• Sirolimus (rapamycin)
• Mycophenolate mofetil

• Methotrexate
• Sulfasalazine
• penicillamine
• Gold compounds: sodium aurothiomalate, auranofin
• Chloroquine/hydroxychloroquine
• Leflunomide

• Abatacept
• Anakinra
• Daclizumab, basiliximab
• Muromonab
• Infliximab (remicade),Etanercept
• Tocilizumab, Natalizumab

epoetin alfa

darbepoetin alfa

1. Binds to cyclophillin
2. Complex binds to calcineurin 
3. Blocking of calcineurin blocks nuclear transloaction of transcription factor (NF-ATc)
4. Decreased expression of IL-2
5. No IL-2, no proliferation of CD4+, CD8+ T cells

Is cyclosporine soluble or insoluble?

How is it administered?

• Soluble
• Administered in vehicle w/ EtOH and oil
• Standard formulation (sandimmune) gives variable absorption leading to unpredictable bioavailability

• CYP3A-4 mediated--> Increased clearance (decreased activity) w/ phenytoin, phenobarbital, and other drugs inducing P-450
• Decreased clearance w/ erythromycin, ketoconazole, amphotericin B (inhibitors of CYP3A4) or St. John's Wart

• Organ Transplants (w/ corticosteroids)
• Graft versus Host disease, after allogenic stem cell transplantation
• Selected autoimmune disorders

• Neurotoxicity (tremor, seizure)
• Nephrotoxicity
• Hypertension
• Hirsutism
• Hyperlipidemia
• Gingival hyperplasia

1. Binds to cytoplasmic protein (FKBP-12)
2. Complex binds to calcineurin
3. Blocks NFAT transcription of IL-2
4. No Il-2--> decrease CD4+/CD8 T cells

• Prophylaxis after kidney and liver transplants
• Rescue therapy in pts experiencing graft rejection
• Atopic dermatitis

• Nephrotoxicity
• Neurotoxicity (peripheral neuropathy, tremor, headache, seizures, insomnia)
• Hypertension, Pleural effusion
• Inhibition of pancreatic B cell fxn
• Inc risk of malignant lymphoma

1. Binds to FKBP-12
2. Complex inhibits PI 3 kinase-related kinase protein mTOR (mammalian target of rapamycin)
3. Lack of response to growth stimulatory signals
4. Inhibition of T and B cell proliferation

• Combo therapy after renal transplant (w/ cyclosporine because of little renal toxicity)
• Experimentally after islet cell transplantation

1. Hydrolized by liver esterases to MPA
2. MPA inhibits inosine monophosphate dehydrogenase (for de novo purine biosynthesis)
3. T and B cells need purines via de novo biosynthesis
4. Dec T and B cells

• Renal & heart transplantation
• Do not use w/ antacids containing magnesium or aluminum hydroxide (dec absorption

• Diarrhea
• Leukopenia

• Folic acid antagonist allosterically inhibits dihydrofolate reductase (DHFR)
• DHFR is needed for tetrahydrofolate production for nucleoside biosynthesis
• Cytotoxic/anti-proliferative activity on lymphocytes
• Blocks T cell activation from inh of purine metabolism & adenosine accumulation

• First-line therapy for moderate to severe Rhuematoid arthritis
• Cancer chemotherapy

• Ulcerative stomatitis
• leukopenia
• DO NOT use during pregnancy

1. Prodrug made of sulfonamide and salicylate
2. Processed by gut bacteria--> 5-aminosalicylic acid
3. MOA unclear--> scavenge reactive oxygen species

• Relieves joint pain & swelling
• Induces remission in active RA
• Crohn's disease

• GI distress
• Leukopenia
• Maybe anaphylactic rxns

• Dimethylcysteine produced by hydrolysis of penicillin.  
• Possible decreased IL-1 production and collagen maturation in inflamed joints

• Anti-rhuematoid activity in ~75% of pts
• metal chelator for Wilson's disease
• Heavy metal poisoning

• Rashes
• Stomatitis
• GI distress
• Potential proteinuria, leukopenia, thrombocytopenia
• DO NOT use in pts w/ hx of Renal disease or in Pregnancy

Sodium aurothiomalate

Auranofin

• Reduce joint pain & swelling
• Slow progression of joint damage
• Slow in onset (3-4 months)

...nobody knows...

BOO!

