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WO1990006760A1 - Compositions pharmaceutiques contenant de la brucella ou des derives de celle-ci - Google Patents

Compositions pharmaceutiques contenant de la brucella ou des derives de celle-ci Download PDF

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Publication number
WO1990006760A1
WO1990006760A1 PCT/EP1989/001500 EP8901500W WO9006760A1 WO 1990006760 A1 WO1990006760 A1 WO 1990006760A1 EP 8901500 W EP8901500 W EP 8901500W WO 9006760 A1 WO9006760 A1 WO 9006760A1
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WIPO (PCT)
Prior art keywords
brucella
phials
series
microorganisms
phial
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Ceased
Application number
PCT/EP1989/001500
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English (en)
Inventor
Alberto Indrio
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Publication of WO1990006760A1 publication Critical patent/WO1990006760A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/098—Brucella

Definitions

  • the present invention relates to pharmaceutical compositions active against depression, anxiety, multiple sclerosis, Alzheimer's disease and Parkinson's disease.
  • the invention also relates to the use of anti-melitensis vaccines for the preparation of pharmaceutical compositions useful in the treatment of said diseases.
  • anxiety and/or depression are used to define a pathological condition which is increasing in frequency and which is characterized by psycho-motor symptoms, neuro-vegetative symptoms and behavioral symptoms.
  • the therapeutic treatments presently used consist in administering pharmaceutical drugs such as benzodiazepines , tricyclic anti-depressants, mono-amino- oxydase inhibitors, etc. which have produced a temporary effect with some patients, but are rarely a permanent cure. Also, the use of such preparations presents many undesirable problems such as side effects, acute intoxication phenomena, physical and psychic dependence and possible interactions with other pharmaceuticals.
  • Multiple sclerosis is an inflammatory disease of the central nervous system, probably induced by unidentified viral agents, characterized by random patches or plaques of inflammation, with loss of myelin (a protective material surrounding nerve fibers in the white matter of the brain and spinal cord) .
  • myelin a protective material surrounding nerve fibers in the white matter of the brain and spinal cord.
  • the most frequent symptoms of this disease are motor disturbances (paresis and paralysis) , cerebral disturbances (trepidation, scandium, ataxia) and ocular disturbances.
  • Functional disturbances and psychic disorders such as anxiety and depression are also frequent.
  • the recommended remedy for acute multiple sclerosis has been the administration of steroids at high dosages and ACTH (adrenocorticotropic hormone) at high and then decreased dosages. For the chronical situation no valid cure for the .-disease has yet been found.
  • Alzheimer's disease senile dementia
  • the histologic changes (senile plaques, neurofibrillar changes, etc.) abundantly damage the cortex cerebri, although this process is sometimes limited to the frontal or temporal lobes.
  • the intellectual functions deteriorate; at the beginning the clinical pattern can present itself like a psychogenic disorder with anxiety and depression, then being followed by disorientation, ⁇ e memory disorders and reduced comprehension and judgment capacity. So far no effective therapy to cure this disease exists.
  • Parkinson's disease affects people between 50 and 70 years old.
  • the primary damage consists of a progressive atrophy of the black substance of neuron cells and a resulting degeneration of dopaminergic systems.
  • the three main symptoms are: trepidations, holotonia and akinesia.
  • the known therapies comprise an inhibiting factor of the cholinergic system.
  • One aspect of the invention is a pharmaceutical composition having activity against depression, anxiety, multiple sclerosis, Alzheimer's disease and Parkinson's disease, containing as the active ingredient microorganisms of the Brucella genus.
  • Another principal aspect of the invention is the use of microorganisms of the Brucella genus or derivatives thereof for the manufacture of a pharmaceutical composition for the treatment (other than for the treatment or prevention of brucellosis) of depression, anxiety, multiple sclerosis, Alzheimer's disease and Parkinson's disease.
  • the invention furthermore relates to and proposes a method of treatment of a human affected by the above mentioned diseases which consists in administering to said human microorganisms of the Brucella genus at doses which correspond generally to about 1/5 to about 1/250 of the doses of the microorganism conventionally used and effective for antibrucellosis therapy.
  • At least one non-attenuated or substantially non-attenuated strain of Brucella melitensis, Brucella abortus and Brucella suis (sometimes also called Brucella intermedia) is used, particularly a combination of at least two different strains of Brucella melitensis, Brucella abortus and Brucella suis.
  • a preferred combination of these three microorganisms contains 1-10 parts of Brucella melitensis, 1-10 parts of Brucella abortus and 1-10 parts of Brucella suis, based on the number of cells of the microorganisms.
  • Attenuated microorganisms and their derivatives such as the phenol-insoluble fraction of delipidated Brucella microorganisms, advantageously the phenol-insoluble fraction of delipidated Brucella abortus, preferably strain Buck 19, will sometimes be preferred.
  • the microorganisms are usually contained in a plurality of phials , for example in a series containing a progressively increasing number of cells.
