HIGH FREQUENCY APPLICATION OF BOTULINUM TOXIN THERAPY

Abstract

The present invention relates to methods for treating diseases and disorders by administering a composition containing the neurotoxic component of a Clostridium botulinum toxin complex, wherein the composition may be devoid of any other protein of the Clostridium botulinum toxin complex and wherein the composition is administered at short intervals and/or in high doses.

Claims

1. A method of treating a disease or condition caused by or associated with hyperactive cholinergic innervation of muscles in a patient, the method comprising administering a composition comprising a therapeutically effective amount of a neurotoxic component of a Clostridium botulinum toxin complex, the composition being devoid of any other protein component of the Clostridium botulinum toxin complex, to remove partially or completely the treated disease or condition symptoms, wherein (a) the patient is a human, (b) the composition is locally administered by injection of a non-lethal dose to a muscle exhibiting hyperactive cholinergic innervation, and (c) the composition is administered at an interval that provides a stable quality of life for the patient, the interval comprising a first treatment and a second treatment, wherein the second treatment is carried out at a point in time when the efficacy of the first treatment begins to decline.

2. The method of claim 1, wherein the second treatment is performed in order to improve the treatment effect of the first treatment.

3. The method of claim 1, wherein the patient is a human, who has been treated with a Clostridium botulinum toxin but who complains about a decrease of the treatment effect and who requires an additional treatment within 3 months of a previous treatment.

4. The method of claim 1, wherein the disease or condition is or involves dystonia of a muscle.

5. The method of claim 4, wherein the dystonia (a) is selected from the group consisting of cranial dystonia, blepharospasm, oromandibular dystonia of the jaw opening type, oromandibular dystonia of the jaw dosing type, bruxism, Meige syndrome, lingual dystonia, apraxia of the eyelid opening, cervical dystonia, antecollis, retrocollis, laterocollis, torticollis, pharyngeal dystonia, laryngeal dystonia, spasmodic dysphonia of the adductor type, spasmodic dysphonia of the abductor type, spasmodic dyspnea, limb dystonia, arm dystonia, task specific dystonia, writer's cramp, musician's cramp, golfer's cramp, leg dystonia involving thigh adduction, thigh abduction, knee flexion, knee extension, ankle flexion, ankle extension, equinovarus deformity, foot dystonia involving striatal toe, toe flexion, toe extension, axial dystonia, Pisa syndrome, belly dancer dystonia, segmental dystonia, hemidystonia, generalized dystonia, dystonia in Lubag, dystonia in corticobasal degeneration, tardive dystonia, dystonia in spinocerebellar ataxia, dystonia in Parkinson's disease, dystonia in Huntington's disease, dystonia in Hallervorden Spatz disease, dopa-induced dyskinesia, dopa-induced dystonia, tardive dyskinesia, tardive dystonia, paroxysmal dyskinesia, paroxysmal dystonia, paroxysmal kinesiogenic dyskinesia, paroxysmal non-kinesiogenic dyskinesia, and paroxysmal action-induced dyskinesia; or (b) involves a clinical pattern selected from the group consisting of torticollis, laterocollis, retrocollis, anterocollis, flexed elbow, pronated forearm, flexed wrist, thumb-in-palm and clenched fist.

6. The method of claim 4, wherein the muscle is selected from the group consisting of ipsilateral splenius, contralateral sternocdeidomastoid, ipsilateral stemocleidomastoid, splenius capitis, scalene complex, levator scapulae, postvertebralis, ipsilateral trapezius, levator scapulae, bilateral splenius capitis, upper trapezius, deep postvertebralis, bilateral stemocleidomastoid, scalene complex, submental complex, brachioradialis, biceps brachialis, pronator quadratus pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor pollicis longus, adductor pollicis, flexor pollicis brevis, flexor pollicis opponens, flexor digitorum superficialis, and flexor digitorum profundus.

