WO1994002138A1

WO1994002138A1 - Pharmaceutical composition and method of treatment for serotonin depletion illness

Info

Publication number: WO1994002138A1
Application number: PCT/US1993/006554
Authority: WO
Inventors: Nicolaas Johannes Jacobus LÖTTER
Original assignee: Ivy, Mary, Elizabeth
Priority date: 1992-07-15
Filing date: 1993-07-15
Publication date: 1994-02-03
Also published as: EP0651638A1; AU4674693A; ZA935078B

Abstract

This invention relates to the treatment of a condition characterized as serotonin depletion illness (SDI) with compositions and methods comprising a serotonin agonist in combination with sulpiride. SDI is an illness which may be commonly identified by fatigue, irritability, sleep disorders and pain in afflicted patients. Preferred serotonin agonists for use in the treatment of SDI are tricyclic antidepressants, maprotiline and mianserin.

Description

PHARMACEUTICAL COMPOSITION AND METHOD OF TREATMENT FOR SEROTONIN DEPLETION ILLNESS

Field of the Invention

THIS invention relates to the treatment of patients presenting with synaptic fatigue related conditions and to pharmaceutical compositions for use in such treat- ent. More particularly this invention relates to the treatment of a condition which the inventor has characterised as serotonin depletion illness [herein¬ after referred to as SDI] .

Background of the Invention

Various studies, hypothesis, laboratory findings, signs and symptoms point to the fact that SDI is a central neurochemical disorder involving the all important mid- line raphe nucleus in the medulla, the RAS, hypothalmus and the entire autonomic nervous system.

SDI is a physical condition found mainly in urban societies where an abundance of sensory input [popular¬ ised as stress] exhausts the midline raphe nucleus in its production of serotonin [5-Hydroxytryptamine] and in this way causes sleep disturbances, hyperalgesia [defective pain modulation] and alteration of mood [depression and irritability].

The clinical manifestation of this illness is normally associated with the following symptoms:

MAJOR CRITERIA

1. Fatigue.

2. Irritability.

3. Sleep disorder.

4. Pain:

SUBSTITUTE SHEET [a] Headache.

[b] General body aches and pains.

[c] Low backache.

[d] Abdominal pain. [e] Dysmenorrhoea.

[f] Joint pains.

[g] Chest pain, [h] Otalgia.

[i] Neck pain. [j] Scapular pain.

MINOR CRITERIA

1. Flatulence.

2. Paraesthesia.

3. Subjective swelling. 4. Cold extremities.

5. Nausea.

6. Dizzy spells.

7. Burning feet.

8. Restless legs. 9. Catarrh.

10. Palpitations.

11. Tremor.

12. Tight chest and throat.

13. Neck stiffness. 14. Oliguria.

15. Irritable bladder.

16. Dyspnoea.

17. Pruritis ani.

18. Diarrhoea/constipation. 19. Reduced mental ability:

[a] Concentration loss.

[b] Thought process inhibition.

[c] Indeciciveness.

[d] Sluggishness.

SUBSTITUTE SHEET [e] Sense of failure.

20. Behavioural alterations:

[a] Inactivity.

[b] Inhibitedness. [c] Unsociability.

[d] Sexual, dietary and physical alterations.

[e] Mood swings.

The inventor is of the view that conditions such as myofascial syndrome, fibromyalgia, fibrositis, masked depression, yuppie flu [epidemic myalgic encephalomyel- itis syndrome] and a host of chronic pain conditions as well as indications of altered immunity may be placed under one umbrella, namely that of SDI. cordingly it is suggested that SDI should be included in the differential diagnosis of a multiplicity of conditions which include:

1. Musculoskeletal conditions:

[a] Non-articular, psychogenic, sero-negative, and tension rheumatisms as well as rheumatoid and osteoarthritis.

[b] Bursitis, tendonitis, costocondritis [Tietze syndrome] Bornholm's disease, tennis elbow, shoulder-hand-syndrome, condromalasiae patellae and shin splints. [c] Temporomandibular joint [T M J] disorders, [d] Low backstrain and herniated disc.

