AU727739B2

AU727739B2 - Method of treating a cholinergic influenced secretion

Info

Publication number: AU727739B2
Application number: AU16366/00A
Authority: AU
Inventors: Roger K. Aoki; Steven R. Carlson; Michael W. Grayston; Judith M. Leon
Original assignee: Allergan Sales LLC
Current assignee: Allergan Inc
Priority date: 1993-12-28
Filing date: 2000-02-11
Publication date: 2000-12-21
Anticipated expiration: 2014-12-16
Also published as: AU1636600A

Description

METHOD FOR TREATING A CHOLINERGIC INFLUENCED

SECRETION

FIELD OF THE INVENTION The present invention provides novel methods for treating various disorders and conditions, with Botulinum toxins. Importantly, the present invention provides methods useful in treating cholinergic influenced secretions and cholinergically influenced glands.

The invention also relates to relieving pain related to muscle activity or contracture and therefore is of advantage in the treatment of, for example, muscle spasm such as Temporomandibular Joint Disease, low back pain, myofascial pain, pain related to spasticity and dystonia, as well as sports injuries, and pain related to contractures in arthritis. The invention also provides compositions suitable for use in the methods.

15 BACKGROUND OF THE INVENTION 9;* Heretofore, Botulinum toxins, in particular Botulinum toxin type A, has been used in the treatment of a number of neuromuscular disorders and conditions involving muscular spasm; for example, strabismus, blepharospasm, spasmodic torticollis (cervical dystonia), 20 oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). The toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetylcholine release. This results in local paralysis and hence relaxation of the muscle afflicted by spasm.

For one example of treating neuromuscular disorders, see U.S. Patent No.

5,053,005 to Borodic, which suggests treating curvature of the juvenile P \WPDOCS\KDRSPECSDIV 7 DESCRIPTIONDOC-I I Fcbmary Our Ref: 7464527 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT *b Applicant(s): Address for Service: Allergan Sales, Inc 2525 Dupont Drive Irvine palifornia 92612 United States of America DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Invention Title: Method for treating a cholinergic influenced secretion The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 -2spine, scoliosis, with an acetylcholine release inhibitor ,Preferably Botulinum toxin

A.

For the treatment of strabismus with Botulinum toxin type A, see Elston, et al., British Journal of Ophthalraoiogy 1985, 69, 718-724 and 891- 896. For the treatment of blepilarospasm with Botulinum toxin type A, see Adenis, et al., J. Fr. OPhthalmol., 1.990, 13 at pages 259-264.

For treating squint, see Elston, Eye, 1990, 4(4):VII. For treating spasmodic and orojuandibular dystonia torticollis, see Jankovic et al., Neurology, 1987, 37, 61.6-623.

Spasmodic dysphonia has been treated with Botulinum txntype A. See Bl1itzer et al., Ann.

*.Otol. Rhino. Laryngol .1985, .94, 591-594. Lingual dystonia was treated with Botujlinum toxin type

A

according to Brin et al., Adv. Neurol. (1987) 50, 599- 2 60. Finally, oe et alNeurolc. gy (187 37 (Supp1 1) 123-4, discloses the treatment of writerIs cramp with Botulinum toxin type

A.

The term Botulinum toxin is a generic termi embracing the family of toxins produced by the anae- robic bacterium Clostridium botulinum and, to date, se .ven imnlgclydistinct neuotoxi.ns haebeen identified. These have been given the designations

A,

B, C, D, E, F and G. For further in formation concerning the properties of the various Botulinum toxins, reference is made to the article by Jankovic and Brin, The New England Journal of Medicine, No. 17, 1990, Pp. 1186-1194, and to the review by Charles

L.

Hatheway in Chapter 1 Of the book entitled Botulinum Neurotoxin and Tetanus Toin L. L. Simpson, Ed., -3- Published by Academic Press Inc. of San Diego, California, 1989 the disclosures in which are incorporated herein by reference.

