WO1992022302A1

WO1992022302A1 - Treatment of human diseases involving dysregulation or dysfunction of the nervous system

Info

Publication number: WO1992022302A1
Application number: PCT/US1992/004540
Authority: WO
Inventors: Jonathan Leeds Costa; Jesus Alberto-Diazgranados Sanchez
Original assignee: Fractal Laboratories, Incorporated
Priority date: 1991-06-07
Filing date: 1992-06-01
Publication date: 1992-12-23
Also published as: AU2160492A; US5189026A; US5302583A

Abstract

A method of preventing, treating and/or controlling diseases caused by dysregulation and/or dysfunction of various portions of the nervous system which comprises administering to a patient, an effective amount of a compound of the avermectin family, e.g. ivermectin, in single or multiple doses of up to 1.6 mg/kg at intervals of from 3 days to 4 months.

Description

TREATMENT OF HUMAN DISEASES INVOLVING DYSREGULATIQN OR DYSFUNCTION OF THE NERVOUS SYSTEM

Background

Field of Invention

This invention relates to the use of the C-076 family of compounds, i. e. avermectins, for the preven¬ tion, treatment and control of various diseases in humans caused by dysregulation and/or dysfunction of various

10 portions of the human nervous system. More particularly, this invention relates to the administration of the avermectin class of compounds (1) to prevent, treat, and control such diseases in humans as seizures, dystonic movements, tremors, degenerative conditions of the brain,

15 spinal cord, and peripheral nerves, spasticity of both brain and ^■ spinal cord origin, and various types of psy¬ choses and personality disorders, (2) to increase tonic activity of the parasympathetic nervous system, as in bladder and bowel control, (3) to decrease activity of

*^° the sympathetic nervous system at cutaneous and cardio¬ vascular levels, (4) to ameliorate depression, (5) to regularize the sleep-wake cycle, (6) to decrease addic¬ tive and abusive behavior, (7) to increase attention span and improve behavior of mentally-deficient children and

25 adults. (8) to treat autoimmune disorders, (9) to treat

SUBSTITUTE SHEET malignant states, and (10) to prevent or ameliorate anoxic or ischemic damage to the nervous system, as well as specific pharmaceutical formulations and treatment regi¬ mens for such prevention, treatment and control.

The preferred compound which is used to illustrate this invention is ivermectin. Ivermectin is a semi- synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroaver- mectin B_la and less than 20% 22,23-dihydroavermectin B-_j^. The following structural formula represents the avermec¬ tin series of compounds, which compounds can be chemical¬ ly converted to useful derivatives as discussed below.

wherein R is the 4 -(alpha-L-oleandrosyl)-alpha-L- oleandrose group of the structure:

SUBSTITUTE SHEET and wherein the broken line indicates a single or double bond; Ri is hydroxy and is present only when said broken line indicates a double bond; R₂ is isopropyl or sec- butyl; and R3 is methoxy or hydroxy. Prior Art

The avermectin family, of which ivermectin, a chemi¬ cally produced analog, is a member, is a series of .com¬ pounds isolated from the fermentation broth of a C-076 producing strain of Streptomyceε avermi ti lli s and also chemically produced derivatives thereof. At least eight distinct but closely related compounds are produced by S . avermi ti l l i s , A_la> A_lb, A_2a , A_2b , B_χa , B_lb , B_£a , and B_2b . Their production is described in US Patent 4,310,519. The preparation of ivermectin is disclosed in US Patent 4,199,569. The disclosures of each of the foregoing patents are incorporated herein by reference. The aver¬ mectin family of compounds is a series of very potent antiparasitic. agents known to be useful against a broad spectrum of endoparasiteε and ectoparasites in mammals and also to have agricultural uses against various nema- toάe and insect parasites found in and on crops and in soil .

Some of tne avermectins contain a 22,23-double bond.

Tnis may be selectively reduced to prepare the ivermectin compounds. In addition, the avermectins possess a disac- oharide moiety at the 13-position consisting of the aipha-L-olearidroεy] -alpha-L-oleandrosyl group. One or

SUBSTITUTE SHEET both of these saccharide groups may be removed as de¬ scribed in US Patent 4,206,205. The thus produced agly- cone derivatives have a h droxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in US Patent 4,171,314 and 4,173,571; the latter patent also describes the 13-halo derivatives. The aver ectin compounds and derivatives have several hydroxy groups which may be acylated as described in US Patent 4,201,861. Other derivatives of avermectin and ivermectin are disclosed in US Patents 4,333,925 and 4,963,667. All the aforementioned patents are incorpo¬ rated herein by reference. The compounds disclosed in the patents mentioned above share the property of antipara¬ sitic activity with ivermectin. Since all the compounds mentioned and referred to above share the spectrum of anti-parasitic biological activity of ivermectin, varying only in degree, it is expected they will share the activity spectrum needed to make them suitable for use in this invention. In order to establish their potency and selectivity as compared to ivermectin, other members of the avermectin class could be screened utilizing in vitro and in vivo models already known from the literature. Compounds which look promis¬ ing for preventing, treating or controlling a particular indication in the in vitro screens are tested further in animal models. Those with the potency desired in the animal models are then further selected for testing in

SUBSTITUTE SHEET human pharmacodynamic models and clinical trials.

