      Document 0139
 DOCN  DRG0139
 UNIQUE IDENTIFIER        DRG-0108
 NAME OF SUBSTANCE        Pentosan polysulfate sodium [USAN 1996]
 REGISTRY NUMBER          116001-96-8
 RELATED REGISTRY NUMBER  CB 8061
 RELATED REGISTRY NUMBER  SP-54
 RELATED REGISTRY NUMBER  PZ-68
 STANDARD CHEMICAL NAME   (1-4)-Beta-D-Xylan 2,3-bis(hydrogen sulfate),
                          sodium salt [USAN 1996]
 SYNONYMS                 Pentosan polysulfate [Mol Cell Biochem 1993
                          Mar 24;120(2)]
 SYNONYMS                 Xylan hydrogen sulfate [Merck Index 1989]
 SYNONYMS                 Xylan polysulfate [Merck Index 1989]
 SYNONYMS                 Fibrase [Merck Index 1989]
 SYNONYMS                 Hemoclar [Merck Index 1989]
 SYNONYMS                 Sodium pentosan polysulfate [Merck Index
                          1989]
 SYNONYMS                 Sodium xylan polysulfate [Merck Index 1989]
 SYNONYMS                 Thrombocid [Merck Index 1989]
 SYNONYMS                 Beta-D-Xylan,(1-4), 2,3-bis(hydrogen
                          sulfate), sodium salt [USAN 1993]
 SYNONYMS                 Elmiron [USP DI 1995]
 PROTOCOL ID NUMBERS      NCI 90 C-69
 SECONDARY SOURCE ID      CB-8061 [Merck Index 1989]
 SECONDARY SOURCE ID      SP-54 [Merck Index 1989]
 SECONDARY SOURCE ID      PZ-68 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Pentosan is cleared from the
                          body via desulfation in the liver and spleen,
                          and depolymerization in the kidney, with
                          excretion in the urine of desulfated, lower
                          molecular weight material. A little of the
                          drug (4-8%) is excreted unchanged in the
                          urine so it appears that the drug is
                          eliminated mainly by a metabolic process.
                          There is some evidence that the desulfation
                          and depolymerization mechanisms can be
                          saturated at pharmacologically relevant
                          doses. Elimination follows a bimodal
                          distribution, with an initial rapid clearance
                          of an IV dose (90% cleared by 80 mins)
                          followed by a slower second phase. Terminal
                          half-life of this second phase is between 24
                          and 193 hours. Because of saturation of
                          degradation pathways, the possibility exists
                          of increased drug accumulation with prolonged
                          administration. Peak levels appear to be
                          related to the administered parental dose in
                          a linear fashion. Peak levels obtained 60-80
                          mins following SC administration were 1/10
                          obtained following the same dose IV. Oral
                          absorption has been found to be < 10 percent
                          (and likely is substantially less). Studies
                          have shown pentosan to possess
                          anti-retroviral activity in vitro. One
                          hypothesis of the mechanism for this
                          anti-retroviral activity was inhibition of
                          reverse transcriptase. However, it is
                          currently believed that it acts by a
                          mechanism other than this. It is also
                          believed the mechanism of action is a
                          CD4-indepedent mechanism. It has been
                          discovered that pentosan inhibits the
                          activities of protein tyrosine kinases from
                          lymphocytes and rat lung in a concentration
                          dependent manner. These results suggest that
                          the ability of pentosan polysulfate to
                          inhibit various protein serine/threonine and
                          tyrosine kinases may be one of the mechanisms
                          by which this compound exerts its inhibitory
                          effect of HIV-1 replication. Pentosan is also
                          reported to have anti-tumor activity.  Two
                          mechanisms for this activity have been
                          proposed: 1) Pentosan antagonizes the binding
                          of FGF to its cell surface receptors in
                          certain cell lines (but unlikely this is the
                          sole mechanism because pentosan exhibits
                          antitumor activity against cell lines which
                          do not respond to FGF, and full inhibition
                          requires greater than 7 days); and 2) it
                          inhibits EGF tyrosine kinase activity in cell
                          lysate but not in intact cells. [Mol Cell
                          Biochem 1993 Mar 24;120(2)] [Int Conf AIDS
                          1990 Jun 20-23;6(1):(abstract no. Th.A.238)]
                          [NCI 90 C-69]
 DISEASES STUDIED/TREATED Primary HIV infection [NCI 90 C-69] [The
                          Extra Pharmacopoeia 1993]
 DISEASES STUDIED/TREATED Kaposi's sarcoma [NCI 90 C-69] [The Extra
                          Pharmacopoeia 1993]
 CLASSIFICATION CODE      Antiviral [Mol Cell Biochem 1993 Mar
                          24;120(2)]
 CLASSIFICATION CODE      Antineoplastic [Mol Cell Biochem 1993 Mar
                          24;120(2)]
 CLASSIFICATION CODE      Anticoagulant [Merck Index 1989]
 CLASSIFICATION CODE      Anti-inflammatory [USAN 1996]
 CLASSIFICATION CODE      Antiretroviral [NCI 90 C-69]
 OTHER MAJOR USES         Anticoagulant, especially during the
                          immediate post-operative period; Orphan drug
                          indication for interstitial cystitis [USP DI
                          1995] [NCI 90 C-69]
 SUBSTANCE INTERACTIONS   May react synergistically with AZT. [AIDS Hum
                          Retroviruses 1990 May;6(5)]