The neurotoxic component of Botulinu a molecular weight of about .linum toxin has tha molecular weight of about 150 kilodaltons and is thought to comprise a short polypeptide chain of about kD which is considered to be responsible for the toxic properties of the toxin, by interering with the exocytosis of acetylcholine, by nterferasing the frequency of acetylcholine release, and a larger Polypeptide chain of about 00 kD whichis believed to be necessary to enable thtoxinto bind to the presynaptic membrane, The "short" and "long chains are linkedtogether by means of a i l i n k e d t ogether by means of a simple disulfide bridge. (It is noted that certain seroty e. I t i s noted that certain serotypes of Botulinum toxin, type may exist in theform o e g oxie E, may exist in the form of a single chain un-nicked 20 protein, as opposed to a dichain The single chain form is less active ut i T h e s i n gl e chain form is less active but may be converted to the corresponding dichain by nicking with a protease trypsin. Both th n g poe se.g., n trypsin. o ththe single and the dichain are useful in the method of the present invention.) In general, four physiologic grous of C. botuli- Snum are recognized II, III, IV). The organisms capable of producinga T h e oranisms capable of producing a serologically distinct toxin may come from more than one physiological group. For example, Type B and F toxins can be produced by strains from Group I or II. In addition, other strains of clostridial species baratii, type

F;

C. butyricum, type E; C. novyi, type C 1 or D) have been identified which can produce botulinum neurotoxins.

Immunotoxin conjugates of ricin and antibodies, which are characterized as having enhanced cytotoxicity through improving cell surface affinity, are disclosed in European Patent Specification 0 129 434. The inventors note that botulinum toxin may be utilized in place of ricin.

Botulinum toxin is obtained commercially by establishing and growing cultures of C. botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known techniques.

Botulinum toxin type A, the toxin type generally utilized in treating neuromuscular conditions, is currently available commercially from several sources; for example, from Porton Products Ltd. UK, under the trade name "DYSPORT," and from Allergan, Inc., Irvine, California, under the trade name BOTOX@.

It is a preferred object of the invention to provide novel treatments of neuromuscular disorders and conditions with various Botulinum toxin types. It is another preferred object of the present invention to relieve pain with various Botulinum toxin types.

20 SUMMARY OF THE INVENTION According to a first aspect of the present invention there is provided a method of treating a cholinergic influenced secretion, the method comprising the step of administering to a patient an effective amount of a botulinum toxin in order to treat a 25 cholinergic influenced secretion.

According to a second aspect of the present invention there is provided a method for treating a cholinergically influenced gland, the method comprising the step of administering to a cholinergically influenced gland a botulinum toxin in order to treat a secretory activity of the gland.

According to a third aspect of the present invention there is provided use of a botulinum toxin in the preparation of a medicament for the treatment of a cholinergic influenced secretion.

According to a fourth aspect of the present invention there is provided use of a botulinum toxin in the preparation of a medicament for the treatment of a secretory ctivity of a cholinergically influenced gland.

P 1WPDOCS\KD\SPECS\DIV7 DESCRIPTIONDOC-II Fd&-y 2000 The present invention provides a method for relieving pain, associated- with muscle contractions, a composition and a method of treating conditions such as cholinergic controlled secretions including excessive sweating, lacrimation and mucus secretions and a method for treating smooth muscle disorders including, but not limited to, spasms in the sphincter of the cardiovascular arteriole, gastrointestinal system, urinary, gall bladder and rectum, which method comprises administering to the patient suffering from said disorder or condition a therapeutically effective amount of Botulinum toxin selected from the group consisting of Botulinum toxin types B, C, D, E, F and G.

Each serotype of Botulinum toxin has been identified as immunologically different proteins through the use of specific antibodies. For example, if the antibody (antitoxin) recognises, that is, neutralises the biological activity of, for example, type A it will not recognise types B, C, D, E, F or G.

