Therapeutic agents
1) NSAIDs
2) Corticosteroids
3) Anti-allergy drugs
4) Cytostatic drugs
5) Non-cytostatic immunosuppressive drugs
6) Other antiinflammatory drugs
7) Biologicals
NSAIDs effects + side effects
Most important effect:
- Inhibition of arachidonic acid metabolism
- Inhibits COX => no prostanoid metabolism => decreased inflammation
Side effects:
- Main: Peptic ulcer, erosive gastritis-duodenitis
- GI: vomit, diarrhea, obstipation, ulcer, erosions
- Liver: toxic hepatitis
- Kidney: decreased function, interstitial nephritis
- CNS: head ache, tremor, depression, psychosis
- Blood: bone marrow depression, hemolytic anaemia, haemophilia
- Allergy:, exanthema, asthma
- Other: drug interactions
Symptoms of aspirin overdose
- CNS: Restlessness, irritability, excessive unorganized talking, fear or nervousness, dizzy, confusion, excited mood, hallucinations, drowsiness, loss of consciousness
- Systemic: fever
- Eyes: double vision
- Muscles: uncontrollable shaking, seizures
- Throat: burning, pain
- Stomach: vomiting, pain
- Kidneys: decreased urination
COX-1
Constitutional, makes cytoprotective prostaglandins
Inhibitors:
- NSAIDs (non-COX-2)
- Aspirin
COX-2
Inducible, makes inflammatory prostaglandins Inhibitors: - COX-2 inhibitors - NSAIDs (non-COX-2) - Aspirin Inducers: - Cytokines - Growth factors
Corticosteroids functions
1) Transactivation
- GRE: glucose response element
- Transcription: Annexin 1, SLPI (secretory leukoprotease inhibitor), IL-10
2) Transrepression
- Switching off inflammatory genes
Use of cortisol (hydrocortisone)
- Rarely and locally
- It’s synthetic derivatives are administered per os (orally), parenterally or locally
Cortisol effects
1) Decreased inflammation (Decreased IL-1, TNFα, GM-CSF, IL-3, IL-4, IL-5, IL-8)
2) Decreases NO (Decreased NOS)
3) Decreased PGs and LTs (Decreased phospholipase A2 and COX-2, increased lipocortin-1)
4) Reduced emigration leukocytes from vessels (Decreased adhesion molecules)
5) Induction apoptosis in lymphocytes+eosinophils (Increased endonucleases)
Antiallergic drugs
1) Antihistamines
- H1 R antagonists: dermatological diseases, allergic rhinitis (e.g Claritine, side effects: somnolence, reduced concentration)
- H2 R antagonists: inhibit gastric HCl secretion (Cimetidine, Rantidine, Famotidine)
2) Leukotriene inhibitors: therapy bronchial asthma
Antiallergic drugs targets mast cell
- IgE: Anti-IgE
- cKit: cKit antagonists or blocking SCF Ab
- Syk kinase: Syk kinase inhibitors
Cytostatic drugs
“Cell stopping drugs”
1) Alkylating agents: bind to DNA and prevent DNA synthesis (Cyclophosphamide, chlorambucil. Major side effects: bone marrow depression)
2) Folic acid antagonists: Methotrexate
3) Purine antagonists: Azathioprine (Imuran)
4) Pyrimidine antagonists: Leflunomide
5) Vinca alkaloids: anti-mitotic, anti-microtubule agents (Vinblastin, Vincristin)
Non-cytostatic immunosuppressive drugs
Cyclosporine A and tacrolimus (!)