 ADVERSE EFFECTS          Use as an anticoagulant has been associated
                          with relatively little toxicity. Elevations
                          of hepatic transaminases have been reported,
                          as well as decreases in hemoglobin and
                          thrombocytopenia. Animal studies with long
                          term administration (>3 mos) have revealed
                          abnormalities of the spleen, liver, kidney,
                          thyroid, adrenal and pituitary glands,
                          especially at high doses. Sterile abscesses
                          were seen at SC injection sites, again mainly
                          at high doses. Side effects which occur
                          rarely include the following: headache,
                          dizziness, nausea, diarrhea, dyspepsia,
                          peripheral edema and skin rash. [NCI 90 C-69]
                          [USP DI 1995]
 CONTRAINDICATIONS        Contraindicated in patients with a history of
                          bleeding diasthesis that was not
                          self-limited, history of hepatic cirrhosis or
                          present hepatic dysfunction, or
                          hypersensitivity to pentosan or other
                          sulfated polysaccharides. Also
                          contraindicated in pregnant women. [NCI 90
                          C-69]
 CHEMICAL/PHYSICAL DATA   DESCRIPTION: Semi-synthetic sulfated
                          polyanion composed of beta-D-xylopyranose
                          residues with properties similar to heparin
                          (polysulfate) [Merck Index 1989] [NCI 90
                          C-69]
 CHEMICAL/PHYSICAL DATA   DESCRIPTION: Synthesized by treatment of
                          hemicellulose from beech wood; chemically
                          related to the drug suramin, a sulfated
                          naphthylurea [Merck Index 1989] [NCI 90 C-69)
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: (C5H6Na2O10S2)n (n=6 to
                          12) (polysulfate sodium) [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 4000-6000 (polysulfate
                          sodium) [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in water [Merck Index
                          1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: pH of 10 percent aqueous
                          solution approximately 6.0 (polysulfate
                          sodium) [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White odorless powder,
                          slightly hygroscopic (polysulfate sodium)
                          [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intramuscular (IM),
                          intravenous (IV) and subcutaneous (SC). [Int
                          Conf AIDS 1989 Jun 4-9;5: abstract no. W.P.B.
                          299] [NCI 90 C-69] [USP DI 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral (although absorption
                          is poor with oral dosage form). [Int Conf
                          AIDS 1989 Jun 4-9;5 (abstract no. W.B.P.
                          299)] [NCI 90 C-69] [USP DI 1995]
 MANUFACTURERS            National Cancer Institute
 REFERENCES               Hampson SJ, Woodhouse CR. Sodium
                          pentosanpolysulphate in the management of
                          haemorrhagic cystitis: experience with 14
                          patients. Eur Urol. 1994;25(1):40-2.
 REFERENCES               Tardy-Poncet B, Tardy B, Grelac F, Reynaud J,
                          Mismetti P, Bertrand JC, Guyotat D. Pentosan
                          polysulfate-induced thrombocytopenia and
                          thrombosis. Am J Hematol. 1994
                          Mar;45(3):252-7.
 REFERENCES               Goad KE, Horne MK 3rd, Gralnick HR.
                          Pentosan-induced thrombocytopenia: support
                          for an immune complex mechanism. Br J
                          Haematol. 1994 Dec;88(4):803-8.
 REFERENCES               Pluda JM, Shay LE, Foli A, Tannenbaum S,
                          Cohen PJ, Goldspiel BR, Adamo D, Cooper MR,
                          Broder S, Yarchoan R. Administration of
                          pentosan polysulfate to patients with human
                          immunodeficiency virus-associated Kaposi's
                          sarcoma. J Natl Cancer Inst. 1993 Oct
                          6;85(19):1585-92.
 REFERENCES               Schwartsmann G, Sander E, Prolla G, Sprinz E,
                          Zampese M, Vinholes J, Jung F, Kronfeld M,
                          Kalakun L, Mans DA, et al. Phase II trial of
                          pentosan polysulfate (PPS) in patients (pts)
                          with AIDS-related Kaposi's sarcoma (KS)
                          (Meeting abstract). Proc Annu Meet Am Soc
                          Clin Oncol. 1993;12:A18.
 REFERENCES               Parsons CL, Benson G, Childs SJ, Hanno P,
                          Sant GR, Webster G. A quantitatively
                          controlled method to study prospectively
                          interstitial cystitis and demonstrate the
                          efficacy of pentosanpolysulfate. J Urol. 1993
                          Sep;150(3):845-8.
 REFERENCES               Peters M, Witvrouw M, De Clercq E, Ruf B.
                          Pharmacokinetics of intravenous pentosan
                          polysulphate (HOE/BAY 946) in HIV-positive
                          patients [letter]. AIDS. 1991
                          Dec;5(12):1534-5.
 REFERENCES               Maffrand JP, Herbert JM, Bernat A, Defreyn G,
                          Delebassee D, Savi P, Pinot JJ, Sampol J.
                          Experimental and clinical pharmacology of
                          pentosan polysulfate. Semin Thromb Hemost.
                          1991;17 Suppl 2:186-98.
 ENTRY MONTH              9201
 LAST REVISION DATE       960311
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
