DE4324877A1 - Novel therapeutic mixtures, based on the prevention of intracellular Ca<2+>i overloading and Ca<2+>i independent influencing of the intracellular pHi of immunocompetent cells - Google Patents

Abstract

A composition for influencing hyperactivated immunological effector cells is described which comprises (I) a calcium antagonist and (II) a composition reducing the intracellular quotients of cAMP/cGMP.

Description

After 15 years of intensive work with immunology human, molecular-biological and cell-biochemical aspects of immune-competent cells (macrophages / monocytes, helper (T4), suppressor (T8), NK / K-ADCC and B cells) came Applicant for the invention specified in more detail below Improvements to existing and the introduction of new Thera pien.

One of the key findings of the applicant is that on at first glance surprising fact that so under various diseases, such as tumors, autoimmune diseases genes, arteriosclerosis (which according to our own investigations to trigger an autoimmune promoter or starter needs), bacterial and viral infections, incl. HIV defect and even some due to immunological derailments or "modern" diseases based on deviations, e.g. B. that CFS (chronic fatigue syndrome) - immunologically speaking - have important common dysregulation elements. These common elements are e.g. B. a persistent or excessive activation of certain leukocyte subpopula ions, mostly macrophages and helper T cells, not infrequently also suppressor T cells; in the case of simultaneous hyperak Activation of macrophages and helper T cells as ent against the initial opinion also with AIDS / ARC / LAS- Patient is observed, it can stimulate each other lation ("rocking") of both interdependent Leukocyte subpopulations are coming.

Another common element is the unblocking of blastogen pre-transformed T4 and plasma (B) cells as Sequence of previous, longer lasting latent or overt immunosuppression; it is based on the "Dilution" of the autoantigen or pathogen specific Monitor cells, d. H. the autoantigenic or pathogenic specific suppressor T cells.  

From a molecular-biological point of view, the various diseases mentioned above have in common the persistence of an increased intracellular Ca ²⁺ _i level, which on the one hand leads to immunosuppressive counter-regulation and on the other hand to reduced immunostimulability to new antigenic stimuli. This results not only in an impairment of the existing set of immunocompetent cells, but also in a disrupted recruitment of new, yet controllable immunocytes.

The substances and mixtures listed below provide for deblocking the wrongly programmed immunocytes, primarily the hyperactivated and thus on the "wound healing" or "tissue repair" function from umpro grammed macrophages and cytokine-hypersecreting Helper T cells.

This "calming down" of the hyper- or persistently activated effector cells is achieved on the one hand by preventing the Ca ²⁺ i-rigid, ie blocking the cell overload with Ca ²⁺ i-ions; on the other hand, they circumvent the Ca ²⁺ _i dependence by regulating the intracellular pH _i value. Another mechanism is the control of electrolyte transport through the cell membrane (influencing the Ca ²⁺ , Na⁺ and K⁺ channels or the Na⁺ / K⁺, Na⁺ / H⁺, K⁺ / H⁺- , HCO₃⁻ / Cl⁻-, Ca ²⁺ / Na⁺- and the Ca ²⁺ / H⁺ exchange mechanisms, ie various ATPases, anti and Symport).

With some BGA-approved combinations, the second part this application are listed individually, meanwhile not only in tumor patients (tumor or meta stasis reduction by 1 / 3-2 / 3 within a few Weeks, without simultaneous chemotherapy or radiotherapy), son  also in patients with autoimmune diseases, e.g. B. Mul tiple sclerosis or even in patients with CFS (see above) surprising therapeutic success can be achieved. That's why is recommended according to the invention, which in Part 1 (Active substances in general) and in the 2nd part (new types of 2, 3, 4, etc. combinations of BGA-approved preparations ten, in the sense of a "2nd indication" patent protection) lying registration individually enumerated substances as 2, 3, 4. . . n-combinations with each other and / or with all clinically and experimentally used immune stimuli gates (immunomodulators, BRMs) in (a) neoplastic and (b) autoimmune diseases, further (c) arterio sclerotic vascular changes (d) also with macro phage and T cell hyperactivation related Plasma-destabilizing diseases (e.g. Amy loidosis, M. Alzheimer), for "modern" managerial diseases, including CFS, and - last but not least - for bacterial and viral infections (incl. AIDS / ARC / LAS therapy) therapeu use table.

