| United States Patent |
6,136,860 |
| Rushton |
October 24, 2000 |
Use of L-lysine in the treatment
of hair loss
Abstract
The use of L-lysine in a composition and method
for the prophylaxis and treatment of telogen effluvium is
provided. A kit is also provided which includes a plurality
of separate containers each containing at least one active
agent useful in a combination therapy for said method.
| Inventors: |
Rushton; David Hugh (Rickmansworth,
GB) |
| Assignee: |
Bio-Scientific Limited
(London, GB) |
| Appl. No.:
|
194998 |
| Filed: |
March 15, 1999 |
| PCT Filed: |
June 6, 1997 |
| PCT NO: |
PCT/GB97/01542 |
| 371 Date: |
March 15, 1999 |
| 102(e) Date: |
March 15, 1999 |
| PCT PUB.NO.:
|
WO97/47276 |
| PCT PUB. Date:
|
December 18, 1997 |
Foreign Application Priority Data
| Current U.S. Class: |
514/561; 424/647;
514/171; 514/185; 514/275; 514/474 |
| Intern'l Class:
|
A61K 031/195 |
| Field of Search:
|
514/171,185,275,561,474
424/647 |
References Cited
U.S. Patent Documents
| 3778502 |
Dec., 1973 |
Aubin et al.. |
|
| 5122369 |
Jun., 1992 |
Dye. |
|
| 5133958 |
Jul., 1992 |
Stuckler. |
|
| 5470876 |
Nov., 1995 |
Proctor. |
|
| Foreign Patent Documents |
| 0327263 |
Aug., 1989 |
EP. |
|
| 0 571 198 |
Nov., 1993 |
EP. |
|
| 0652012 |
May., 1995 |
EP. |
|
| 0 747 035 |
Dec., 1996 |
EP. |
|
| 2 609 393 |
Jul., 1988 |
FR. |
|
| 2 669 224 |
May., 1992 |
FR. |
|
| 31 18 882 |
Jan., 1983 |
DE. |
|
| 40 12 148 |
Oct., 1990 |
DE. |
|
| 720561 |
Apr., 1953 |
GB. |
|
| 1381649 |
Oct., 1972 |
GB. |
|
| WO8700427 |
Jan., 1987 |
WO. |
|
Other References
WPIDS AN 1995-171716, Naito, EP 652012, abstract, May
10, 1995.
Embase AN 94173949, Randall, Clinical Endocr 40/4 (43957)
abstract, 1994.
Clinical Endocrinology (1994), "Androgens And Human Hair
Growth", V. A. Randall, p. 439-457.
Clinical And Experimental Dermatology 1990, "Amino-Acid
Composition In Trichorrhexis Nodosa", D. H. Rushton,
M. J. Norris & K.C. James, Publication Jul. 24, 1989,
p. 24-28.
Derwent AN85-220782, abstract Kanebo, "Hair tonic compsn.--comprising
water-soluble salt of dehydroepi-androsterone sulphate",
Jul. 29, 1985.
Chemical Abstracts, vol. 83, No. 7, Aug. 18, 1975, Columbus,
Ohio, US; abstract No. 57121h, U. Prusiewicz-Witaszek:
"Changes in the synthesis of keratin in the hair after
supplementing the basic feed of rabbits with methionine
and lysine", p. 368. |
Primary Examiner: Cook; Rebecca
Attorney, Agent or Firm: Harness, Dickey & Pierce,
P.L.C.
Parent Case Text
This is a 371 of PCT/GB01542 filed Jun. 5, 1997.
Claims
What is claimed is:
1. A method for the treatment or prophylaxis of telogen effluvium
in a human, consisting of administering to said human in need
of said method an effective amount of L-lysine.
2. A method for the treatment or prophylaxis of telogen effluvium
in a human, comprising administering to a human in need of said
method a composition comprising of an effective amount of L-lysine
and one or more of the following:
(i) an iron compound selected from the group consisting of iron
(II) sulphate or a chelated iron compound, the daily dosage
of elemental iron being 14 mg to 300 mg;
(ii) vitamin C in a daily dosage of 14 mg to 300 mg;
(iii) vitamin B.sub.12 in a daily dosage of 3 .mu.g to 24 .mu.g.
3. The method according to claim 1, wherein said effective amount
of L-lysine consists of a daily dosage of 200
mg to 2000 mg.
4. The method according to claim 1, wherein said chelated iron
compound is selected from the group consisting of iron (II)
fumarate, iron (II) gluconate, iron (II) succinate and iron
(II) glycine sulphate.