In vitro screens which are suitable include (1) the binding of the test compounds as radio labeled deriva¬ tives thereof to preparations of gamma-aminobutyric. acid (GABA) receptors, subtypes A and B, (2) the displacement of the binding of other known GABA A and B receptor agonists by the avermectin compounds, (3) examination of the ability of either the avermectin compounds, or of other GABA agonists plus the avermectin compounds, to bind in the presence of GABA, and (4) effects of the avermectin compounds on the release and uptake of GABA by brain or nerve preparations. The tests described herein are disclosed in the following publications: Sigel, et al. Mol. Pharmacol., 3_2, 749-52 (1987); Soderlund, et al., Biochem. Biophys . Res. Comm. 146 , 692-698 (1987) ; Kirkness, et al . , Eur. J. Pharmacol. , 150 , 385-388 (1988); Robertson, Br. J. Pharmacol. , 98_., 167-176 (1989) ; Chu, et al., Neurol . , 3_J_, 1454-1459 (1987); Bhisitkul, et al . , Exp. Brain Res., 6_6_, 659-663 (1987); Kerr, et al . , Brain Res. , 405 , 150-154 (1987); Price, et al . , Nature, 307 , 71-74 (1984); Bowery, et al . , Neuropharmacol . , 2J3, 219-231 (1984); Olsen, et al . , FASEB J., £, 1469-1480 (1990) ; and Erickson, Sci . Amer. , 264_., 124 (1991). All four types of assays can be performed using GABA prepara- tions derived from different regions of the brain, spinal cord, peripheral nerves, and various body organs.

In vivo screens suitable for testing include using animal models for seizures and for spasticity. Suitable

SUBSTITUTE SHEET seizure models are disclosed in Porter, et al. , Cleveland Clin. Quart., 5_1_, 293-305 (1984); McNamara, et al . , Neuro- pharmacol., 2_, 563-568 (1988); and McNamara, Epilepsia,

_*

30, (Suppl 1) S13-S18 (1989). Suitable spasticity models are disclosed in Coward, Triangle, 20_., 151-158 (1981); Davies, Br. J. Pharmacol., 76_., 473-481 (1982); Davies, et al., Br. J. Pharmacol., 78_., 137-1432 (1983), and Sayers, et al., Arzneimittel-Forschung, 30_., 703-803 (1980).

Comparative human pharmacodynamic studies are then conducted using the compounds with the particular biolog¬ ical profile predicted from the in vitro and animal screens. The human tests which are suitable are dis¬ closed in Hagbarth, J. Neurol. Neurosurg. Psychia. , 23, 222-227 (I960); Hagbarth, et al. , J. Neurol. Neurosurg. Psychia., 31_, 207-213 (1968); Hassan, et al. , J. Neurol. Neurosurg. Psychia., 43_., 1132-1136 (1980); Knutsson, et al., Scand. J. Rehabil. Med. , 12., 93-106 (1980); Knuts¬ son, Triangle, 2JL_., 13-20 (1982); Knutsson, et al. , J. Neurol. Sci. , 5_.3, 187-204 (1982); and Kugelbert, Elec- troenceph. Clin Neurophysiol. , Suppl. 2__ , 103-111 (1962) .

The only use for human patients described in the literature for the avermectins, and ivermectin in partic¬ ular, is for treating nematode parasites, particularly onchocerciasis (river blindness) utilizing dosages of up to 150 micrograms per kilogram of body weight. No side effects of significance were reported and no teratogenic

SUBSTITUTE SHEET activity was found, Pacque, et al. , Lancet, 335 , 1377- 1380 (1990) and Pacque, et al. , Lancet, 336, 1486-1489 (1990).

Many members of the avermectin class, in particular ivermectin, are potent and highly selective parasiticides which are lethal for invertebrates from a variety of phyla, ranging from insects to nematode worms. Much work has been done to determine the mechanism of action and the safety for use in mammals. Many investigators con- elude that ivermectin and avermectin B achieve their results in invertebrates by indirectly potentiating or mimicking the action of the neurotransmitter GABA. See Campbell, et al . , Science, 221 , 823-828, (1983); Camp¬ bell, et al . , J. Vet. Pharmacol. Therap. , 7_, 1-16, (1984); Terada, et al.,Exp. Parasitol., 5_7_, 149-157, (1984); Bennett, JAVMA, 1_8_9, 100-104, (1986); Chalmers, et al . , Eur. J. Pharmacol. 129, 371-374, (1986) . Some investigators find other explanations and cast doubt on the accuracy of the GABA agonist theory. See Martin, et al. , Br. J. Pharmacol .£8_., 747-756, (1989). The parasites are believed to be killed as a consequence of centrally- or peripherally-mediated muscular paralysis. In the families of invertebrates affected, excessive GABA-ergic activity inhibits the process of neuromuscular transmis- sion, see Bennett, supra.

Studies and experiments, attempting to determine if ivermectin exhibits GABA agonistic properties, have shown that ivermectin exhibits εucn properties in mammalian

SUBSTITUTE SHEET nervous tissues in vitro, at concentrations ranging from 10~⁷ M to 10~° M, with levels of 10^~6 M or higher gener¬ ally being required to produce a 50% change in the param- eters studied, Sigel, et al. , (1987) supra; Soderlund, et al. , (1987) supra; Kirkness, et al. , (1988) supra; and Robertson, (1989) supra.

