WO1996001107A1 - Emploi d'agents pharmaceutiques retablissant, ameliorant ou traitant la deficience immunitaire et notamment ameliorant ou traitant certains troubles immunitaires lies a des infections par le vih - Google Patents

Emploi d'agents pharmaceutiques retablissant, ameliorant ou traitant la deficience immunitaire et notamment ameliorant ou traitant certains troubles immunitaires lies a des infections par le vih Download PDF

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Publication number
WO1996001107A1
WO1996001107A1 PCT/DK1995/000286 DK9500286W WO9601107A1 WO 1996001107 A1 WO1996001107 A1 WO 1996001107A1 DK 9500286 W DK9500286 W DK 9500286W WO 9601107 A1 WO9601107 A1 WO 9601107A1
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Prior art keywords
infection
alleviation
treatment
cells
restoring
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PCT/DK1995/000286
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English (en)
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Bo Arne Hofmann
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Bo Arne Hofmann
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Priority to AU28805/95A priority Critical patent/AU2880595A/en
Publication of WO1996001107A1 publication Critical patent/WO1996001107A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom

Definitions

  • HIV Human Immunodeficiency Viruses
  • This invention relates to the use of an agent which inter ⁇ acts with 5HT receptors as defined below for increasing the proliferative capacity of immune cells from individuals suffering from one or more of the above- mentioned dysfunctions.
  • the invention relates to an agent for increasing the CD4 T cell count in such individuals.
  • the agent is also for the preparation of a medicament for restoring, alleviation or treatment of immuno deficiency, including the alleviation or treatment of the immune dysfunction related to infection with Human Immunodeficiency Viruses (HIV) or related viruses.
  • HIV Human Immunodeficiency Viruses
  • the invention relates to the immune dysfunction seen in pre-AIDS and AIDS.
  • the medicaments are to be used in human or veterinary medicine.
  • the invention also relates to a method for increasing the proliferative capacity of immune cells from individuals suffering from one or more of the above-mentioned dysfunctions.
  • the actions of the agents are considered to be related to a stimulation of receptor sites of cells of the immune system. Said stimulation results in the maintenance and/or reestablishment of a balanced function of the immune cells affected by a virus, virus components or other antigens.
  • the present invention provides means for the pre- vention and/or restoration of the impaired immune function observed in a number of pathological pictures. Decreased immune function follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions.
  • the present invention provides means for the prevention and/or restoration of the impaired immune function - observed in infection with Human Immune deficiency Virus (HIV), pre-AIDS, and AIDS, infection with Cytomegalo virus (CMV) , Epstein Barr virus (EBV) , measles virus and varicella virus all associated with cellular immune deficiency.
  • HIV Human Immune deficiency Virus
  • CMV Cytomegalo virus
  • EBV Epstein Barr virus
  • measles virus and varicella virus all associated with cellular immune deficiency.
  • Said means enables the subject treated to better cope with infections and/or avoid development of various forms of neoplasia.
  • HIV Human Immune deficiency Virus
  • CMV Cytomegalo virus
  • EBV Epstein Barr virus
  • varicella virus a virus that causes cellular immune deficiency.
  • a clinical sign of this is the occasional outbreak of herpes zoster in otherwise healthy individuals following those infections.
  • Pneumonia caused by bacteria is also common following these infections and indicates a decreased immune function.
  • Major surgical procedures and blood transfusion are also associated with a high frequency of infections. After blood transfusions, the immune deficiency seems to be induced by the content of donor leukocytes in the blood unit. The importance of the immune deficiency induced by major surgical procedures and bloodtransfusions is accentuated by the association with more frequent recidives of cancer af er these procedures.
  • Cancer forms which are related to immune deficiency are in particular colon cancer, but also pancreas cancer and stomach cancers and various lymphoma in particular non- Hodgkins lymphom.
  • HIV Human Immunodeficiency Virus
  • medicaments directed to interfere with virus repli ⁇ cation e.g. azidothymidine (AZT) described in DE patent 3 608 606, have not yet proven effective in restoring the immune capacity of the treated subject.
  • ZHT azidothymidine
  • medicaments for the treatment of functional deficiencies due to HIV infection are described.
  • medicaments inhibiting the cAMP/PKA pathway are the Chinese herb extract "dan-shen", antagonists of adenylate cyclase, antibodies immunologically reactive with adenylate cyclase, dideoxyadenosine, and polyadeny- lates.
  • agents according to the present invention should enable the employment of substances which - like all medicaments - have certain side effects - but which nevertheless - when administered in dosages carefully adapted to the individual subject - should provide for an increase in the proliferative capacity of immune cells, and an increase in the CD4 T cell count in such individuals, and prevention or alleviation of immune dysfunction without causing side effects so devastating that administering to humans or animals is dissuaded.
  • HIV Human Immune deficiency Virus
  • CMV Cytomegalo virus
  • EBV Epstein Barr virus
  • measles virus measles virus and varicella virus all associated with cellular immune deficiency.
  • agents according to the present invention is related to the fact that HIV infected patients do not primarily suffer from the HIV infection itself, but from the impact of HIV on cells of the immune system.