5. A pharmaceutical composition for the prophylaxis or treatment
of telogen effluvium in a human, said composition containing
from 200 mg to 2000 mg of L-lysine and one or
more of the following:
(i) an iron compound selected from the group consisting of iron
(II) sulphate or a chelated iron compound, the amount by weight
of elemental iron being 14 mg to 300 mg;
(ii) from 14 mg to 300 mg of vitamin C; and
(iii) from 3 .mu.g to 24 .mu.g of vitamin B.sub.12.
6. The pharmaceutical composition according to claim 5, wherein
said chelated iron compound is selected from the group consisting
of iron (II) fumarate, iron (II) gluconate, iron (II) succinate
and iron (II) glycine sulphate.
7. A kit comprising a plurality of at least four separate containers
differing from each other, wherein at least one of said containers
contains from 200 mg to 2000 mg of L-lysine, at
least one different container contains an iron compound selected
from the group consisting of iron (II) sulphate or a chelated
iron compound, the amount of elemental iron being 14 mg to 300
mg, at least one still different container contains from 14
mg to 300 mg of vitamin C, and at least one yet different container
contains from 3 .mu.g to 24 .mu.g of vitamin B.sub.12.
8. The kit according to claim 7, wherein said chelated iron
compound is selected from the group consisting of iron (II)
fumarate, iron (II) gluconate, iron (II) succinate and iron
(II) glycine sulphate.
Description
The present invention provides a medicament for the prophylaxis
and treatment of hair loss, particularly telogen effluvium,
in humans. It further provides a kit useful in a combination
therapy for the treatment of genetic hair loss.
Scalp hair loss can be divided into the following three main
groups and any one group or combinations of said groups may
be operating in an individual at any point in time:
1. Hair loss caused by a reduction in the number of hairs per
unit area (cm.sup.2);
2. Hair loss caused by a reduction in the diameter of hair;
and
3. Hair loss caused by an increase in the number of hairs in
the telogen (resting) phase, or an increase in the length of
time (latency period) between the end of the telogen phase and
the initiation of the next anagen (growing) phase.
It is normal to lose some scalp hair each day. There are natural
fluctuations in the hair cycle which in turn influence the amount
of hair shed from the scalp on a daily basis. It is therefore
important to establish if a problem involving excessive hair
shedding really exists and that the individual has not just
become aware of their normal daily loss.
For most humans, scalp hair has a life cycle of between 1000
and 2000 days (23/4 and 51/2 years), following which there is
a short period of rest (the telogen phase), which lasts approximately
one hundred days. For the majority of its life cycle, scalp
hair is in a growth phase known as the anagen phase. As the
new hair grows up the follicle it loosens the old resting hair
(telogen hair) which is usually dislodged with brushing, combing
or shampooing. This cycle continues unless the hair metabolism
is disturbed. Since shed hair is almost entirely telogen hair,
the loss from the scalp is seen 10 to 12 weeks later.
For normal individuals having 100,000 hairs, the above process
results in about 100 hairs per day being lost from the scalp,
while for individuals with 150,000 hairs around 150 per day
are lost. These figures are for a 1000 day cycle. For a 2000
day cycle, these values would be halved. Scalp hair grows around
0.33 mm per day and with a growth cycle of 1000 days the hair
would grow to a length of 33 cm and for 2000 days 66 cm.
Most transient and temporary effects on the hair cycle, which
also cause increased hair shedding, correct themselves and no
further action is required. Sometimes it is difficult to determine
if the natural rate of hair shedding has increased or excessive
shedding has declined, since an individual may be unaware of
their normal rate. However if a true problem exists, such as
occurs in a nutritional imbalance, the consequences can be detected
as a reduction in hair volume. This is because the prolonged
effect upon the hair cycle causes significant change to the
overall amount of hair present.
Many women are aware of an increase in the amount of hair shed
daily which will be seen as more hair in the brush, comb, on
the bathroom floor, or when they shampoo. When there is no obvious
cause (e.g. an illness within the past three months, taking
medication known to produce hair loss, or pregnancy), then it
is important to consider suboptimal hair growth where increased
hair shedding is the primary feature.
The problem of increased hair shedding (telogen effluvium) and
suboptimal hair growth principally affects women in the menstrual
years and may co-exist with other hair loss disturbances either
of a hormonal or nutritional basis. The loss of hair in this
condition is the result of an increase in the amount of telogen
hair shed from the scalp. It may also involve a reduction in
the length of hair grown.
