Methods of preventing and reducing the size of Striae distensae lesions

Striae distensae lesions may be prevented and/or reduced in size by topically applying to the skin affected with the lesions an effective amount of a retinoid, preferably retinoic acid, preferably by daily application in a dermatologically acceptable vehicle, such as a cream base, at a concentration of about 0.025 to 0.1 weight percent retinoic acid. When applied during the striae rubrae stage, the retinoid may be effective to prevent the formation of striae albae lesions, and when applied in either stage, the retinoid may be effective to reduce the width and depth of the lesions, with improved texture and softness.

FIELD OF THE INVENTION 
The present invention is directed to methods of preventing and/or reducing 
the size of lesions of striae distensae. More particularly, the invention 
is directed to a method of preventing the formation of stride albae and a 
method of reducing the size of lesions of both striae albae and striae 
rubrae. 
BACKGROUND OF THE INVENTION 
Striae distensae are very common lesions. They are present in most healthy 
adult women, having originated either during puberty or at the time of the 
first pregnancy. Stretching of the skin, as in rapid weight gain, or 
mechanical stress, as in weight lifting, often precedes their development. 
About 50 percent of pregnant women will develop these lesions, often 
referred to as stretch marks, on thighs, abdomen and breasts, starting at 
about 3 to 4 months of gestation. However, such lesions are also noted in 
cachectic states, for example in tuberculosis and typhoid fever, and they 
have also been noted after intense slimming diets. 
The pathogenesis of stride distensae lesions is unclear. Some pregnant 
women do not develop the lesions; lesions have not been produced 
experimentally, and there is no animal model. 
Clinicians are aware that striae distensae evolve over time passing through 
an early phase of inflammation (striae rubrae) and ending in the typical 
white stretch mark (striae albae). The striae rubrae are red, slightly 
elevated, linear lesions that may be tender. Later, the lesions flatten 
and the redness fades, leaving a permanent, wavy depression, which is the 
striae albae. The striae albae lesions may be 5 to 15 mm wide, depressed 
with a crinkly surface. These are the stretch marks which last for life, 
since to date there has been no known treatment. 
The histopathology of striae, which always have the same appearance 
regardless of cause, has generated much dispute. However, P. Zheng, et 
al., "Anatomy of Striae," British Journal of Dermatology, 112:185-193 
(1985) present evidence that striae albae are true scars resulting from an 
earlier inflammatory process that destroys elastic fibers. They are not 
formed by stress-induced rupture of the dermal fibrous network. 
Retinoids, particularly retinoic acid, have been previously applied 
topically to the skin for the treatment of many skin disorders. See, for 
example the review of Thomas et al., "The Therapeutic Uses of Topical 
Vitamin A Acid," Journal of the American Academy of Dermatology, 4:505-513 
(1981). It is known that tretinoin has an anti-inflammatory action useful 
in ameliorating chronic dermatoses such as psoriasis and lichen planus. 
According to my U.S. Pat. Nos. 4,603,146; 4,877,805 and 4,888,342, topical 
retinoids have been effective to stimulate formation of new collagen 
fibers, generate new blood vessels, correct abnormalities in elastic 
fibers, and eliminate neoplastic growths in chronically sundamaged skin. 
Retinoic acid is used world-wide to retard and reverse photodamage from 
excessive exposure to ultra-violet radiation in sunlight. 
The literature also reports the improvement of post-ache, elevated, 
hypertrophic scars of the back with topical retinoic acid. These 
hypertrophic scars have a very different origin, following severe cystic 
lesions, resulting in a high increase in collagen. In striae distensae the 
opposite happens; there is loss of collagen with atrophic scarring. 
BRIEF SUMMARY OF THE INVENTION 
According to the present invention, it has been found that striae distensae 
lesions may be prevented and reduced in size by applying a retinoid, 
preferably tretinoin, topically to the area of the skin affected or likely 
to be affected with the lesions. The retinoid is applied in a 
dermatologically acceptable vehicle, such as a cream base, preferably in a 
concentration of about 0.025 to 0.1 weight percent in the case of 
tretinoin, generally by daily application. When applied in the striae 
rubrae stage, the retinoid prevents or reduces the formation of striae 
albae. When applied in the striae albae stage, the scars become less 
noticeable, less wrinkled, and softer, though the lesions do not disappear 
altogether. When applied early in pregnancy before any clinical change, 
stretch marks may be almost completely prevented. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The retinoid, preferably retinoic acid, also referred to as Vitamin A acid, 
and more particularly the all-trans isomer of retinoic acid, also known as 
tretinoin, is applied topically to striae distensae lesions according to 
the present invention. The topical application may be by spreading on with 
the fingers or by use of a suitable applicator such as a cotton swab. 