As a result, the initial immunological derailment, d. H. hyperactivation of leukocyte subpopulations be undone; the restoration of the original Immune status can then occur spontaneously. One should basically according to a 2- or 3-stage therapy scheme Action.

The 2-stage therapy scheme consists of: Phase I. . . Unblock immunocompetent, but wrong "programmed" effector cells, primarily macrophages and T- Cells, and: phase II. . . controlled stimulation of the Immunocytes. The 3-stage therapy scheme still contains phase III:. . . "Freeze" the controlled stimulated cell befitting, d. H. "Freeze", more precisely, extension of the Phase II  

For phase I (deblocking), 2, 3 series are suitable. . . n- he combinations of the 1st and 2nd part of this Registration of listed individual components.

All clinical or experimental are suitable for phase II tell used immunostimulants (specific and unsp specific immunomodulators / BR). Suitable for phase III all Phase I preparations, except that they are lower should be dosed (e.g. 20-50% of the phase I dose tion).

Recommended dosage for phase I: 5-100% of that in the Red list given dosage, optimal however 20-50% the same.

Part 1 (active substances in general)

Note: The substances and mixtures listed below are used to unblock incorrectly "programmed" leukocytes ten subpopulations and here to restore the sti mululability of immunocompetent cells used.

Details about unblocking the immunocompetent Cells in the hypoxic and / or acidified environment of chronically inflamed tissues, including necrotizing Tumor tissues were described in patent application P 42 21 071.2 wrote.

Only a few more details should be discussed here the.

Macrophages that are hyper- or persistently activated consume Chen 15 to 20 times more oxygen than resting; in property Gamma interferon increases this O₂ consumption much stronger.  

In the phagocytosis of opsonized particles (bacteria, Latex, etc.) and immune complexes via the Fc-gamma-Re The macrophage switches to the Embden-Mayerhof-gly colytic glucose breakdown; this makes the molecular Oxygen for the formation of microbicidal oxygen Radicals (ROI) provided. Education too of leukotrienes C, D and E, which are reduced glutathione requires the transfer of electrons or Pro toning of oxygen radicals (using cytochrome P450) sacrificed. The leuko formed instead of leukotriene C, D and E. trien B directly stimulates the cytochrome P450-mediated ROI formation.

This switch-over to the Glycolysis leads via lactic acid overproduction and secretion tion for strong acidification of the micromilieu by hyperacti fourth macrophages. Along with the hypoxic tissue acidification leads to local pH drop and hereby to Inhibition of immunocyte function. The disturbed formation of Leukotriene C, D and E caused by ROI products are still too is additionally impaired, resulting in inhibited Gly cosylation and secretion of cytokines and immune globulins.

The disrupted by angiogenesis and hyperactivated macro phage-induced hypoxia in the inflammatory tissue, e.g. B. Necrotizing tumor tissue involves several steps to decrease the intracellular pH. This expresses first in a strong inhibition of cell activity (below pH 6.8) and ends with further decrease in Cell death.

According to their own ideas, both the apoptotic as well as autolytic cell death on a drop in intracellular pHs, which makes lysosomal enzymes active  the; previously the H⁺ pump fails, the one in the lysosomes pH maintained at 4.5-5.0.

