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Anticoagulants
drugs that decrease the formation of FIBRIN clots.
- -Oral anticoagulants (Warfarin) --> decrease hepatic synthesis of II, VII, IX, X
- -Heparin--> inhibits activity of activated clotting factors (esp. IIa, Xa)
- -Endogenous anticoagulants (Protein C, S)--> proteolyze V, VIII
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Heparin
- anticoagulant
- -mix of large sulfated polysacch, water-soluble (Parenteral!)
- -cofactor for Antithrombin III (ser-protease inhibitor)-->breakdown II,IX,X,XI, XII (intrinsic path!)
- -works both in vivo, in vitro
- -short half-life. Does NOT cross placenta (safe in pregnancy)
- -monitor w/ PTT
USE- immediate anticoagulation for Pulm embolism, stroke, acute coronary syndrome, MI, DVT, DIC, unstable angina, (safe in pregnancy)
- SE- bleeding, Osteoporosis, Heparin-induced thrombocytopenia (type II)- anti-heparin-PF4 IgG
- (actually thrombosis!)
- Antidote for HIT- Protamine sulfate Alternative- Argatroban, Lepirudin, Bivalirudin
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Enoxaparin
- low molecular weight heparin
- -bind, activate thrombin
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Antidote for Heparin-induced thrombocytopenia
Protamine sulfate
- - + charged molecule, bind and block Heparin
- -fast onset
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Low molecular weight Heparins
(ex) Enoxaparin
- Advantages over unfractionated Heparin:
- -longer half life, better bioavailability
- -LESS heparin-induced thrombocytopenia
- -better action against Thrombin (Xa)
- -can be given SubQ
- -no need to monitor
- Disadvantages:
- -Not easily reversible.
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Lepirudin, Bivalirudin, Argatroban
- Thrombin-specific anticoagulant
- -Hirudin
- -directly inhibit Thrombin
- -does NOT need antithrombin (like Heparin does)
USE- alternative to Heparin for anticoagulating patients with HIT!
Bivalirudin- use with Aspirin in unstable angina when doing PTCA.
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Warfarin (coumadin)
- Long term Anticoaglant
- -small, lipid soluble, vit-K derivative
- -inhibit liver epoxide reductase--> prevent gamma carboxylation of vit-K dependent coag factors (II, VII, IX, X, Protein C, S)
- -more effect on Extrinsic pathway (b/c VII shortest half life)
- -works only in vivo
- -long half life, PO
- -HIGH protein binding, metabolized by Cyps
- -CROSS placenta! teratogenic!
- -monitor w/ PT/INR (intrinsic)
USE- long-term anticoagulation (ambulatory) for thromboses, emboli, post-MI, heart valve, atrial arrhythmias
SE- Bleeding, Hemorrhagic skin necrosis! (low protein C initially), Teratogenic, drug interactions (Cyp-inducers decrease efficacy, Cyp inhibitors increase toxicity), Cholestyramine (trap bile salt) decrease absorption!, Displaced by other drugs (ASA, sufonamides, phenytoins--> incr PT)
Antidote or overdose- Vit K (takes time), FFP (immediate reversal)
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Warfarin induced hemorrhagic skin necrosis
- Warfarin inhibits syn of II, VII, XI, X, Protein C, S
- -VII, protein C have the shortest half lives.
-Warfarin initially cause transient deficiency of Protein C b/c protein C has shorter half life than others, first one to decrease--> inactivate extrinsic pathway, Protein C but intrinsic coag path remain active for a few more days--> hypercoagulability--> vascular thrombosis, skin necrosis!
- RX- start the patient on Heparin and very small dose of Warfarin initially.
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Drug interactions of Warfarin
- Highly protein bound, but weakly bound, so can be displaced by other highly protein bound drugs:
- -Phenytoin
- -Sulfonamides
- -ASA
- Broken down by Cyps
- Decrease efficacy w/ Cyp inducers:
- -Phenobarbital
- -Phenytoin
- -Rifampin
- -Carbamazapine
- Increase toxicity with Cyp blockers:
- -Cimetidine
- -Amiodarone
- -Metronidazole
- -TMP-SMX
- note: many A-fib patients on both Amiodarone + Warfarin!
- Warfarin is PO, lipid soluble, so absorbed via Bile micellization like Fat soluble vitamins:
- -Cholestyramine decrease GI absorption of Warfarin!
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Thrombolytics/ Fibrinolytics
- Break thrombi by catalyzing formation of endogenous fibrinolytic plasmin (serine protease)!!
- -enhance Plasminogen---> Plasmin--> degrade Thrombin, Fibrinogen, Fibrin.
- -increase PT, PTT, no change in Plts!