While all of the Botulinum toxins appear to be zinc endopeptidases, the mechanism of action of different serotypes, for example, A and E within the neuron appear to be different than that of Type B. In addition, the neuronal surface "receptor" for the toxin appears to be different for the serotypes.

In the area of use of the Botulinum toxins in accordance with the present invention with regard to organ systems which involve the release of neurotransmitter, it is expected to introduce the toxins A, B, C, D, E, F, and G directly by local injections.

25 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

DETAILED DESCRIPTION The Botulinum toxins used according to the present invention are Botulinum toxins type A, B, C, D, E, F and G.

P WPDOCS\KDF\SPECS\DjV 7 DESCRIPTIONDOC.I I Fcbmaq 2(X) -6- The physiologic groups Of ClOstridjum botulin..m types are listed in Table 1.

Table L. PhYsiologic Groups or Clostiidiwrn bofzdinurn p S n. Milk GIUCxzW Phagpz PhCypaiJy Typep ffID- Dip=s Pcrmcn.. LJaPW R~ e I A,8,FPprweCOIYtic Saccharolytic snrenics If B.E, flofproteol) jc Saccharolytic 9 meq PsychOirophic II C.D flonpmojeolytc SaccharoInic Cn w IV G proteolylic nonsaccharoyi 11,11:u1 e,'1n- p **These toxin types may be produced by selection from the. appropriatephsogi bthe nu orhyis s iogoguc of ClOst-r d um botlinm ogan~~ 5 the organisms. designated as Group I are usually referred to as proteolytic and Produce Botulinum t oxins of types A, B and iF. The *.organisms designated as .Group 11 are saccharolytic and Produce Botulinum toxins OftpsB, Eand F. The organisms designated as Group III produce only Botulinum toxin types C and D and are distinguished 20 from organisms of Groups I and II by the production of .significant amounts of propionic acid. Group

IV

organisms only produce neurotoxin of type G. The production of any and all of the Botulinum toxin types A, B, C, Dr E, F and G are described in Chapter 1 of Botulinum Neurotoxin and retanus--Toxjn, cited Above, and/or the references cited therein. Botulinum toxins types B, C, D, E, F and G are also available from various species of clostridia.

Currently fourteen species of clostridia are considered pathogenic. Most of the pathogenic strains produce toxins which are responsible for the various pathological signs and symptoms. organisms which pro- -7dUce Botulinum toxins have been isolated from botulism Outbreaks in humans (types A, B, E and F) and animals (types C and D) Their identities were described through the use Of specific antitoxins (antibodies) developed against the earlier toxins. Type ton was found in soil and has low toxigenicity GHove it has been isolated from autopsy specimens, but thus far there has not been adequate evidence that type

G

botulism has occurred in humans.

Preferably, the toxin is administered by mneans of intramuscular injection directly into a local area such as a spastic muscle, preferably in the region of theneuomscuarjunction, althoughalentvtys ofadministration subcutaneous injection), which cndeliver the toxin directly to the affected region, may be employed where appropriate. The toxin can be presented as a sterile pyrogen-.free aqueous solution or dispersion and as a sterile powder for reconstitutio into a sterile solution or dispersion.

Where desired, tonicity adjusting agents such as sodium chloride, glycerol and various sugars cnbe added. Stabilizers such as human serum albumin may also be included. The formulation may be preserved by **means of a suitable phraeuial acceptable pe servative such as a kpLLr1Len, alhog pref'erably itis unpreserved.

It is preferred that the toxin is formulated in Unit dosage form; for example, it can be Provided as a sterile solution in a vial or as a vial or sachet containing a lyophilized Powder for reconsti tut ing a suitable vehicle such as sajaine for injection.

-8- In one embodiment, the Botulinum toxin is formulated in a solution containing saline a n d pasteurized human serum albumin, whic h stabilizes the tion. The solution oss through non-specific adsorp- 5 tion. The solution is sterile filtered (0.2 micronfilter), filled into individual vials and then vacuumdried to give a sterile lyophilized powder. In use, the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).