7. The method of claim 1, wherein the disease or condition is or involves spasticity of a muscle.

8. The method of claim 7, wherein the spasticity is or is associated with a spastic condition in encephalitis and myelitis relating to autoimmune processes, multiple sclerosis, transverse myelitis, Devic syndrome, viral infections, bacterial infections, parasitic infections, fungal infections, hereditary spastic paraparesis, postapoplectic syndrome resulting from hemispheric infarction, postapoplectic syndrome resulting from brainstem infarction, postapoplectic syndrome resulting from myelon infarction, a central nervous system trauma involving a hemispheric lesion, a central nervous system trauma involving a brainstem lesion, a central nervous system trauma involving a myelon lesion, a central nervous system hemorrhage, an intracerebral hemorrhage, a subarachnoidal hemorrhage, a subdural hemorrhage or an intraspinal hemorrhage, a neoplasia, a hemispheric tumor, a brainstem tumor, a myelon tumor, post-stroke spasticity, or spasticity caused by cerebral palsy.

9. The method of claim 7, wherein the muscle is a smooth or striated muscle.

10. The method of claim 1, wherein the neurotoxic component is selected from the group consisting of type A, B, C, D, E, F, G or a mixture thereof.

11. A method of treating a disease or condition caused by or associated with hyperactive cholinergic innervation of muscles in a patient, the method comprising administering a composition comprising a therapeutically effective amount of a neurotoxic component of a Clostridium botulinum toxin complex, to remove partially or completely the treated disease or condition symptoms, wherein (a) the patient is a human, (b) the composition is locally administered by injection of a non-lethal dose to a muscle exhibiting hyperactive cholinergic innervation, and (c) the composition is administered at an interval that provides a stable quality of life for the patient, the interval comprising a first treatment and a second treatment, wherein the second treatment is carried out at a point in time when the efficacy of the first treatment begins to decline.

Description

EXAMPLE 1: BOTULINUM TOXIN THERAPY FOR TREATMENT OF CERVICAL DYSTONIA

[0207] A 45 year-old male patient suffering from cervical dystonia is evaluated for botulinum toxin therapy. After all appropriate examinations an injection scheme is constructed and botulinum toxin free of complexing proteins is applied accordingly in a total dose of 300 MU. On re-evaluation after 2 weeks the symptomatology is improved, but there is a need to include additional target muscles and to increase the botulinum toxin dose in initially injected target muscles. Two weeks later the patient is re-evaluated again and the treatment result is optimal.

[0208] Adverse effects do not occur. So far, on 7 subsequent injection series the treatment re-suits are maintained without any indication of antibody-induced therapy failure.

EXAMPLE 2: BOTULINUM TOXIN THERAPY FOR TREATMENT OF BLEPHAROSPASM. SHORT DURATION OF ACTION

[0209] A 61 year-old female patient suffering from blepharopsasm is treated with a medicament containing the neurotoxic component of the present invention, free of complexing proteins, in a total dose of 48 MU with excellent results. 4 weeks after the injections with the neurotoxic component the effect begins to wane. After 2 more weeks the effect of the treatment has almost completely ceased. Re-Injections are performed 7 weeks after the initial injection series. Therapy with the neurotoxic component is repeated in the initial dose and with identical effects. Therapy with the neurotoxic component is continued for 6 subsequent injection series with excellent therapeutic results and without any indication of antibody-induced therapy failure.

EXAMPLE 3: BOTULINUM TOXIN THERAPY FOR TREATMENT OF GENERALISED SPASTICITY. HIGH DOSE APPLICATION

[0210] A 35 year-old male patient suffering from hypoxic brain damage with generalized spasticity. The neurotoxic component of the present invention, free of complexing proteins in a total dose of 750 MU, is administered in three aliquots of 250 MU given with 1 day intervals. 2 weeks after the application the condition has improved substantially. Adverse effects, neither local nor regional nor systemic, cannot be detected. On 7 subsequent injection series the therapeutic effect is stable without occurrence of adverse effects. There is no indication of antibody-induced therapy failure.

EXAMPLE 4: COSMETIC USE OF BOTULINUM TOXIN. DIFFICULTIES IN CONSTRUCTING THE INJECTION SCHEME AND SHORT DURATION OF ACTION

[0211] A 40 year old female client presenting with muscular frowning lines and horizontal frontal lines was treated with 20 MU of botulinum toxin free of complexing proteins (i.e. the neurotoxic component of the present invention). 2 weeks later there is an improvement of the symptomatology, but additional injection of 20 MU of botulinum toxin are necessary. 2 weeks later the outcome is fully satisfactory for the patient. 4 weeks later the favorable effect starts to wane, so that botulinum toxin re-injections in a total dose of 40 MU become necessary. So far, the client has undergone 4 subsequent injection series with total doses of 40 MU each. There is no indication of antibody-induced therapy failure.