  • the microorganisms are usually contained in a pharmaceutically sterile preservant liquid, i.e. an inert excipient alone or combined with a pharmaceutically active material.
  • a pharmaceutically sterile preservant liquid i.e. an inert excipient alone or combined with a pharmaceutically active material.
  • One embodiment comprises at least one non-attenuated or substantially non-attenuated strain of Brucella melitensis, Brucella abortus and Brucella suis in a series of phials containing a progressively increasing number of cells, the series beginning with at least one phial containing about 20 million cells of said microorganisms at most, the last phial of the series containing about 2000 million cells at most.
  • the 1st and 2nd phials could contain 2-10 million cells each; the 3rd phial 5-20 million cells; the 4th phial 10-50 million cells; the 5th phial 20-100 million cells; the 6th phial 40-200 million cells; the 7th phial 50-300 million cells; the 8th phial 75-400 million cells; the 9th phial 100-500 million cells; and the 10th phial 200 million to 2000 million cells.
  • Attenuated microorganisms such as the phenol-insoluble fraction of delipidated Brucella
  • they can be contained in a series of phials containing a progressively increasing quantity of the fraction.
  • the series consists of four to ten phials, the series beginning with at least one phial containing from about 2 to about 20 meg (microgram ⁇ ) of said fraction, the last phial of the series containing from about 6 to about 60 meg of said fraction.
  • At least the first phials of the series should preferably not contain multiple doses the total amount of which, if inadvertently administered in one injection, could lead to such a reaction.
  • Phials containing larger doses of the microorganisms may be obtained by using a suitable dilution.
  • concentration expressed as the number of cells (respectively micrograms) per millilitre of solution should not exceed the number of cells (respectively
  • the figure given above as the number of cells (micrograms) per phial corresponds to the equivalent concentration in cells/ml (mcg/ml) for those cases where the phial contains more than that number of cells (mcg/ml) .
  • One available vaccine against brucellosis in humans contains strains of Brucella melitensis, Brucella abortus bovis, Brucella suis in the ratio of 1:1:3.
  • This vaccine is commercialized by the Istituto Biochimico Sardo (IBS) , Cagliari, and consists (for the normal brucellosis
  • the first and second phials contain 25 million cells/ml; the third contains 50 million/ml; the fourth contains 100 million/ml; the fifth contains 250 million/ml; the sixth contains 500 million/ml; the seventh contains 1000 million/ml; the eighth contains 1500 million/ml; the ninth contains 2000 million/ml.
  • Another known vaccine for human use contains only the phenol-insoluble fraction of delipidated Brucella abortus.
  • This vaccine as commercially available from the Institut Merieux of Lyon, consists of a suspension of 1 mg of the phenol-insoluble fraction of Brucella abortus (strain Buck 19) in 0.5 ml of an aqueous solution containing, per liter, 8.5 g of sodium chloride, 0.5672 g of NaH PO .2H O, 2.5 g of NaH PO .12H 0 and 5 g of phenol as preserving agent.
  • This vaccine is prepared according to French patent No.
  • the administered effective doses are substantially about 1/100 to about 1/5 less than the doses recommended for anti-melitensis therapy. Larger and smaller doses than those mentioned have also been administered but, for most of the treated cases, the choice has been 0.1 ml (i.e.
  • the treatment according to the invention is therefore carried out for example every 2 to 3 days, according to the following list and using 0.2 ml of each phial of the IBS vaccine: 1st administration corresponding to 5 million cells 2nd administration corresponding to 5 million cells 3rd administration corresponding to 10 million cells 4th administration corresponding to 20 million cells 5th administration corresponding to 50 million cells 6th administration corresponding to 100 million cells 7th administration corresponding to 200 million cells 8th administration corresponding to 300 million cells 9th administration corresponding to 400 million cells 10th administration corresponding to 400 million cells.
  • the vaccine from Institute Merieux it has been found useful for the therapy according to the present invention, to dilute the phial (containing the suspension of 1 mg of the phenol-insoluble fraction of Brucella abortus in 0.5 ml of the specified solution); with a physiological solution to a final volume of 3.5 ml ("Dilution I") containing about 285 meg (micrograms) of phenol-insoluble fraction of Brucella abortus per ml.
  • the invention is not limited to the above-mentioned therapeutic schemes because it can be foreseen that other ways of administration with respect to the method of application, dosage, frequency and pharmaceutical forms, should lead to the same results. Therefore, the dosages described in the example mentioned above for the IBS type vaccine (which correspond to 1/5 of the dose recommended for brucellosis vaccination therapy) could be even less (for example 1/20) or greater (for example 1/3) than the dose recommended for anti-brucellosis vaccination, while the treatment with the vaccine of the Institut Merieux may be effected with 2-8 meg of PIFBA in the lst-3th administrations, with 4-12 meg in the 4th-6th, administrations and with 6-30 meg in the subsequent administrations.
  • intervals between one administration and another can be increased and it has been noted that this is advisable especially if the injected doses are increased with regard to those found most advisable for the therapy according to the present invention which foresees, for . some diseases of the nervous system,the possibility to use concentrations , intervals and number of administration very different from case to case.
