      Document 0081
 DOCN  DRG0081
 UNIQUE IDENTIFIER        DRG-0166
 NAME OF SUBSTANCE        Delavirdine mesylate [USAN 1996]
 STANDARD CHEMICAL NAME   1-(3-(Isopropylamino)-2-pyridyl)-4-((5-methan-
                          e sulfon amidoindol-2-yl)carbonyl)piperazine
                          monomethane sulfonate [USAN 1996]
 PROTOCOL ID NUMBERS      NIAID 93 I-109
 PROTOCOL ID NUMBERS      FDA 228A
 PROTOCOL ID NUMBERS      FDA 228B
 PROTOCOL ID NUMBERS      NIAID ACTG 260
 PROTOCOL ID NUMBERS      NIAID ACTG 261
 PROTOCOL ID NUMBERS      FDA 125A
 SECONDARY SOURCE ID      U-90152 [AmFAR Tx Dir 1995;7(4)]
 SECONDARY SOURCE ID      U-90152S [USAN 1996]
 PHARMACOLOGICAL ACTION   BHAP compounds, non-competitively inhibit
                          HIV-1 (RT), probably through direct binding
                          with the enzyme. It is mutually competitive
                          with nevirapine. Researchers report that
                          U-90152 inhibits HIV-1 in vitro at lower
                          concentrations than U-87201E. Resistance to
                          BHAP compounds develops rapidly in vitro.
                          BHAP-resistant virus results from a single
                          amino acid substitution at position 236. It
                          has been reported that the development of
                          high-level resistance to BHAP compounds in
                          vitro sensitizes HIV-1 RT to inhibition by
                          other non-nucleoside RT inhibitors. [AmFAR Tx
                          Dir 1995;7(4)]
 DISEASES STUDIED/TREATED HIV infection [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1995;7(4)]
 SUBSTANCE INTERACTIONS   Interacts with ketoconazole, fluconazole,
                          rifampin, isoniazid, cimetidine, and
                          ranitidine. Synergistic with ddC and AZT.
                          [AmFAR Tx Dir 1995;7(4)] [NIAID 93 I-109]
 ADVERSE EFFECTS          Side effects include a transient non-serious
                          maculopapular skin rash often associated with
                          itching and, infrequently, a transient and
                          reversible mild-moderate elevation in liver
                          function tests. [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: U-90152 is a BHAP compound.
                          BHAP (bis(heteroaryl)piperazine) compounds
                          are non-nucleoside chemicals with anti-HIV-1
                          activity [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: BHAP compounds have in
                          vitro activities comparable to other
                          non-nucleoside reverse transcriptase
                          inhibitors (TIBO derivatives, nevirapine, and
                          L-697,661) [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: However, all these
                          compounds have unique structures [AmFAR Tx
                          Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C22H28N6O3S.CH4O3S [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 522.68 [USAN 1996]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [NIAID 93 I-109]
 MANUFACTURERS            National Institute of Allergy and Infectious
                          Diseases
 REFERENCES               Gu Z, Quan Y, Li Z, Arts EJ, Wainberg MA.
                          Effects of non-nucleoside inhibitors of human
                          immunodeficiency virus type 1 in cell-free
                          recombinant reverse transcriptase assays. J
                          Biol Chem. 1995 Dec 29;270(52):31046-51.
 REFERENCES               Fan N, Rank KB, Evans DB, Thomas RC, Tarpley
                          WG, Sharma SK. Simultaneous mutations at
                          Tyr-181 and Tyr-188 in HIV-1 reverse
                          transcriptase prevents inhibition of
                          RNA-dependent DNA polymerase activity by the
                          bisheteroarylpiperazine (BHAP) U-90152s. FEBS
                          Lett. 1995 Aug 14;370(1-2):59-62.
 REFERENCES               Balzarini J, Perez-Perez MJ, Velazquez S,
                          San-Felix A, Camarasa MJ, De Clercq E,
                          Karlsson A. Suppression of the breakthrough
                          of human immunodeficiency virus type 1
                          (HIV-1) in cell culture by thiocarboxanilide
                          derivatives when used individually or in
                          combination with other HIV-specific
                          inhibitors (i.e., TSAO derivatives). Proc
                          Natl Acad Sci USA. 1995 Jun 6;92(12):5470-4.
 REFERENCES               Fan N, Evans DB, Rank KB, Thomas RC, Tarpley
                          WG, Sharma SK. Mechanism of resistance to
                          U-90152S and sensitization to L-697,661 by a
                          proline to leucine change at residue 236 of
                          human immunodeficiency virus type 1 (HIV-1)
                          reverse transcriptase. FEBS Lett. 1995 Feb
                          13;359(2-3):233-8.
 REFERENCES               Pagano PJ, Chong KT. In vitro inhibition of
                          human immunodeficiency virus type 1 by a
                          combinaion of delavirdine (U-90152) with
                          protease inhibitor U-75875 or
                          interferon-alpha. J Infect Dis. 1995
                          Jan;171(1):61-7.
 REFERENCES               Peterson PK, Gekker G, Hu S, Chao CC.
                          Anti-human immunodeficiency virus type 1
                          activities of U-90152 and U-75875 in human
                          brain cell cultures. Antimicrob Agents
                          Chemother. 1994 Oct;38(10):2465-8.
 REFERENCES               Althaus IW, Chou JJ, Gonzales AJ, Deibel MR,
                          Chou KC, Kezdy FJ, Romero DL, Thomas RC,
                          Aristoff PA, Tarpley WG, et al. Kinetic
                          studies with the non-nucleoside human
                          immunodeficiency virus type-1 reverse
                          transcriptase inhibitor U-90152E. Biochem
                          Pharmacol. 1994 Jun 1;47(11):2017-28.
 REFERENCES               Chong KT, Pagano PJ, Hinshaw RR.
                          Bisheteroarylpiperazine transcriptase
                          inhibitor in combination with
                          3'-azido-3'-deoxythymidine or
                          2',3'-dideoxycytidine synergistically
                          inhibits human immunodeficiency virus type 1
                          replication in vitro. Antimicrob Agents
                          Chemother. 1994 Feb;38(2):288-93.
 REFERENCES               Freimuth B, Davey R, Batts D, Lane C, Cox S,
                          Wathen L, Peel B, Daenzer C, Morse G, Chaitt
                          D, et al. Phase II clinical trials of
                          delavirdine mesylate combination therapy. Int
                          Conf AIDS. 1994 Aug 7-12;10(2):59 (abstract
                          no. 512B).
 REFERENCES               Cox S, Anderson RD, Driver M, Carel B. Effect
                          of fluconazole (FLU) on the clinical
                          pharmacokinetics of delavirdine (DLV). Int
                          Conf AIDS. 1994 Aug 7-12;10(1):214 (abstract
                          no. PBO284).
 ENTRY MONTH              9303
 LAST REVISION DATE       960308
 

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