The dose of toxin administered to the patient will depend upon the severity of the condition; e.g the number of musc condition; e.g. the number of e groups requiring treatment, the and size of the patient and the potency of the toxin. The Potency of the toxin is expressed as a "*to multiple of the LDso value for the mouse, one unit of toxin being defined as being the euivalent to thatmou, one uit (U) Sbasis, that kills 50% at amount, on a per mouse basis, and 2at2 grams 50% of a group of Swiss-Webster mice weighing between 17 20 and 22 grams each.

The dosages used in human therapeutic applications are rouo1 i hum" t h e apeutic applications are roughly proportional to the mass of muscle being injected. Typically the dose admin- 25 istered to the patient T y p ic a l l y t h e d o se administered to the patient may be up from about 0.01 to about 1,000 units; for example, up to about 500 units, andits Per ablyin the range from ab-ut-so to about 460 units per patient per treatment, although smaller of larger doses may be administered in appropriate circumstances such as up to about 50 units for the relief of pain and in cntrollingcholinergic secretions.

As the physicians become more familiar with the use of this product, the dose may or e fa liar wth the Botulinum toxin type A, available ch an from Porton, ype A, available from Porton, -9- DYSPORT, 1 nanogram (ng) contains 40 units. 1 ng of the Botulinum toxin type A, available from Allergan, Inc., BOTOX contains 4 units. The potency of Botulinum toxin and its long duration of action mean that doses will tend to be administered on an infrequent basis. Ultimately, however, both the quantity of toxin administered and the frequency of its administration will be at the discretion of the physician responsible for the treatment and will be commensurate with questions of safety and the effects produced by the toxin.

In some circumstances, particularly in the relief of pain associated with sports injuries, such as, for :5 .5 example, charleyhorse t s nju r i e s s u c h as, f or example, charleyhorse, botulinum type F, having a short duration activity, is preferred.

The invention will now be illustrated by reference to the following nonlimiting examples.

Ic n each of the examples, appropriate areas of :each patient are injected with a sterile solution containing the confirmation of Botulinum toxin. Total Satient doses range from about 0.01 units to 460 units. Before injecting any muscle group, careful .r consideration is given to the anatomy of the muscle group, the aim being to inject the area with..the highest concentration of neuromuscul ar junctiot known. Before ine e u r omuscular junctions, if known. Before injecting the muscle, the position of the needle in the muscle is confirmed by putting the muscle through its range of motion and observing the resultant motion of the needle ed. General anaesthesia, local anaesthesia and sedation are used according to the age of the patient, the number of sites to be injected, and the particular needs of the patient. More than One injection and/or sites of injection may be necessary to achieve the desired result. Also, some o a c h i e v e t h e desired resulte Also, some injections, depending on the scl e to be injected may require the Use of fine, hollow, teflon-coated needles, guided by electromyography., guided by Following injection, it is noted that there are "o systemic or l ocal l t i s n o t e d that there are 1 0 no systemic or local side effects and none of the patients are found to develop extensive local hypotonicity. The mority of p e x t e n s i v e local hypotonicity. The majority of patients show an improvement in function both subjectively and when measured objectively.ctively easured E'aJ^e 1 A male patient, age 45, sufferin from tardve dYskinesia esulting from th treatment with an treated ith unit T hor a z i ne or Haldol, is ree with 15e units of Botulinum toxin type B by Sdics injectsn I such toxin into the facial uscles. After 1-3 days, the symptoms of tardive S 25 dyskinesia, orofacial dyskinesia, athetosis eted with 50 units of Botulinum toxin type a) The method of Example i Spatient suffering d s r e p e a t e d e x c e p t t h a t S injected sith n from tardive dyskine s i a is SA sinj ar result is ouits of Botulinum toxin type

C.

A similar result is obtainedx -11- E~anLe 1(b) The Method Of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with 50-200 units of BotulimumtoityeD A similar result is obtained.txnypDo Exajnle 1 c) The method of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with 50-200 units of Botulinum toxin type

E.