  • certain agents ident ⁇ ified and registered for the use as CNS active pharmaceuticals e.g. antimigraine agents, anxiolytica, antidepressiva, and certain neurotransmitters
  • CNS active pharmaceuticals e.g. antimigraine agents, anxiolytica, antidepressiva, and certain neurotransmitters
  • when used according to the present invention are effective for the increase in proliferative capacity of immune cells as well as an increase in the CD4 T cell count and for restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions, as well as the immune dysfunction seen for virus infections associated with cellular immune deficiency when an infected individual is exposed to said agents.
  • Sumatriptan is an antimigraine agent which is described in e.g. US patent 4 816 470.
  • US patent 3 717 634 as a non-benzodiazepine anxiolytic - and in WO 93/04681 for the prevention or treatment of cognitive disorders.
  • - Gepirone is structurally related to buspirone, and is described in US patent 4 423 049 as a non-benzodiazepine tranquillizer .
  • Ipsapirone which is also structurally related to buspirone, is described in US patent 4 818 756 as a non- benzodiazepine anxiolytic.
  • Serotonin has for a number of years been considered to have effect as a neurotransmitter in the central nervous system, and the function of serotonin as such is well investigated (cf. ref. 14 and 15). Serotonin is present in large amounts in the peripheral blood bound in throm- bocytes and granulocytes. The function of serotonin in these cells is unclear.
  • DPAT 8-hydroxy-2-(di-N-propylamino)tetralin
  • HIV infected individuals should be able to fight common infection and possibly also the develop- ment of neoplasia.
  • a main aspect of the present invention is the use of an agent which interacts with 5HT receptors as defined herein for the preparation of a medicament for restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions.
  • the main aspect of the present invention is in particular relates to the immune dysfunction seen for virus infections associated with cellular immune deficiency.
  • 5HT receptors means receptors which have been shown - or can be shown - to interact with 5HT (serotonin). Said interacting may be of the nature of an agonistic or a partially agonistic action, or an antagonistic or a partially antagonistic action. Said 5HT receptors comprise the 5HT receptors and subtypes thereof already identified in research.
  • restoring, alleviation, or treatment means providing a subject with the agent in question in an amount which is sufficient to prophylactically slow or prevent the development of an unhealthy state due to diseases such as infections and cancer, as well as major surgical procedures and blood transfusions, including the infection with Human Immunodeficiency virus or other viruses associated with cellular immune deficiency; or sufficient to alleviate the symptoms or the diseased state; or sufficient to permanently eliminate the symptoms or treat the infection itself.
  • Human Immunodeficiency viruses or related viruses means HIV or other retroviruses causing immune dysfunction similar to the dysfunction seen in HIV infec ⁇ tion, pre-AIDS and AIDS.
  • Other examples may be infections caused by HTLV1 and HTLV2, and some of the feline and bovine retroviruses.
  • the restoring, alleviation, or treatment of the immune dysfunction is mediated via a direct interaction between said agent and a responsive site present on some of the immune cells in the virus infected individual.
  • immune cells means cells present in the blood and/or in the hemopoietic tissue of the individual which may be infected with HIV or related viruses. Methods of determining the responsiveness of said immune cells - the target cells - are described below.
  • certain subpopulations of such responsive cells may be determined and "targeted", e.g. cells present in lymph nodes, thymus (e.g. thymocytes) and/or spleen.
  • thymus e.g. thymocytes
  • spleen e.g. IL-4 T cells
  • One par ⁇ ticular subpopulation of lymphocytes may be responsive forms of CD4 T cells and CD8 T cells.
  • the medicaments according to the present invention can be used to provide a targeted restoration of the cellular functional capabilities.
  • One measure for this restoration is an increased CD4 T cell count and/or an increased CD4/CD8 cell ratio.
  • the responsive site present on some of the immune cells in the virus infected individual may be a cellular receptor site which is structurally or functionally related to the neuronal 5HT receptors or subtypes thereof, i.e. the 5HT receptors present on cells in the nervous system.
  • the response obtained by the use according to the present invention may be due to various molecular actions at the site of a receptor or near to a receptor present on the immune cells. Many of said actions are considered to be initiated and/or to prevail outside the cell exhibiting the receptor, i.e. primarily at the "exterior" side of the cell membrane.
  • classes of agents to be used accor ⁇ ding to the present invention are the following: sumatriptan, 3-[2-(dimethylamino)ethyl]-n-methyl- lH-indole-5-methansulfonamide, or the class of related compounds as defined below;
  • buspirone 8- ⁇ 4-[4-(2-pyrimidinyl)-l-piperazi- nyl]butyl ⁇ -8-azaspiro[4, 5]decane-7, 9-dione, or the class of related compounds as defined below;
  • gepirone 4,4-dimethyl-l- ⁇ 4-[4-(2-pyrimidinyl)-l- piperazinyl]butyl ⁇ -2, 6-piperidinedione, or the class of related compounds as defined below;
  • Suitable members from the class considered to interact with the 5HT1 receptors are selected to be used according the present invention.
  • One important class of subtypes of the 5HT1 receptors is the class comprising the 5HTld receptors.
  • sumatriptan and related compounds are considered to first of all interact with said 5HTld receptors.
  • Another important class of subtypes of the 5HT1 receptors is the class comprising the 5HTla receptors.
  • buspirone and related compounds are considered to first of all interact with said 5HTla receptors.
  • a further aspect of the invention is a method for increasing the proliferative capacity of immune cells of an individual comprising exposing said immune cells to an effective amount of an agent selected from the group consisting of agonists and antagonists of the 5HT receptors of said cells, said individual being infected with HIV or a related retrovirus.
