"Hydroxyurea (Hydrea)" TUMOR TIDBITS, A BIWEEKLY VETERINARY ONCOLOGY E-LETTER Volume 3; Number 10; March 15, 2002. Editor: Kevin A. Hahn, DVM, PhD, Dipl - ACVIM (Oncology) & Overall Nice Guy! ANNOUNCEMENTS March 23rd!!!! Come Celebrate! We're having a Celebration of Life reception Saturday March 23rd at Gulf Coast Veterinary Oncology from 2-5 pm. Bring a picture of your pet to place in our new display case. Sorry, no pets allowed since we will be celebrating in our Deli. Please RSVP at 713-693- 1166. These are exciting times for us at Gulf Coast Veterinary Oncology - Please call us (Drs. King, Hahn, Cerraras, Freeman & Turner) at any time and check our web site regulary for more information! ====================================================== THIS WEEK'S TUMOR TIDBIT: HYDROXYUREA (HYDREA) OVERVIEW Many of use Hydroxyurea for the management of pets with polycythemia vera, basophilic leukemia and mast cell disease. Here's some helpful information about the use of Hydroxyurea and recent clinical results reported by others: CLINICAL PHARMACOLOGY Mechanism of Action: The precise mechanism by which Hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which Hydroxyurea produces its beneficial effects in human patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of Hydroxyurea that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium. Absorption: Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and A.C. are observed. There are no data on the effect of food on the absorption of hydroxyurea. Distribution: Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2: 1 to 7.5: 1. Hydroxyurea concentrates in leukocytes and erythrocytes. Metabolism: Up to 50% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. In one minor pathway, hydroxyurea may be degraded by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea. Excretion: Excretion of hydroxyurea in humans is a nonlinear process occurring through two pathways. One is saturable, probably hepatic metabolism; the other is first-order renal excretion. In adults with SCA, mean cumulative urinary hydroxyurea excretion was 62% of the administered dose at 8-hours. Renal Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with renal impairment. As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients. Hepatic Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients. Drug Interactions: There are no data on concomitant use of hydroxyurea with other drugs in humans. Other: Adverse events associated with the use of hydroxyurea in the treatment of neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema and facial erythema. Hyperpigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with hydroxyurea. Skin cancer has been reported. Dysuria and alopecia occur very rarely. Large doses may produce moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chills, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. The association of hydroxyurea with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely. CLINICAL STUDIES: J Vet Intern Med 2001 Jul-Aug;15(4):418-21 Hydroxyurea for treatment of polycythemia secondary to right-to-left shunting patent ductus arteriosus in 4 dogs.Moore KW, Stepien RL. Four adult dogs with polycythemia secondary to reversed patent ductus arteriosus (rPDA) were treated with hydroxyurea, a myelosuppressive agent, for 6-22 months. Regardless of initial hematocrit, clinical signs attributed to the presence of polycythemia improved with hydroxyurea treatment. Chronic hydroxyurea therapy (40-50 mg/kg PO q48h) was well tolerated in this group of animals; mild, clinically silent thrombocytopenia and leukopenia were detected in some animals but resolved with decreased dosage or dose frequency. Chronic hydroxyurea therapy may provide an alternative to repeated phlebotomy for therapy of polycythemia secondary to rPDA. J Vet Intern Med 1997 Mar-Apr;11(2):92-4 Basophilic leukemia in a dog. Mears EA, Raskin RE, Legendre AM. Basophilic leukemia with thrombocytosis was diagnosed in a 4-year-old Shih Tzu. This diagnosis was based on cytochemical staining and cytologic examination of blood and bone marrow smears. Hydroxyurea, an inhibitor of DNA synthesis, at a dose of 50 mg/kg PO bid induced hematologic remission after 7 days of treatment. Adverse effects observed included pruritus, erythema of the ventral abdomen, generalized alopecia, and possibly, diabetes mellitus. The dog remained in remission for 21 months before becoming lethargic, at which time the owners requested euthanasia but did not allow a necropsy. J Am Vet Med Assoc 1983 Sep 15;183(6):686-9 Chronic myelogenous leukemia in the dog. Leifer CE, Matus RE, Patnaik AK, MacEwen EG. Chronic myelogenous leukemia was diagnosed in 7 dogs. In each case, marked neutrophilia in the absence of infection was observed in association with nonspecific illness. Diagnosis was based on morphologic cytology of blood smears, bone marrow aspirates, and in 1 case, a lymph node biopsy specimen. In 5 cases, treatment with hydroxyurea was successful in lowering circulating WBC counts, but was of questionable value in the prevention of leukemic blast crisis. J Am Vet Med Assoc 1982 Feb 15;180(4):415-8 Diagnosis of canine primary polycythemia and management with hydroxyurea. Peterson ME, Randolph JF. Severe polycythemia was found in 3 dogs with PCV 68% to 70%. Direct RBC mass determinations were increased in all dogs, confirming absolute polycythemia. Cause for secondary polycythemia was not found in any of the dogs; serum erythropoietin concentrations were undetectable, consistent with primary polycythemia. The polycythemia and associated clinical signs were controlled successfully for extended periods (mean, 16.6 months), using phlebotomy followed by oral administration of hydroxyurea in loading and in daily maintenance dosages. J Am Vet Med Assoc 1975 Feb 15;166(4):376-80 Treatment of basophilic leukemia in a dog. MacEwen EG, Drazner FH, McClelland AJ, Wilkins RJ. Basophilic leukemia in a 6-year-old dog was characterized by marked splenomegaly, anemia, and leukocytosis in which 89% of the circulating leukocytes were basophilis. After an attempt at busulfan therapy, the dog was treated with hydroxyurea and was maintained on this drug for 2 months. After withdrawl of hydroxyurea, the dog remained in remission and was still in remission at the time of writing (8 months later). MORE QUESTIONS ABOUT HYDROXYUREA? Don't hesitate to call or email us at Gulf Coast Veterinary Oncology! ALL THE BEST, Kevin Hahn Kevin A. Hahn, DVM, PhD Diplomate ACVIM (Oncology) & Overall Nice Guy Gulf Coast Veterinary Specialists 1111 West Loop South, Suite 150 Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 http://www.gcvs.com mailto:drhahn@gulfcoastvetspec.com