  • some diseases of the nervous system the possibility to use concentrations , intervals and number of administration very different from case to case.
  • nearly all patients treated to date have shown signs of a complete recovery after a single series of administrations according to the above dosage schemes.
  • a recall treatment at set periods of for example one year or whenever further treatment needs to be prescribed, ' is beneficial.
  • the dosage for recall treatments can be the same as or different from the initial amount injected and/or the number of injections; often a medium dosage will be selected.
  • compositions prepared purposely to be used against anxiety and as anti-depressants also fall within the scope of the present invention, i.e. pharmaceutical compositions which contain for instance selected strains of Brucella in a predetermined dosage.
  • the preparation of such pharmaceutical compositions is carried out according to known and conventional methods such as described in for instance Remington's Pharmaceutical Science Handbook,hack Pub. Co. New York U.S.A.
  • Brucella micro ⁇ organisms with other microorganisms, for example vaccines which are known for the treatment of other diseases, especially attenuated forms of such microorganisms.
  • vaccines which are known for the treatment of other diseases, especially attenuated forms of such microorganisms.
  • the same new therapeutic effect may be obtained with derivatives of the known vaccines or with derivatives or modifications of Brucella micro ⁇ organisms produced by known methods, i.e. including known techniques for killing or partially killing the bacteria, and for separating specific fractions thereof.
  • the scale of autoevaluation of depression used is the scale of Zung (SDS, Self Depression Scale) , according to which patients are classified as follows: individuals who are not depressed, or on the borderline, between 20 and 29; individuals who are anxious and depressed, between 30 and 42; individuals with moderate depression, between 43 and 59; individuals with serious depression, between 60 and 80.
  • SDS Self Depression Scale
  • the patient's thyroid function is checked because the treatment according to the invention does not have the same surprising effect for states of anxiety due to thyroid malfunction.
  • the product(s) used, their dosage and duration of the treatment are noted.
  • the previous treatments can be stopped, abruptly in the case of benzodiazepines, but gradually and carefully for other products, in order to avoid rebound phenomena or slowing or reducing the action of the treatment according to the invention.
  • the therapy can still be performed but the patient should be treated with an antibiotic of the amoxicillin type for instance at 2 g per day for five to six days.
  • the usual treatment consists of a series of ten intramuscular injections in the deltoid area, one every two or three days, of small calibrated doses of the Brucella-based vaccine as specified above.
  • Other administration methods are possible, for example skin scarification.
  • the treatment can be stopped as soon as a clear improvement appears. This happens very often after five or six injections. Should an improvement after the first five or six injections appear to be sluggish, the treatment can be pursued combined with the administration
  • a typical evolution of the treatment and its progress is as follows. The patients initial response is noted and possible minor local reactions are checked after the second injection. The first signs of improvement usually appear after the third injection, especially with patients previously under treatment with other products. The general response can and preferably is evaluated after the fourth injection. Most patients voluntarily express feelings of satisfaction and well being after the 5th injection. From the 6th to 10th injections normally a marked improvement should continue and become stable. If, however, the improvement does not progress as desired, higher doses can then be used, as set out above. Generally speaking, further increase of the dosage is not dangerous but will not improve the effect.
  • the patients compile new Hamilton and Zung rating scales for comparison with the initial ones.
  • Table I gives results obtained with the IBS type vaccine according to the first dosages specified above. Similarly, Table II gives results obtained with treatments using the Merieux type vaccine with the second dosage scheme given above. TABLE I
  • the invention is based on the fact that anti-melitensis vaccine administered in low doses has been identified as a powerful stimulator of the immune system in general which influences the state of the nervous system and, furthermore, has a synergistie effect in the cure of disorders either of the nervous system or of the immune system or of the endocrine system alone or in combination with known pharmaceuticals. Obviously the exact interpretation of the mechanism of action of the claimed pharmaceutical composition does not constitute a factor limiting the scope of the invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Mycology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques présentant une activité contre la dépression, l'angoisse, la sclérose multiple, la maladie d'Alzheimer et la maladie de Parkinson, contenant à titre de constituant actif un vaccin anti-brucellose comprenant diverses formes de microorganismes de Brucella tels que Brucella melitensis, Brucella abortus bovis et Brucella intermedia.
PCT/EP1989/001500 1988-12-13 1989-12-06 Compositions pharmaceutiques contenant de la brucella ou des derives de celle-ci Ceased WO1990006760A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT8822934A IT1227892B (it) 1988-12-13 1988-12-13 Composizioni farmaceutiche ad attivita' antidepressiva e ansiolitica
IT22934A/88 1988-12-13

