Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF INFLAMMATORY DERMATOSES COMPRISING ERYTHROMYCIN OR
CLARYTHROMYCIN,
METRONIDAZOLE AND A GASTROINTESTINAL HYDROGEN PUMP INHIBITOR
Field of the Invention
The present invention relates to the treatment of skin
conditions such as rosacea and similar inflammatory
dermatoses, and in particular to the treatment of certain
kinds of rosacea, and also perioral papular and pustular
acne, and other papulopustular dermatoses.
Background to the Invention
Rosacea is a chronic inflammatory disease which
affects the face. It is characterised by episodic
flushing, erythema, and telangiectasia affecting the
cheeks, chin, forehead, and nose. It may be further
complicated by inflammatory swelling, papules and pustules.
It is observed more frequently in women than in men, with
an age of onset between 30 and 50, most commonly in those
of Celtic or northern European descent.
Current treatments of rosacea include long-term the
use of systemic or topical antibiotics, such as
tetracycline, minocycline, doxicycline, erythromycin and
metronidazole. However, such treatments are ineffective in
achieving eradication of the condition, even for relatively
short periods of time.
Many theories have been proposed to explain the
aetiology of rosacea, with a view to finding alternative
treatments thereof. An association with gastrointestinal
disease has been considered as long ago as 1920 when
achlorhdria and hypochlorohydria were thought to be
predisposing factors. However, attempts to confirm such an
association have been unsuccessful. Hypersensitivity to
Demodex folliculorum, a mite which inhabits the facial
pilosebaceous follicle, has also been postulated to be of
relevance, and increased numbers of Demodex mites have been
demonstrated in rosacea.
The association between rosacea and gastrointestinal
disease has been revisited since the discovery that the
Gram-negative bacterium Helicobacter pylori (H.Pylori) is
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the cause of gastritis and duodenal ulcer disease. Based
on case-series studies of rosacea, several authors have
reported higher than expected H. pylori seroprevalance and
antibody titres, and have commented on improvement in the
dermatological condition following H. pylori eradication
therapy; see Rebora et al, Dermatology (1995) 89:1603-1604,
Kolibasora et al, Archives of Dermatology (1996) 132:1393,
and Utas et al, J.AM.Acad. Dermatology (1999) 40:433-435.
Yet none of these studies employed proper controls for
their results to be considered meaningful. Furthermore, a
number of other studies have failed to confirm the alleged
relationship between H.Pylori and rosacea; see Jones et a1,
Archives of Dermatology (1998) 134:511, and Bamford et al,
Archives of Dermatology (1999) 135:659-663.
The situation in this respect, therefore, remains
conflicting and unclear, as does the cause of this common,
yet poorly understood, facial dermatosis.
Summary of the Invention
Surprisingly, and as a result of case-controlled
studies, we have now found that rosacea and similar
inflammatory skin dermatoses can be effectively treated by
administering to a patient a treatment regime comprising i)
erythromycin, clarithromycin or an analogue or derivative
thereof, ii) metronidazole or an analogue or derivative
thereof, and iii) a gastrointestinal hydrogen pump
inhibitor, such as omeprazole or an analogue or derivative
thereof. The three drugs may be formulated for
simultaneous, separate or sequential use.
These studies have also lead us to believe that the
different signs of rosacea expressed by patients may in
fact have different causes, and may not be linked to one
another. For some time, it has beers believed that the
different signs of rosacea are merely symptomatic of
different, progressive, stages of the same general
condition. Specifically, it has been suggested that the
seemingly lesser signs of inflammatory rosacea (erythema
and telangiectasis) progress to lesions and/or
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papulopustular signs (pimples on the skin). We believe
that this may not be true, as patients have been observed
to exhibit either inflammatory signs or papulopustular
signs. Instead, the different signs may represent distinct
types of rosacea.
While the triple drug combination described above is
useful in treating rosacea as a generality, we have
discovered that it is particularly useful in the treatment
of papulopustular rosacea, perioral dermatitis (perioral
rosacea), and perioral pustular or papular acne.
At present, it is not understood how the triple drug
combination according to the present invention functions in
achieving the desired results. One possibility is that
there may be a causal relationship between the dermatoses
to be treated and H.pylori, such that eradication of
H.pylori may lead to resolution of these dermatoses.
Another possibility is that as, in certain instances, the
presence of H.pylori has been found in pustules on the
skin, the triple drug combination may act directly to
eradicate that external form of H.pylori. Yet another
possibility is that the triple drug combination works in
another manner, such that any apparent relationship between
its use in the present invention and H.pylori may simply be
coincidental, such that further study will be necessary
elucidate its precise mode of action.