It was found by investigators that intravenous administration of 0.3 mg/kg in rats resulted in very smail amounts of ivermectin entering the central nervous system. See Campbell, et al., (1983) supra; Campbell et al. , (1984) supra, and Bennett, (1986) supra. Utilizing high doses in dogs and swine resulted in signs suggestive of activity at the level of the central nervous system. See Campbell et al. , (1984) supra. However, in the investigations in vitro, the activity of ivermectin does not conclusively demonstrate that it acts as a GABA agonist. The results Indicate it has a relatively slow onset of action, loses its activity within minutes of administration, and at times acts as a blocker rather than an activator of GABA-sensitive chloride channels, Sigel, et al. , (1987) supra; and Robertson, (1989) supra; In mouse brain preparations, ivermectin may actually inhibit the channel-opening actions of GABA as noted by Soderlund, et al. , (1987) supra. In guinea pig brain preparations, investigators found that many actions of ivermectin resemble those of the GABA antagonist picotox- in, Kirkness, et al . , (1988) supra.

SUBSTITUTE SHEET In investigations to determine the effects of doses large enough to affect the central nervous system of mammals, the clinical signs produced indicated that the central nervous system was profoundly depressed, as 5 evidenced by listlessness and ataxia, followed by loss of upright posture and death, Campbell et al . , (1984) supra and Soderlund et al . , (1987) supra, citing the unpub¬ lished paper of Bloomquist, et al .

There is nothing in the aforesaid publications which

10 shows, speculates or predicts the effects of avermectins in general or ivermectin specifically on humans, i.e. on cardiovascular, gastrointestinal, parasympat^'hetic or sympathetic systems, immune systems, on disease states or dysregulations of the nervous system, or on personality,

15 mood, behavior, memory, attention span or cognitive status. Other GABA agonists known to be active in humans, such as the benzodiazepine tranquilizers , baclo- fen muscle relaxants and anti-convulsants such as valpro- ic acid and gabapentin, are active to some extent in

20 treating anxiety, as minor anesthesia agents, in treating spasticity, and for seizure control. They also have strong potential to cause cognitive changes, lethargy, somnolence, depression, psychotic behaλ'ior, respiratory depression, coma and death, particularly when taken in

^••"5 overdoses or for long periods of time. There is there¬ fore a need for an active agent with GABA agonist proper¬ ties that possesses all the beneficial effects of the putative GABA agonists, without the potential for toxici-

SUBSTITUTE SHEET ty of the other known members of this pharmacological class.

SUMMARY OF INVENTION

«

We have discovered that, surprisingly, the avermec- tins, when administered to humans in single or multiple doses of up to 1.6 mg/kg of body weight, have the pharma¬ ceutical activities in humans which are generally consid¬ ered to be due to GABA agonist properties, as well as other activities which may or may not be traceable to GABA agonist properties in humans, and yet are very safe with little or no adverse side effects.

The preferred avermectin for use in this invention is ivermectin, which displays superior effects compared to other so-called GABA agonists when administered in effective amounts as an agent to treat diseases caused by dysregulation or dysfunction of various portions of the nervous system. Thus, this invention is a method for prevention, treatment and control of disease states in humans caused by nervous system dysregulation and dys- function, which comprises administering to a patient in need of such treatment an effective amount of an avermec¬ tin compound. The amount of the avermectin compound administered to be effective is preferably from 0.1 to 1.6 mg/kg of body weight, at intervals of from 3 days to 4 months. The methods of administration are preferably rectal or subcutaneous. The avermectin compound pre¬ ferred for use in this invention is ivermectin. The

SUBSTITUTE SHEET methods of prevention, treatment and control for which the active compounds are effective according to this invention are seizure control, diminution of dystonic movements and tremors, significantly decreasing spastici- ty of both brain and spinal cord origin, e.g. closed head injuries, cerebral palsy, strokes, and spinal cord in¬ juries. In addition, the compounds are effective to increase tonic activity of the parasympathetic nervous system in the bladder and the bowel, to decrease activity of the sympathetic nervous system at cutaneous and cardi¬ ovascular levels, to ameliorate depression, to improve mood, to regularize the sleep-wake cycle, to decrease addictive behavior, and to markedly increase the atten¬ tion span and to improve the behavior of mentally defi- cient children and adults.

The avermectins are also effective in the re-estab¬ lishment of normal and appropriate body homeostatic mechanisms. Thus, the compounds are also active in the treatment or palliation of malignancies, or in the alter- ation of the sensitivity of malignant cells to exogenous chemotherapeutic agents. For the former reason, i.e. re- establishment of normal and appropriate body homeostatic mechanisms, the avermectins are also active in the treat¬ ment of rheumatoid arthritis, osteoarthritis, systemic lupus erythe atosus , spondylarthropathies, Crohn's dis¬ ease, ulcerative colitis and connective tissue disorders in general.

DETAILED DESCRIPTION

SUBSTITUTE SHEET This invention is based on the discovery that aver¬ mectin compounds, including synthetic derivatives there¬ of, surprisingly have properties which enable them to be used to treat a large number of disease states in humans which are caused, directly or indirectly, by dysregula¬ tion and/or dysfunction of various portions of the nervous system.