From the myocardial cells it is known that cell death in the presence of oxygen is preferred as the terminal electron acceptor of respiratory chain phosphorylation, with simultaneous cell activation or simultaneously increased intracellular Ca _i level. Therefore, the only sensible aerobic glucose degradation pathway in the presence of O₂ must be inhibited by medication via the TCC / citrate cycle in the hypoxic or ischemic tissue. This also prevents the overproduction of NADH₂ (and NADPH₂), which leads to accelerated glycolytic lactic acid production and thus pH decrease.

According to the invention, it is recommended to use BRMs (immunomodulators) generally to be combined with deblocking substances or unblocking the immune component cells from others to carry out (immune) therapeutic steps.

Deblocking substances to be protected under patent law, the (a) individually or (b) combined with each other or (c) Combined to use individually or with each other with BRMs are:

• (1) Alkalizing substances such as alkali (bi) carbonate as well as alkali salts of metabolisable ("combustible") organic acids (e.g. Na lactate, Na gluconate, Na, K- Citrate).
• (2) Reversible competitive inhibitors of citric acid Further oxidation in the cancer (citrate) cycle, i.e. H. Inhibitors the tricarboxylic acids of the citrate cycle (e.g. tricarballylate, Methyl / ethyl succinate, malonate and the like. a.).

Annotation:
The individual inhibitor substances were examined in detail in our laboratory in animal experiments (Wistar rats).

The principle of action is the prevention of cellular (e.g. Macrophages) overactivity in the absence of O₂ electrons acceptor (see above).

• (3) β-blockers in general
  The principle of action here is to prevent the intracellular increase in cAMP and the associated activity of the A-kinase (PKA).
• (4) Ca antagonists in general
  The principle of action: Inhibition of the influx of Ca into the hyper-activated (hypoxic) cell, which prevents the Ca _i -stimulated continuation of the cancer cycle in the absence of the O ₂ electron acceptor and indirectly prevents the pH drop or cell death. In the case of hyperactivated macrophages, this can inhibit ROI production. These ROI in turn inhibit glycosylation and thus the secretion of cytokines.
• (5) Ca agonists in general
  The principle of action: Both the ß-blocker discussed under point (3) and the Ca agonists increase the intra-cellular Ca _i .

Important note: Who should proceed in two stages den: First, with the CA discussed in point (4) Antagonists the activity of the "wrongly programmed", d. H. hyperactivated macrophages stopped become; then with Ca agonists and / or β-blockers the activation of the immune competent cells in general be supported.

• (6) Substances that prevent the decline of the intracellular PH _i by passing through the cell membrane and intracellularly binding the excess Hulär ions.

They are all representatives of membrane-based basi substances, e.g. B. to derivatives of TRIZMA, of HEPES, of Mono-, di- and triethanolamines as well as products from Chloroquine and other antimalarials, also monensin as well as intracellular NH₃-releasing compounds, for. B. the two substrates of cytosolic glutaminase or Asparaginase, glutamine and asparagine.

Other pH _i -increasing substances are lithium (Li), cesium (Cs), rubidium (Rb) salts of carbonic acid and combustible organic acids.

Note: The weak bases that pass through the membrane (see above) are allowed fen as free bases or as (bi) carbonate or as salts metabolizable organic acids, but not as Chloride, sulfate, nitrate, etc. are used. The the same applies to glutamine and asparagine.

Note: These substances can be mixed with alkali salts flammable acids (point (1)) and / or the TCC / Ci pedal cycle inhibitors can be combined.

• (7) inhibitors of LDH (lactate dehydrogenase) and XOD (xanthine oxidase)
  Principle of action: By inhibiting the formation of lactic acid, the excess acidification of the cytosol and the extracellular milieu can be prevented.

Note: These LDL and XOD inhibitors can be inhibited with Hem Combine the acids of the TCC / cancer cycle.