A similar result is obtained.

X plle _d *.:ooThe method of Example I is repeated, except that a patient suffering. from tardive dYskinesia is injected with 50-200 units of Botulinur toxin type

F.

Asimilar result is obtained.

too.

*Example (e) Temethod of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injetedwith 50-200 units of Botulinum toxin type

G.

A similar result is-obtained.

EaMP -1e 2 The UseAo Bou~ifln t xin T ie B n the Treatment of S asmodic Torticollis: A male, age 45, suffering from spasmodic torticollis, as manifested by spasmodic or tonic contractions of- the neck musculature, producing -12stereotyped abnormal deviations of the head, the chin being rotated to one side, and the shoulder being elevated toward the side at which the head is rotated, is treated by injection with 100-1,000 units of Botulinum toxin type E. After 3-7 days, the symptoms_ are substantially alleviated; the patient is able to hold his head and shoulder in a normal position.

Example 2(a) The method of Example 2 is repeated, except that a patient suffering from spasmodic torticollis is injected with 100-1,000 units of Botulinum toxin type B. A similar result is obtained.

.Example 2(b) The method of Example 2 is repeated, except that a patient suffering from spasmodic torticollis is injected with 100-1,000 units of Botulinum toxin type C. A similar result is obtained.

Example 2(c :The method of Example 2 is repeated, except that a patient suffering from spasmodic torticollis is injected with 100-1,000 units of Botulinum toxin type D. A similar result is obtained.

Examle 2 (d) The method of Example 2 is repeated, except that a patient suffering from spasmodic torticollis is -13injected with 100-1,000 units of Botulin toxin type E. A similar result is obtained.

Example 2(e) The method of Example 2 is repeated, except that a patient suffering from spasmodic torticollis is injected with 100-1,000 units of Botulinum toxin type F. A similar result is obtained.

Example 2(f) method except that The method of Example 2 is repeated, except that SEssential Trenmor 1,000 Units of Botulinum toxin type B. After two to eight weeks, the symptoms are substantially 0 alleviated; the patient 5 head or hand ceases tor scillate as a rhyticillation .ostue or ad uscles and is provoked by maintenance of po o r mo e is treated by injection with 50ei00 untsof Botulinum toxin type B. After two to ihlviatedek, e symptoms are substantially oscllate.; the patient's head or hand ceases to -14- Example 3(a The method of Example 3 is repeated, except that a patient suffering from essential tremor is injected with 100-1,000 units of Botulinum toxin type C. A similar result is obtained.

Example 3(b) 0 The method of Example 3 is repeated, except that a patient suffering from essential tremor is injected with 100-1,000 units of Botulinum toxin type D. A similar result is obtained.

Example 3c) The method of Example 3 is repeated, except that a patient suffering-1000 from essential tremor is injected with 100-1,000 units of Botulinum toxin type E.

A

similar result is obtained.

Example 4 The Use of Botulinum toxin in the Treatment of Spasmodic Dsphonia A male, age 45, unable to speak clearly, due to spasm of the vocal chords, is treated by injection of the vocal chords with Botulinum toxin type B, having an activity of 80-500 units. After 3-7 days, the patient is able to speak clearly.

Example 4(a) The method of Example 4 is repeated, except that a patient suffering from spasmodic dysphonia is 15 injected with 80-500 units of Botulinum toxin type

C

A similar result is obtained.

Example 4(b) 20 The method of Example 4 is repeated, except that a patient suffering from spasmodic dysphonia is .i injected with 80-500 units of Botulinum toxin type D A similar result is obtained.

Example 4(c) The method of Example 4 is_repeated,. except that a patient suffering from spasmodic dysphonia is injected with 80-500 units of Botulinum toxin type

E

A similar result is obtained.

Example 4(d) The method of Example 4 is repeated, except that a patient suffering from spasmodic dysphonia is -16injected with 80-500 units of Botulinum toxin type

F.

A similar result is obtained.

