Note: Descriptions are shown in the official language in which they were submitted.
~O~i3~;
~ his invention relates to impro~ements to drugs contain-
ing as an active substance the 5-methoxypsoralene of for~
mula: OCH3
~0
French Patent No 77.31719 filed on octo~er 21, 1977 in
the name of the present Applicant disclosed these new drugs
as having a very high therapeutic index due to the very low
toxicity of 5-methoxypsoralene compared to that of other
psoralenes. The patent made clear that one could use
therapeutic doses o~ 5-methoxypsoralene up to five times
greater than those used for the 8-methoxypsoralene and
advocated the administration of oral doses of 20 mg to 300
mg of 5-methoxypsoralene per day, followed by a daily
exposure to A ultraviolets, at a rate of 1.5 to 10 joulest
cm2 .
For topical administration, the patent advocated 5-
methoxypsoralene concentrations between 100 ppm and 1000
ppm. The experimentations of the therapeutical activity of
the new drugs had been carried out in the treatment of
psoriasis, vitiligo, atypical eczema and mycosis fungoides.
It should be recalled here that the mycosis fungoides
is a weli known skin cancer of the lymphoma type, that is
characterized by the proliferation of the lymphocyte cells
more present in the lymph, that is the interstitial liquid
irrigating notably the dermis and epidermis.
The clinical experimentations which resulted in Patent
No 77 31719 had been of course applied both on patients
affected with psoriasis and patients affected with skin
- 35 ~ `
~l~
cancer, since one and the other of said illnesses are
characterized by a more rapid than normal proliferation
phenomenon of the cutaneous cells. Such a phenomenon of a
too rapid proliferation of the cells is at the level of the
deoxyribonucleic acid molecule present in the cell nucleus.
But it is known that the 5-methoxypsoralene, under the
energetic action of a UV.A radiation gets fixed on each of
the two helixes of the DNA molecule and therefore blocks
any transmission of the message along said helixes, thereby
stopping altogether the proteine synthesis and the cellular
multiplication. In the normal cells, said blocking of the
DNA helixes is cought up in speed by the DNA self-repair
phenomena either by excision or by replication.
But in the case of cells affected with psoriasis or
cancer, that is cells where the multiplication phenomena
are very accelerated, the self-repair systems do not have
time to set to work. In the same cells however the psoralene,
by forming bridges between the two DNA helixes, stops the
anarchical cellular multiplication. This explains that the
5-methoxypsoralene does not disturb in any way the multi-
plication of the normal cells and blocks selectively the
diseased cells with accelerated proliferation which are the
psoriatic cells and the cancerous cells.
After the satisfactory results obtained with the treat-
ment of the mycosis fungoides lymphoma (cancer of the lymphcells) by administration of 5-methoxypsoralene and UV.A
exposure, the Applicant had the idea of carrying on with
investigations on other types of cancers~or pre-cancerous
lesions of the skin, that is proliferation tumours of the
3~ epidermic cells and no more the proliferation of the cells
of the interstitial liquid such as the baso-cellular
epithelioma, the spino-cellular epitheliolna, the Hutchinson
freckles, the actinic hyperkeratosis, the cutaneous mela-
nomas, etc.
Such an idea was contrary to the well established
general preconceived idea that the therapy associating the
5-methoxypsoralene and the UV.A radiation was totally
inadvisable in the case of epidermal profileration tumours,
~Z05~6
since it was the solar radiation which was producing such
tumours.
It is therefore quite unexpectedly that the Applicant
found out that the 5-methoxypsoralene could heal epidermal
proliferation cancerous tumours when administered under new
and special conditions, notably as regards posology.
The pharmacological activity of the drug was brought to
the fore by topical administration of 5-methoxypsoralene on
mice having cancerous tumours produced by ultraviolets.
It appeared that the 5-methoxypsoralene necessary
concentrations of the topical preparations used were very
high: from 10 to 100 times more than the previously used
concentrations, and this as a function of the excipient.
The general toxicity of the topical preparations having
1,000 to 10,000 ppm of 5-methoxypsoralene has been studied
on the mouse with various excipients, and has shown that
the active substance was well tolerated, even at such high
doses. This corresponds to the fact the 5-methoxypsoralene
is far less toxic than the 8-methoxypsoralene.