• Rashes
• stomatitis
• proteinuria
• thrombocytopenia
• potential neuropathy/hepatitis in some pts

• Designed to interact w/ a single target molecule to neutralize it (usually)
• Usually used as immunosuppressive agents in transplantation, inflammatory, or autoimmune disorders

• Recombinant chimeric mAbs

1. Directed against α chain (CD25) of high affinity IL-2 receptor
2. Inhibits IL-2 mediated T cell activation

• Used for: reducing incidence of acute rejection when used in combo w/ cyclosporine/prednisone/azathioprine in kidney/cardiac transplantation
• Basiliximab--> acute hypersensitivity

• mouse mAbs directed against ε chain of Tcell surface CD3 protein

1. Blocks cellular interaction w/ CD3 protein responsible for T cell signal transduction
2. Blocks T cell receptor engagement

• Reversal acute rejection of heart, liver, kidney transplants
• Immunosuppression after kidney transplant

• Activate T cells upon 1st infusion--> 
• cytokine release syndrome-->
• inflammatory response
• Hypersensitivity

• Chimeric human-mouse mAbs

1. Targets against proinflmmatory cytokine TNFα

• Crohn's disease
• Ulcerative colitis
• Rheumatoid/psoriatic arthritis
• Plaque psoriasis
• Ankylosing spondylitis

Pts may experience:

• Inc infection chances (tuberculosis)
• Reactivation of Hep B, malignancies, hepatotoxicities
• Large incidence of anti-infliximab antibodies
• Adalimumab (human versions)

• Recombinant chimera of soluble p75-TNF receptor type II and Fc portion of human IgG

1. Neutralizes free TNF 

Rx of:

• RA
• Ankylosing spondylitis
• Plaque psoriasis

• Recombinant nonglycosylated analog of human IL-1 receptor antagonist (IL-1RA)
• For tx of RA and pts w/ mutations in IL-1 RA gene

-Helps with wound healing, helps maintain skin barrier, and helps activate some other stuff. 
-In excess, it is an endogenous pyrogen secreted by macrophages.  Causes fever, acute inflammation.  Activates endothelium to express adhesion molecules; induces chemokine secretion to recruit leukocytes

• IL1= fever (hot)

What is tocilizumab and what does it do?

What can it treat?

• Humanized mAbs directed against Il-6 receptor to block it
• RA in pts unresponsive to TNF-α inhibitors (like etanercept, infliximab)

What is natalizumab and what does it do?

• Humanized monoclonal antibody against α₄β₁-integrin
• Inhibits lymphocyte migration through endothelial cell sites of inflammation

Crohn's disease

Multiple sclerosis

• Recombinant chimera of extracellular domain of CTLA-4 and Fc portion of human IgG₁ 

1. Binds to CD80&CD86 ==> 
2. Block binding to CD28==>
3. Prevents T cell activation (works upstream from infliximab/etanercept)

Purine analog metabolized invivo to 6-mercaptopurine

1. Disrupts de novo purine synthesis (toxic to proliferating lymphocytes)
2. Incorporated in DNA
3. Inhibits transcription

• Kidney transplantation
• Autoimmune disorders (glomerulonephritis, hemolytic anemia)
• Combo therapy (w/ predinose/cyclosporine/tacrolimus) of RA

• Bone marrow suppression-->leukopenia
• Mercaptopurine metabolized by xanthine oxidase
• Avoid Allopurinol bec it blocks xanthine oxidase so it decreases metabolization of drug and increases side effects

What is fingolimod and what does it do?

1. Phosphorylated by sphingosine kinase 2
2. Binds to sphingosine 1 phosphate receptors
3. Blocks migration of lymphocytes out of lymph nodes

• Contains antibodies to numerous T cell surface antigens
• Depletes peripheral T cells
• Blocks cell surface receptors for T cells and directly cytotoxic

What are anti-lymphocyte and anti-thymocyte globulins used for?

What are the side effects?

• In combo with other agents to prevent transplant rejection, GVHD, aplastic anemia
• 
  SE: fever, chills, leukopenia, thrombocytopenia, skin reactions
  

• Purified polyvalent human IgG to replace antibodies in immunodeficiencies to give passive immunity
• Idiopathic thrombocytic purpura

What is IFN-β used for?

What does IFN-β normally do?

• Treatment of multiple sclerosis

• Inhibits viral protein along with IFN-α

Stimulates hematopoeisis in pts after:

• chemo
• bone marrow transplant
• mobilization of peripheral stem cells prior to apheresis

What is epoetin alfa and what does it do?

What can go wrong?

• Recombinant erythropoeitin analogue
• Stimulates formation of RBCs in anemic pts
• *Darbepoetin alfa has longer half life
• May stimulate tumor cell prolif., inc risk of stroke and cardio SE

Azatioprine

Fingolimod