Retinoids have been defined narrowly as comprising simply vitamin A 
(retinol) and its derivatives such as vitamin A aldehyde (retinal), 
vitamin A acid (retinoic acid), comprising the so called natural 
retinoids. However, subsequent research has resulted in a much larger 
class of chemical compounds that are termed retinoids due to their 
biological similarity to vitamin A and its derivatives. Compounds useful 
in the present invention include all natural and/or synthetic analoguss of 
vitamin A or retinol-like compounds which possess the biological activity 
of vitamin A in the skin, particularly the prevention and reduction in 
size of striae distensae lesions, among other effects. Accordingly, as 
used herein for purposes of the present invention, the term "retinoid" 
will be understood to include any of the foregoing compounds. Examples of 
suitable retinoids for use in the present invention are set forth in Table 
I, although it will be understood that the invention is not limited 
thereto. 
TABLE I 
Chemical, Common and/or Commercial Name 
Isotretinoin 13-cis-retinoic acid ACCUTANE 
Etretinate TEGISON 
(all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetra 
enoic acid ethyl ester 
Etretin 
(all-E)-9-(4-methoxy-2,3,6,-trimethylphenyl)-3,7-dimethyl-2,4,6,8,-nonatet 
raenoic acid 
Motretinide 
N-ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetra 
enamide 
(E,E)-9-(2,6-dichloro-4-methoxy-3-methylphenyl)3,7-dimethyl-2,4,6,8-nonatet 
raenoic acid ethyl ester 
7,8-didehydroretinoic acid 
(E,E)-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadienyl] 
benzoic acid 
(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexatrienyl] 
benzoic acid 
(all-E) -3,7-dimethyl-9- (3-thienyl)-2,4,6,8-nonatetraenoic acid 
(E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)- 
2,4,6-octatrienoic acid 
(E)-6-[2-(2,6,6-trimethyl-l-chclohexen-1-yl)ethenyl]-2-naphthalenecarboxyli 
c acid 
(E,E,E)-7-(2,3-dihydro-1,1,3,3-tetramethyl-1H-inden-5-yl)-3-methyl-2,4,6-oc 
tatrienoic acid 
(E)-4-(2,3-dihydro-1,1,3,3,-tetramethyl-1H-inden-5-yl)-1-propenyl] benzoic 
acid 
TTNPB 
(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl 
] benzoic acid 
(E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl)-1 
-propenyl] benzoic acid 
(E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2-phenylethyl) 
naphthalene 
6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxyl 
ic acid 
(E)-6-[2-[4-(ethylsulfonyl)phenyl-1-methylethenyl]-1,2,3,4-tetrahydro-1,1,4 
,4-tetramethylnaphthalene 
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl] benzoic 
acid 
(E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl-[4-tetrazol-5-yl)p 
henyl]-1-propene 
(E)-4-[2-(5,6,7,8,-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl) 
-1-propenyl] benzyl alcohol 
AM-80 
2-(4-Carboxybenzamido)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene 
AM-580 
2-[N-4-(Carboxyphenyl)carbamoyl]-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnap 
hthalene 
CH-55 1-[3,5-(Di-tert-butyl)benzoyl]-2-(4Carboxyphenyl)ethene 
TTNT 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo(b) 
thiophene carboxylic acid 
TTNF 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-benzo(b) 
furancarboxylic acid 
TTNI 
2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-indolecarboxylic 
acid 
TTNN 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-6-naphthalene 
carboxylic acid 
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid 
Esters or amides of 13-trans retinoic acid or 13-cis retinoic acid wherein 
the --OH group of the carboxylic acid (--COOH) group is substituted by 
--OR.sup.1 or --NR.sup.2 R.sup.3 wherein R.sup.1 R.sup.2 and R.sup.3 are 
such that these esters or amides can be converted to 13-trans retinoic 
acid or 13-cis retinoic acid through hydrolysis, metabolism, cleavage, 
etc. 
Also encompassed within the term "retinoid" are geometric and stereoisomers 
of the retinoids. While the specific examples below use tretinoin 
(all-trans retinoic acid), isotretinoin (13-cis-retinoic acid) may also be 
used, although somewhat higher concentrations are needed to obtain 
equivalent results. 
Retinoids may be formulated in bland, moisturizing bases, such as creams or 
ointments, usually in low concentrations, although higher concentrations 
may be used for darker skins. The retinoid should preferably be applied in 
an amount which is not excessively irritating to the skin. Other 
non-toxic, dermatologically acceptable vehicles or carriers in which 
retinoids are stable will be evident to those of ordinary skill in the 
art. In general, emollient or lubricating vehicles, such as oleaginous 
substances, which help hydrate the skin are preferred. As used herein, the 
term "emollient" will be understood to refer to the non-irritating 
character of the composition as a whole. That is, the nature of the 
vehicle and amount of retinoid therein should be selected so as to provide 
a sub-irritating dose for topical application. Volatile vehicles which dry 
or otherwise harm the skin, such as alcohol and acetone, should be 
avoided. 
An ointment base (without water) is preferred in the winter and in subjects 
with very dry skin. Examples of suitable ointment bases are petrolatum, 
petroldrum plus volatile silicones, lanolin, and water in oil emulsions, 
such as Eucerin (Beiersdorf). 
