B.27

Question 1

Immunopharmacology II (inhibitors of cytokine gene expression, 5-ASA derivatives)

Answer 1

1. Calcineurin inhibitors: Cyclosporin A, Tacrolimus
2. mTOR inhibitors: Sirolimus
3. JAKi: Tofacitinib
4. Inhibitors of cytokine gene expression: Sulfasalazine

Question 2

Cyclosporin A

Answer 2

Chemistry: hydrophobic cyclic peptide isolated from Polypocladium infaltum. It contains some irregular AAs; MOA: blocks calcineurin (→binds cyclophylline → inhibits calcineurin → blocks NFAT activaition→ ↓activation of immune reponse genes like IL-2), It blocks cellular immunity;
Kinetics: can be given in i.v solution injection (contains polyoxyethylated ricin oil→risk of anaphylactic shock), BAp.o is 20-50%, high plasma protein binding (should be monitored from whole blood), Hepatic metabolism (CYP3A4) and also a substrate of glycoprotein P;
IND: Transplantations (Kidney, liver, heart), GVH disease (BM transplantation), Rheumatoid arthritis (in comb. with MTX), Psoriasis, asthma, Xerophtalmia (eye drops);
SEs: nephrotoxicity, hepatotoxicity, HTN, Hyperglycemia, Gingival hyperplasia, Hirsutism, CNS disorders

Question 3

Tacrolimus

Answer 3

Chemistry: macrolide structure (isolated from Streptomyces tsubanesis);
MOA: Bind to FKBP-12 →the complex inhibits calcineurin (more potent than Cyclosporin A)→ blocks NFAT activation→ ↓activation of immune response genes like IL-2, it blocks cellular immunity;
Kinetics: administered p.o / i.v, BAp.o is low (14-25%), hepatic metabolism (CYP3A4);
IND: Transplantation (liver, kidney, heart, lung), Autoimmune disease, Atopic dermatitis, GVH disease;
SEs: Nephrotoxicity, Hepatotoxicity, hyperglycemia, HTN, Hirsutism, Psychological problems are more prominent than cyclosporinA

Question 4

Sirolimus

Answer 4

Chemistry: Sirolimus is structurally similar to tacrolimus (isolated from Streptomyces Hygroscopicus);
MOA: Binds FKBP-12→ the complex inhibits mTOR (mammalian target or rapamycin), mTOR has a central role in IL-2 activation pathway in lymphocytes, in other cells mTOR is important in cellular response to growth factors, mTOR is important for (→angiogenesis, fibroblast proliferation, atuphagy, metabolism etc), Sirolimus blocks T and B cell function as well;
Kinetics: adm. p.o, T1/2-60h, hepatic metabolism (CYP3A4);
IND: Kidney transplantation, GVH disease, coating cardiac stents (prevents stenosis after coronary angioplasty);
SEs: BM suppression (thrombocytopenia), Hepatotoxicity, Pneumonitis, Hyperglycemia, Hyperlipidemia, GI disturbances

Question 5

Tofacitinib

Answer 5

Chemistry: low molecular weight drug;
MOA: Inhibits JAK1 and JAK3 → blocking IL-2, 4, 6, 7, 9, 15 and 21 - mediated pathways in T-cells;
Kinetics: adm. p.o (good BA), has short T1/2 (prolonged release forms are available), hepatic metabolism by CYP450 pathway;
IND: Rheumatoid arthritis (alone/in comb.), Juvenile idiopathis arthritis, Psoriatic arthritis, Ankylosing spondylitis, Ulcerative colitis;
SEs: airway infections, Hyperlipidemia, CK elevation, Liver enzyme elevation, BM suppression;
Drug-interaction: MTX comb. is more dangerous

Question 6

Sulfasalazine

Answer 6

MOA: is cleaved in the colon to 5-ASA (mesalazine) and sulfapyridine (→ Sulfapyridine is resorbed from the GIT), 5-ASA is NOT absorbed from the GIT (→plays important role in IBD treatment), 5-ASA induces PPARγ expression (→inhibiting the activation of NF-κB and TLRs), 5-ASA also blocks the function of IL-1, TNFα, IL-2, IL-8, COX and LOX, and it is an antioxidant. The MOA of Sulfapyridine is unknown;
Kinetics: 10-20% of sulfasalazine is absorbed (without cleavage) and is excreted partially via urine and bile. Sulfapyridine is metabolized in the liver;
IND: Rheumatoid arthritis (mild efficacy), Ankylosing spondylitis (Bechterew’s disease), IBDs (Ulcerative colitis-very effective, in Crohn’s disease not so effective);
SEs: Nausea, Vomiting, Headache, rash (common), BM suppression, Oligospermia

Question 7

Immunopharmacology II

Answer 7

1. Cytotoxic agents
2. Inhibitors of cytokine gene expression, 5-ASA derivatives:
   -. Calcineurin inhibitors:
   -. mTOR inhibitors:
   -. Janus Kinase inhibitors (JAKi):
3. Inhibitors of cytokine gene expression:
   Corticosteroids
   Sulphasalazin
4. Immunosuppressive antibodies
5. Other non-specific immunosuppressants
6. Interferon
7. Immunostimulants

Question 8

2. Inhibitors of cytokine gene expression, 5-ASA derivatives:

Answer 8

1. Calcineurin inhibitors:
   Cyclosporin A
   Tacrolimus
2. mTOR inhibitors:
   Sirolimus (rapamycin)
3. Janus Kinase inhibitors (JAKi):
   Tofactinib