Example 4(e) The method of Example 4 is repeated, except that a patient suffering from spasmodic dysphonia is injected with 8-500 units of Botulinum toxin type

G.

A similar result is obtained.

Example The Use of Botulinm toxin Types A-G in the Treatment of Excessive Sweatin Lacrimation or 15 Mucus Secretion oreOther Chlineric Controlled 1Secretions A male, age 65, with excessive unilateral sweating is treated by administering 0.01 to 50 units of Botulinum toxin, depending upon degree of desired 20 effect. The larger the dose, usually the greater spread and duration of effect. Small doses are used initially. Any serotype toxin alone or in combination could be used in this indication. The administration i.s to the gland nerve plexus, ganglion, spinal cord or central nervous system to be determined by the physician's knowledge of the anatomy and physiology of t. he target-glands- and-secretary-cel-ls. -In addition, the appropriate spinal cord level or brain area can be injected with the toxin (although this would cause many effects, including general weakness). Thus, the gland (if accessible).or the nerve plexus or ganglion are the targets of choice. Excessive sweating, tearing (lacrimation), mucus secretion or gastrointestinal secretions are positively influenced by the cholinergic nervous system. Sweating and -17tearing are under greater cholinergic control than mucus or gastric secretion and would respond better to toxin treatment. However, mucus and gastric secretions could be modulated through the d holinergic ystem. All symptoms would be reduced or eliinergic with toxin therapy i abu 1 aec o r e l i m i n a t e d with toxin therapy in about 1-7 days. Duration would be weeks to several months.

Ecample 6 10 The Use of BotulMtxi t nTe Treatment of Muscle Sasms in Smooth Mscle 15 Bladder, Rectal, Etc 1 5 A male, age 30-40, no ve e, agprevents h3-4 with a constricted pyloric valve which prevents his stomach from emptying, is treated by administering 1-50 units of Botulinum toxin The administrat ion is to the pyloric valve (which controls release of stomach contents into the intestine) divided into 2 to 4 quadant s into the made with any endoscop d2o4uad r a n t s inje c t i o n s m. made with any endoscopic device or during surgery. n about 1-7 da e uring surgery. about 1-7 days, normal emptying of the stomach, elimination or drastic reduction in regurgitation occurs.

ExamiEe.

7 The Use of Botulin toxin T es it e Tment of Muscle S asms and Control of Pain Associated with Muscle s asms in Temoral Mandibular "Joint Disorders A female age 35, is treated by administration of 0.

5 to 50 units total of Botulinum toxin. The administration is to the muscles controlling the -18closure of the jaw. Overactive muscles may be identified with EMG (electromyography) guidance.

Relief of pain associated with muscle spasms, possible reduction in jaw clenching occurs in about 1-3 days.

Example 8 The Use of Botulinum toxin Tves A-G in the Treatment of Muscle asms anControl of Pain Associated with Muscle S asms in Conditions Secondary to ports Injuries (Charleyhorse A male, age 20, with severe cramping in thigh S. after sports injury is treated by administration of a short duration toxin, possible low dose (0.1-25 units) of preferably type F to the muscle and neighboring muscles which are in contraction ("cramped"). Relief of pain occurs in 1-7 days.

Exazple 9 20 The Use of Botulinm toxin Tes A-G in the Treatment ofMuscle S sms and Control of Pain Associated with Muscle Snasms in Smooth Muscle Disorders Such as Gastrointestinal Muscles 25 A female, age 35, with spastic colitis, is treated with 1-100 units of Botulinum toxin divided S into several--arease-nema- (1-5--uit-s)--del-ivered-in the standard enema volume, titrate dose, starting with the lowest dose. Injection is to the rectum or lower colon or a low dose enema may be employed. Cramps and pain associated with spastic colon are relieved in 1-10 days.