For this topical administration of 5-methoxypsoralene,
various carriers have proven satisfactory. The hereafter
examples are given by way of illustrations and are not
limiting:
- the pure petroleum jellies of various viscosities of
the Codex,
- the modified petroleum jellies as the salycilated
petroleum jelly,
- mineral oils,
- vegetable oils, particularly the ethylenic oils
3~ comprising a small number of double bonds,
- lanoline,
- oily continuous phase emulsions,
- alcoholic solutions, etc.
Due to the powerful barrier developped by the cancerous
cells with regards to their environment, and notably the
thickening phenomenon of the cellular membranes, the
penetration of the drug by the topical route is slow and
. difficult.
According to the invention, it has been found that it
was advantageous to introduce in the 5-methoxypsoralene
topical preparation penetration agents such as:
- the isopropyl myristate,
- the dimethyl sulphoxide (DMSO), etc.
The following clinical experimentations have been
carried out with preparations containing 10,000 ppm p~ 5-
methoxypsoralene in pure petroleum jelly.
All volontary patients (a hundred about of them) had
family antecedents and personal antecedents of a skin
cancer. They all had had previously many ablations of skin
cancers, and all the prior trea~emnts had not checked the
formation of recurrent cancers.
The types of cancers or pre-cancerous lesions of these
patients which had been histologically proven were the
following:
- baso-cellular epitheliomas,
- spino-cellular epitheliomas,
- ~utchinson speckles,
2~ - actinic hyperkeratoses.
Some of these patients showed bilateral effects on the
body or lim~s allowing subjecting a lateral area to the
tr~ment and keeping the other as a reference.
~ 11 the patients chosen had otherwise no serious
illness.
All patients have been treated for five weeks in the
following manner:
Twice a week, a pure petroleum jelly based preparation
containing 10,000 ppm of 5-methoxypsoralene was applied on
the tumour and on its sound close periphery (1 to 2 cm
beyond the clinically evaluated limit of the tumour). From
one to three hours after this application, the patient was
subjected to an UY.A exposure with an energy of 5 joules/
cm2 to 10 joules/cm2 (at the end of the treatment) after
3S havin~ re-applied the product a quarter of an hour prior to
the exposure. The irradiation was applied to the whole area
on which had been applied the 5-metlloxypsoralene preparation.
~)53~i
The result~ were ~he followiny: the biopsies carried
out at the end o~ the treatment, that is from the sixth
week and l~ter, showed a total necrosis of the tumour
cancerous cells ~as well as a healiny up of the normal
tissues)
New biopsies were carried out every six months follow-
ing the treatment and showed no sign of recurrent or
residual illness over a period of three years.
The tolerance to the drug and irradiation was perfect,
tO that is without major phototoxic incident causing a prolong-
ated stop of the treatment. Localized actinic erythemas,
rap~dly regressive, appeared on some patients who had a
higher sensibility due mainly to their type of skin.
It should be remarked in this respect that the patients
thus treated with total success had generally types of skin
of the so-called type I, that is particularly Iiable to the
s~in cancers and notably to phototoxic incidents.
In other clinical experimentations on the same types of
e~idermic prolieration tumours, the treatment consisted in
2~ a topical administration of the 5-methoxypsoralen~ with
concentrations of 1,000 to lO,000 ppm, doubled by an oral
administration of tablets containing 5-methoxypsoralene and
a UV.A exposure with an average energy of 5 joules/cm2.
There again the results were spectacular and showed the
total necrosis o~ the cancerous cells.
The daily posology for the oral treatment of the
cancerous tumours can reach 400 to 800 mg of 5-methoxypso-
ralene due to the low toxicity of the latter. It is always
preferable to increase the dosis of active substance rather
than the quantity of energy distributed so that the UV.A
exposure should remain always within the range of 10 jou-
les/cm2 .
In the case of cancerous tumours on the mucous membra-
nes accessible by the natural routes, the treatment such as
hereabove described is directly applicable, being under-
stood that the UV.A radiation is penctrating to the very
depth of the dermis. In the case of inner cancerous tu-
mours, the administration of 5-methoxypsoralene has to be
~os~
followed by an exposure to a more penetrating radiation
with appropriate wave-lengths in order to bring the neces-
sary energy to the deep sites.