- Inhibit calcineurin => no dephosp of NFATc (cannot move to nucleus as a transcription factor)
- Used in the case of transplanted patients
- Affects T cells, B cells and granulocytes (immunosuppressive)
Other antiinflammatory drugs
Primarily base therapy of RA: DMARDs (disease modifying antirheumatic drugs)
- Gold compounds
- Penicillamine
- Anti-malaria agents
- Sulfasalazine
- Dapson
- Thalidomide
Biologicals (therapeutic agents)
1) Vaccines: against oncogenic or potentially oncogenic virus infections
2) Tolerization:
3) Cytokine therapy and cytokine antagonists
4) Antibody therapy
5) IVIG (Intravenous immunoglobulin)
6) Stem cell transplantation
7) Gene therapy
Monoclonal Ab therapies
Use laboratory-made monoclonal Ab’s to attack specific targets (e.g cancer cells)
- Most of the Ab is human, but parts of the variable region are exchanged with mouse Ab parts
1) Murine: fully mouse (muromonab-CD3)
2) Chimeric: Fc is human, variable part of Fab is mouse
3) Humanized: only CDR (complement determining region) is mouse, rest is human - Longer half-life
- Reduced immunogenicity
- More efficient (ADCC, complement) effector mechanisms
4) Fully human
Denosumab
- Fully human monoclonal Ab
- IgG2
- High affinity and specificity to human RANKL
=> inhibit osteoclast => inhibit bone resorption/prevent osteoporosis
Omalizumab
- Humanized monoclonal Ab
- Anti-IgE
- Reduce sensitivity to inhaled/ingested antigens
- Used for asthma
Abatacept
- Fusion protein (monoclonal Ab therapy)
- Human IgG1 Fc part + extracellular part of CTLA4
- Inhibit T cell activation (CD80/86-CTLA4)
- Used for rheumatoid arthritis
Cytokine antagonists
1) IL-1R antagonists
- Anakinra (RA)
2) TNFα-blockers (RA, ankylosing spondylitis, psoriasis)
- Infliximab (chimera - also Crohn’s disease, ulcerative colitis)
- Adalimumab (human)
- Etanercept (fusion molecule: 2 TNF R + Fc of IgG1)
- Golimumab (human)
- Certolizumab (pegol - PEGylated, mainly against Crohn’s and RA)
PEGylation of Certolizumab
Fab of a monoclonal antibody that has been conjugated to polyethylene glycol (PEG)
=> Longer halflife
=> Protection: from degrading enzymes and Ab’s
=> Reduced immunogenicity
Other immunsuppressive agents
Sirolimus (rapamicin)
- mTOR inhibition
=> Inhibition of B and T cell proliferation
- After transplantation
Anti Rh(0)-D immunoglobulin
- Prevent morbus haemolyticus neonatorum
- Given to Rh- mother within 24-72 hrs postpartum
Side effects of immunosuppressive agents
- Increased susceptibility to infections
- Bone marrow and mucosal membrane damages
- Cyclosporine may cause kidney damage
- Late consequence: elevated freq of malignant diseases
Immunstimulant agents
1) Natural
- Cytokines
- Endogen regulators and their derivatives
2) Synthetic
- Inosiplex
- Imiquimod: TLR7/8 agonist
Immunstimulant cytokines
1) Interferons
- IFN α: antiviral, anti-tumor
- IFN β: multiple sclerosis
- IFN γ: Increased IL1 production, chronic granuloma
2) Colony stimulating factors
* Induces colony formation of bone marrow stem cells
- G-CSF: filgrastim
- GM-CSF: molgramostim, sargramostim
3) Interleukins
- IL2 (aldesleukin): metastatizing kidney tumors
- IL11 (oprelvekin): thrombocytopenia by tumor chemotherapy
4) Other cytokines: TNF
Desenzitation - allergen-specific immuntherapy
Subcutaneous or sublingual administration of the allergen: stepwise increasing teh dose
IVIG therapy requirements
- Should be from at least 1000 different human donors
- All 4 IgG subclasses should be represented
- IgG activity for >21 days
- Not contain HIV, hepB/C
- Should be handled in a way that destroys viruses
Inflammatory bowel disease important inducer
Psychological distress
HPA axis
Hypothalamus: CRH => ACTH => cortisol => decr. IL-6
Stress
- Acute: fight/flight
- Short: days-weeks
- Chronic: months-years
- Stress can be a part on the inducers of chronic inflammation
Effects of stress on immune response
Increases immune response in acute and short
Decreases in chronic
Impact of stress enhanced in
- Elderly
- People with depression
- People who recieve low psychological support (lonely)
Caregiver of Alzheimer patients effect (chronic stress)
- Enhanced telomer erosion
- Decreased T cell proliferation
- Increased IL-10
- Increased TNF α
Physical exercise
Advantageous psychological and immunological
- Efficient first line treatment for mild or intermediate depression
- Reduces depression symptoms caused by stress
- Reduces inflammation and oxidative stress
Vitamin D3
Antiinflammatory effect, antidepressant
- Increase monocytes/macrophages
- Decrease dendritic cells
- Decrease effector or memory T cell
- Decrease B cells or ASC (APC?)
Activation induced cell death (AICD)
Fas -> apoptosis
Regulatory T-cells
Tr1: IL-10 producing regulatory T cells
CD4+/CD25+ regulatory T-cells
TH3 cells: TGF beta