• (8) Substances that have the intracellular redox potential correct e.g. B. fumarate / maleinate, vitamin C, vitamin A, Vitamin E, alkali (K) -ferrocyamide, Se compounds (e.g. Na- Selenite), Na / K thiosulfate, alkali sulfate, but also the reduced forms of mercaptyl / thionyl - (- SH) groups containing compounds, e.g. B. glutathione, penicillamine, Thiola (thiopronin), cysteine, methionine and the like. a ..
• (9) Substances that affect the intracellular (NAP (P) ⁺ / - Correct NAD (P) H₂ or GSSG / 2GSH quotient, e.g. B. N-acetylcysteine and the like. a.
• (10) Substances that replace the terminal electron acceptor (molecular O₂) of the respiratory chain phosphorylation, e.g. As ascorbate, dehydro ascorbate, dehydro ascorbate, unsaturated fatty acids and others
  Note: The substances under points (8), (9) and (10) work in a similar direction; it is z. T. same substances.
• (11) radical scavengers (ROI scavenger) or antioxidants
  Examples: (a) phenols such as tocopherols, flavonoids, phenolic acids plus esters, benzodioxoles, lignans (NDGA), BHT, BHA, THBP (b) amines such as tetramethyl-p-phenylenediamine (c) heterocycles such as ethoxyquin, barbiturates, carbazoles, Phenothia zine, levamisole, nafazatron, naloxone and tinoridine, (d) various other compounds such as vitamin C, glutothione, (GSH), β-carotene and vitamin A derivatives.
• (12) Cl⁻ channel blocker
• (13) Cyclooxygenase inhibitors / non-steroidal anti-inflammatory drugs
• (14) Anti-H2-histamines (antagonists of H2-histamine zeptors), e.g. B. cimetidine  
• (15) Inhibitors of cAMP or cGMP phosphodiesterase / methyl xanthines, e.g. B. theophylline or theobromine
• (16) Because immune complexes (IC) via special receptors, the Fc (gamma) -R and / or CR1, CR3, C1q- u. a. Receptors macro phages / monocytes, suppressor T cells (TG / TS) and NK cells len suppress, the IC-induced, persistent Activation, which ultimately turns out to be immunosuppression expresses, according to the invention (a) by the Fc (gamma) sub of Ig (IgG), (b) due to the genetic modification complement subunits (exchange of key Amino acids), e.g. B. C3b, C3bi or C1q and / or (c) by IgG excess inhibited.
• (17) substances that are anti-denaturing and e.g. T. re-natu based on proteins in general and on bio-relevant proteins act in particular, e.g. B. formamide, acetamide, anilide (Formanilide, acetanilide) and their alkyl and dialkyl (e.g. methyl / dimethyl) derivatives, especially the untoxi monomethyl derivatives and other non-toxic, water miscible compounds.

Principle of action: weakening of hydration and Dielek Tricity constant (DK) of the medium.

These substances could be combined with PEG, PVP and / or DMSO be kidneyed. The same substances or their combinations ions with PEG, PVP, glycerin and / or DMSO are suitable also as cryoprotective substances for freezing (Preservation) of cells and proteins.

Note: The PVP is particularly interesting physiologically, that has been used clinically for years as a plasma expander that is.  

De-block the individual classes of those described above The substances are also used as additives to conventional ones Suitable for vaccines.

• (18) anti-gamma interferon, anti-M and GM-CSF and anti TNF alpha
• (19) Liposomes containing (a) cytostatic drugs, (b) other cytotoxic agents toxins, e.g. B. Ricin, Abrin u. a.
• (20) Substances that release histamine from mast cells prevent e.g. B. Cromoglycat and Intal
• (21) Substances that determine the Cl⁻ concentration of the extracellu Reduce liquid (ECF)
• (22) Substances that the ECF concentration of the HCO₃⁻ ion increase

Then some preparations are listed, which as Novel two, three or multiple combinations (A + B, A + C. . . , B + C, B + D. . . , A + B + C, A + B + D. . . ) under patent law be protected; their particular advantage is that they as single preparations are already BGA approved and direct can be used clinically. You can - as a single or as combination products - with immunomodulators (BRM) be combined.