Publications (1)

Publication Number Publication Date
WO1990006760A1 true WO1990006760A1 (fr) 1990-06-28

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PCT/EP1989/001500 Ceased WO1990006760A1 (fr) 1988-12-13 1989-12-06 Compositions pharmaceutiques contenant de la brucella ou des derives de celle-ci

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AU (1) AU4666389A (fr)
IT (1) IT1227892B (fr)
WO (1) WO1990006760A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009624A1 (fr) * 1989-12-22 1991-07-11 Alberto Indrio Compositions pharmaceutiques de traitement de la dependance vis-a-vis de drogues

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2334370A1 (fr) * 1975-11-28 1977-07-08 Agronomique Inst Nat Rech Procede et presentations pharmaceutiques pour la vaccination contre la brucellose
FR2506615A1 (fr) * 1981-06-01 1982-12-03 Merieux Inst Vaccin contre les brucelloses humaines et son procede de fabrication

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2334370A1 (fr) * 1975-11-28 1977-07-08 Agronomique Inst Nat Rech Procede et presentations pharmaceutiques pour la vaccination contre la brucellose
FR2506615A1 (fr) * 1981-06-01 1982-12-03 Merieux Inst Vaccin contre les brucelloses humaines et son procede de fabrication

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"The Merck Manual of Diagnosis and Therapy", Editor R. BERKOW et al., 13th Edition, 1977, Merck Sharp & Dohme Research Labratories, (Rahway, N.J., US), pages 98-99 *
Unlisted Drugs, Vol. 21, No. 3, March 1969, Section g: "Bruceloral", pages 36, & MDM Man Drogas 3(15):19, Sep-Oct 68 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009624A1 (fr) * 1989-12-22 1991-07-11 Alberto Indrio Compositions pharmaceutiques de traitement de la dependance vis-a-vis de drogues

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Publication number Publication date
IT8822934A0 (it) 1988-12-13
IT1227892B (it) 1991-05-14
AU4666389A (en) 1990-07-10

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