       Document 1189
 DOCN  M9591189
 TI    Trimetrexate. A review of its pharmacodynamic and pharmacokinetic
       properties and therapeutic potential in the treatment of Pneumocystis
       carinii pneumonia.
 DT    9509
 AU    Fulton B; Wagstaff AJ; McTavish D; Adis International Limited, Auckland,
       New Zealand.
 SO    Drugs. 1995 Apr;49(4):563-76. Unique Identifier : AIDSLINE MED/95309143
 AB    Trimetrexate is a folinic acid analogue structurally related to
       methotrexate, whose primary mechanism of action is believed to be
       inhibition of dihydrofolate reductase. This reduces the production of
       DNA and RNA precursors and leads to cell death. Trimetrexate is
       lipophilic and can passively diffuse across cell membranes including
       those of Pneumocystis carinii and its mammalian host. To minimise
       toxicity, trimetrexate must be coadministered with calcium folinate
       (leucovorin calcium), a reduced folate coenzyme, which is transported
       into, and protects, mammalian host cells but not P. carinii cells. In
       noncomparative trials trimetrexate was effective in the treatment of P.
       carinii pneumonia (PCP) in patients with AIDS who were intolerant of or
       refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and
       pentamidine treatment. In these patients, 2- to 4-week survival rates of
       48 to 69% were reported. In a comparative trial in the initial therapy
       of PCP, trimetrexate was less effective than cotrimoxazole in moderate
       to severe disease as evidenced by a significantly higher failure rate.
       Trimetrexate was better tolerated than cotrimoxazole when used in this
       setting, however. Significantly fewer patients receiving trimetrexate
       plus calcium folinate discontinued treatment because of adverse events
       than did patients receiving cotrimoxazole. The most common adverse
       effect associated with trimetrexate is myelosuppression (neutropenia and
       thrombocytopenia); this is mitigated by coadministration of calcium
       folinate and is generally reversible upon dosage reduction or
       discontinuation. Other adverse effects include increases in serum
       aminotransferase levels, anaemia, fever, rash/pruritus, and increased
       alkaline phosphatase or serum creatinine levels. Further research into
       the use of trimetrexate, including its efficacy as prophylaxis, in
       combination with other agents and as an oral formulation, is needed to
       clearly define its role in the treatment of PCP and to identify patients
       most likely to benefit. Currently, trimetrexate should be considered as
       an alternative treatment option in immunocompromised patients with
       moderate to severe PCP who have not responded to or are intolerant of
       first-line therapy.
 DE    Animal  AIDS-Related Opportunistic Infections/*DRUG THERAPY  Clinical
       Trials  Human  Pneumonia, Pneumocystis carinii/*DRUG THERAPY  Rats
       Trimetrexate/ADMINISTRATION & DOSAGE/*PHARMACOKINETICS/  *THERAPEUTIC
       USE  JOURNAL ARTICLE  REVIEW  REVIEW, TUTORIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

