QUESTIONS

1. What popular immunosuppressive drug is associated with pancreatitis?
    
2. The cell growth cycle is divided into G1, S, G2, M, and G0
   
   a)  in which stage does the cell rest?
   b)  in which stage does DNA synthesis occur?
   c)  In which stage does RNA & protein synthesis predominate?
    
3. In which stage does azathioprine work?  Explain the mechanism of action of azathioprine.
    
4. How is imuran (azathioprine) metabolized?
    
5. At which cell phase does cyclophosphamide (cytoxan) work?  What is its mechanism of action?
    
6. You have a patient on cytoxan who develops hematuria.  You wisely switch to chlorambucil.  Every thing appears to be going well for a good stretch of  time but then the hematuria recurs.  List a differential.
    
7. There is a popular immunosuppressive drug which stops IL-2 production by T helper cells & reduces IL-2 receptors on T killer cells.  What drug am I thinking of?
    
8. You have a patient with immune-mediated thrombocytopenia.  How might vincristine be useful in treatment?
    
9. How does vincristine actually kill cells?
    
10. How is Danezol supposed to help in the treatment of ITP?
     
11. How does Cromolyn sodium work?
     
12. List as many mechanisms as you can think of to account for the immunosuppressive effects of corticosteroids.
     
13. BONUS:  What clotting factor is missing in hemophilia B & what blood product is best to treat hemophilia B?
    
    
    
     

ANSWERS

1. Azathioprine (Imuran) is associated with pancreatitis though, in reality, it isn�t associated with tons of pancreatitis.  Dogs have about a 5% incidence.  Humans apparently have a higher incidence.
   
   
   
   
    
2. a)  The cell rests in G0.
   b)  DNA synthesis occurs in the S phase.
   c)  RNA & protein synthesis predominate in both G1 and G2.  G2 is when the cell prepares for division. G2 occurs between S & M.
   
   
   
   
    
3. Azathioprine works in the S phase.  Azathioprine is an antimetabolite.  It is an imidazolyl derivative of 6-mercaptopurine.  In English, this means Aza. is sulfur analog of adenine & it competes with adenine in DNA synthesis.  It is especially cytotoxic to stimulated T cells.
   
   
   
   
    
4. It is activated to 6-mercaptopurine in the liver (so in liver failure, imuran won�t work because it can�t be activated).. Later it is inactivated by xanthine oxidase for renal excretion.  (If your patient is a Dalmatian on allopurinol you must cut your imuran dose to 1/4 to 1/3 normal because xanthine oxidase will be inhibited by allopurinol).
   
   
   
   
    
5. Trick question.  Alkylating agents such as cytoxan are cell stage independent.  Alkylating agents cross link DNA which leads to cell death.
   
   
   
   
    
6. Okay, first the obvious causes of hematuria:  UTI, liths in the urinary tract, trauma, clotting disorder.  The first time hematuria occurred, you were concerned about �hemorrhagic cystitis,�  a known side effect of cytoxan use which occurs in 7-24% of patients.  This time, the additional thing to consider is a secondary neoplasm caused by the cytoxan (transitional cell carcinoma or squame).
   
   * By the way, treatment for hemorrhagic cystitis is said to involve lavage of the bladder with 1% formalin.  Does anyone actually do this or is this a really old recommendation?
   
   
   
   
    
7. I was thinking of cyclosporine.
   
   
   
   
    
8. Long ago I was taught that vincristine stabilizes platelets.  In fact, it seems to raise platelet numbers but the bad news is that it does this by interfering with platelet function.  My impression is that weekly vincristine injections in ITP are no longer recommended. BUT here�s a new thought presented at ACVIM.  Incubate platelet rich plasma in vincristine.  The platelets will take up the vincristine.  Transfuse the patient.  When the macrophages phagocytize the vincristine treated platelets, they will be poisoned and die.  This puts an end to the removal of normal platelets.
   
   
   
   
    
9. Vincristine is a vinca alkaloid.  It depolymerizes microtubules thus screwing up mitosis.  It is metabolized in the liver & excreted fecally.
   
   
   
   
    
10. I could hardly find any info on Danezol but here�s what I found.  It is an attenuated androgen originally used to treat endometriosis in women.  IT works in ITP by stabilizing platelet membranes, normalizing CD4/CD8 lymphocyte ratios & inhibiting the monocyte/macrophage line.
    
    
    
    
     
11. It inhibits the release of mast cell granules (but not basophil granules).  It is generally used in humans as an inhalant & is currently thought to be not to applicable to small animals.
    
    
    
    
     
12. Here�s my list:
    - cause a pronounced lymphopenia ( thus reducing CMI)
    - reduced monocyte function (they can�t take up opsonized
       material)
    - inhibit interferon, IL-1 & IL-2 production
    - inhibit PMN migration
    - reduced number of eosinophils
    - reduced amount of serum complement.
    
    
    
    
     
13. Hemophilia B is a factor IX deficiency. (Factor IX falls in the  intrinsic pathway, thus PTT will be abby normal.)  The blood product used in treatment is - not cryoprecipitate - but cryosupernatant!  That�s the supernatant after you remove the cryoprecipitate.  It is rich in prothrombin & clotting factors including IX.