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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pneumocystis carinii was obtained in high yield from the lungs of immunosuppressed rats by rupturing mammalian host cells, washing away the soluble mammalian dihydrofolate reductase, and harvesting intact organisms in association with the mammalian plasma membranes. P. carinii dihydrofolate reductase, measured in the 100,000 x g supernatant from sonicated organisms, was obtained in yields ranging up to 62 IU per rat. The enzyme prepared in the presence of protease inhibitors was stable when frozen in liquid nitrogen. P. carinii dihydrofolate reductase differed from the mammalian enzyme in that the former was slightly inhibited by 150 mM KCl, whereas the latter was stimulated over twofold by 150 mM KCl. The standard assay for P. carinii dihydrofolate reductase contained 0.12 mM NADPH and 92 microM dihydrofolic acid. Under these conditions, the 50% inhibitory concentrations of the known inhibitors trimethoprim, trimetrexate, and pyrimethamine were 12 microM, 42 nM, and 3.8 microM, respectively. These standard compounds were also tested against dihydrofolate reductase from rat liver to allow an assessment of the selectivity of the drugs. Although it was the least potent, trimethoprim was the most selective. Pyrimethamine was more potent but was nonselective. Trimetrexate was extremely potent but was selective for mammalian dihydrofolate reductase. A series of experimental compounds was obtained from the National Cancer Institute and other sources through the Developmental Therapeutics Branch of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. Among the first 87 compounds tested, 11 had 50% inhibitory concentrations below that of trimetrexate and 3 were more selective than trimethoprim. The most promising compounds in this original group were chemically related to methotrexate.
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PMID:Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs. 192 92

Trimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in less than 2% of patients.
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PMID:Hypersensitivity reactions to trimetrexate. 214 1

Pneumocystis carinii pneumonia (PCP) is the commonest opportunistic infection in AIDS patients. The diagnosis should be strongly suspected in patients who are cyanosed and who present with interstitial pneumonia. The management of PCP in AIDS patients is very similar to that in other groups with the same infection. Trimethoprim-sulphamethoxazole (TMP/SMZ) combinations or pentamidine remain the therapies of choice. Side effects of TMP/SMZ are much greater in AIDS patients than in other immuno-suppressed patients and are similar in frequency to those of pentamidine. Occasionally, pentamidine produces life-threatening complications. Trimetrexate with folinic acid is likely to be as effective against pneumocystis as the two first-line drugs and trimethoprim/dapsone combinations can be given orally and are clearly effective in moderately severe infections. Prophylaxis following an attack of PCP undoubtedly reduces the risk of re-infection, but may not materially alter the overall prognosis. The best drug regimen remains controversial but fortnightly inhaled pentamidine has the advantage of patient acceptability and very low risk of side-effects.
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PMID:Pneumocystis carinii pneumonia and its treatment in patients with AIDS. 265 17

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.
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PMID:Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. 295 10

Trimetrexate is a promising new lipophilic antifolate with antitumor and antimicrobial activity, which is currently undergoing clinical trials. It differs from methotrexate in its transport and intracellular retention, and may be useful against tumors resistant to methotrexate because of impaired transport or deficient polyglutamylation. In preclinical studies, it has demonstrated a broader spectrum of antitumor activity than methotrexate, and appears to have synergistic antitumor activity when combined with a number of other agents. In clinical trials, the primary toxicity has been hematologic, with rapid recovery and no evidence of cumulative dose effect. Nonhematologic toxicity has been sporadic. Preliminary results of phase II trials indicate activity against breast, non-small-cell lung, and head and neck tumors. In addition, trimetrexate with simultaneous leucovorin rescue appears to be a promising new treatment for pneumocystis pneumonia in AIDS patients, with minimal toxic side effects.
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PMID:Trimetrexate: a second generation folate antagonist in clinical trial. 296 Jul 88