This invention provides a method of administering an avermectin compound, preferably ivermectin,to patients in need of such administering for preventing, treating and controlling (1) seizure disorders, i.e. epilepsy, (2) diseases associated with damage to or dysfunction of the extrapyramidal system resulting in dystonia and/or tre¬ mors, e.g. movement disorders such as Huntington's chorea, familial tremors, muscular dystonia and spastic retrocollis, and congenital degeneration of the basal ganglia, (3) diseases associated with degenerative states such as ulti-infarct dementia or Binswanger's dementia, amyotrophic lateral sclerosis, myotonic dystrophy, con- genital (hereditary) muscular dystrophies, e.g. Du- chenne's and Becker's, motor neuron diseases, spinal muscular atrophy, and Parkinson's disease, (4) diseases caused by acquired lesions of the central nervous system associated with spasticity, e.g. closed head injury, multiple sclerosis, cerebrovascular accidents, cerebral palsy, and eningoencephalitis, (5) spinal cord injury and concomitant spasticity, (6) diseases associated with

SUBSTITUTE SHEET dopaminergic dysregulation, e.g. schizophrenia and other neuropsychiatric disorders in which excessive dopaminer¬ gic activity may play a role, such as manic depressive illness, major affective disorders, behavior disorders and borderline personality states, (7) diseases associat¬ ed with cortical or subcortical dysregulation of GABA, giutamate, or dopamine, e.g. lesions of peripheral nerves, depression, snoring, sleep apnea, dysregulation of the sleep-wake cycle, seizure disorders, comatose states, causalgia, reflex sympathetic dystrophy, acute or chronic pain associated with the peripheral nervous system, habituation to or dependency on addictive sub¬ stances, and acute ischemic episodes of varying etiolo¬ gies such as traumatic closed head injury, subarachnoid hemorrhage, anoxic encephalopath , infectious or metabol¬ ic encephalopathy, and hemorrhagic or embolic/atherscle- rotic cerebrovascular accidents, (8) dysregulation of the sympathetic and parasympathetic nervous systems, e.g. constipation, hypertension, congestive heart failure, reflex sympathetic dystrophy, causalgia, autonomic hyper- reflexia, diabetic neuropathj-, renal failure and asthma, (9) cardiovascular disorders caused by excessive activity of the sympathetic nervous system such as angina, hyper¬ tension, atherosclerosis, congestive heart failure, and arrhythmias, (10) disorders of behavior, personality, affect, and cognition, e.g. patients in need of cogni¬ tive/learning/memory enhancement, depressive states, behavior, mental retardation, sociopathic and

SUBSTITUTE SHEET psychopathic personality disorders, (11) malignant states, e.g. indirectly by altering the activity of the nervous system or directly by changing the sensitivity of

« malignant cells to exogenous chemotherapeutic agents and

5 (12) autoimmune disorders in which the nervous system plays a role, such as rheumatoid arthritis, osteoarthri- tis, systemic lupus erythematosus, spondyloarthropathies, Crohn's disease, ulcerative colitis and general connec¬ tive-tissue disorders. 10 The preferred avermectin compound is ivermectin; however, others of the avermectin family of compounds have the same spectrum of activity, even though all the compounds are not equally potent. For example, ivermec¬ tin, when administered at dosages from 0.1 to 1.6 mg/kg 15 at intervals of from 3 days to 4 months, causes no sig¬ nificant side effects. Depending on the disease treated, its effects after single-dose administration may last from about three days to about three months . The dosage regimen and strength are determined by the attending on clinician's judgment, based on the condition and age of the patient and on the severity and etiology of the disease, as well as on the response to treatment.

The method of administration is preferably rectal, however, subcutaneous, transcuxaneous (transdermal ) , oral, intravenous, intramuscular or intrathecal routes can be used. The dosage forms can be made by convention¬ al means using generally-recognized-as-safe (GRAS ; addi-

SUBSTITUTE SHEET tives, solvents and excipients, taking into account the highly lipophilic nature of the avermectin compounds. Thus the preferred rectal dosage form comprises the active compound dissolved in a suitable solvent such as 5 propylene glycol plus glycerol formal. This same formu¬ lation can be used for subcutaneous injections. It is the same formulation used for veterinary purposes under the trademark IVOMEC. The oral dosage can be capsules, tablets, dragees, syrups, and the like. The capsules,

10 tablets and dragees, and other solid oral dosage forms, comprise the active ingredient admixed with a pharmaceu¬ tically acceptable carrier vehicle such as starch, talc, magnesium stearate, or dicalcium phosphate. The trans- dermal dosage form can be a conventional patch generally

15 used to deliver lipophilic drugs.

In using the active compounds of the avermectin family, mixtures of the compounds may be used; this is particularly true when using fermentation products of the C-076 producing microorganisms because the isolated

20 components usually contain a major amount of one compo¬ nent and another amount of a minor component. It is not practical to separate the components, and the biological activity of the major component is negligibly affected. Also, when the fermentation products comprising the two

^■*--*' components are derivatized chemically, the components are not separated in either the starting materials or the final product. Thus, the preferred ivermectin compound is normally used as the mixture of at least 80% 22, 23-

SUBSTITUTE SHEET dihydroavermectin B_χa and at most 20% 22, 23-dihydroaver- mectin B_χb.

The following examples which illustrate the inyen

EXAMPLE 1 5 Ivermectin Injectable Solution

A sterile solution suitable for rectal or subcutane¬ ous administration is prepared using the following formu¬ lation to provide a concentration of lOmg/mL.