- Drugs:
- -Alteplase- recombinant tPA
- -Streptokinase (bacterial)
- -Urokinase
USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!
- -Effectiveness depends on TIMING for MI!
- must give within 4 hrs! (when still reversible)
- -ASA, beta-blockers, nitrates further decrease mortality
- -Adenosine decrease infarct size
SE- bleeding, intracerebral hemorrhage
Antidote: treat toxicity w/ Aminocaproic acid, Tranexamic acids
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Streptokinase
- Thrombolytic/ fibrinolytic
- -derived from bacteria (beta-hemolytic streps)
- -Act on both bound and free plasminogen (not clot specific)--> deplete circulating plasminogen and V, VIII.
- -Bind plasminogen to activate it to plasmin
- -increase PT, PTT, no change in plts
USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke- but SCAN it first to rule out Hemorrhagic stroke!
- SE- antigenic! (strep antibodies may decrease efficacy), bleeding, intracerebral hemorrhage
- DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN
Rx toxicity w: A minocaproic acid, Tranexamic acid
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Alteplace
- Thrombolytic/ Fibrinolytic
- -recombinant tPA
- -catalyze Plasminogen--> Plasmin
- -increase PT, PTT, no change in Plts
- -Clot specific! acting mainly on Fibrin-bound plasminogen
- -natural activator, so NO allergy problems!
- -expensive!
USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!
- SE- bleeding, intracranial hemorrhage.
- DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN
Rx toxicity w: Aminocaproic acid, Tranexamic acid
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Platelet aggregation
-Inhibitors and Activators
- Platelet aggregation:
- Increase by:
- -ADP, 5-HT, TXA2, Thrombin, Alpha-2 agonists
- Decrease by:
- -PGI2, cAMP, ASA, Ticlopidine, Clopidogrel
- gP IIb/IIIa blockers
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Aspirin (ASA)
- Antiplatelet
- -acetylate, irreversibly inhibit Cox-1 and Cox-2 (at high dose)--> prevent TXA2--> increase bleeding time
- -NO effect of PT, PTT.
- USE- low dose prevent MI, recurrence
- -prophylaxis in atrial arrhythmias
- -antipyretic, analgesic, anti-inflammatory, anti-platelet
- SE- gastric ulcer (decr PGE2), Bleeding, Hyperventilation, Reye's syndrome, Tinnitis (CN VIII)
- Salicylim (very high dose)- vertigo, tinnitis, hearing loss, stimulate respiratory drive--> hyperventilate--> resp alkalosis plus salicilate metabolic acidosis
Samter's triad: Asthma, aspirin hypersensitivity (nasal, bronchospasm, flushing), nasal polyposis (b/c increase leukotriens!!)
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Clopidogrel (plavix), Ticlopidine
- Antiplatelet
- -irreversibly block ADP-receptor-->block platelet activation/ aggregation (decrease gP IIb/IIIa expression)
- USE- acute coronary syndrome, coronary stenting!
- -alternative to ASA in TIA, post-MI, unstable angina (decrease recurrence of thrombotic stroke)
- SE- Hemorrhage,
- Ticlopidine--> Neutropenia!! (fever, mouth ulcers, neutropenia, ITP (do CBC every 3 weeks initially)
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Abciximab
(also Eptifibatide, Tirofiban)
- Antiplatelet
- -monoclonal antibody block gp IIb/IIIa (fibrinogen receptor) on activated platelets--> decrease plt aggregation
USE- Acute coronary syndromes, PTCA, Post angioplasty (mainly hospital use)
SE- bleeding, thrombocytopenia
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Desmopressin acetate
- Synthetic vasopressin analog
- -also release vWF and VIII from endothelium!
- USE- Central Diabetes Insipidus
- -Hemophila A, von-Willebrand disease
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Cancer therapy principles
Log-kill therapy
Growth fraction
- Log kill-therapy
- -cytotoxic actions of anticancer drugs follow 1st-order kinetics
- -Kill fixed Percentage of tumor cells, NOT fixed number
- -why used in combo
- Growth fraction
- -More effective against tumors w/ high growth fraction
- -So normal cells with high growth fractions (bone marrow, GI mucosa) more sensitive to anticancer drugs
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M phase cancer drugs
- -all screw up the microtubule
- Vinblastin
- Vincristine
- Paclitaxel
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G0 phase cancer drugs / DMA damaging
- Alkylating agents
- -Cyclophosphamide
- -Ifosfamide
- -Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin)
- -Busulfan-Cysplatin
- Antitumor antibiotics
- -Dactinomycin
- -Daunorubicin
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S phase anticancer drugs
- Antimetabolites
- -Methotrexate
- -5-Fluorouracil
- -6-Mercaptopurine
- -6-thioguanine
- -Cytarabine
-Etoposide (antitumor antibiotic)
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G2 phase anticancer drugs
- antitumor antibiotics
- -Etoposide
- -Bleomycin
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Methotrexate
- S-phase anticancer drug
- -antimetabolite
- -Folic acid analog
- -block Dihydrofolate reductase--> decrs dTMP--> block DNA, protein synthesis
- USE- Leukemia, Lymphoma, Choriosarcoma
- Non-cancer- Abortion, ectopic pregnancy, Rheumatoid arthritis, Psoriasis
- SE- Marrow suppression (reverse with Leucovorin- folinic acid), Macrovesicular fatty change in liver
- -Mucositis, Teratogenic!