Description of the Invention
The preferred treatment regime comprises erythromycin
or clarithromycin, metronidazole and omeprazole, and the
most preferred treatment regime comprises clarithromycin,
metronidazole and omeprazole. As mentioned above, however
analogues or derivatives of any of these drugs may be used
provided that their combined administration achieves the
desired result. For instance, another similar-acting
macrolide antibiotic to erythromycin or clarithromycin may
be used, for instance azithromycin or dirithromycin.
Similarly, lanzoprazole or any other drug which acts to
inhibits a gastrointestinal hydrogen pump, may be used
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instead of omeprazole. Additionally, other drugs may be
useful which have a similar or equivalent pharmacological
mode of action to the drugs named above. Pharmaceutically-
acceptable salt forms of the drugs may also be used.
Treatment may be by administration of the three drugs
by any suitable means. Conveniently, however, the three
drugs will be administered by one or a combination of oral
administration, topical application to a patient's skin, or
parenteral administration, e.g. intravenous, intramuscular
or subcutaneous administration. For instance, one or more
of the three drugs may be formulated for administration by
a different route to the other drug(s). Typically, it is
desirable to administer omeprazole or an analogue thereof
orally, but the other drugs may be formulated for oral,
topical or parenteral administration, or any combination
thereof. For instance, it may be preferred to administer
omeprazole orally and the other two drugs topically,
optionally as a combined topical formulation.
If the triple drug combination is to be administered
orally, it may take the form of separate pills containing
each of the separate drugs, for simultaneous, separate or
sequential administration. Preferably, however, the three
drugs will be combined into a single dosage form,
preferably a tablet, capsule or linctus, for patient
convenience. In the case of topical or parenteral
administration, the drugs are incorporated into a suitable
pharmaceutically-acceptable carrier. Such formulations
have not been disclosed in the prior art, and constitute
further aspects of the claimed invention.
The relative proportions of the three drugs necessary
for effective treatment may vary depending on the route of
administration, and the particular patient to be treated.
Typically, however, a patient will receive 200 to 600 mg,
preferably 300 to 500 mg of erythromycin, clarithromycin or
an analogue thereof, 200 to 500 mg, preferably 300 to 500
mg, metronidazole, and 10 to 100 mg, preferably 20 to 60
mg, omeprazole, on a daily basis. A particularly preferred
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treatment regime, however, comprises about 250 mg
erythromycin, clarithromycin or an analogue thereof, about
400 mg metronidazole and about 20 mg omeprazole. Treatment
periods vary from patient to patient, from one week to a
5 number of years.
The results upon which the present invention are based
are summarised in the following example.
Example
42 patients with rosacea and evidence of infection
with H.pylori were studied. At week 0, an initial
assessment of the severity of each of the patient's skin
disease was made, using the so-called "Coventry Scoring
System"; see Br. J. Derm. (1995) 133, Suppl. 45, 34. This
scoring system, developed in the Dermatology Department at
Walsgrave Hospital, Coventry, UK, measures the severity of
rosacea in five different facial areas and for six
different parameters. The different facial areas are
depicted in Figure 1, below. The different parameters are
erythema, telangiectasia, papules, pustules, oedema and
scaling. For each parameter in each area, a score of one
is given if less than half the area involved is affected by
that parameter, and a score of two if half or more of the
area is affected. The scores for the different parameters
in the different facial areas are added together to give a
total score for the patient.
Each patient was subjected to clinical photography,
and then treated with an oral dosage of 20 mg omeprazole,
400 mg metronidazole, and 250 mg clarithromycin for one
week. Disease severity scoring and clinical photography
were repeated at the end of weeks 6, 12, 18, and 24, and
fourteen patients were followed for a period of 52 weeks.
At week 0 the mean severity score was 10 (range 3-24) .
Following treatment, at week 6 the mean score had fallen to
5.8 (range 2-12) , falling further to 4.6 (range 2-8) at
week 12. At weeks 18 and 24 the mean severity scores were
4.5 (range 2-12) and 5.6 (range 2-14) respectively. There
was a significant difference between scores at week 0 and
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weeks 6 and 12 (p<0.0001), and also between scores at week
0 and weeks 18, and 24 (p<0.001). Five relapses were
recorded, one at week 18 and four at week 24, with rosacea
severity scores returning to values seen at week 0.
The study demonstrates that the combined treatment of
omeprazole, metronidazole and clarithromycin was effective
in the treatment of symptoms associated with rosacea in
general. It was noted in particular that the treatment
significantly reduced papules and/or pustules on patients'
faces .
While the study treated patients with evidence of
infection with H.pylori, because a causal relationship
between successful treatment of rosacea and eradication of
H.pylori is yet to be confirmed, it is believed that the
triple drug combination of the present invention may be
useful in the treatment of patients who are not infected
with H.pylori.