Ingredients Amount

10 Ivermectin 1.0% w/v

Glycerol Formal 40.0% v/v

Propylene Glycol q.s. 100.00% v/v

Dissolve the ivermectin in either the glycerol formal, the propylene glycol or a mixture of the sol- 5 vents. When the dissolution is complete, adjust the volume to the final desired volume. Sterilize the final solution by membrane filtration and package it aseptical- ly, providing 10 mg of ivermectin per mL of solution.

EXAMPLE 2 ^**-° Ivermectin Injectable Solution

Ingredients Amount

25 Ivermectin 1.0% w/v

Water for Injection 10.0% v/v

SUBSTITUTE SHEET Propylene Glycol ^' q.s. 100.00% v/v Dissolve the ivermectin in a part of the propylene glycol. Add the water for injection so the precipitation of ivermectin is avoided and adjust the volume with the remaining propylene glycol to the desired final concentra¬ tion. Sterilize the solution by membrane filtration and package it aseptically.

EXAMPLE 3 Treatment of Seizure Disorders Eleven patients ages 7 to 79 years were treated with the ivermectin composition prepared in Example 1. The doses ranged from 0.2 mg/kg to 1.3 mg/kg. The methods of administration were either by subcutaneous injection or rectal administration. The ivermectin was administered at intervals of from 3 days to 7 days. Patients Nos . 1- 10 were afflicted with epilepsy, manifesting as either absence, focal, or generalized (tonic-clonic) or gran al seizures. Five patients had concomitant mental retarda¬ tion and five were of normal intellectual status. One patient, No. 11, had Alzheimer's disease of approximately 4 years' duration, with essentially complete loss of short-term memory. She had evolved to the stage of mild- moderate paranoid ideation and occasional aggressive, combative conduct prior to ivermectin administration.

The following table shows the results.

SUBSTITUTE SHEET Table 1

Treatment of Normal or Mentally Deficient Patients with or without Seizure Disorders

Patient Type of Dosage Dosage Mode of Results

No. Seizure Amount Frequency Administration Observed

(mg/kg)

1.* generalized 0.2- q 5-6 days subcutaneous seizures (nocturnal) 0.4 or rectal controlled**, no spasticity, increased attention span, increased responsiveness and emotions

2.* gran mal 0.4-0.6 q 6-7 days subcutaneous seizures or rectal con¬ trolled** not agg¬ ressive and combative, sleeps well, happj-, shows emotions

3.-*- none (spastic 0.6 q 5-6 days subcutaneous much less quad ripare sis ) or rectal spasms, happy,non- combative, sleeps well, more interest in surroundings and initiation, improved mobility

4.* gran mal and 0.7-1.3 q 5-6 days subcutaneous seizures absenceivery or rectal controlled** frequent) better sleep less agitateσ increased attention span

5.* focal (Jacksonian) 0.4- q 3 days subcutaneous seizures con- (continuous) 0.7 or rectal trolled** sleeps well, now speaks

SUBSTITUTE SHEET Table 1 (continued) 6. generalized 0.2 weekly subcutaneous seizures con¬ trolled**, sleeps well, less depression, increased emotional expression

7. generalized 0.2- weekly subcutaneous seizures con¬ and absence 0.3 trolled**, less depression, sleeps well, better mood, stopped snoring

8. generalized 0.2-0.4 weekly subcutaneous seizures and absence controlled**, sleeps well, less depressed, increased emotional expression, stopped snoring

9. generalized 0.2-0.4 weekly subcutaneous seizures con¬ and focal (Jacksonian) trolled**, less depressed, better mood, better stress tolerance

10. generalized 0.2-0.3 weekly subcutaneous seizures con¬ trolled**, sleeps well, less de¬ pressed, no abusive and violent behavior

11. none 0.2 weekly subcutaneous marked improve¬

(Alzheimer's disease) ment of behavior

*Mentally retarded

* * Decreased or no dose of other anti -epileptic drugs needed after ivermectin

As can be seen from the results in Table 1 , a con¬ siderable degree of seizure control was obtained in all epileptic patients. Administration two times a week was required in some cases. The intellectually normal pa¬ tients reported improved sleep-wake cycles, resolution of constipation, less angry behavior, less depression, and a marκedly better mood. Two patients with partial sleep

SUBSTITUTE SHEET apnea (Nos. 7 and 8) have stopped snoring at night. The most striking changes have occurred in the patients with seizures and concomitant mental retardation. Aggressive, violent behavior has virtually ceased, and the patients are much more attentive to and affectionate toward the caretaker. Where there previously was apathy and disin¬ terest in the environment, there is now a marked interest in the surroundings and the patients now appear to be capable of pleasure. They have also begun to utter sounds and to attempt to ambulate and to assist in self- feeding and dressing. Severe constipation has resolved, and bladder control is much improved. During the day, the patients signaled the need to urinate and at night bedwetting either stopped or diminished. The patient with Alzheimer's disease has shown marked improvement in her conduct, although memory and orientation remain impaired.

EXAMPLE 4 Treatment of Movement Disorders Three patients with Huntington's chorea, two pa¬ tients with generalized (familial) tremor, one patient with muscular dystonia and spastic retrocollis, and two patients with congenital degeneration of the basal gan¬ glia, one patient with dystonia musculorum deformans, and one patient with Parkinson's disease were treated with the ivermectin composition prepared in Example 1. The doses ranged from 0.2 mg/kg to 1.0 mg/kg. The methods of

SUBSTITUTE SHEET administration were either by subcutaneous injection or rectal administration. The ivermectin was administered at intervals of from 7 days to 4 months.