Increased scalp hair shedding results from an excessive amount
of telogen hair. Increased hair shedding of this type is usually
identified by measuring the ratio of hair in the anagen and
telogen phases. In the chronic state there may be no perceived
increase in shedding because of a plateau effect in the anagen/telogen
ratio, but its consequence is an increase in the number of hairs
unable to grow to a given length. Frequently, female sufferers
complain of a reduction in the amount of hair they can pin,
clip or tie-up, compared to previously. The variable measured
to identify this aspect is usually the amount of hair less than
30 mm in length.
Few successful treatments have yet been discovered for the prophylaxis
and treatment of hair loss in humans. In particular, no reliable
treatment has yet been found for the treatment of telogen effluvium
in humans. We have now made the surprising discovery that treatment
with the essential amino acid lysine results in
a substantial increase in hair growth in patients suffering
from hair loss and in particular those suffering from telogen
effluvium. Compositions for the treatment of hair loss are disclosed
in U.S. Pat. No. 5,470,876, U.S. 5,133,958, U.S. Pat. No. 5,122,369
and DE-A-3118882 which may contain lysine in combination
with other ingredients. However, none of these documents discloses
the use of L-lysine as an active principle in
the prophylaxis or treatment of telogen effluvium.
The present invention provides the use of L-lysine
in the manufacture of a medicament for the prophylaxis and treatment
of hair loss in humans, provided that said L-lysine
is not in the form of a complex with a transition metal and
that said medicament does not contain one or more of the following:
(i) a combination of trigonelline and vitamin B6;
(ii) a combination of divalent iron, pantothenic acid and methionine;
(iii) garlic oil or garlic extract.
In particular, L-lysine is especially useful in
the manufacture of a medicament for the treatment of telogen
effluvium in humans.
Studies involving the administration according to the present
invention of L-lysine to women suffering from
increased hair shedding show a remarkable increase in scalp
hair growth. This hair growth appears to involve an increase
in the proportion of growing hair (anagen phase) and an accompanying
decrease in the proportion of resting hair (telogen phase),
an increase in the length of hair grown (shown as a decrease
in the proportion of hair which is less than 30 mm in length)
and a reduction in the amount of hair being shed from the scalp.
Typically, the L-lysine is administered in a daily
dose of from 200 to 2000 mg, and more usually in a daily dose
of 500 to 1500 mg, e.g. in the form of a 500 mg dose administered
orally once, twice or three times a day. The L-lysine
may be included in a formulation suitable for oral administration
which also includes other essential elements, e.g. iron in the
form of a salt or chelate such as ferrous sulphate, ferrous
fumarate, ferrous gluconate, ferrous succinate, ferrous glycine
sulphate or other chelated iron compounds (the typical daily
dose of elemental iron being 14 mg to 300 mg); vitamin C (in
a quantity equal to the iron content); and vitamin B.sub.12
(the typical daily dose being 6 .mu.g to 200 .mu.g).
L-lysine may conveniently be administered orally,
for example as tablets, capsules, granules, powders, mixtures,
suspensions or syrups. These formulations can be prepared by
conventional means and, if desired, the L-lysine
may be mixed with any conventional additive, such an excipient,
a binder, a disintegrating agent, a lubricant, a corrigent,
a solubilising agent, a suspension aid, an emulsifying agent
or a coating agent.
We have also discovered that administration of lysine
to patients results in a dramatic increase in the efficacy of
known treatments for genetic hair loss (which term covers a
number of conditions variously referred to as androgen-dependent
alopecia, androgenic alopecia, androgenetic alopecia, common
baldness, female baldness, diffuse hair loss and male pattern
baldness).
Thus, in a further aspect of the present invention there is
provided a kit including a plurality of separate containers,
each containing at least one active agent useful in a combination
therapy for the treatment of genetic hair loss, wherein said
kit includes L-lysine and at least one further
active agent selected from minoxidil, anti-androgens, 5.alpha.-reductase
inhibitors, aromatase inhibitors and corticosteroids.
There is also provided a therapeutic combination for the treatment
of genetic hair loss comprising L-lysine and at
least one further active agent selected from minoxidil, anti-androgens,
5.alpha.-reductase inhibitors, aromatase inhibitors and corticosteroids.
Typical examples of anti-androgens which can be used include
cyproterone acetate, spironolactone, medroxyprogesterone acetate
and flutamide which can, for example, be formulated for oral
or topical administration. Type I, type II or mixed type I and
type II 5 .alpha.-reductase inhibitors can be used, e.g. finasteride.
A typical example of a suitable corticosteroid is dexamethasone.
