      Document 0205
 DOCN  DRG0205
 UNIQUE IDENTIFIER        DRG-0042
 NAME OF SUBSTANCE        Butyldeoxynojirimycin [MeSH]
 REGISTRY NUMBER          72599-27-0
 SYNONYMS                 N-Butyl-DNJ [Int Conf AIDS 1993 Jun
                          6-11;9(1): (abstract no. WS-A11-2)]
 SYNONYMS                 Butyl-DNJ [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 SC-48334 [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 N-Butyldeoxynojirimycin [AmFAR Tx Dir
                          1995;7(4)]
 PROTOCOL ID NUMBERS      NIAID ACTG 100
 PROTOCOL ID NUMBERS      FDA 057A
 PROTOCOL ID NUMBERS      FDA 057B
 IND NUMBER               32,634
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: This drug may be effective in
                          vivo at breaking the cycle of HIV infection
                          by progressive elimination of HIV. In vitro
                          studies in certain lymphocyte-derived cell
                          lines have shown that a minimum drug
                          concentration of between 0.5-20 mcg/ml
                          markedly inhibits HIV-induced syncytial
                          formation and reduces p24 core antigen
                          production. The antiviral effect in vitro of
                          aminosugar derivatives such as
                          castanospermine, deoxynojirimycin (DNJ) and
                          SC-48334 (n-butyl-DNJ), is attributed to
                          alteration of N-linked oligosaccharide
                          biosynthesis through inhibition of
                          glucosidase activity. In animal studies
                          (Rhesus primates), a dose of 165 mg/kg/day
                          achieved a minimum plasma level of 10.9
                          mcg/ml; the drug was not substantially
                          metabolized and was excreted unchanged in the
                          urine; oral bioavailability was 72 percent,
                          with a plasma half-life of about 2 hours).
                          Preclinical studies showed inhibition of
                          cytopathic effect and 4-log reduction in
                          tissue culture infectious dose (TCID) in
                          HIV-infected T-45 cells by a 10 ug/ml
                          concentration of the drug.  At 50 and 100
                          ug/ml, the drug showed a 5-log reduction in
                          TCID. Similar results were seen against HIV-2
                          and reported for a section T-cell line,
                          MOLT-4.  Similar results were seen in another
                          HIV-1 infected T-cell line, H-9.  The drug
                          was also shown to markedly inhibit p24
                          antigen production in acutely infected HIV-1
                          H9 cells. Related derivatives (N-methyl- and
                          N-ethyl-deoxynojirimycin) produced inhibition
                          of glucosidase. [Int Conf AIDS 1993 Jun
                          6-11;9(1): (abstract no. WS-A11-2)] [NIAID
                          ACTG 100]
 DISEASES STUDIED/TREATED Primary HIV infection. Trials in AIDS/ARC
                          patients indicated that the drug had no
                          significant effect on p24 antigen levels or
                          CD4 cell counts [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Alpha glucosidase I inhibitor [Int Conf AIDS
                          1993 Jun 6-11;9(1): (abstract no. WS-A11-2)]
 SUBSTANCE INTERACTIONS   Animal studies (mice) showed that the drug
                          did not inhibit the development of an
                          antibody response to 2,4,6-trinitrophenyl
                          keyhole limpet hemocyanin (a t-cell dependent
                          antigen). [NIAID ACTG 100]
 ADVERSE EFFECTS          Inhibition of intestinal disaccharides in
                          vivo can lead to carbohydrate malabsorbtion
                          and diarrhea. Based on animal toxicology
                          studies, adverse effects that might be
                          experienced are gastrointestinal disturbances
                          (diarrhea, gastric irritation, nausea,
                          emesis), decreased platelet counts, elevated
                          transaminases, and hepatic changes
                          (vacuolization, hepatomegaly, changes in
                          liver enzymes); with escalating doses (Rhesus
                          primates), clinical symptoms increased in
                          severity. In vitro studies have indicated the
                          drug to be non-toxic to the target
                          lymphocyte. [Int Conf AIDS 1993 Jun
                          6-11;9(1): (abstract no. WS-A11-2)] [NIAID
                          ACTG 100]
 CONTRAINDICATIONS        Pregnancy.  Known hypersensitivity to this
                          study drug. [NIAID ACTG 100]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Powder [ACTG 100]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM:  Opaque white gelatin capsules
                          of 100 mg and 500 mg. [NIAID ACTG 100]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [NIAID ACTG 100]
 MANUFACTURERS            G.D. Searle
 REFERENCES               Fischl MA, Resnick L, Coombs R, Kremer AB,
                          Pottage JC Jr, Fass RJ, Fife KH, Powderly WG,
                          Collier AC, Aspinall RL, et al. The safety
                          and efficacy of combination
                          N-butyl-deoxynojirimycin (SC-48334) and
                          zidovudine in patients with HIV-1 infection
                          and 200-500 CD4 cells/mm3. J Acquir Immune
                          Defic Syndr. 1994 Feb;7(2):139-47.
 REFERENCES               Acosta EP, Fletcher CV. Agents for treating
                          human immunodeficiency virus infection. Am J
                          Hosp Pharm. 1994 Sep 15;51(18):2251-67; quiz
                          2286-7
 REFERENCES               Bryant M, Mueller R, Smidt M, Tiemeier D,
                          Jacobs G, Platt F, Butters T, Karlsson N,
                          Houseman K, Marr J. Anti-HIV properties of
                          alpha-glucosidase inhibitor SC-48334, the
                          active component of prodrug SC-49483. Int
                          Conf AIDS. 1993 Jun 6-11;9(1):33 (abstract
                          no. WS-A17-6).
 REFERENCES               Fischl M, Resnick L, Coombs R, Pottage J,
                          Smith S, Wallemark C. The preliminary
                          efficacy and safety of
                          N-butyl-deoxynojirimycin (SC-48334), an
                          alpha-glucosidase I inhibitor, in combination
                          with zidovudine (ZDV). Int Conf AIDS. 1993
                          Jun 6-11;9(1):475 (abstract no. PO-B26-2039).
 REFERENCES               Ratner L, Vander Heyden N. Mechanism of
                          action of N-butyl deoxynojirimycin in
                          inhibiting HIV-1 infection and activity in
                          combination with nucleoside analogs. AIDS Res
                          Hum Retroviruses. 1993 Apr;9(4):291-7.
 REFERENCES               Groopman JE. Current advances in the
                          diagnosis and treatment of AIDS: an
                          introduction. Rev Infect Dis. 1990
                          Sep-Oct;12(5):908-11.
 ENTRY MONTH              8909
 LAST REVISION DATE       960310
 

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