The following table shows the results.

TABLE 2

Treatment of Movement Disorders Patient Disease Dose Dose Route of Results No. Amount Frequency Administration Observed

(mg/kg)

1. Huntington's 0.4 weekly and subcutaneous much less intense chorea q month or rectal dystonia, sleeps well, less depressed, better mood, more emotionally responsive

Huntington's 0.3- weekly and subcutaneous 40-50% decrease in chorea 0.8 q 1-2 weeks or rectal dystonia, less depressed, sleeps well, better mood, more emotionally respo¬ nsive

Huntington's 0.3- weekly and subcutaneous much less intense chorea 0.6 q month or rectal dystonia, less depressed, stopped smoking and drink¬ ing, no abusive be¬ havior

4. Generalized 0.3- weekly and subcutaneous 90% decrease in tremor 0.4 q 2 months tremor, sleeps well,

(familial) speech improved

5. Generalized 0.2- weekly and subcutaneous 90% decrease in tremor 0.4 q 2 months tremor, no dystonia,

(familial) sleeps well, better

(with dystonia) mood, not aggressive and angry

6. Spastic 0.2 q 4 months subcutaneous retrocollis and retrocollis dystonia markedly (with dystonia) decreased, sleeps well, better mood

7. Dystonia 0.2- weekly subcutaneous less dystonia, musculorum 1.0 or rectal markedly better def^'ormans body posture

SUBSTITUTE SHEET Table 2 (continued)

8. Basal ganglia 0.4- q 5-10 subcutaneous 80% decrease in degeneration 0. 6 days or rectal dystonia and (familial) spasticity, speech improved, walking improved

9. Basal ganglia 0.4 weekly subcutaneous much less dystonia degeneration or rectal and spasticity, (familial) speech improved, swallowing better

10. Parkinson's 0.3 weekly subcutaneous 100% decrease in disease or rectal rigidity, variable decrease in tremor

As can be seen from the data in the table, the two patients with generalized (familial) tremor have experi¬ enced an estimated 90% reduction in the tremor. In addition, their sleep-wake cycles and frequency of bowel movements have improved, their associated dystonic move¬ ments have disappeared, their mood and enjoyment of life is far better, and they are much less depressed. In one of the two patients (patient No. 5), blood pressure after drug administration has remained well controlled despite discontinuation of her usual antI-hypertensive medica¬ tion. Before drug administration, another patient (patient No. 4) suffered from moderately severe conges¬ tive heart failure with 2-pillow orthopnea and frequent paroxysmal nocturnal dyspnea. These symptoms disappeared after the first dose of drug and have not returned.

The data show that the patient with spastic retro- collis is estimated to have 70%-90% less intense and frequent retrocollis spasms. He also reports no pain, less constipation, a regularized sleep-wake cycle, a better mood, and less depression.

SUBSTITUTE SHEET The data also show that the three patients with Huntington's chorea have experienced a marked diminution, estimated at 50-80%, of their dystonic movements. In addition, they are no longer irritable, withdrawn and depressed, enjoy life more, sleep better, and report no more constipation. One patient, (patient No. 3) who was frankly abusive to his family and a heavy smoker and drinker, reports that his work performance is better and that he no longer has a desire to smoke or drink. His family reported that his angry mood and abusive behavior have ceased.

As the data show, the two patients with congenital degeneration of the basal ganglia noted an estimated 80% decrease in both spasticity and dystonic movements. They also are no longer constipated, sleep well, and are no longer depressed. Their severe spastic dysarthria has improved, approximately 50% for patient No. 10 and ap¬ proximately 80% in the case of patient No. 9.

EXAMPLE 5 Treatment of Patients with Acquired Lesions of the Central

Nervous System Associated with Spasticity

Four patients in this group were treated with the ivermectin composition prepared in Example 1. The doses ranged from 0.1 mg/kg to 0.8 mg/kg. The methods of administration were by subcutaneous injection. The ivermectin was administered at weekly intervals. The following table shows the results.

SUBSTITUTE SHEET TABLE 3 Treatment of Patients with Spasticity from Nervous-System Dama

Patient Disease Dosage Dosage Route of Results No. Amount Frequency Administration Observed mg/kg

1. Left cerebro- 0.3 weekly subcutaneous decreased vascular accident spasticity, gait (ischemic) better, marked improvement in speech fluency

2. Meningo- 0.2- weekly subcutaneous markedly encephalitis 0.8 decreased spasticity, gait better weekly subcutaneous less spasticity, gait better

weekly subcutaneous less spasticity, gait better,

improvement in speech fluency

As is apparent from the data in Table 3, the spas¬ ticity of each of the patients decreased, and all had increased fluidity of movement and improved gait. The most striking change in the aphasic patients was more fluent and less dysarthic speech.

EXAMPLE 6 Treatment of Spasticity Caused by Spinal Cord Injury Thirteen patients with spinal cord injury and con¬ comitant spasticity were treated with the ivermectin composition prepared in Example 1. The doses, which were administered in an ascending-dose fashion, ranged frorr.

SUBSTITUTE SHEET 0.2 mg/kg to 1.6 mg/kg. The methods of administration were either by subcutaneous injection or rectal adminis¬ tration. The etiologies included trauma from gunshot wound (patients Nos. 2, 4, 10, 11, 12, and 13), blunt trauma (patients Nos. 1, 8, and 9), penetrating instru¬ ment wound (patient No. 3), arachnoiditis (patient No. 5), tropical spastic paraparesis (patient No. 6), and cervical myelopathy (patient No. 7). The ivermectin was administered at intervals of from 7 days to 3 months. The following table shows the results.