After reviewing the immunological anomalies provoked by the human immuno-deficiency virus (HIV) as well as their implications in pulmonary pathology, the authors enumerate the diagnostic and therapeutic methods currently available in the treatment of patients suffering from AIDS and pulmonary diseases. The clinical features as well as the chest radiograph--an essential first line tool--may lead to atypical features. Respiratory function tests and scintigraphy to Gallium may be a useful additional diagnostic technique but for a full pulmonary investigation a bronchoalveolar lavage is required and/or transbronchial biopsy. Open lung biopsy is rarely required, and then only as a last resort. The treatment of pneumocystis remains centred on Trimethoprim sulfamethoxazole and Pentamidine, with a similar efficacy (80% care) but both have side-effects which are less frequent but more severe with Pentamidine. Administration of Pentamidine by aerosol, Eflornithine and Trimetrexate are under study. The level of lactic dehydrogenase (LDH) seems to be a prognostic factor. The value of prophylaxis is discussed. If the treatment of tuberculosis, an infection which is seen more and more frequently, still rests on classical triple therapy, the treatment of atypical mycobacterial infections is even more deceptive than in non-immuno-suppressed hosts. The same is true with pneumonia due to cytomegalovirus. The treatment of lymphoid interstitial pneumonia which is probably a direct result of HIV infection, remains controversial. On the other hand, pulmonary Kaposi's sarcoma is associated with an elevated mortality, and all treatment (interferon and chemotherapy) is disappointing.
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PMID:[Pulmonary manifestations of acquired immunodeficiency syndrome]. 306 2

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.
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PMID:Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia. 778 90

Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin versus trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to TMP-SMZ and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with TMP-SMZ. By study day 21, failure rates were 20% with TMP-SMZ and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs. 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ.
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PMID:Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. 801 93

A series of eight previously undescribed 2,4-diaminothieno[2,3-d]pyrimidine analogues of the potent dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMQ) and piritrexim (PTX) were synthesized as potential drugs against Pneumocystis carinii and Toxoplasma gondii, which are major causes of severe opportunistic infections in AIDS patients. 2,4-Diamino-5-methyl-6-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 3,4,5-trimethoxy or 2,5-dimethoxy substitution in the aryl/aralkyl moiety and 2,4-diamino-5-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 2,5-dimethoxy substitution in the aryl/aralkyl moiety were obtained by reaction of the corresponding 2-amino-3-cyanothiophenes with chloroformamidine hydrochloride. The aryl group in the 5,6-disubstituted analogues was either attached directly to the hetero ring or was separated from it by one or two carbons, whereas the aryl group in the 5-monosubstituted analogues was separated from the hetero ring by two or three carbons. 2-Amino-3-cyano-5-methyl-6-(aryl/alkyl)thiophene intermediates for the preparation of the 5,6-disubstituted analogues were prepared from omega-aryl-2-alkylidene-malononitriles and sulfur in the presence of a secondary amine, and 2-amino-3-cyano-4-(aryl/aralkyl)thiophene intermediates for the preparation of the 5-monosubstituted analogues were obtained from omega-aryl-1-chloro-2-alkylidenemalononitriles and sodium hydrosulfide. Synthetic routes to the heretofore unknown ylidenemalononitriles, and the ketone precursors thereof, were developed. The final products were tested in vitro as inhibitors of DHFR from Pneumocystis carinii, Toxoplasma gondii, rat liver, beef liver, and Lactobacillus casei. A selected number of previously known 2,4-diaminothieno[2,3-d]pyrimidines lacking the 3,4,5-trimethoxyphenyl and 2,5-dimethoxyphenyl substitution pattern of TMQ and PTX, respectively, were also tested for comparison. None of the compounds was as potent as TMQ or PTX, and while some of them showed some selectivity in their binding to Pneumocystis carinii and Toxoplasma gondii versus rat liver DHFR, this effect was not deemed large enough to warrant further preclinical evaluation.
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PMID:2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. 823 96

The clinical efficacy of trimetrexate, a dihydrofolate reductase inhibitor with potent in vitro antitoxoplasma activity, was assessed in 9 sulfonamide-intolerant patients with AIDS and biopsy-proven cerebral toxoplasmosis. The 9 patients were treated for 28-149 days with trimetrexate (30-280 mg/m2/day) plus leucovorin (20-90 mg/m2 every 6 h). Radiographic responses were documented in 8 patients, and clinical responses in 5 patients. Despite continued therapy, all patients deteriorated clinically and radiographically within 13-109 days of their initial improvement. Trimetrexate at very high doses for extended periods was not associated with serious toxicity. Trimetrexate alone had dramatic but transient activity in sulfonamide-intolerant patients and thus is not adequate as single-agent therapy for AIDS-associated toxoplasmosis.
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PMID:Salvage trial of trimetrexate-leucovorin for the treatment of cerebral toxoplasmosis in patients with AIDS. 850 35


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