  • Another aspect of the invention is a method for increasing the CD4 T cell count in an individual, comprising exposing said CD4 T cells to an effective amount of an agent selected from the group consisting of agonists and antagonists of the 5HT receptors of said cells, said individual being infected with HIV or a related retrovirus.
  • a further aspect of the invention is a method of allevi ⁇ ating, restoring, or treating the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions.
  • This further aspect of the present invention in particular relates to the immune dysfunction seen for virus infections associated with cellular immune deficiency, which method comprises administering an effective amount of an agent which interacts with 5HT receptors as defined above.
  • an agent which interacts with 5HT receptors as defined above.
  • a particular aspect of the invention therefore relates to a method of alleviating or treating individuals infected with HIV and a related retrovirus which do not also suffer from one or more CNS diseases usually treated by the agents described above.
  • Another main aspect of the invention is the use of a serotonin uptake inhibitor as defined below for the preparation of a medicament for the restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions - in particular, when said infection is related to infection with HIV or other viruses associated with cellular immune deficiency.
  • paroxetine trans-(- )-3-[(1,3-benzodioxol-5- yloxy)methyl]-4(4-fluorophenyl) iperidine;
  • Another aspect of the invention is a method of allevi- ating, restoring, or treating the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions, which method comprises administering to subject an agent which is a serotonin uptake inhibitor.
  • Said serotonin inhibitor may be selected from the group mentioned just above.
  • Said administration may be conducted extracorporally.
  • T cells being primed against antigens e.g. micro ⁇ organisms such as Candida albicans, Cytomegalo virus, etc. will - when they encounter such microorganisms become activated. The cells will undergo a clonal expansion (proliferation) and provide a large number of T cells directed against the microorganism. This "army" of T cells will perform a direct killing (cytotoxicity) of the microorganism.
  • antigens e.g. micro ⁇ organisms such as Candida albicans, Cytomegalo virus, etc.
  • One aspect of the invention is the use of the agent
  • sumatriptan or the class of related compounds means the compounds described in US patent 4 816 470, In so far as the biochemical actions of said compounds on an individual are similar to that of sumatriptan with respect to increase of the proliferative capacity of immune cells, increase of the CD4 T cell count and/or the stimulation of receptor sites of cells of the immune system, where said stimulation results in the maintenance and/or reestablishment of a balanced function of the immune cells affected by a virus, virus components or other antigens.
  • agents used according to the present invention may also be chosen from physiologically acceptable derivatives of sumatriptan formulated as depot compositions or sustained release preparations.
  • the compounds may be produced by a number of processes described in said US patent, which is incorporated herein by reference.
  • a further aspect of the present invention is the use of the agent
  • buspirone 8- ⁇ 4-[4-(2-pyrimidinyl)-l-piperazi- nyl]butyl ⁇ -8-azaspiro[4,5]decane-7,9-dione, or the class of related pharmaceutical compounds as defined herein; or gepirone and ipsapirone or the classes of related pharmaceutical compounds as defined herein,
  • buspirone or the class of related pharmaceuti ⁇ cal compounds, as defined herein
  • buspirone means the compounds described in US patent 3 717 634 - in so far as the physiological actions of said compounds on an individual are similar to that of buspirone with respect to increase of the proliferative capacity of immune cells, increase of the CD4 T cell count, and the restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions - in particular, when said infection is related to infection with HIV or other viruses associated with cellular immune deficiency.
  • the compounds may be produced by a number of processes described in said US patent which is incorporated herein by reference.
  • a further aspect of the present invention is the use of the agent 15
  • gepirone or the class of related compounds as defined herein;
  • gepirone or the class of related pharmaceutical compounds as defined herein means the compounds described in US patent 4 423 049 - in so far as the physiological actions of said compounds are similar to that of buspirone with respect increase in the proliferative response in immune cells, increase in the CD4 T cell count, and to the restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions - in particular, when said infection is related to infection with HIV or other viruses associated with cellular immune deficiency.
  • the compounds may be produced by a number of processes described in said US patent which is incorporated herein by reference.
  • ipsapirone or the class of related pharmaceuti ⁇ cal compounds as defined herein means the compounds described in US patent 4 818 756 - in so far as the physiological actions of said compounds are similar to that of buspirone with respect to increase in the proliferative response in immune cells, increase in the CD4 T cell count, and the restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions - in particular, when said infection is related to infection with HIV or other viruses associated with cellular immune deficiency.
  • the compounds may be produced by a number of processes described in said US patent which is incorporated herein by reference.
  • a further aspect of the invention is the use of
  • serotonin-creatinine sulphate is serotonin-creatinine sulphate.
  • An example of a precursor for serotonin is 5-hydroxy tryptophane.
  • a further aspect of the invention is the use of the agent
  • derivative thereof means any of the physiologically acceptable compounds having similar structure and equivalent function to that of DPAT.
  • physiologically acceptable derivatives of DPAT formulated as depot compositions or sustained release preparations are included.
  • the present invention relates to the use of agents which interact with 5HT receptors. Said interacting has to be adapted so as to result in - or to promote - the restoration of a balanced immune function in the infected individuals.
  • SUBSTITUTESHEET This may also apply to certain compounds considered to interact with 5HT2 or 5HT3 receptors.
  • Yet another overall aspect is the use of a serotonin uptake inhibitor as defined herein for the preparation of a medicament for restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions - in particular, when said infection is related to infection with HIV or other viruses associated with cellular immune deficiency.