-19- Example The Use of Botulinum toxin es A-G in the Treatment of Muscle S asms and Control of Pain Associated with Muscle S asms in Sasticit Conditions Secondar to Stroke Traumatic Brain or SPinal Cord ITnury A male, age 70, post-stroke or cerebral vascular event, is injected with 50 to 300 units of Botulinum toxin in the major muscles involved in severe closing of hand and curling of wrist and forearm or the muscles involved in the closing of the legs such that the patient and attendant have difficulty with hygiene. Relief of these symptoms occurs in 7 to 21 days.

Example 11 The Use of Botulinum toxin Tpes A-G in the STreatment of Patients wit Swalowing disorders A patient with a swallowing disorder caused by excessive throat muscle spasms is injected with about 1 to about 300 units of Botulinum toxin in the throat muscles. Relief the swallowing disorder occurs in 25 about 7 to about 21 days.

••ooo Example 12 The Use of Botulinum toxin Types A-G in the Treatment of Patients with Tension Headache A patient with a tension headache caused by excessive throat muscle spasms is injected with about 1 to about 300 units of Botulinum toxin in muscles of the head and upper neck. Relief of the tension headache occurs in about 1 to about 7 days.

Although there has been hereinabove described a use of Botulinum toxins for treating various disorders, conditions and pain, in accordance with the present invention, for the purpose of illustrating the manner in which the invention may be used to advantage, it should be appreciated that the invention is not limited thereto since many obvious modifications can be made, and it is intended to include within this :invention any such modifications as will fall within the scope of the appended claims. Accordingly, any and all modifications, variations, or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended o: 25 claims.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims

1. A method of treating a cholinergic influenced secretion, the method comprising the step of administering to a patient an effective amount of a botulinum toxin in order to treat a cholinergic influenced secretion.

2. The method of claim 1, wherein the botulinum toxin is botulinum toxin type A.

3. The method of claim 1, wherein the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F and G.

4. The method of claim 1, wherein the botulinum toxin is administered in an amount of between about 0.01 units and about 500 units. *000

5. The method of claim 1, wherein the botulinum toxin is administered in an amount of between about 0.01 units ane about 50 units.

6. The method of claim 1, wherein the cholinergic influenced secretion treated is a Voss non-gastric secretion.

7. A method for treating a cholinergic influenced secretion of a human patient, the method comprising the step of administering to a human patient a therapeutically effective amount of botulinum toxin type A thereby reducing a cholinergically *oo influenced secretion. S

8. A method for treating a cholinergically influenced gland, the method comprising the step of administering to a cholinergically influenced gland a botulinum toxin in order to treat a secretory activity of the gland.

9. The method of claim 8, wherein tlhe gland is an excessively secreting gland. The method of claim 8, wherein the botulinum toxin is botulinum toxin type A. P \WPDOCS\KDRSPECS\DIV 7 CLAIMS.DOC-I I Fbn.-y 2000 -22-

11. The method of claim 8, wherein the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F and G.

12. The method of claim 8, wherein the botulinum toxin is administered in an amount of between about 0.01 units and about 500 units.

13. The method of claim 8, wherein the botulinum toxin is administered in an amount of between about 0.01 units and about 50 units.

14. The method of claim 8, wherein the botulinum toxin is administered by injection into the gland or into the local area of the gland.

15. The method of claim 8, wherein the cholinergic influenced secretion gland is a non-gastric gland. e S16. A method for treating an excessively secreting, cholinergically influenced gland, the method comprising the step of injecting an excessively secreting, cholinergic influenced gland or local gland area of a human patient with a therapeutically effective amount of botulinum toxin type A thereby reducing the excessive glandular secretion.

17. Use of a botulinum toxin in the preparation of a medicament for the treatment of a cholinergic influenced secretion.

18. Use of a botulinum toxin in the preparation of a medicament for the treatment of a secretory activity of a cholinergically influenced gland. DATED this 1 1th day of February 2000 ALLERGAN SALES, INC. By their Patent Attorneys DAVIES COLLISON CAVE I\WPDOCSKDFSPECS\D1V 7 CLAIMS.DOC.I I Febn.-,r 21O)