Note: The list below must be done by Immunoglobu lin / gamma globulin preparations are supplemented; this bankruptcy with immune complexes (IC) around the Fc (gamma) receptor on immunocompetent effector cells, e.g. B. macrophages, NK- and T8 cells and prevent their immunosuppressive Wir kung. With the BGA-approved preparations from the red  Make sure that the product is not listed as Dry matter or lyophilisate is supplied because of this like gamma globulins e.g. T. IC-like effects have.

• 1. Ca antagonists (objective: prevention of intra cellular Ca overload and the associated Hem Guanylcyclase, as well as the 5-Lipoxygenase on the one hand and the Ca, more specifically stimulated CaM (Ca-Modulin) Ca-ATPase or adenylcyclase on the other hand)
• 1.1 on the nifedipine basis: Adalat (26.071) or Aprical 5 / -10 / -retard (26.072), or Bayotensin / -mite (26.075)
• 1.2 on the Verapamil basis: Azupamil 40 / -80 / -120 (26.073) or Dignover 40 / -80 (2,081) or Drostreakard 40 / -80 / -120 (26.083) or Verapamil-ratiopharm (26.108)
• 1.3 on the basis of cinnarizine: Cinnarizine ratiopharm (36.035) or cinnarizine Siegfried (36.036) or cinnarizine R.A.N. (36.034) or Cinnacet (36.033) or Cerepar (36,032).
• 2. beta-blocker (objective: inhibition of cAMP-increasing Sub-receptors for catecholamines, PGEI / PGE2 and histamine (H2-R))
• 2.1 on the acebutolol basis: Neptal 400 (26.036) or Prent 400 (26,040)
• 2.2 on the metoprolol basis: Lopresor / -mite (26.035)
• 2.3 based on propanolol: Indobloc 10/40/80 (26.032) or Efektolol 10/40/80 (26.024) or Elbrol 40 / Elbrol 80 (26,027)
• 3. Combination preparations: Ca antagonists plus beta blockers
  Belnif (26.070) or Tredalat (16.132) Nif-Ten 50 (16.131)
• 4. Non-steroidal anti-inflammatory drugs / anti-inflammatory drugs (Hem of cyclooxygenase / prostaglandin synthetase)  
• 4.1 on the Diclofenac basis: Diclofenac-Wolff-25/50 (05.142) or Diclo-OPT 50,100 retard (05.143) or Diclo phlogent (05.144)
• 4.2 on the ibuprofen basis: Dolgit 200/400 / SL (05.149) or Ibuphlogent 200 / -400 (05.161)
• 4.3 on the indomethacin basis: Indo-Tablinen (05.170) or Indomet retard-ratiopharm 75 (05.167) or Amuno / Retard (MSD) (05.129)
• 4.4 on the ketoprofen basis: Alrheumun (05.128)
• 4.5 on the basis of acetylsalicylic acid: gap (05.122) or Solpyron (05.121) or Cheetah (05.117)
• 5. The intracellular pHi-influencing preparations (objective: influencing intracellular pH, K and Na ions and the HCO³ / Cl⁻ ratio and associated deblocking of hyper- or persistently activated immune competent cells, primarily macrophages)