  • Another aspect of the invention is an agent and method for increasing the proliferative capacity of immune cells from individuals suffering from one or more of the above immune dysfunctions.
  • a still further aspect is an agent and method for increasing the CD4 T cell count in such individuals.
  • statin uptake inhibitor means an agent which has been shown to increase the amount of 5HT at the site of or near to the site of a 5HT receptor as defined herein.
  • inhibitors at least par ⁇ tially prevent serotonin from being removed from an environment close to a 5HT receptor or a subtype thereof.
  • Said serotonin uptake mechanism can be described as follows: After release from serotonergic neurons, much of the released serotonin is recaptured by an active reuptake mechanism. It is well known that certain inhibitors may interfere with said mechanism.
  • the agents known to increase the availability of serotonin by inhibiting serotonin uptake may be considered to also promote said restoration of the immune function.
  • said agents promote the wanted physiological response by making more serotonin available at appropriate sites in the body.
  • Citalopram 1-[3-(dimethylamino)propyl]-1- ⁇ fluo ⁇ rophenyl)-l,3-dihydro-5isobenzofurancarbonitrile, or a precursor or a derivative thereof.
  • Fluvoxamine 5-methoxy-l-(4-trifluoromethyl)phe- nyl)-l-pentanone 0-(2-aminoethyl)oxime; or a precursor or a derivative thereof.
  • Fluoxetine ( ⁇ )-N-methyl-Y-[4-(trifluoromethyl)- phenoxy]benzenepropanamine, or a precursor or a derivative thereof.
  • Paroxetine trans-(-)-3-[ (1,3-benzodioxol-5-yl- oxymethyl]-4(4-fluorophenyl)piperidine; or a precursor or a derivative thereof.
  • “Seroxat”. praroxetine
  • Novo Nordisk A/S an antidepressivum.
  • a further aspect of the use according to the present invention is the use of a combination of any one of the described medicaments.
  • the combinations may be combinations of
  • Said combinations may be formulated so as to provide com ⁇ bined pharmaceutical effects or even synergistic effects.
  • Said combinations may also - or alternatively - be formulated with the purpose of trying to minimize the side effects induced by the individual medicaments.
  • the following regimen may be employed: Regardless of which agents are selected to be used according to the present invention, the use may further comprise the use in combination with a specific antiviral medicament.
  • Said combination may be formulated so as to obtain combined effects or even synergistic effects.
  • Said combination may also - or alternatively - be formulated so as to minimize the side effects induced by the individual medicaments.
  • the present invention provides for a method of the restoring, alleviation, or treatment of the immune dysfunction related to the decreased or deficient immune function, which follows diseases such as infections and cancer, as well as major surgical procedures and blood transfusions, which method eomprises administering an effective amount of an agent capable of stimulating a site present on some of the immune cells as defined herein.
  • the administering is conducted extracorporally in order to specifically target the action of the agent employed to the cells in question.
  • treatment of the cells may also be performed using extracorporal circulation of the blood by using a technique similar to regular plasmapheresis. In this way it is possible to use a higher concentration of the active ingredient.
  • the active ingredient is removed, e.g. by filtration or active binding to specific membranes.
  • Another advantage of such administration is that the total amount of medicament to be administered "internally” may be reduced as compared to systemic administration. "Surplus” of medicament may also be eliminated extracorporally - this also reducing the total amount administered to the patient. DETERMINATION OF DOSAGE FORMS AND AMOUNTS OF THE AGENTS
  • An aspect of the invention is to employ tests on living cells obtained from infected individuals in order to assess the effect of the agents on cellular immunity. Whenever appropriate or necessary, the dosage forms and amount of the agents may be determined according to the procedures described herein.
  • the starting material may be blood or other cell contain ⁇ ing body fluids, and also samples containing hemopoietic tissue, e.g. obtained by biopsy/aspiration procedures. Important material is also fluids containing bone marrow cells.
  • Examples of cells to be examined are in particular white blood cells, leucocytes, such as lymphocytes and prede ⁇ cessors thereof, including blast cells and other immature cells representing various stages in the maturation process starting from stem cells.
  • Measurements based on blood cells or various other cells from healthy donors may be used as standard/reference values.
  • the starting material is peri ⁇ pheral blood
  • the first step is the isolation of a fraction enriched in mononuclear cells.
  • peripheral blood mononuclear cells containing about 70% T lymphocytes are isolated from blood.
  • the method involves a centrifugation step, such as density gradient centrifugation.
  • An important aspect is to perform preliminary experiments designed to determine suitable ranges of cell concentra ⁇ tion in relation to various concentrations of agents. Such experiments provide for reference curves applicable for deciding the optimal ratios between cell amount and agent so as to ensure a suitable biochemical response.
  • a predetermined amount of these cells e.g. 5 000 to 100 000 cells, such as from 25 000 to 75 000 cells, typically approximately 50 000 of these cells are added to each well in a microtitre plate.
  • said wells are designed to each contain a maximal volume of 200 ⁇ l.
  • a standard "activating" stimulus is added to the cultures.
  • This stimulus may be selected from the following:
  • mitogenic agents e.g. poke weed mitogen (PWM) or phytohaemagglutinin (PHA); non-specific activators of most T cells; or recall antigens, i.e. antigens from microorganisms e.g. tetanus toxoid or Candida albicans.
