alopecia ( baldness ) a deficiency of either normal or abnormal hair , is primarily a cosmetic problem in humans . it is a deficiency of terminal hair , the broad diameter , colored hair that is readily seen . however , in the so - called bald person although there is a noticeable absence of terminal hair , the skin does contain vellus hair which is a fine colorless hair which may require microscopic examination to determine its presence . this vellus hair is a precursor to terminal hair . in accordance with the invention as described herein , compounds represented by wherein r 1 , r 2 , a , b , z and x are defined above , can be used to stimulate , such as stimulating the conversion of vellus hair to growth as terminal hair as well as increasing the rate of growth of terminal hair . in the course of treating patients having glaucoma , treatment may only be appropriate in one eye . within the course of daily practice it was discovered that a patient who been treated with bimatoprost has lashes that were longer , thicker and fuller in the treated eye than in the non - treated eye . on examination the difference was found to be very striking . the lashes were longer and had a more full dense appearance in the treated eye . the lash appearance on the lids of the treated eye would have appeared quite attractive if it represented a bilateral phenomenon . because of its asymmetric nature , the long lashes on one side could be construed as disturbing from a cosmetic standpoint . because of the very unusual appearance a systematic examination of other patients who were taking bimatoprost in only one eye was made . it soon became apparent that this altered appearance was not an isolated finding . comparison of the lids of patients who were taking bimatoprost in only one eye revealed subtle changes in the lashes and adjacent hairs of the bimatoprost - treated side in several patients . definite differences could be identified to varying degrees in the lashes and adjacent hairs of all patients who were taking the drug on a unilateral basis for longer than 6 months . these findings were totally unexpected and surprising . minoxidil is thought to stimulate hair growth by its ability to cause vasodilation suggesting that agents with such a capability may be uniquely effective in stimulating hair growth . the finding that bimatoprost , which , as explained below , is not a prostaglandin derivative , such as latanoprost stimulates hair growth is especially surprising and unexpected . the changes in the lashes were apparent on gross inspection in several patients once attention was focused on the issue . in those with light colored hair and lashes , the differences were only seen easily with the aid of the high magnification and lighting capabilities of the slit lamp biomicroscope . in the course of a glaucoma follow up examination , attention is generally immediately focused on the eye itself . because of the high power magnification needed only one eye is seen at a time and the eye is seen at a high enough power that the lashes are not in focus . at these higher powers , any lash asymmetry between the two eyes is not likely to be noticed except by careful systematic comparison of the lashes and adjacent hairs of the eyelids of the two eyes . observed parameters leading to the conclusion that more robust hair growth occurred in the treated area following administration of bimatroprost were multiple . they included increased length of lashes , increased numbers of lashes along the normal lash line , increased thickness and luster of lashes , increased auxiliary lash - like terminal hair in transitional areas adjacent to areas of normal lash growth , increased lash - like terminal hairs at the medial and lateral canthal area , increased pigmentation of the lashes , increased numbers , increased length , as well as increased luster , and thickness of fine hair on the skin of the adjacent lid , and finally increased perpendicular angulation of lashes and lash - like terminal hairs . the conclusion that hair growth is stimulated by bimatoprost is thus supported not by evidence of a difference in a single parameter but is based on multiple parameters of hair appearance in treated vs . control areas in many subjects . this finding is entirely unexpected and represents a previously unrecognized effect of bimatoprost on stimulation of hair follicles . the modified hairs of the lashes normally turn over slowly and are in their resting phase longer than hair on , for example , the scalp . the ability to cause differences in appearance of lashes , the ability to stimulate conversion of vellus or intermediate hair to terminal hairs in transitional areas and the ability to stimulate growth of vellus hair on the skin indicates that bimatoprost is a diversely effective and efficacious agent for the stimulation of hair growth . thus , the present invention provides a treatment by bimatoprost of hair of the scalp , eyebrows , beard and other areas that contain hair that results in increased hair growth in the corresponding areas . patients that are treated in or around the eye with compounds of the invention , such as bimatoprost , regularly develop hypertrichosis including altered differentiation , numbers , length , thickness , curvature and pigmentation in the region of treatment . some examples of representative compounds useful in the practice of the present invention include the compounds shown in table 1 : one presently preferred compound for use in the practice of the present invention is cyclopentane n - ethyl heptanamide - 5 - cis - 2 -( 3α - hydroxy - 5 - phenyl - 1 - trans - pentenyl )- 3 , 5 - dihydroxy , [ 1 α , 2 β , 3 α , 5 α ], also known as bimatoprost and sold under the name of lumigan ® by allergan , inc ., california , usa . this compound has the following structure : the synthesis of the above compounds described above has been disclosed in u . s . pat . no . 