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Cladribine
- Purine analog
- -resistant to degradation by adenosine deaminase
- -can reach high conc in cell
USE- hairy cell leukemia
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Symptoms of marrow suppression from chemotherapy
- fever
- apthous ulcers
- pancytopenia
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5-Fluorouracil
- S-phase anticancer drug
- -antimetabolite
- -Pyrimidine analog
- -activated to 5F-dUMP-->complex w/ folic acid--> block Thymidylate synthase--> decr dTMP--> block DNA, protein synthesis
- USE- Colon cancer, solid tumors
- -topical for basal cell carcinoma
- -synergy with Methotrexate!
- SE- Marrow suppression (NOT rescued by Leucovorin!) rescue w/ Thymidine
- -Photosensitivity
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6-Mercaptopurine (6-MP)
- S-phase anticancer drug
- -antimetabolite
- -Purine analog
- -block de novo purine synthesis
- -activated by HGPR transferase (Leish-Nayan)
- -metabolized by Xanthine oxidase
- USE- Leukemias, Lymphomas (NOT CLL or Hodgkins)
- -immunosuppression
- SE- Marrow suppression, GI, Liver
- -increased toxicity with Allopurinol!
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6-Thioguanine (6-TG)
- S-phase anticancer drug
- -antimetabolite
- -Purine analog
- -block de novo purine synthesis
- -activated by HGPR transferase (Leish-Nayan)
USE- ALL
- SE- Marrow suppression, liver
- but you CAN give with allopurinol (unlike 6-Mercaptopurine!)
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Cytarabine (ara-C)
- S-phase anticancer drug
- -antimetabolite
- -Pyrimidine antagonist--> block DNA polymerase!
USE- AML, ALL, high grade non-Hodgkin's lymphoma
USE- Leukopenia, thrombocytopenia, megaloblastic anemia!
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Dactinomycin
- Anticancer drug
- -antitumor antibiotic
- -intercalate into DNA!
- USE-Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma
- -for childhood tumors!
SE- Marrow suppression
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Doxorubicin
- Anticancer drug
- -antitumor antibiotic
- -gen free radicals, noncovalently intercalate into DNA--> break DNA--> block replication
- -inhibit topoisomerase
USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)
- SE- Cardiotoxic! delayed CHF (Dexrazoxane- antidote!- Fe-chelating agent prevent FR form)
- Marrow suppression, alopecia
- -toxic to tissues with extravasation.
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Daunorubicin
- Anticancer drug
- -antitumor antibiotic
- -gen free radicals, noncovalently intercalate into DNA--> break DNA
- --> block replication
- -inhibit topoisomerase
USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)
SE- Cardiotoxic! delayed CHF ( Dexrazoxane- antidote!- Fe-chelating agent prevent FR form) Marrow suppression, alopecia-toxic to tissues with extravasation.
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Bleomycin
- Anticancer drug
- -G2 block!
- -antitumor antibiotic
- - complex w/ Fe, O2, free radical formation--> break DNA strands
- -NO marrow suppression!
USE- Testicular cancer, Hodgkins lymphoma
- SE- Pulmonary fibrosis, Skin changes,
- no marrow suppression!!
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Etoposide
Teniposide
- Anticancer drug
- -S and G2 block!
- -antitumor antibiotic
- -block topoisomerase II--> increase DNA breakdown!
- USE- small cell carcinoma of lung, prostate,
- testicular carcinoma
SE- Marrow suppression, GI, alopecia
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Podophyllin
same as Etoposide, but used for genital warts!
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Cyclophosphamide
- Anticancer drug
- -alkylating agent!
- -Covalently crosslink DNA at guanine N-7
- -must be activated by liver--> Acrolein
USE- Non-hodgkin's lymphoma, breast, ovarian carcinoma, Neuroblastoma
- SE- Marrow suppression, Hemorrhagic cystitis!
- (prevent w/ Mesna- thiol group bind toxic metabolite)
-similar: Ifosfamide
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Nitrosoureas
(four of them)
Carmustine, Lomustine, Semustine, Streptozocin
Anticancer drug- -Alkylating agents
- -must be activated--> cross BBB--> CNS!!