2. Other pain conditions:

[a] Angina and mitral valve prolapse.

[b] Migraine and all other types of headaches. [c] Irritable bowel [IBS].

SUBSTITUTE SHEET [d] Trigeminal neuralgia.

[e] Dysmenorrhoea.

[f] Proctalgia vivax.

3. Psychogenic disorders:

[a] Psychoneurosis :

[i] Anxiety, [ii] Depression.

[b] Insomnia.

[c] Premenstrual syndrome [PMS]. [d] Behavioural disorders.

4. Conditions as a result of direct sensory overload:

[a] Post partum depression.

[b] Post operative depression.

[c] Post traumatic syndrome. [d] Shell shock.

With regard to laboratory findings it is rather an absence of positive special investigations which characterises this condition. A low unbound or plasma free tryptophan level may be characteristic.

It has been found that SDI is an easily recognisable clinical diagnosis and not a single laboratory or other special examination is necessary before institution of treatment.

Description of the Invention

This invention provides for the use of a serotonin agonist in combination with sulpiride in the production of an intravenous infusion composition for use in the

SUBSTITUTE SHEET treatment of SDI in a patient.

The serotonin agonist is preferably selected from the group consisting of the tricyclic anti-depressants, maprotiline hydrochloride and mianserin hydrochloride.

The serotonin agonist is preferably amitriptyline.

In the most preferred form of the present invention there is provided an intravenous infusion composition comprising amitriptyline in combination with sulpiride in a physiologically acceptable carrier.

The carrier may be a normal saline solution.

In another form of the invention there is provided an intravenous infusion product in unit dosage form for use in the treatment of a stress related condition, including SDI, comprising a container and an hypodermic needle secured thereto, the container containing a composition comprising between 10 and 50 mg amitriptyline and between 50 and 200 mg sulpiride in a normal saline carrier. The container may be in the form of an infusion bag.

In the most preferred form of this aspect of the invention there is provided a three day treatment course of the infusion product of the invention com¬ prising three infusion products in unit dosage form as described above, the three containers each containing about 50 millilitres of normal saline, about 100 mg sulpiride and respectively about 10 mg to 40 mg amitriptyline.

The treatment course described above has been admini¬ stered over an infusion time of 5 to 10 minutes on three consecutive days in the order of increasing

SUBSTITUTE SHEET amitriptyline dosage to a number of patients presenting with the typical synaptic fatigue symptoms described above. This treatment regimen usually resulted in excellent pain modulation, mood elevation and restor- ation of delta sleep after which the patients were kept on low dosage amitriptyline or another serotonin agonist [per os] for at least six months.

The invention also relates to a method of treating SDI by the simultaneous or sequential intravenous infusion of a serotonin agonist and sulpiride as described above.

A number of examples of the beneficial effects of the treatment and composition of the present invention will now be described. The tests described here were all performed by the inventor, a qualified physician, and although they were uncontrolled they serve to demon¬ strate the invention. The examples are selected as typical and are not exhaustive of all the trials performed.

All cases were treated with amitriptyline 20 mg in combination with sulpiride 100 mg in 50 cc of a normal saline solution intravenously infused over five minutes in the consulting rooms on three consecutive days followed by low dose amitriptyline [10 mg] and magnesium chloride [1-2 grams] orally at bedtime as maintenance medication.

The case studies are grouped according to the main complaints with which the patients presented.

E X A M P L E 1

Treatment of Fatigue

[a] A thirty-two year old wife of a university

SUBSTITUTE SHEET academic was suffering from chronic fatigue to such an extent that she was virtually bedridden for seven years and was diagnosed with myalgic encephalomyelitis. She had been extensively investigated and treated by her specialist physician for the previous seven years, using mainly vitamins and magnesium supplementation. She had been prescribed bed rest and the exclusion of various foodstuffs. One day after treatment according to the invention she felt so much better that she went for a run of several kilometers.