5 , 607 , 978 . this patent also shows , particularly in examples 1 , 2 , 5 and 7 that these compounds are not prostaglandins , in that they do not behave as prostaglandins in art - recognized assays for prostaglandin activity . the invention thus relates to the use of the above compounds , or prodrugs of the active compounds , for treatment for the stimulation of hair growth . as used herein , hair growth includes hair associated with the scalp , eyebrows , eyelids , beard , and other areas of the skin of animals . in accordance with one aspect of the invention , the compound is mixed with a dermatologically compatible vehicle or carrier . the vehicle which may be employed for preparing compositions of this invention may comprise , for example , aqueous solutions such as e . g ., physiological salines , oil solutions or ointments . the vehicle furthermore may contain dermatologically compatible preservatives such as e . g ., benzalkonium chloride , surfactants like e . g ., polysorbate 80 , liposomes or polymers , for example , methyl cellulose , polyvinyl alcohol , polyvinyl pyrrolidone and hyaluronic acid ; these may be used for increasing the viscosity . furthermore , it is also possible to use soluble or insoluble drug inserts when the drug is to be administered . the invention is also related to dermatological compositions for topical treatment for the stimulation of hair growth which comprise an effective hair growth stimulating amount of one or more compounds as defined above and a dermatologically compatible carrier . effective amounts of the active compounds may be determined by one of ordinary skill in the art but will vary depending on the compound employed , frequency of application and desired result , and the compound will generally range from about 0 . 0000001 to about 50 %, by weight , of the dermatological composition , preferably , from about 0 . 001 to about 50 %, by weight , of total dermatological composition , more preferably from about 0 . 1 to about 30 %, by weight of the composition . the present invention finds application in all mammalian species , including both humans and animals . in humans , the compounds of the subject invention can be applied for example , to the scalp , face , beard , head , pubic area , upper lip , eyebrows , and eyelids . in animals raised for their pelts , e . g ., mink , the compounds can be applied over the entire surface of the body to improve the overall pelt for commercial reasons . the process can also be used for cosmetic reasons in animals , e . g ., applied to the skin of dogs and cats having bald patches due to mange or other diseases causing a degree of alopecia . the pharmaceutical compositions contemplated by this invention include pharmaceutical compositions suited for topical and local action . the term “ topical ” as employed herein relates to the use of a compound , as described herein , incorporated in a suitable pharmaceutical carrier , and applied at the site of thinning hair or baldness for exertion of local action . accordingly , such topical compositions include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin surface to be treated . conventional pharmaceutical forms for this purpose include ointments , liniments , creams , shampoos , lotions , pastes , jellies , sprays , aerosols , and the like , and may be applied in patches or impregnated dressings depending on the part of the body to be treated . the term “ ointment ” embraces formulations ( including creams ) having oleaginous , water - soluble and emulsion - type bases , e . g ., petrolatum , lanolin , polyethylene glycols , as well as mixtures of these . typically , the compounds are applied repeatedly for a sustained period of time topically on the part of the body to be treated , for example , the eyelids , eyebrows , skin or scalp . the preferred dosage regimen will generally involve regular , such as daily , administration for a period of treatment of at least one month , more preferably at least three months , and most preferably at least six months . for topical use on the eyelids or eyebrows , the active compounds can be formulated in aqueous solutions , creams , ointments or oils exhibiting physiologically acceptable osmolarity by addition of pharmacologically acceptable buffers and salts . such formulations may or may not , depending on the dispenser , contain preservatives such as benzalkonium chloride , chlorhexidine , chlorobutanol , parahydroxybenzoic acids and phenylmercuric salts such as nitrate , chloride , acetate , and borate , or antioxidants , as well as additives like edta , sorbitol , boric acid etc . as additives . furthermore , particularly aqueous solutions may contain viscosity increasing agents such as polysaccharides , e . g ., methylcellulose , mucopolysaccharides , e . g ., hyaluronic acid and chondroitin sulfate , or polyalcohol , e . g ., polyvinylalcohol . various slow releasing gels and matrices may also be employed as well as soluble and insoluble ocular inserts , for instance , based on substances forming in - situ gels . depending on the actual formulation and compound to be used , various amounts of the drug and different dose regimens may be employed . typically , the daily amount of compound for treatment of the eyelid may be about 0 . 