In warm weather and often for younger persons, oil in water emulsion 
(cream) bases, are preferred. Examples of suitable cream bases are Nivea 
Cream (Beiersdorf), cold cream (USP), Purpose Cream (Johnson & Johnson), 
hydrophilic ointment (USP), and Lubriderm (Warner-Lambert). 
Some retinoids are mild irritants and may cause redness and scaling, which 
may be accompanied by some tenderness and tightness. These reactions are 
transient and quickly disappear when the applications are stopped. 
However, the skin rapidly accommodates, and even when retinoids are 
applied excessively to produce visible inflammation, the reaction slowly 
disappears leaving no permanent sequellae. Systemic side reactions are 
unknown and are not to be expected from such low concentrations according 
to the present invention. Selection of an appropriate emollient vehicle 
will more readily allow the use of a highly effective but sub-irritating 
does ot the retinoid. 
Retinoic acid may be applied in any dermatologically acceptable vehicle 
such as a gel or a cream base. Retinoic acid in a cream base is available 
commercially for the treatment of ache from Johnson & Johnson under the 
trademark RETIN-A, which is available in concentrations ranging from 0,025 
to 0.1 weight percent. Gel bases of RETIN-A are also available. Other 
suitable formulations will be apparent to those skilled in the art based 
upon the present disclosure. 
For purposes of the present invention where the retinoid is retinoic acid, 
the retinoic acid is generally applied in a concentration of about 0.025 
to 0.1 weight percent of the total composition, and preferably about 0.25 
to 0.1 weight percent of the composition. Such concentrations are too low 
to cause birth defects (teratogenicity). Also, concentrations of 0.1 
percent or less are insufficient to cause any side effects other than some 
minor early irritation to which the skin gradually accommodates. No 
systemic effects have been reported in the treatment of many millions of 
ache sufferers. 
Generally, the topical applications are made once daily, although twice 
daily or thrice weekly applications may prove beneficial or satisfactory 
in some cases. Clinically significant improvement is usually seen after 4 
to 5 months of daily treatment. The width and depth of stretch marks is 
greatly reduced. Tenderness and redness are ameliorated. 
For best results, the topical applications of retinoid are started in the 
early red stage (striae rubrae) in the first few months after conception. 
When started at this stage, not only will the lesions become narrower, 
shallower and much less noticeable, but permanent scarring will be largely 
prevented in at least about half of the patients treated. The prophylactic 
strategy of beginning the treatment of the invention in early pregnancy 
yields optimal results. The treatment should continue at least until 
birth, and possibly for another few months after birth, although the 
benefits of post-natal therapy are still being investigated. 
When the topical retinoid treatments of the present invention are not 
started until the lesions have reached the striae albae stage, it is still 
possible to soften the scars, reduce their depth, and improve the texture 
of the skin with the topical applications. In these cases, the dreaded and 
embarrassing stretch marks can be significantly reduced in size so that 
they are less noticeable. Old, long-standing striae albae lesions improve 
only slightly. 
While applicant does not wish to be bound by any particular theory, it is 
believed that the mechanism of action of retinoids in preventing and 
reducing the size of stride distensae is due to two actions: (1) 
suppression of inflammation present in stride rubrae (we have shown that 
there is an intense inflammatory reaction in biopsies from stride rubrae) 
and (2) stimulation of new collagen formation resulting in shallower, 
softer scars in both stride rubrae and stride albae. 
The invention will now be illustrated in further detail by reference to the 
following specific, non-limiting examples.

EXPERIMENTAL EXAMPLES 
Over forty women with striae distensae were treated according to the 
present invention. The lesions on one side of the abdomen were treated 
with 0.05 to 0.1 percent RETIN-A cream, generally once daily, while Nivea 
Cream alone was applied to the other side of the abdomen as a control. 
Most of the forty test subjects were 3 to 5 months pregnant, showing 
stride rubrae. The remainder had stride albae of varying duration, usually 
not greater than 5 years. Tretinoin was applied once daily at the start of 
therapy. This was sometimes increased to twice daily in those who 
experienced little irritation. 
In the cases where treatment was begun in the stride rubrae stage, about 
half were greatly improved in comparison to the control. In three cases 
where treatment was started in the first few weeks of pregnancy before any 
evidence of striae distensae, the suppression of striae on the treated 
side was impressive (almost complete) in two of the cases. Where the 
treatment did not begin until the striae albae stage, about one third 
showed clinically significant improvement after 4 to 5 months of daily 
treatment. The improved women were impressed with the results. The only 
side effects have been some early irritation, which was temporary. 
In the four cases which were biopsied, the histology showed nearly normal 
skin, with good collagen bundles, on the side treated with RETIN-A. The 
control side showed fine fibers, tightly packed in parallel array, typical 
of a scar. 
The present invention may be embodied in other specific forms without 
departing from the spirit or essential attributed thereof, and 
accordingly, reference should be made to the appended claims, rather than 
to the foregoing specification as indicating the scope of the invention.