In a preferred embodiment, the kit comprises L-lysine
and at least one further active agent selected from minoxidil
and one or more anti-androgens, which are preferably chosen
from cyproterone acetate, spironolactone and medroxyprogesterone
acetate. In a particularly preferred embodiment, the kit comprises
L-lysine which is formulated for oral administration
and minoxidil which is formulated for topical application.
The co-administration of L-lysine with known treatments
for genetic hair loss such as minoxidil and anti-androgens results
in a significant improvement in the efficacy of the treatment.
The reason for this improvement in efficacy is not currently
understood.
Typically, L-lysine is administered in a daily
dose of from 200 mg to 2000 mg, and preferably in a daily dose
of 500 to 1500 mg, e.g. in the form of a 500 mg dose administered
orally once, twice or three times a day. The known treatment
for (genetic hair loss (e.g. topical application of minoxidil
to the scalp) is administered concurrently.
The surprising effect of L-lysine in the treatment
of various forms of hair loss is illustrated by the following
tests.
Treatment of Telogen Effluvium in Women
Eight women were treated over a 16 week period with L-lysine,
a 500 mg oral dose being given once, twice or three times a
day (500 mg to 1500 mg total daily dose). Various biochemical
investigations were performed on the women in the test programme
before the start of the said programme and after 16 weeks of
therapy, the details of which are given in Table 1 below together
with the results obtained (mean values).
The effect of the administration of L-lysine on
hair growth was determined by measuring three scalp hair variables--the
percentage of hair in the anagen phase, the percentage of hair
in the telogen phase and the percentage of hair less than 30
mm in length. These three variables were evaluated using the
bio-assay known as the unit area trichogram (see Rushton
et al, British Journal of Dermatology, 1990, 123, 187-197; Rushton
et al, Clinical and Experimental Dermatalogy, 1991, 16, 188-192;
and Rushton et al, Clinical Endocrinology, 1992,
36, 421-427). The values obtained at the start of the test and
after sixteen weeks are shown in Table 2 below.
TABLE 1
______________________________________
Variable Time - 0 weeks
Time - 16 weeks
P value
______________________________________
Haemoglobin (hb)
12.2 12.6 ns
Serum ferritin 50.0 49.5 ns
senim zinc 13.6 13.9 ns
______________________________________
Blood based variables determined basally and after 16 weeks in eight
female subjects complaining of increased hair shedding (mean values
obtained, n = 8). Statistical significance was assessed with Student's
ttest for paired samples.
TABLE 2
______________________________________
Variable Time - 0 weeks
Time - 16 weeks
P value
______________________________________
Anagen % 82.6 88.5 <0.05
Telogen % 17.4 11.5 <0.05
Hair <30 mm % 17.4 12.4 <0.05
______________________________________
Hair variables determined basally and after 16 weeks in eight female
subjects complaining of increased hair shedding (mean value obtained, n =
8). Statistical significance was assessed with Wilcoxon signed rank test.
The results in Table 2 demonstrate clearly that the administration
of L-lysine resulted in an increase in the proportion
of hair in the anagen (growth) phase and a corresponding reduction
in the proportion of hair in the telogen (resting) phase in
women suffering from telogen effluvium. Additionally, there
was a significant reduction in the percentage of hair less than
30 mm in length.
The results in Table 1 show that there was no significant change
in the haemoglobin, serum ferritin or serum zinc levels in the
blood between the start and finish of the treatment. It appears
to be reasonable to conclude, therefore, that the significant
increase in hair growth observed after the administration of
L-lysine to women suffering from telogen effluvium
was not due to an increase in the blood iron or zinc level as
a result of the administration of L-lysine.
For women suffering from telogen effluvium who have low iron
or zinc stores, a further effect was observed, as shown in the
following tests.
A group of women exhibiting chronic telogen effluvium who were
being treated for reduced iron stores (serum ferritin concentrations
below 40ng/ml) failed to achieve adequate increases of serum
ferritin despite taking an iron supplement containing 50 to
100 mg of iron per day. However, when a daily L-lysine
supplement of 1.0 g or 1.5 g was added to their existing daily
iron supplement a significant (P<0.002) increase in serum
ferritin concentration was observed (Table 3).
TABLE 3
______________________________________
Serum ferritin concentration basal and after 4 or 6 months of treatment
with 50 mg twice daily with and without L-lysine (1 to 1.5 g) daily.