  • (a) Hanooxygen (03.007) or Gelum oral -rd (03.006)
  • (b) Acidovert (03.005) or acetolyte (03.001) or Nephro trans (03.004) or sodium hydrogen carbonate 1 g (03.003)
  • (c) Histinorm (05.210)
• 6. Redox potential (NAD (P) H / NAD (P) + or GSH / GSSH) cor preparations
• 6.1 Mercaptyl (thionyl, sulfhydryl) / disulfide quotient-improving preparations
  • (a) acetylcysteine (23.119) or acetylcysteine ratiopharm 100/200 (23.120)
  • (b) Metalcaptase 150 / -300 (05.201) or Trolovol (05.206)
• 6.2 Reducing preparations
  Cebion (83.099) or Cedoxon Cassis (83.100) or Cetebe (83.102)
• 7. Chloroquine and derivatives (influencing the lysosomal and indirectly the cytoplasmic pH value) Resochin (05.2p3) or Quensyl (05.202) or Tauredon 10/20/50 (05.205)
  Note: The first two preparations are more suitable because of the oral intake
• 8. Gold preparations (should - similar to chloroquine - contribute to the stabilization ("calming down") of the hyperactivated macro phages)
  Ridaura (05.204) or Aureostan 10/25/50/100 (05.199) or Auro-Detoxin (05.200)
  Note: Only the first-mentioned preparation is taken orally
• 9.Methylxanthines (e.g. theophylline) (objective: stabilization of the increased cGMP level after correction of the cAMP / cGMP ratio; methylxanthines not only inhibit cAMP phosphodiesterase, but also cGMP-PDE):
  Theophylline retard - ratiopharm 125/250/350/500 (27.082) or Theospirex (27.084)
• 10. Antidiabetic drugs (simulating insulin activity or Antagonization of the glycolysis and TCC inhibiting or Glucone-promoting glucagons)
• 10.1 on the biguanidine (metformin) basis: glucophage retard / -mite (11.070)
• 10.2 on the tolbutamide basis: Artosin 1.0 (11.037) or Rastinon Hoechst (11.065) or tolbutamide 0.5 g / lg (11.067)
• 10.3 based on glibenclamide: azuglucon -3.5 / -1.75 (11.038) or Diamicron (11.041) or Gluconorm 1.75 / 3.5 (11,051)
• 10.4 based on glisoxepid: Pro-Diaban (11.064)  
• 11. Guanyl cyclase (cGMP) stimulating preparations
• 11.1 based on isosorbide dinitrate: Coleb 20 / -40 (54.044) or dignonitrate 40 / -60 / -100 (54.049)
• 11.2 based on isosorbide mononitrate: Conpin 20 / -40 (54.054) or Coragin 20 / -40 / -60 (54.046)
• 11.3 based on glycerol trinitrate: nitroglycerin retard ratiopharm (54.023)
  Note: A good alternative is the sydnonimine derivative molsidomine (e.g. molsidomine 1/2/4 from ct Berlin).