[b] A thirty-nine year old wife of a fellow general medical practitioner had been used to walking long distances became so ill from fatigue and pain in the lower half of her body that she could hardly walk from her bedroom to the kitchen. Before undergoing the treatment of the present invention she was extensively investigated by a health institution and by a private physician. In both cases all the tests proved to be negative and she was prescribed an anti-inflammatory to no avail.

She was then referred by the physician to a rheumatologist who repeated the investigation and again prescribed an anti-inflammatory. Again it did not improve her condition. After intravenous administration of amitriptyline and sulpiride she improved to such an extent within a day that she reported that she "felt like climbing mountains".

E X A M P L E 2

Treatment of Headaches

[a] A thirty-four year old housewife suffered from daily blinding headaches and had been taking up to

SUBSTITUTE SHEET a 100 combination analgesics per week. She had seen various consultants and had a multiplicity of special examinations. After the treatment of the invention she sent a letter of appreciation, stating that her life was changed.

[b] A lady in her early thirties who had admitted to often having wanted to drive her car into a road¬ side telegraph post in a suicidal attempt to get away from her blinding headaches, reported complete control after three days of the present treatment.

[c] A sixteen year old girl admitted to a private clinic and treated by a physician for meningitis. After twelve days her blinding headache and vomiting was still not controlled and the treatment of the present invention was administered on request of her father. She was discharged completely symptom free after the first infusion.

[d] A housewife in her thirties who had suffered from migraines for five years received one infusion according to the invention in the consulting room and two were administered by her husband [a plastic surgeon] at home. She has now been head- ache free for eleven months except for one mild migraine.

E X A M P L E 3

Enhanced Immunity

[a] A forty-six year old male presented with recurrent boils on his face. He had undergone twenty-one incision and drainage procedures under general

SUBSTITUTE SHEET anaesthesia during the preceding four years. He has been abscess-free since undergoing the treat¬ ment of the invention.

[b] A forty-six year old working female presented with Sjorgens disease. She had severe swelling of all her lacriminal glands. She was virtually unable to eat because of the severe dryness of her mouth and was referred to a surgeon, a physician and rheumatology clinic at a nearby university institute, all offering no meaningful treatment. She received the treatment of the invention for an understandable reactive depression and experienced rapid and complete control of her Sjorgens disease.

E X A M P L E 4

Mast cell and basophil stabilisation

[a] A sixty-two year old pensioner who had taken oral steroid preparations for twenty-one years to control a pruritic eczematous skin rash, was given the treatment of the invention and consequently weaned off his steroid medication with complete success.

[b] A forty-five year old overweight businessman, with maturity onset diabetes and hypertension, complained of pruritic oedema which presented recurrently on different parts of his body, e.g. a swollen periorbital area to such an extent that he was unable to see with that particular eye. This allergic condition had been resistant to standard antihistamine treatment and so he was given oral steroids. After treatment, according to the inventio , he has been reaction free for an

SUBSTITUTE SHEET extended period and his diabetes as well as blood pressure has been controlled without other medication except for a strict dietary program.

E X A M P L E 5

Irritable Bowel Syndrome

[a] A sixty-seven year old lady presented with severe abdominal distension and increased bowel sounds. She had not vomited and has passed soft stool the previous day. Bowel sounds were increased. She had undergone five previous laparotomies for intestinal obstruction. Treatment according to the invention literally deflated her.

[b] A forty-nine year old menopausal woman complained that she looked pregnant and was even mocked by her friends because of lower abdominal distension. She had undergone barium enemas, sonar and C T scanning of the abdomen and various blood investigations which all proved negative. After treatment according to the invention her lower abdomen was deflated.

E X A M P L E 6

Proctalgia Vivax

[a] A seventy year old lady presented with the severe feeling of bearing down in her perineal area. On examination she had a prolapsed uterus and rectocele. She was referred to a gynaecologist for a vaginal hysterectomy and repair which made her symptom free for only two months.

After treatment according to the invention she had

SUBSTITUTE SHEET been symptom free.