  • PWM poke weed mitogen
  • PHA phytohaemagglutinin
  • non-specific activators of most T cells i.e. antigens from microorganisms e.g. tetanus toxoid or Candida albicans.
  • a suitable culture medium containing appro ⁇ priate nutrients and buffers e.g. RPMI supplemented with 10% fetal calf serum and antibiotics
  • a suitable culture medium containing appro ⁇ priate nutrients and buffers e.g. RPMI supplemented with 10% fetal calf serum and antibiotics
  • a known total volume e.g. 200 ⁇ l.
  • microplate cultures are incubated in an incubator under suitable conditions (such as with 5% C0 2 and 100% humidity at 37°C) for e.g. 6 days.
  • suitable conditions such as with 5% C0 2 and 100% humidity at 37°C
  • a labelling agent such as H-thymidine (for instance 1 ⁇ Ci) is added to all cultures.
  • cultures are harvested on glass filter plates, transferred to counting vials, and a suitable developer is added (e.g. 5 ml of scintillation fluid).
  • the amount of label incorporated e.g. the amount of 3 H-thymidine incorporated in the DNA of the dividing cells, is measured according to methods known in the art.
  • cAMP concentrations in various cells from infected individuals may also be determined during the testing of agents and during treatment in order to elucidate the possible role of cAMP as an endogenous compound useful for monitoring of various cellular functional states.
  • CD4 T cells and CD8 T cells may be determined by means of flow cytometry. Said cell determinations may he used to ident ⁇ ify individuals susceptible to treatment, and said cell determinations may also be one of the parameters of a system designed to monitor the effect of treatments.
  • the agent is added to the blood or other cell contain- ing body fluids before the step of cell isolation is performed;
  • the agent is added to the cell enriched fraction placed in the microtitre plate prior to the addition of the mitogenic stimulus (e.g. 10 - 30 minutes earlier).
  • reaction media containing the agent to be tested is kept under suitable conditions including a suitable temperature until the addition of stimulus.
  • suitable conditions including a suitable temperature.
  • a commonly employed temperature is room temperature.
  • agents used according to the present invention should be administered in amounts effective to attain the above mentioned restoration of immune function without inducing unbalanced effects or severe side effects.
  • the concentrations relate to amount of active compound.
  • the agents are used to prepare medicaments containing physiologically acceptable addi- tives known in the art.
  • Administration on a daily basis in a dose of 100-300 mg, e.g. administered as the only single initial treatment which may enable determination of the degree of response.
  • results obtained are used as the basis for the choice of urther dosages and for the set-up of an individually adapted regimen.
  • a suitable protocol for a re-treatment or maintenance treatment would be the following:
  • the maximal therapeutic non-toxic dose of buspirone is considered to be approximately 2400 mg per day.
  • the medicament "Buspar” . , Bristol-Myers Squibb, may be employed.
  • the results obtained are used as the basis for the choice of further dosages and for the set-up of an individually adapted regimen.
  • a suitable protocol for a re-treatment or maintenance treatment would be the same or a somewhat higher dosaging - with regular intervals adapted individually.
  • Serotonin is preferably administered i.v., e.g. by infu ⁇ sion to patients admitted to hospitals, or out patients with catheters placed intravenously.
  • serotonin has a systemic effect when administered in a concentration of 15 nM/min/kg. If serotonin is administered in this concentration for 2-4 hours most lymphoid cells in the peripheral blood and possibly also in the tissues have been reached. This - treatment must be repeated with regular intervals, e.g. every day. Other preparations of serotonin may be employed, e.g. sustained release preparations for sub ⁇ cutaneous injection of depot preparations.
  • This drug is a specific agonist of the 5HTla receptor.
  • the dosaging should be monitored carefully with respect to toxicity and side effects.
  • a suitable dosage for this drug would be in the range of 10-1000 mg, e.g. 50 mg, given daily as tablets administered orally 1-3 times daily. Alternatively parenteral administration may be employed.
  • Another approach is to increase the circulating concen ⁇ tration of serotonin by preventing the removal of serotonin produced in the body.
  • Such drugs may be given as tablets on a daily basis.
  • Fig. 1 illustrates the effect of Imigran (sumatriptan) on lymphocytes isolated from blood from HIV seropositive subjects.
  • peripheral blood mononuclear cells were incubated in wells of microtitre plates. Imigran was added in 8 different ten fold dilutions starting with 10 ⁇ g/ml. After 10 minutes the activator poke weed mitogen (PWM) was added.
  • PWM poke weed mitogen
  • the measurements are expressed in "cpm" (counts per minute) indicating the amount of labelled DNA incorporated into the dividing cells.
  • the results are given as medians of triplicate determinations.
  • the first column in the diagram represents cultures to which no agents had been added.
  • the second and third column represents the control cultures to which Imigran - but not PWM - had been added in different concentrations.
  • the fourth column represents cultures to which PWM had been added, and the fifth and sixth column represents - cultures to which both PWM and Imigran had been added.
  • Fig. 2 illustrates the effect of Buspar (buspirone) on lymphocytes isolated from blood from HIV seropositive subjects.
  • peripheral blood mononuclear cells were incubated in wells of microtitre plates.
  • Buspar was added in 8 different ten fold dilutions starting with 10 ⁇ g/ml. After 10 minutes the activator poke weed mitogen (PWM) was added.
  • PWM poke weed mitogen
  • the measurements are expressed in "cpm" (counts per minute) indicating the amount of labelled DNA incorporated into the dividing cells.