The mechanism of action at the cellular level is likely to be that correspond to the nitro body; in both cases Activity of guanylcyclase and hereby intracellular cGMP levels rise.

• 12. Inhibitors of xanthine oxidase (XOD) with the aim of Formation of oxygen radicals at least partially suppress (see also point 5!): Allopurinol 300 Stada (43.007) or Allopurinol Cod (43.008) or Allopurinol retard Woelm (43.011).
• 13. Some, K-saving diuretics (due to K-retard effect or indirectly because of the promotion of H⁺ / K⁺ antiport and thus the pHi increase)
• 13.1 based on the aldosterone antagonist Spirono lactons: Spironolactone ratiopharm 50 / -100 (02.016)
• 13.2 on the triamterene basis: Jatropur tablets (35,060)
• 13.3 based on amiloride: Amilorid comp.-ratiopharm (35.063)
  Note: The latter preparation is an amiloride combination with hydrochlorothiazide; an amiloride monopreparation would be better.
• 14. Carbonic anhydrase inhibitors, e.g. B. Acetazolamide (reason: Influence on pHi as well as on glycolysis, gluconeogenesis and TCC / cancer (citrate) cycle; Inhibition of glycolysis dros selective FPK / fructose phosphate kinase): Diamox retard (67.151) or Diamox (39.006)
• 15. Oxygen carrier (purpose: better O₂ supply to the hypoxic inflammatory tissue) Oxoferin or TCDO (Tetra chlordekaoxid)
  Note: These are two, to my knowledge, not BGA-approved preparations. Oxygen therapy can be expected to have the same or better effect. Oxoferin or TCDO can be combined with ascorbic acid and / or succinic acid or fumaric acid.
• 16. Parathormone-inhibiting preparations (reason: PTH has a cell-suppressing effect via adenylcyclase or cAMP, similar to e.g. glucagon, histamine (via H2 receptor), adenosine, PGE2 and noradrenaline (via beta1-adrenergic receptor) as well as adrenaline and isoproterenol (via beta2-adrenergic receptor))
  Note: The macrophages express receptors for (a) insulin, (b) glucagon, (c) histamine, (d) serotonin, (e) parathyroid hormone, (f) calcitonin, (g) somatotropin, (h) somato statin, ( i) PGE2, (j) cAMP, (k) 4b-adrenergic receptor, (1) neuropeptides (endorphin), (m) arginine-vasopressin and (n) transferrin.
• 16.1 based on etidronic acid: Diphos (65.005)
• 16.2 based on clodronic acid: Ostac (65.007)  
• 17. Selenium compounds (objective: ROI neutralization; Simulation of glutation peroxidase)
• 17.1 based on sodium selenite pentahydrate: selenase (GN.Pharm)
• 17.2 on the Ebselen basis
• 18. Lithium compounds (objective: increasing the cyto plasma pH)
• 18.1 based on lithium aspartate: lithium aspartate Coated tablets 120 (70,235)
• 18.2 on the lithium orotate basis: lithium orotate tablets (70,237)
• 18.3 based on lithium carbonate: Hypnorex retard (70,234)
• 18.4 based on lithium sulfate: lithium duriles (70.236)
• 19. Some essential building blocks (objective: ready position of the biosynthetic building blocks after switching from catabolic to the anabolic function of the immunocompetent cells)
• 19.1 L-glutamine
• 19.2 Ribose
• 19.3 creatine
• 19.4 ATP (ADP, AMP) and / or GTP (GCP / GMP), guanine
• 19.5 Unsaturated fatty acid + _- ascorbic acid
• 19.6 EPL
• 19.7 Vanadium compounds
• 19.8 glutathione
• 19.9 folic acid
  Note: Particularly recommended combinations are:
  1 plus 2; 1 plus 5 or 3 plus 5; 1 plus 6 or 3 plus 6; 1 plus 5 plus 6 or 3 plus 5 plus 6; 5 plus 6.
  6 is best suited to 6.1.a ± 6.2.
  1.3 is particularly suitable for 1.
  At 5, hanooxygen is best.

All of the above combinations can continue with 4, 12, 17 and / or 18 can be combined.

Combinations with 7, 8 and 10 are also of interest. The conventional stimulation procedures (see phase II), e.g. B. with BRMs can with heavily subdosed preparations 11th and / or some low-dose lymphokines (IL-2, gamma IFN u. a.) are supported.

The CA agonists that are also suitable are clinical not yet approved.

Claims (7)

1. comprising means for influencing hyperactivated immunological effector cells

• (I) a calcium channel blocker
• (II) an agent reducing the intracellular quotient of cAMP / cGMP.

2. Composition according to claim 1, characterized indicates that the calcium antagonist Calcium overload blocker. 3. Means according to claim 1 or 2, characterized characterized in that the calcium antagonist Cinnarizine is. 4. Agent according to one of the preceding claims, characterized in that Component (II) is an agent that increases the content of cAMP diminished in the cell and / or an agent that the CGMP content increased. 5. Composition according to claim 4, characterized in that the content of cAMP-reducing agents is an antagonist of G _s -coupled receptors and / or an agonist of G _i / G _p / G₀-coupled receptors. 6. Composition according to claim 4 or 5, characterized characterized in that component (II) Antagonist of β-adrenergic receptors, histamine receptors and / or A2 purinergic receptors. 7. Composition according to claim 6, characterized in that the Antagonist for β-adrenergic receptors is propranolol.