E X A M P L E 7

Post Traumatic Syndrome

[a] A twenty-one year old male model and dynamic salesman had a motor vehicle accident. He had two minor lacerations on his forehead which were sutured at the local hospital . The next day he presented with severe fatigue, irritability and rages. He received the treatment according to the invention and after the first day he was already so subdued that he reacted philosophically to his car being towed away by the city's traffic depart¬ ment.

[b] A thirty-one year old engineer drove with his truck into the back of a stationary vehicle. The accident was non-injurious but the next day the patient presented with severe fatigue, irrit¬ ability, headache and dizziness. He had low back¬ ache and a temperature of 38.2. The treatment according to the invention reversed his condition within one day.

E X A M P L E 8

Multiple Pathology

[a] A forty-eight year old male presented with daily severe headaches and an lgesic abuse. He was hypertensive but well controlled on medication and also suffered from hyperlipidaemia with a fasting cholestrol of 11.2 on medication.

He received the treatment which not only reversed

SUBSTITUTE SHEET his headaches but also controlled his blood pressure and cholestrol without any further treatment necessary.

[b] A forty-three year old lady presented with a pain of her left calf followed by anxiety and a feeling of pressure on her chest. Without special examinations her doctor brother-in-law diagnosed DVT with pulmonary embolus. The diagnoses caused severe anxiety, headache, fatigue and worsened the chest pain and hyperventilation. An extensive examination, investigation and reassurance by a specialist physician could not clear her symptoms. The treatment according to the invention resulted in daily improvement that was evident in progressive blossoming and twinkle in her eyes.

E X A M P L E 9

Cluster Headaches

A fifty-five year old bank manager with cluster headaches and accompanied Horner Syndrome was cured by the treatment according to the invention after many years of multiple examinations, hospital admissions and consultations.

E X A M P L E 10

Tinnitus

A fifty-two year old post office worker gave up on medication of many years for a noise in his right ear. He received the treatment of the invention which dulled the noise considerably. He received two further courses of the standard treatment and reported almost

SUBSTITUTE SHEET complete recovery.

E X A M P L E 11

Chest Pain

[a] A fifty-one year old assistant chief editor of a daily newspaper experienced an attack of a severe chest pain radiating down his left arm while he was working in his office, and having had six inquiring telephone calls awaiting at the same time. He was rushed to the consulting room and an ECG was completely normal. Administration of a single infusion of the treatment according to the invention reduced the pain within minutes to his absolute amazement.

[b] A forty-five year old female experienced recurrent daily chest pains, which had been diagnosed as angina. She did receive an angioplasty seven years before but the pain started recurring one year post-operatively.

The pain was reasonably controlled for some time by a calcium channel blocker but had again become severe and recurrent. She also reported severe fatigue and was unable to attend work. Her examination was completely normal . She had strong bilateral dorsalis pedis pulses and an ECG with effort was completely normal. The treatment according to the invention abolished both the chest pain and fatigue.

E X A M P L E 12

Dizziness

A thirty-two year old manual labourer experienced

SUBSTITUTE SHEET severe dizziness when he got out of bed in the morning. He was unable to drive his car and was brought in by his spouse. After the first medication according to the invention was infused the dizziness disappeared, he could turn his head quickly. He was completely normal and recovered to such an extent that he could drive his own car home.

E X A M P L E 13

Bolimia

A twenty-one year old attractive art student with a history of long term bolimia which required long term admission to psychiatric institutions, was treated with several courses of the treatment according to the invention and made slow progress. A sex hormone profile was done on her which pointed to low oestradiol progestrone, testosterone, a high prolactin and a low FSH and LH. She received the necessary hormone supplementation together with our standard treatment with major success.

E X A M P L E 14

Endocrine Control

A forty-two year old housewife and a forty-four year old part-time worker presented with the same blood pictures after treatment failure, which was corrected after attending to their hormone picture.

E X A M P L E 15

Depression

A twenty-two year old rape victim was under psychiatric

SUBSTITUTE SHEET care and taking up to a 150 mg of a well-known tricylic anti-depressant which made her feel severely dopey, tired and unable to work. This treatment was discontinued and she turned into a blossoming, happy, energetic bank worker within three days of the treatment of the invention.

