Enari et al. found that exposure of mouse scrapie-infected neuroblastoma
cells to phosphatidylinositol-specific phospholipase C or to a monoclonal
anti-prion protein antibody (6H4) both cured chronically infected cells
and prevented infection of susceptible cells. Their experiments indicated
that the level of the scrapie prion in infected cells is determined by
a steady state equilibrium between degradation and formation, and that
depletion of the normal cellular form of the prion protein can interrupt
propagation of the aberrant scrapie prion form. They suggest that passive
immunisation may provide a therapeutic approach to prion-related disease.
- Mod.CP]
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- ******
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- 2) Date: Tue 14 Aug 2001 18:53:31 -0400 (EDT) From: Jay
Lieberman <jmlieberman@pol.net Source: Reuters Health Online, Tue 14
Aug 2001 [edited]
-
- Acridine and phenothiazine derivatives inhibit the formation
of pathogenic prion proteins and may even enhance their clearance from
infected cells, investigators at the University of California at San Francisco
report in the August 14th issue of the Proceedings of the National Academy
of Sciences.
-
- Dr. Stanley B. Prusiner and colleagues screened drugs
known to penetrate the blood-brain barrier for their ability to inhibit
pathogenic prion formation. They used as their model cultured neuroblastoma
cells chronically infected with scrapie prions.
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- Chlorpromazine, promazine, and acepromazine at concentrations
of 2-10 micromolar caused disappearance of the protein after 6-day treatments.
The antimalarial agent quinacrine, a structural antecedent of the phenothiazines,
was effective at doses as low as 200 nM.
-
- What the inhibitors all had in common was a tricyclic
structure with an aliphatic side chain extending from the middle ring moiety.
Furthermore, since phenazine and phenothiazine did not act as prion inhibitors,
the tricyclic scaffold alone must not be sufficient for antiprion activity,
the researchers add.
-
- Dr. Prusiner's team believes that quinacrine could be
an immediate candidate for the treatment of patients dying of prion diseases.
Even though less potent, the investigators posit that phenothiazines may
be even more effective than quinacrine if they cross the blood brain barrier
more efficiently. Another option would be use of the 2 types of drugs in
combination.
-
- Dr. R. Anthony Williamson, of the Scripps Research Institute
in La Jolla, California, told Reuters Health, "It's a case of using
well-known drugs for a different application." He continued, "Their
research has the advantage that it's using drugs that have already been
through the Food and Drug Administration approval mechanisms. People know
the pharmacokinetics and the toxicology of the drugs."
-
- A spokesman for the Department of Health in London stressed
that there is currently no way of diagnosing vCJD until after death. This
makes it difficult to be certain the drug is treating the disease and not
another condition with similar symptoms.
-
- Jay M. Lieberman, M.D. Pediatric Infectious Diseases
Miller Children's Hospital Long Beach, CA <jmlieberman@pol.net
-
- [The reference to the paper cited in the above report
is the following: Carsten Korth, Barnaby C. H. May, Fred E. Cohen, and
Stanley B. Prusiner (2001). Acridine and phenothiazine derivatives as pharmacotherapeutics
for prion disease. Proceedings of the Academy of Sciences of the USA. 2001;98
9836-9841 <http://www.pnas.org/cgi/content/abstract/98/17/9836 - Mod.CP]
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