the botulinum toxins used according to the present invention are botulinum toxin serotype a , 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 ) recognizes , that is , neutralizes the biological activity of , for example , type a it will not recognize 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 . the physiologic groups of clostridium botulinum types are listed in table i . table i physiologic groups of clostridium botulinum phenotypically toxin glucose phages related sero - milk fermen - & amp ; clostridium group type biochemistry digest tation lipase plasmids ( nontoxigenic ) i a , b , f proteolytic saccharolytic + + + + c . sporogenes ii b , e , f nonproteolytic saccharolytic − + + + psychotrophic iii c , d nonproteolytic saccharolytic ± + + + c . novyi iv g proteolytic nonsaccharolytic + − − − c . subterminale these toxin types may be produced by selection from the appropriate physiologic group of clostridium botulinum organisms . the organisms designated as group i are usually referred to as proteolytic and produce botulinum toxins of types a , b and f . the organisms designated as group ii are saccharolytic and produce botulinum toxins of types b , e and f . the organisms designated as group iii produce only botulinum toxin types c and d and are distinguished 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 , d , e , f and g are described in chapter 1 of botulinum neurotoxin and tetanus toxin , 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 produce 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 g toxin was found in soil and has low toxigenicity . however , it has been isolated from autopsy specimens , but thus far there has not been adequate evidence that type g botulism has occurred in humans . in general , four physiologic groups of c . botulinum are recognized ( i , ii , iii , iv ). the organisms 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 ( c . baratii , type f ; c . butyricum , type e ; c . novyi , type c 1 or d ) have been identified which can produce botulinum neurotoxins . preferably , the toxin is administered by means of intramuscular injection directly into a spastic muscle , in the region of the neuromuscular junction , although alternative types of administration ( e . g ., subcutaneous injection ), which can deliver the toxin directly to the affected muscle 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 reconstitution into a sterile solution or dispersion . where desired , tonicity adjusting agents such as sodium chloride , glycerol and various sugars can be added . stabilizers such as human serum albumin may also be included . the formulation may be preserved by means of a suitable pharmaceutically acceptable preservative such as a paraben , although preferably it is 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 reconstituting a suitable vehicle such as water for injection . in one embodiment , the botulinum toxin is formulated in a solution containing saline and pasteurized human serum albumin , which stabilizes the toxin and minimizes loss through non - specific adsorption . the solution is sterile filtered ( 0 . 2 micron filter ), filled into individual vials and then vacuum - dried 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 muscle groups requiring treatment , the age and size of the patient and the potency of the toxin . the potency of the toxin is expressed as a multiple of the ld 50 value for the mouse , one unit ( u ) of toxin being defined as being the equivalent amount of toxin that kills 50 % of a group of 18 to 20 female swiss - webster mice , weighing 20 grams each . the dosages used in human therapeutic applications are roughly proportional to the mass of muscle being injected . typically , the dose administered to the patient may be up to about 1 , 000 units ; for example , up to about 500 units , and preferably in the range from about 80 to about 460 units per patient per treatment , although smaller of larger doses may be administered in appropriate circumstances . as the physicians become more familiar with the use of this product , the dose may be changed . in the botulinum toxin type a , available from porton , dysport , 1 nanogram ( ng ) contains 40 u . 1 ng of the botulinum toxin type a , available from allergan , inc ., i . e ., botox ®, contains 4 u . 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 . the invention will now be illustrated by reference to the following nonlimiting examples . in each of the examples , the appropriate muscles of each patient are injected with sterile solutions containing the botulinum toxins . total patient doses range from 80 u to 460 u . before injecting any muscle group , careful consideration is given to the anatomy of the muscle group , the aim being to inject the area with the highest concentration of neuromuscular 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 end . 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 . in accordance with the present invention , multiple injections are necessary to achieve the desired result , due to the patient &# 39 ; s experiencing loss of clinical response to an initial treatment . also , some injections , depending on the muscle to be injected , may require the use of fine , hollow , teflon - coated needles , guided by electromyography . following injection , it is noted that there are no systemic or local side effects and none of the patients are found to develop extensive local hypotonicity . the majority of patients show an improvement in function both subjectively and when measured objectively . the use of botulinum toxin serotype a , b and f in the treatment of tardive dyskinesia a patient , suffering from tardive dyskinesia resulting from the treatment with an antipsychotic drug , such as haloperidol , is treated with an effective amount of botulinum toxin type a by direct injection of such toxin into the muscles identified by the physician . after two to four days , the symptoms of tardive dyskinesia , i . e ., orofacial dyskinesia , athetosis , dystonia , chorea , tics and facial grimacing , etc ., are markedly reduced . upon continued administration of the botulinum toxin type a , a loss of clinical response is noted . thereafter , an effective amount of botulinum toxin type b is injected and the symptoms of tardive dyskinesia continue to be markedly reduced . the method of example 1 is repeated , except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type a , followed by injection of an effective amount of botulinum toxin type c . similar results are obtained . the method of example 1 is repeated , except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type a , followed by injection of an effective amount of botulinum toxin type d . similar results are obtained . the method of example 1 is repeated , except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type a , followed by injection of an effective amount of botulinum toxin type e . similar results are obtained . the method of example 1 is repeated , except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type a , followed by injection of an effective amount of botulinum toxin type f . similar results are obtained . a male , suffering from spasmodic torticollis , as manifested by spasmodic or tonic contractions of the neck musculature , producing stereotyped 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 up to about 300 units , or more , of botulinum toxin type e , ( having an activity of one to four days ) in the dystonic neck muscles . after the symptoms are substantially alleviated and the patient is able to hold his head and shoulder in a normal position , the patient develops antibodies . thereafter the patient is injected with botulinum toxin type b and the symptoms continue to be substantially alleviated . although there has been hereinabove described a use of botulinum toxin serotype for treating neuromuscular disorders and conditions 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 claims .
a method of treating a patient suffering from a disease , disorder or condition includes the administration to the patient of a therapeutically effective amount of botulinum toxin of a selected serotype until the patient experiences loss of clinical response to the administered botulinum toxin and thereafter administering to the patient a therapeutically effective amount of another botulinum toxin of a different serotype .