E X A M P L E 16

Irritability

A thirty-five year old male divorce victim showed severe anger and rages. He sought psychological counselling because he felt self-destructive. He felt rested and self-contented after the first infusion of the composition according to the invention and recovered fully after the standard treatment.

E X A M P L E 17

Intellect

A nineteen year old college student was referred by an orthopaedic surgeon for the treatment of an atypical low backache. She had accompanying joint pains, fatigue and loss of memory and an inability to concentrate. She reported complete recovery of all her symptoms as well as a 15% improvement in her college year end marks after receiving the treatment of the invention.

E X A M P L E 18

Barlow's Syndrome

A twenty-nine year old business entrepreneur experienced chest pains which had been fully

S investigated by a cardiologist and diagnosed as Barlow's Syndrome. His chest pain disappeared after treatment according to the invention.

E X A M P L E 19

Tremor

A sixty-five year old suffered of Parkinson's Disease had been treated by a neurologist with L-Dopa but experience severe shacking of her head. She also reported to have had numerous courses of urinary antiseptics for bladder infections and undergone several cystoscopies by an urologist.

The embarrassing shaking of her head stabilised and she volunteered that she no longer had bladder problems after undergoing treatment according to the invention.

E X A M P L E 20

Al lergies

A twenty-seven year old attractive ballet teacher complained of burning eyes, sneezing and a runny nose. She requested something for her hayfever and also for a bladder infection presenting with burning on micturition and frequency. Urine dipstick tests as well as an MC&S proved negative. She recovered completely, both her allergy and her bladder condition, after receiving the treatment according to the invention.

Without thereby wishing to be bound by this theory, it is suggested that amitriptyline, a serotonin agonist [it promotes the recycling of this important modulator] together with Sulpiride, which stimulates the secretion

SUBSTITUTE SHEET of the endogenous opoids, have a potent synergistic action. In accordance with the invention it is given intravenously to obtain bolus infusion over the blood brain barrier into the aquaductus of Sylvius so that the medicated cerebral spinal fluid will attend to the dry synaptic vesicles of not only the synaptic knobs in the medulla but also of the synaptic knobs of the dendrites and axons in other parts of the central nervous system.

In contrast, due to slow diffusion over the blood brain barrier with oral medication this form of treatment will only attend to the medulla leaving the patient drowsy, sleepy and tired and cannot achieve the results obtainable by infusion.

It will be understood that many variations of the invention may be devised without departing from the spirit of the invention.

_SUB_ST_ITUTE SHEET

Claims

CLAIMS :

1. The use of a serotonin agonist in combination with sulpiride in the production of an intravenous infusion composition for use in the treatment of SDI in a patient.

2. The use of claim 1 wherein the serotonin agonist is selected from the group consisting of the tri- cyclic anti-depressants, maprotiline hydrochloride and mianserin hydrochloride.

3. The use of claim 2 wherein serotonin agonist is amitriptyline.

4. An intravenous infusion composition suitable for use in the treatment of SDI comprising amitrip¬ tyline in combination with sulpiride in a physio- logically acceptable carrier.

5. The composition of claim 4 wherein the carrier is a normal saline solution.

6. An intravenous infusion product in unit dosage form for use in the treatment of SDI, comprising a container and an hypodermic needle in fluid connection therewith, the container containing a composition comprising between 10 and 50 mg amitriptyline and between 50 and 200 mg sulpiride in a normal saline carrier.

7. The product of claim 6 as a three day treatment course comprising three infusion products in unit dosage form, the three containers each containing about 50 millilitres of normal saline solution, about 100 mg sulpiride and respectively about 10 to 40 mg .amitriptyline.

SUBSTITUTE SHEET

8. A method of treating SDI by the simultaneous or sequential intravenous infusion of a serotonin agonist and sulpride.

9. The method of claim 8 comprising the steps of intravenously administering to a patient suffering from SDI a combination of sulpiride and amitriptyline in the quantities and by use of the product claimed in claim 7 over a period of three days.

SUBSTITUTE SHEET