USE-Brain tumors! (Glioblastoma multiform)
SE- CNS toxicity (dizziness, ataxia)
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Busulfan
- Anticancer drug
- -Alkylate DNA
- USE-CML
- -also for ablating bone marrow before bone marrow transplantation
SE- Pulmonary fibrosis, Hyperpigmentation
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Cisplatin
carboplatin
- Anticancer drug
- -Alkylate DNA--> crosslink DNA
- -NO marrow suppression!, but severe nausea, vomiting!
USE- Testicular cancer, Bladder cancer, Lung cancer
SE- Nephrotoxicity (antidote= Amifostine), VIII nerve damage -deafness! - Severe Nausea, vomiting (give w/ Ondensetron)
- NO marrow suppression!!
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Vincristine
- Anticancer drug
- -M-phase!
- -block microtubules, block polymerization--> block mitotic spindle formation
- -NO marrow suppression!
USE- Hodgkin's lymphoma , Wim's tumor, Choriocarcinoma
- SE- Neurotoxicity- areflexia, peripheral neuritis
- NO marrow suppression!
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Vinblastin
- Anticancer drug
- -M-phase!
- -block microtubules, block polymerization--> block mitotic spindle formation
USE- Hodgkin's lymphoma, Kaposi sarcoma, testicular cancer
SE- Marrow suppression, GI, Alopecia
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Paclitaxel
- Anticancer drugs
- -M-phase!
- -block Microtubule depol (breakdown)! --> anaphase cannot occur!
USE- Ovarian, breast cancer
SE- Marrow suppression, hypersensitivity
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Colchicine
- anti-gout drug
- also block microtubules
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Hydroxyurea
- Anticancer drug
- -S-phase!
- -block Ribonucleotide reductase--> block DNA synthesis
USE- melanoma, CML, sickle cell disease--> increase HbF
SE- Marrow suppression, GI upset
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Prednisone
- USE- most commonly used glucocorticoid in cancer chemotherapy
- -used in CLL, Hodgkins's lymphoma
- -immunosuppressant used in autoimmune diseases
- SE- Cushing-like syptoms, immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcer, hyperglycemia, psychosis.
- may rigger apoptosismay even work on nondividing cells
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Tamoxifen,
Raloxifene
- anticancer drug
- -receptor antagonists in breast and agonist in bone
- -block binding of Estrogen to Estrogen receptor + cells
- USE- breast cancer
- -also useful to prevent osteoporosis
- SE- may increase risk of endometrial carcinoma via partial agonist effects (hot flashes)
- NO increased risk with Raloxifene (b/c endometrial antagonist)
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Trastuzumab (Herceptin)
- anticancer antibody
- -monoclonal antibody against HER-2 (erb-B2)
- -kill breast cancer cells that overexpress HER-2
- (via antibody-dependent cytotoxicity?)
USE- Metastatic breast cancer
SE- cardiotoxicity
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Imatinib (Gleevac)
- anticancer antibody
- -philadelphia chromosome Bcr-abl Tyr-kinase inhibitor
USE- CML, GI stromal tumors
SE- fluid retention
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Rituximab
- anticancer antibody
- monoclonal antibody against CD-20 (on most B-cell neoplasms)
USE- Non-hodgkin's lymphoma. Rheumatoid arthritis (w/ methotrexate)
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Anticancer drugs NOT marrow suppressing
- Cisplatin
- Bleomycin
- Vincristine
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Nephrotoxic anticancer drugs
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Cardiotoxic anticancer drugs
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Neurotoxic anticancer drugs
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Hepatotoxic anticancer drugs
- 6-Mercaptopurine
- Busulfan
- Cyclophosphamide
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Pulmonary toxic anticancer drugs
- Bleomycin
- Busulfan
- Procarbazine
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Immunosuppressive anticancer drugs
- Cyclophosphamide
- Methotrexate
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Ondansetron
inhibit 5-HT3 receptors in GI, area postrema, SNT
USE - nausea, vomiting after chemotherapy
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Amifostine
Cytoprotective FR scavenger
- USE-decrease nephrotoxicity assoc. w/ platinum containing and alkylating chemotherapy drugs
- -decrease xerostomia
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Filgrastin
- G-CSF
- -increase granulocytes
USE- marrow recovery
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Sargramostim
- GM-CSF
- increase granulocytes, macs
USE- marrow recovery
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EPO
USE- anemia esp assoc w/ renal failure
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Thrombopoeitin
USE-thrombocytopenia
note- can also use IL-11 increase platelet formation
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Aldesleukin
- IL-2
- increase lymphocyte differentiation, NK cells
USE- renal cell cancer, metastatic melanoma
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