  • the results are given as medians of triplicate determinations.
  • the first column in the diagram represents cultures to which no agents had been added.
  • the second and third column represents the control cultures to which Buspar but not PWM - had been added in different concentrations.
  • Test cultures The fourth column represents cultures to which PWM had been added, and the fifth and sixth column represents - cultures to which both PWM and Buspar had been added.
  • Fig. 3 illustrates the effect of serotonin (5HT) on lymphocytes isolated from blood from HIV seropositive subjects.
  • peripheral blood mononuclear cells were incubated in wells of microtitre plates. Serotonin was added in 8 different ten fold dilutions starting with 50 ⁇ g/ml. After 10 minutes the activator poke weed mitogen (PWM) was added.
  • PWM poke weed mitogen
  • the measurements are expressed in "cpm" (counts per minute) indicating the amount of labelled DNA incorporated into the dividing cells.
  • the results are given as medians of triplicate determinations.
  • the first column In the diagram represents cultures to which no agents had been added.
  • the second and third column represents the control cultures to which serotonin - but not PWM - had been added in different concentra ⁇ tions.
  • the fourth column represents cultures to which PWM had been added, and the fifth and sixth column represents cultures to which both PWM and serotonin had been added.
  • the results show that serotonin was able to increase/re ⁇ store the proliferative response to an "activating" stimulus (PWM) added to said lymphocytes.
  • PWM activating
  • Fig. 4 illustrates the effect of 8-hydroxy-2-(di-n-pro- pylamino)tetralin (DPAT) on lymphocytes isolated from blood from HIV seropositive subjects.
  • DPAT 8-hydroxy-2-(di-n-pro- pylamino)tetralin
  • peripheral blood mononuclear cells were incubated in wells of microtitre plates.
  • DPAT was added in 8 different ten fold dilutions starting with 50 ⁇ g/ml. After 10 minutes the activator poke weed mitogen (PWM) was added.
  • PWM poke weed mitogen
  • the measurements are expressed in "cpm" (counts per minute) indicating the amount of labelled DNA incorporated into the dividing cells.
  • the results are given as medians of triplicate determinations.
  • the first column in the diagram represents cultures to which no agents had been added.
  • the second and third column represents the control cultures to which DPAT - but not PWM - had been added in different concentrations.
  • the fourth column represents cultures to which PWM had been added, and the fifth and sixth column represents cultures to which both PWM and DPAT had been added.
  • Samples of peripheral whole blood were obtained from HIV infected individuals. Blood mononuclear cells containing about 70% T lymphocytes were separated from whole blood by centrifugation on "Histopac” (density gradient separ ⁇ ation). 50 000 of these cells were added to each well in a microtitre plate for further cultivation and testing.
  • test agent Imigran (sumatriptan) was added to each well in various concentrations.
  • the employed concentra ⁇ tions of Imigran were 8 different ten fold dilutions starting with 10 ⁇ g/ml.
  • RPMI culture medium supplemented with 10% fetal calf serum and antibiotics was added to a final volume of 200 ⁇ l.
  • the microplate cultures were incubated in an incubator with 5% C0 2 and 100% humidity at 37°C for 6 days. At day 5, 1 ⁇ Ci H-thymidine was added to all cul ⁇ tures. At day 6, cultures were harvested on glass filter plates and transferred to counting vials. Scintillation fluid (5 ml) were added, and the H-thymidine incorporated in the DNA of dividing cells was counted.
  • Samples of whole blood were obtained from HIV infected individuals.
  • Peripheral blood mononuclear cells containing about 70% T lymphocytes were separated from blood by cen ⁇ trifugation on "Histopac” (density gradient separation). 50 000 of these cells were added to each well in a micro ⁇ titre plate for further cultivation and testing.
  • test agent Buspar buspiron
  • concentrations of Buspar were 8 different ten fold dilutions starting with 10 ⁇ g/ml.
  • Example 1 RPMI culture medium supplemented with 10% fetal calf serum and antibiotics was added to a final volume of 200 ml. Then the microplate cultures were incubated, labelled, and harvested as described in Example 1. Finally the 3 H-thymidine incorporated in the DNA of dividing cells was determined as described in Example 1.
  • Buspar was able to increase/restore the proliferative response of blood lymphocytes obtained from HIV seropositive subjects.
  • Samples of whole blood were obtained from HIV infected in ⁇ dividuals.
  • Peripheral blood mononuclear cells containing about 70% T lymphocytes were separated from blood by cen- trifugation on "Histopac” (density gradient separation). 50 000 of these cells were added to each well in a micro ⁇ titre plate for further cultivation and testing.
  • test agent serotonin (5HT) was added to each well in various concentrations.
  • concentrations of serotonin were 8 different ten fold dilutions starting with 50 ⁇ g/ml.
  • Example 1 RPMI culture medium supplemented with 10% fetal calf serum and antibiotics was added to a final volume of 200 ml. Then the microplate cultures were incubated, labelled, and harvested as described in Example 1. Finally the H-thymidine incorporated in the DNA of dividing cells was determined as described in Example 1.
  • Patient 2 from 2000 cpm to 3100
  • the concentration of serotonin that resulted in increased responses to tetanus was lower and ranged between 0.5 ⁇ g/ml to 5 ng/ml.
  • Samples of whole blood were obtained from HIV infected individuals.