TABLE 4 Treatment of Spasticity Caused by Spinal Cord Injury

Patient Nature Dosage Dosage Route of Results No. ofInjury Amount Frequency Administration Observed* mg/kg

1. C8-T1 contusion; 0.2- biweekly and subcutaneous 100% decreased Frankel Class A 1.2 q 2-3 months spasms, tone normal, stands with support, moves feet, sensation unchanged

2. T4 gunshot wound; 0.2- biweekly and subcutaneous 80% decreased Frankel Class A 1.6 q 2 months spasms, tone normal, stands & crawls, sensation to L4 level

3. C5 knife wound; 0.2- biweekly and subcutaneous 100% decreased Frankel Class C 1.2 q 3 months spasms, tone normal, better gait, better sensation

4. C5 gunshot wound;0.2- biweekly and subcutaneous 80-100% de- Frankel Class C 0.8 q 3 months creased spasms tone normal, stands, sensat¬ ion to L5-S1 level

SUBSTITUTE SHEET Table 4 (continued) 5. Lumbar 0.2- biweekly and subcutaneous 80-100% de¬ arachnoiditis 1.2 q week creased spasms, Frankel Class D tone normal, walks with walk¬ er, better sensation

Tropical spastic 0.2- biweekly subcutaneous 100% decreased paraparesis; 1.0 spasms, tone still Frankel Class D high, better walk¬ ing, sensation unchange (^•normal)

7. C5 cervical 0.2- biweekly and subcutaneous 80-100% decreased myelopathy; 0.4 q week spasms, tone normal

Frankel Class C walks with support, sensation unchanged (normal)

8. T6 fracture- 0.4- biweekly and subcutaneous 80% decreased dislocation; 0.6 q week spasms, tone normal, Frankel Class A stands, sensation unchanged

9. C5-6 fracture- 0.45 weekly subcutaneous 80% decreased dislocation; spasms, tone normal, Frankel Class B no data on motor and sensory func¬ tion

10. TSgunshot wound; 0.2- biweekly and subcutaneous 80-100% de- Frankel Class A 1.2 q week or rectal creased spasms, tone normal, better trunk control, sensation to LI level

11. C8 gunshot wound; 0.4- weekly subcutaneous no data on motor Frankel Class B 0.8 and sensory func- ion

12. Tl gunshot wound; 0.3- weekly subcutaneous decreased spasms, Frankel Class B 0.6 improved sensation

13. C2 gunshot wound; 0.2 single subcutaneous no changes noted Frankel Class B dose

* Results only on spasms, tone, and motor plus sensory function. See text for other observations.

The data show that as a result of the treatment , at

SUBSTITUTE SHEET least 10 of the 13 patients showed a marked (80-100%) decrease in spasms. Concomitantly, there was a reduction in muscle tone to normal levels.

In addition, in most cases, the anti-spasticity effects were transient, that is, they lasted 24-96 hours or were absent, at doses of 0.2-0.4 mg/kg of body weight. More positive effects became apparent at doses of 0.6-1.6 mg/kg. At the higher dosage range, spasms were essen¬ tially completely abolished, and this effect persisted for intervals up to three months after the last dose of ivermectin. There were clear dose- and time- response relationships as the doses increased in all the patients who received successive doses, with progressively great¬ er decreases in the severity of the spasms and longer periods of spasm diminution or absence after the adminis¬ tration of each dose. Other noteworthy changes included improved mood and emotional status. less depression, improved sexual function, better bladder and bowel action and regulation, moderate to marked improvement in the extent of cutaneous sensation below the level of the lesion, i.e. from T4 to L4 , or from C5 to SI, and a decrease in excessive sympathetic nervous-system activi¬ ty, i.e. , less profuse sweating above the level of the lesion. Using the composition of Example 1 and the dosage regimen of Example 6, the avermectins are expected to interact with G proteins (G proteins bind to guanoεine nucleotides ) , whict are utilized in many organs of the

SUBSTITUTE SHEET body, including the nervous system, to transmit signals to the interior of cells following the binding of molecules to receptors on the cell surface. In addition to being involved with neurotransmitter release and action, G proteins are also present in malignant cells, where they appear to play a role in the creation and maintenance of the malignant sta*te, see Marx, Science, 151 , 1317, (1991). The G proteins may also be associated with the development of resistance to chemotherapeutic agents. 0 See Gisslinger, et al. , Lancet, 336, 1078, (1990). By blocking a G protein active site, the avermectins are expected to successfully treat and palliate malignancies, as well as to reduce or eliminate development of resist¬ ance to chemotherapeutic agents. It is also expected the •**^• avermectins would facilitate the re-establishment of normal and appropriate body homeostatic mechanisms via their actions on the nervous system.

In addition it is expected that the avermectins will, because of their effects on the nervous system, be useful to treat autoimmune diseases in which the nervous system plays a role, e.g. rheumatoid arthritis, osteoar- thritis, systemic lupus erythematosus , spondyloarthropa- thies, Crohn's disease, ulcerative colitis, and other connective-tissue disorders. See Levine, et al . , Science, 226 , 547-549, (1984), Thompson, et al. , Ann. Rheum.Dis. 21_, 370-377, (1962), and Bland, et al. , Ar¬ thritis and Rheum., H_. 72-79, (1968).