Serum Ferritin levels
After 4 or 6 months of treatment
Iron only
Baseline 100 mg/day Iron (100 mg/day) +
Age (ng/ml) (ng/ml) (Lysine 1 or 1.5 g/day)
______________________________________
Subject 1
69 10.90 12.20 27.60
Subject 2 32 31.00 41.00 80.00
Subject 3 34 13.00 15.00 50.00
Subject 4 51 35.00 26.00 71.00
Subject 5 44 27.00 38.00 59.00
Subject 6 31 7.00 15.00 37.00
Mean 20.7 24.5 54.1
P = 0.3 [iron only (NS)]
P < 0.002 (iron +
lysine)
______________________________________
(statistical analysis paired Student's t test)
In Table 4 below serum zinc concentrations are presented for
a group of women (n=10) in whom basal concentrations were below
11.8 .mu.mol/L, i.e. within 10% of the lower limit of normal.
The mean baseline concentration for this group was 10.28 .mu.mol/L
(range 9.0 .mu.mol/L to 11.7 .mu.mol/L). Each was treated with
a daily supplement of L-lysine (1 g to 1.5 g)
for 16 weeks, following which the mean serum zinc concentration
had increased significantly (P<0.001) to 13.78 .mu.mol/L
(range 11.6 to 17.4 .mu.mol/L).
TABLE 4
______________________________________
Changes in serum zinc concentration following daily supplementation
with 1 g-1.5 g of L-lysine over a 16 week period.
Serum Zinc
Serum Zinc
Patient Time 0 After 16 weeks
______________________________________
Subject 1 11.7 17.4
Subject 2 10.4 16.1
Subject 3 10.6 11.6
Subject 4 9.3 11.8
Subject 5 11.7 13.3
Subject 6 9.0 13.8
Subject 7 9.5 14.5
Subject 8 9.0 14.0
Subject 9 10.3 12.3
Subject 10 11.3 13.0
Mean 10.28 13.78
______________________________________
P < 0.001 paired t test
Treatment of Women Suffering from Genetic Hair Loss
The effect of the administration of lysine on
the efficacy of known treatments for genetic hair loss was investigated
as follows.
Women suffering from genetic hair loss, all of whom had adequate
iron stores within the normal range at the start of the test
(i.e. serum ferritin levels of greater than 40 mg/ml) were divided
into four groups.
The first group (17 women) was treated with minoxidil only (in
the form of a topical formulation comprising 3% minoxidil by
weight).
The second group (15 women) had a combined treatment of minoxidil
(again as a topical formulation comprising 3% minoxidil by weight)
and an oral anti-androgen chosen from cyproterone acetate, medroxyprogesterone
and spironolactone. The first two anti-androgens were administered
in combination with ethinylestradiol or an oral contraceptive.
The particular anti-androgen administered was chosen on the
basis of clinical need.
The third group (8 women) received a combined treatment of minoxidil
(again as a topical formulation comprising 3% minoxidil by weight)
and 500 to 1500 mg per day of L-lysine (administered
orally).
The fourth group (13 women) received a combined treatment comprising
minoxidil (again as a topical formulation comprising 3% minoxidil
by weight), an oral anti-androgen (administered as to the second
group above) and 500 to 1500 mg per day of L-lysine
(administered orally). The results of these tests are shown
in Table 5 below.
TABLE 5
______________________________________
Res-
ponse
______________________________________
Minoxidil Only
Minoxidil + Anti-androgens Only
+ 9/17 (52.9%) 11/15 (73.%)
= 6/17 (35.3%) 3/15 (20.0%)
- 2/17 (11.8%) 1/15 (67%)
L-lysine + Minoxidil L-lysine + Minoxidil + Anti-androgens
+ 8/8 (100%) 13/13 (100%)
= None None
- None None
______________________________________
Response key
+ patient noticed an increase in hair quantity.
= patient did not see any change in hair quantity.
- patient felt there had been a decrease in hair quantity.
The results in Table 5 suggest that the co-administration of
L-lysine to patients being treated for genetic
hair loss with known treatments such as the topical administration
of minoxidil and/or the oral administration of anti-androgens
results in a considerable improvement in the efficacy of these
known treatments.
When L-lysine is administered for the treatment
of telogen effluvium in humans according to the present invention,
a typical daily treatment regimen could include:
L-lysine at 200 mg to 2000 mg per day;
Elemental iron at 14 mg to 300 mg;
Vitamin C at 14 mg to 300 mg; and
Vitamin B.sub.12 at 3 .mu.g to 24 .mu.g.
Typically, the L-lysine may be administered as
tablets or capsules containing the following ingredients:
200 mg L-lysine
14 mg Vitamin C
14 mg iron (as ferrous glycine sulphate)
3 .mu.g Vitamin B.sub.12
Typically, 200 mg L-lysine tablets are administered
six times daily during the acute phase of telogen effluvium,
four times daily during chronic phase and two times daily as
a maintenance dose.
* * * * *
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