1 ng to about 100 mg per eyelid . for topical use on the skin and the scalp , the compound can be advantageously formulated using ointments , creams , liniments or patches as a carrier of the active ingredient . also , these formulations may or may not contain preservatives , depending on the dispenser and nature of use . such preservatives include those mentioned above , and methyl -, propyl -, or butyl - parahydroxybenzoic acid , betain , chlorhexidine , benzalkonium chloride , and the like . various matrices for slow release delivery may also be used . typically , the dose to be applied on the scalp is in the range of about 0 . 1 ng to about 100 mg per day , more preferably about 1 ng to about 10 mg per day , and most preferably about 10 ng to about 1 mg per day depending on the compound and the formulation . to achieve the daily amount of medication depending on the formulation , the compound may be administered once or several times daily with or without antioxidants . a study is initiated to systematically evaluate the appearance of lashes and hair around the eyes of patients who are administering bimatoprost in only one eye . the study involves 10 subjects , 5 male , 5 female , average age 70 years , ( ranging from 50 - 94 years ). all patients have glaucoma . each subject is treated daily by the topical application of one drop of bimatoprost at a dosage of 1 . 5 . mu . g / ml / eye / day ( 0 . 03 %, by weight , ophthalmic solution , sold under the name lumigan ® by allergan , irvine , calif ., u . s . a .) to the region of one eye by instilling the drop onto the surface of the eye . the region of the fellow control eye is not treated with bimatoprost and served as a control . in the course of treatment with eye drops , there is typically spontaneous tearing , and excess fluid from the drops and associated tears gathers at the lid margins . in the course of wiping the drug containing fluid from the lid margins and adjacent lid , a thin film of the fluid is routinely spread to contact the adjacent skin of the lid area . this widespread exposure of the skin around the lid to the effect of drops is regularly demonstrated in patients who develop a contact dermatitis . typically the entire area of the upper and lower lid are involved with induration , erythema and edema demonstrating the regular extensive exposure of the ocular adnexa to the influence of topically applied drugs . the study is limited to subjects who have administered bimatoprost to one eye for more than 3 months . the mean duration of exposure to bimatoprost prior to assessing the parameter of lash growth between the control and study eye is 129 days ( range 90 - 254 days ). observations are made under high magnification at the slit lamp biomicroscope . documentation of differences between the control and treatment areas is accomplished using a camera specially adapted for use with the slit lamp biomicroscope . length of lashes : increased length of eyelashes is regularly observed on the side treated with bimatoprost . the difference in length varies from approximately 10 % to as much as 30 %. number of lashes : increased numbers of lashes are observed in the treated eye of each patient . in areas where there are a large number of lashes in the control eye , the increased number of lashes in the bimatoprost - treated eye gave the lashes on the treated side a more thickly matted overall appearance . auxiliary lash - like hair growth : several patients have an apparent increase in lash - like hair in transitional areas adjacent to areas of normal lash distribution . these prominent robust appear lash - like hairs appeared to be of comparable length to the actual lashes . these long , thick lash - like hairs were present in the central portion of the lids of several patients in a linear arrangement just above the lash line . hairs are present at similar locations in the control eyes but are by contrast thinner or more fine in appearance , have less luster and pigment and are more flat against the skin of the lid typical of vellus or intermediate hairs . in several patients , lash - like terminal hairs grow luxuriantly in the medial canthal area in the treated eye . in the corresponding control eye , vellus hairs are seen at the same location . lash - like hairs are also present in the lateral canthal area of the treated eye but not the control eye in several subjects . large lashes are not normally present at the lateral canthus and the area is generally free of all but a few occasional very fine lashes or vellus hairs . increased growth of vellus hair on lids : fine microscopic vellus hair is present on the skin of the lids and is easily seen with the slit lamp biomicroscope . this vellus hair is typically denser adjacent to and below the lateral portion of the lower lids . while remaining microscopic , vellus hairs are increased in number , appear more robust and are much longer and thicker in treated than in control eyes in the areas below and lateral to the lower lid . perpendicular angulation of hairs : in areas where there are lash - like hairs above the lash line and in the medial and lateral canthal areas , the hairs are much longer , thicker and heavier . they also leave the surface of the skin at a more acute angle , as though they are stiffer or held in a more erect position by more robust follicles . this greater incline , pitch , rise or perpendicular angulation from the skin surface gives the appearance of greater density of the hairs . the foregoing observations clearly