SUBSTITUTE SHEET

Claims

We claim:

1

1. A method for preventing, treating or controlling

2 diseases of human nervous system dysregulation and/or

3 dysfunction, which comprises ' administering to a patient

4 in need of such preventing, treating or controlling an

5 effective amount of a compound of the avermectin family.

1 2. A method of claim 1 wherein the human nervous system

2 dysregulation and/or dysfunction which is disease pre-

3 vented, treated or controlled is selected from mental

4 deficiency, seizure disorders, behavior problems, cardio-

5 vascular diseases, movement disorders, spasticity caused ° by lesions of the central nervous system, spasticity 7 caused by spinal cord injury, autoimmune disorders and

6 malignant states.

3. A method of claim 1 wherein the avermectin compound administered is ivermectin.

4. A method of claim 1 wherein the avermectin compound is administered at doses up to 1.6 mg/kg at intervals of from 3 days to 4 months.

5. A method of claim 2 wherein the seizure disorder treated, prevented or controlled is epilepsy.

SUBSTITUTE SHEET 6. A method of claim 2 wherein the mental deficiency prevented, treated or controlled arises from mental retardation, developmental delay, cerebral palsy, or degenerative disease of the nervous system.

7. A method of claim 2 wherein the behavior problems prevented, treated or controlled are caused by major affective disorders, addictive, borderline, or disordered personality states, depression, congenital or acquired brain injury, and Alzheimer's disease.

8. A method of claim 2 wherein the spasticity prevented, treated , or controlled is caused by head injury, ence- phalopathy, multiple sclerosis, cerebrovascular accident, or spinal cord damage.

9. A method of claim 2 wherein the cardiovascular prob- lems prevented, treated or controlled are selected from hypertension and congestive heart failure.

10. A method of claim 2 wherein the movement disorder prevented, treated or controlled is selected from Hunt- ington's chorea, generalized tremor, Parkinson's disease, muscular dystonia, spastic retrocollis, and congenital degeneration of the basal ganglia.

II. A method of claim 2 wherein the malignant state

SUBSTITUTE SHEET prevented, treated or controlled is modulated by actions of the nervous system.

12. A method of claim 2 wherein the malignant state prevented, treated or controlled is characterized by development of resistance to chemotherapeutic agents.

13. A method of claim 2 wherein the autoimmune disorder prevented, treated or controlled is selected from rheuma- toid arthritis, osteoarthritis , systemic lupus erythema- tosus, spondyloarthropathies, Crohn's disease, and ulcer- ative colitis.

14. A method of claim 1 wherein the method of adminis- tration is rectal.

15. A method of claim 1 wherein the method of adminis- tration is subcutaneous injection.

16. A method of claim 1 wherein the method of adminis- tration iε oral.

17. A method of claim 1 wherein the method of adminis- tration is transdermal .

18. The use of a compound of the avermectin family for preventing, treating or controlling diseases of human

SUBSTITUTE SHEET 3 nervous system dysregulation and/or dysfunction.

1 19. The invention of claim 18 wherein said disease is

2 selected from mental deficiency, seizure disorders, •z behavior problems, cardiovascular diseases, movement disorders, spasticity caused by lesions of the central 5 nervous system, spasticity caused by spinal cord injury, ° autoimmune disorders and malignant states.

1 20. The invention of claim 18 wherein the compound of

2 the avermectin family used is ivermectin.

1 21. The invention of claim 18 wherein the avermectin

2 compound is administered at doses up to 1.6 mg/kg at *•' intervals of from 3 days to 4 months.

22. The Invention of claim 18 or claim 19 wherein the disease treated, prevented or controlled is epilepsy.

23. The invention of claim 18 or claim 19 wherein the disease prevented, treated or controlled is mental defi- ciency arising from mental retardation, developmental delay, cerebral palsy, or degenerative disease of the nervous system.

24. The invention of claims 18 or 19 wherein the behav- ior problem prevented, treated or controlled is caused by major affective disorders, addictive, borderline, or,

SUBSTITUTE SHEET disordered personality states, depression, congenital or acquired brain injury, and Alzheimer's disease.

4 25. The invention of claims 18 or 19 wherein the spas- ticity prevented, treated or controlled is caused by head injury, encephalopathy, multiple sclerosis, cerebrovascu- iar accident, or spinal cord damage.

26. The invention of claims 18 or 19 wherein the cardio- vascular problem prevented, treated, or prevented is hypertension or congestive heart failure.

27. The invention of claims 18 and 19 wherein the move- ent disorder prevented, treated or controlled is Hunt- ington's chorea, generalized tremor, Parkinson's disease muscular dystonia, spastic retrocollis, or congenital degeneration of the basal ganglia.

28. The invention of claims 18 or 19 wherein the malig- nant state prevented, treated, or controlled is modulated by actions of the nervous system.

29. The invention of claims 18 or 19 wherein the autoim- mune disorder prevented, treated, or controlled is rheu- matoid arthritis, systemic lupus erythematosus, spondy- loarthropathies , Crohn' s disease, or ulcerative colitis.

SUBSTITUTE SHEET 30. The invention of claim 28 wherein the malignant state prevented, treated, or controlled is characterized by development of resistance to chemotherapeutic agents.

SUBSTITUTESHEET