  • Peripheral blood mononuclear cells containing about 70% T lymphocytes were separated from blood by cen ⁇ trifugation on "Histopac” (density gradient separation). 50 000 of these cells were added to each well in a micro ⁇ titre plate for further cultivation and testing.
  • the test agent 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) was added to each well in various concentrations. The employed concentrations of DPAT were 8 different ten fold dilutions starting with 50 ⁇ g/ml.
  • Example 1 RPMI culture medium supplemented with 10% fetal calf serum and antibiotics was added to a final volume of 200 ml. Then the microplate cultures were incubated, labelled, and harvested as described in Example 1. Finally the 3 H-thymidine incorporated in the DNA of dividing cells was determined as described in Example 1.
  • Stone et al. (1993) describe how 5HT is administrated i.v.
  • the sole side effect was an increase in the diastolic blood pressure of a few mmHg.
  • the procedure of administration described by Stone can be followed step by step.
  • the procedures as described herein aim at continuing the infusion of serotonin over a period of 4 hours.
  • Serotonin is administered according to the following schedule:
  • the administration of serotonin is started by mixing this to the saline i.v. drop using an electronic drop counter.
  • the serotonin solution is 5 mM serotonin dissolved in 0.15 mM saline.
  • the infusion is kept at 8 ml/min using electronic drop counters.
  • the start concentration of serotonin is 21 ng/kg/min and increasing over 15 minutes to max. 21 ng/kg/min. This gives a maximum infusion of 1.5 ⁇ g/min for a person of 70 kg.
  • the only side effect at this dosage level should be an increase in blood pressure of 5 mmHg diastolic (ref. 15, Stone et al. ) .
  • Serotonin infusion is able to affect peripheral T cells and induce a homing.
  • a steady state resulting in enhanced proliferative capacity of peripheral T cells was not achieved during this short experiment, but must be expected with continuous treatment. The strongest effect was achieved in individuals with high CD4 T cell counts.
  • CD4 increase in two patients ending more than 50 CD4 cells higher after 1 week to 1 month.
  • Buspiron is able to affect peripheral T cells and induce a homing to the lymphatic tissues.
  • a steady state resulting in enhanced proliferative capacity of peripheral T cells was not achieved during this short experiment, but an enhancement of the immune system by continuous treatment is expected.
  • Fig. 5 The cell activation. From T cell activation to cell proliferation, the cell is guided by two pathways.
  • the activation pathway which includes the T cell receptor, inositol phospholipid metabolism (PIP2 to IP3 and DAG), calcium influx, and activation of PKC.
  • the inhibitory pathway that balance the other, is the PKA pathway, which only is active in the presence of cAMP.
  • cAMP is generated by the enzyme adenylate cyclase.
  • T l mphocytes from HIV seropositive subjects there is an increased activity of the inhibitory PKA/cAMP pathway. Inhibition of this pathway restores the immune function in T cells from HIV seropositive subjects.
  • Fig. 6 The normal immune system. In the normal immune system T cells circulate through the lymph nodes and other 40
  • lymphatic tissues into the peripheral blood and back. Only about 2% or all lymphocytes are in the peripheral blood. The rest are in the tissues.
  • a T lymphocyte on its passage encounters a macrophage presenting a microbial antigen (virus, fungus etc. ) with the right specificity for the T cell, the cell will start to proliferate. This proliferation generates an army of effector cells that will fight the foreign microbial organism (first generating an expansion of CD4 T helper cells which in turn provide help for B cells and CD8 cytotoxic cells in a cascade) . In HIV infection these final steps are blocked because T cells have decreased proliferative capacity and decreased cytotoxic capacity.
  • Fig. 7 Buspiron increases the proliferative response of lymphocytes from HIV seropositive subjects in vitro.
  • Buspiron increases the T cells' capacity to proliferate in vitro experiments as shown above with relation to Fig. 2.
  • the proliferative capacity of the T cells will increase, first in the tissues, because in vivo the immune reactions will not take place in the peripheral blood, and later, when a steady state is reached, an increased proliferative capacity should also be detected in the peripheral blood. Also an increased proliferative capacity may result in a higher number of newly generated CD4 T cells.
  • PBMC peripheral blood nononuclear cells
  • Fig. 8 Buspiron induces a homing of reactive peripheral lymphocytes to the lymphatic tissues within a few hours when given in a single dose of 60 mg perorally.
  • the lymphocyte proliferative capacity to stimulation with PWM was measured at time 0, 1 h, 4 h, 24 h, 1 week and 1 month (data not ready yet) as described above. Because the drop in reactive lymphocytes happens within one hour, a redistribution is evident.
  • Fig. 9 Two or three patients seem to increase in CD4 T cells. In two patients with decreased CD4 T cell numbers an increase of more than 50 was seen after 1 week/1 month. An increase after one week or more indicates a production more than a redistribution. No changes were seen in the patient who had the highest CD4 T cell count from the beginning. Normal level is above 500 CD4 T cells per. ⁇ l.
  • Fig. 10 Two of three patients increase in their CD4/CD8 T cell ratio. In two patients an increase in CD4/CD8 ratio was seen after one week. Normal ratios are above 1.0.