establish that bimatoprost can be used to increase the growth of hair in man . this conclusion is based on the regular and consistent finding of manifestations of increased hair growth in treated vs . control areas in human subjects . the conclusion that the drug bimatoprost is capable of inducing increased robust growth of hair is based not on a single parameter , i . e ., length , but is based on multiple lines of evidence as described in the results . detailed examination and description of multiple parameters of differences in hair is greatly facilitated by the ability to examine the hairs at high magnification under stable conditions of fixed focal length and subject position utilizing the capabilities of the slitlamp biomicroscope . the figure shows the actual results on the eyelashes of a patient treated for glaucoma with lumigan ® bimatoprost for 6 months . a topical cream is prepared as follows : tegacid and spermaceti are melted together at a temperature of 70 - 80 ° c . methylparaben is dissolved in about 500 gm of water and propylene glycol , polysorbate 80 , and bimatoprost are added in turn , maintaining a temperature of 75 - 80 ° c . the methylparaben mixture is added slowly to the tegacid and spermaceti melt , with constant stirring . the addition is continued for at least 30 minutes with additional stirring until the temperature has dropped to 40 - 45 ° c . finally , sufficient water is added to bring the final weight to 1000 gm and the a topical cream is prepared as follows : tegacid and spermaceti are melted together at a temperature of 70 - 80 ° c . methylparaben is dissolved in water and propylene glycol , polysorbate 80 , and bimatoprost are added in turn , maintaining a temperature of 75 - 80 ° c . the methylparaben mixture is added slowly to the tegacid and spermaceti melt , with constant stirring . the addition is continued for at least 30 minutes with additional stirring until the temperature has dropped to 40 - 45 ° c . finally , sufficient water is added to bring the final weight to 1000 gm and the preparation stirred to maintain homogeneity until cooled and congealed . the composition is applied to bald human scalp once daily to stimulate the growth of hair . an ointment containing 2 % by weight bimatoprost is prepared as follows : white petrolatum and wool fat are melted , strained and liquid petrolatum is added thereto . the bimatoprost , zinc oxide , and calamine are added to the remaining liquid petrolatum and the mixture milled until the powders are finely divided and uniformly dispersed . the mixture is stirred into the white petrolatum , melted and cooled with stirring until the ointment congeals . the foregoing ointment can be applied topically to mammalian skin for increased rate of hair growth , and can be prepared by omitting the zinc oxide and calamine . a dermatological ophthalmic ointment containing 10 % by weight bimatoprost is prepared by adding the active compound to light liquid petrolatum . white petrolatum is melted together with wool fat , strained , and the temperature adjusted to 45 - 50 ° c . the liquid petrolatum slurry is added and the ointment stirred until congealed . suitably the ointment is packaged in 30 gm tubes . the foregoing ointment can be applied to the eyelid to enhance the growth of eyelashes . similarly the composition can be applied to the brow for eyebrow growth . an aqueous solution containing 5 %, by weight , bimatoprost is prepared as follows . bimatoprost is dissolved in water and the resulting solution is sterilized by filtration . the solution is aseptically filled into sterile containers . the composition so prepared can be used in the topical treatment of baldness by application to the scalp daily . a sample of bimatoprost is dissolved in the vehicle of n - methylpyrrolidone and propylene glycol . the composition can be used for application to dogs or cats having hair loss due to mange or alopecia of other causes . an aerosol containing approximately 0 . 1 % by weight bimatoprost is prepared by dissolving the bimatoprost in absolute alcohol . the resulting solution filtered to remove particles and lint . this solution is chilled to about minus 30 ° c . to the solution is added a chilled mixture of dichlorodifluoromethane and dichlorotetrafluoroethane . thirteen ml plastic - coated amber bottles are cold filled with 11 . 5 gm each of the resulting solution and capped . the composition can be sprayed on the scalp daily to stimulate the growth of hair . a powder of the compound bimatoprost is prepared by mixing in dry form with talcum powder at a weight / weight ratio of 1 : 10 . the powdered mixture is dusted on the fur of minks or other commercially valuable fur bearing animals and show animals for increased rate of hair growth . following the procedure of the preceding examples , compositions are similarly prepared substituting an equimolar amount of a compound of table 1 for the bimatoprost disclosed in the preceding examples . similar results are obtained . while the preferred embodiment of the invention has been illustrated and described , it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention .
methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include a cyclopentane heptanoic acid , 2 - cycloalkyl or arylalkyl compound represented by the formula i wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration , a , b , z , x , r 1 and r 2 are as defined in the specification . such compositions are used in treating the skin or scalp of a human or non - human animal . bimatoprost is preferred for this treatment .