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Abstract

L'invention porte sur l'emploi d'agents pharmaceutiques interagissant avec les récepteurs 5HT définis ici servant à la préparation de médicaments rétablissant, améliorant ou traitant la déficience immunitaire pouvant être liée à des interventions chirurgicales majeures, à des transfusions de sang, à des cancers ou des infections virales par le virus Epstein Barr (EBV), le virus Cytomégalo (CMV), le virus des oreillons, le virus de la varicelle ou à des infections par le VIH ou des virus associés tels que celui rencontré dans le pré-SIDA ou le SIDA. L'interaction peut se produire par l'intermédiaire d'un récepteur de cellule immunitaire p. ex. présent dans les cellules T et lié structurellement ou fonctionnellement aux récepteurs 5HT ou à leurs sous types présents dans les cellules du système nerveux.
PCT/DK1995/000286 1994-07-06 1995-07-05 Emploi d'agents pharmaceutiques retablissant, ameliorant ou traitant la deficience immunitaire et notamment ameliorant ou traitant certains troubles immunitaires lies a des infections par le vih WO1996001107A1 (fr)

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AU28805/95A AU2880595A (en) 1994-07-06 1995-07-05 Use of pharmaceutical agents for restoring, alleviation, or treatment of immunodeficiency, including the alleviation or treatment of the immune dysfunction related to infection with human immunodeficiency viruses (hiv) or related viruses

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069439A1 (fr) * 1999-05-12 2000-11-23 Neurosearch A/S Composes chimiques ayant une action de blocage du canal ionique pour le traitement d'une disfonction immunitaire
US6331564B1 (en) 1994-09-16 2001-12-18 Ion Pharmaceuticals, Inc. Use of triaryl methane compounds for inhibiting unwanted cellular proliferation associated with inflammatory disease
AT409084B (de) * 2000-07-13 2002-05-27 Ledochowski Maximilian Dr Antimykotisch wirkendes arzneimittel
US6495567B1 (en) 1996-03-20 2002-12-17 Beth Israel Deaconess Medical Center Triaryl methane compounds and their use in the treatment of diarrhea and scours
WO2004019934A1 (fr) * 2002-08-28 2004-03-11 Antonio Cassar Scalia Utilisation de triptans en tant qu'agents antiviraux
EP1410798A2 (fr) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Traitement et prévention des dommages cellulaires induits par des métabolites réactives d'oxygène
US20150315127A1 (en) * 2009-05-05 2015-11-05 University Of Florida Research Foundation, Inc. Therapeutic compounds
WO2018191603A1 (fr) * 2017-04-14 2018-10-18 University Of Massachusetts Ciblage de récepteurs de tropisme cellulaire pour inhiber une infection par le cytomégalovirus
WO2019088926A1 (fr) * 2017-11-01 2019-05-09 National University Of Singapore Utilisation de médicaments sérotoninergiques pour traiter une thrombocytopénie induite par un virus

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992004015A2 (fr) * 1990-09-04 1992-03-19 Miles Inc. REGULATION DE LA PROLIFERATION DE LYMPHOCYTES T VIA UN NOUVEAU RECEPTEUR, LE 5HT1a

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992004015A2 (fr) * 1990-09-04 1992-03-19 Miles Inc. REGULATION DE LA PROLIFERATION DE LYMPHOCYTES T VIA UN NOUVEAU RECEPTEUR, LE 5HT1a

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6331564B1 (en) 1994-09-16 2001-12-18 Ion Pharmaceuticals, Inc. Use of triaryl methane compounds for inhibiting unwanted cellular proliferation associated with inflammatory disease
US6495567B1 (en) 1996-03-20 2002-12-17 Beth Israel Deaconess Medical Center Triaryl methane compounds and their use in the treatment of diarrhea and scours
EP1410798A2 (fr) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Traitement et prévention des dommages cellulaires induits par des métabolites réactives d'oxygène
EP1410798A3 (fr) * 1999-01-08 2004-10-13 Maxim Pharmaceuticals, Inc. Traitement et prevention des dommages cellulaires induits par des metabolites reactives d'oxygene
US6797694B2 (en) 1999-05-12 2004-09-28 Poseidon Pharmaceuticals A/S Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
WO2000069439A1 (fr) * 1999-05-12 2000-11-23 Neurosearch A/S Composes chimiques ayant une action de blocage du canal ionique pour le traitement d'une disfonction immunitaire
AT409084B (de) * 2000-07-13 2002-05-27 Ledochowski Maximilian Dr Antimykotisch wirkendes arzneimittel
WO2004019934A1 (fr) * 2002-08-28 2004-03-11 Antonio Cassar Scalia Utilisation de triptans en tant qu'agents antiviraux
US20150315127A1 (en) * 2009-05-05 2015-11-05 University Of Florida Research Foundation, Inc. Therapeutic compounds
US10017458B2 (en) * 2009-05-05 2018-07-10 University Of Florida Research Foundation, Incorporated Therapeutic tetrahydronaphthalene compounds
WO2018191603A1 (fr) * 2017-04-14 2018-10-18 University Of Massachusetts Ciblage de récepteurs de tropisme cellulaire pour inhiber une infection par le cytomégalovirus
US11484570B2 (en) 2017-04-14 2022-11-01 University Of Massachusetts Targeting cell tropism receptors to inhibit cytomegalovirus infection
WO2019088926A1 (fr) * 2017-11-01 2019-05-09 National University Of Singapore Utilisation de médicaments sérotoninergiques pour traiter une thrombocytopénie induite par un virus
US11426408B2 (en) 2017-11-01 2022-08-30 National University Of Singapore Use of serotonergic drugs to treat virus-induced thrombocytopenia

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