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

Pneumocystis carinii pneumonia has long been considered the predominant pulmonary disease in patients with HIV, but several factors are changing this perception. The population infected with HIV is increasingly composed of injection drug users, and racial and ethnic minorities, which represent groups that have a high incidence of bacterial pneumonia and tuberculosis. The increased longevity attributed to antiretroviral therapy and P. carinii pneumonia prophylaxis is accompanied by more profound immunosuppression, rendering patients susceptible to Pseudomonas, Aspergillus, and other opportunistic pneumonias. Trimetrexate and atovaquone are now available for the treatment of P. carinii pneumonia. Both are less effective than standard regimens of trimethoprim-sulfamethoxazole, but have fewer adverse effects. The diagnosis of respiratory infections complicating HIV usually depends on isolation of the pathogen. The routine use of transbronchial biopsy during bronchoscopy is controversial because the prevalence of P. carinii pneumonia is high in most centers caring for patients with AIDS, and bronchoalveolar lavage is usually diagnostic in this disease. However, biopsy enhances the yield of bronchoscopy, especially in the diagnosis of noninfectious pulmonary disorders and infections other than P. carinii pneumonia.
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PMID:Respiratory infections in patients with HIV. 936 56

The synthesis and biological activity are reported for 21 6-substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues (4-24) of piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Recombinant DHFR from Pneumocystis carinii (pc) and native DHFR from Toxoplasma gondii (tg) were the target enzymes tested; these organisms are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity for the pathogenic DHFR. The synthesis of S9-bridged compounds 4-6 was achieved by aryl displacement of 2,4-diamino-6-chloropyrido[3, 2-d]pyrimidine (27) with thiol nucleophiles. Oxidation of 4-6 with hydrogen peroxide in glacial acetic acid afforded the corresponding sulfone analogues 7-9. The N9-bridged compounds 10-24 were synthesized from their precursor 3-amino-6-(arylamino)-2-pyridinecarbonitriles via a thermal cyclization with chloroformamidine hydrochloride. Unlike the S9-bridged compounds, the arylamino side chains of the N9-bridged analogues were introduced prior to the formation of the 2, 4-diaminopyrido[3,2-d]pyrimidine nucleus. A reversed two-atom-bridged analogue (25) was also synthesized using a synthetic strategy similar to that utilized for compounds 10-24. The IC50 values of these compounds against pcDHFR ranged from 0.0023 x 10(-6) M for 2,4-diamino-6-(N-methyl-3',4'-dimethoxyanilino)pyrido[3, 2-d]pyrimidine (21), which was the most potent, to 90.4 x 10(-6) M for 2,4-diamino-6-(4'-methoxyanilino)pyrido[3,2-d]pyrimidine (12), which was the least potent. The three S9-bridged compounds tested were more potent than the corresponding sulfone-bridged compounds for all three DHFRs. N9-Methylation increased the potency by as much as 17 000-fold (compounds 15 and 21). None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was again 21 with an IC50 value of 0.00088 x 10(-6) M and the least potent was 12 with an IC50 of 2.8 x 10(-6) M. N9-Methylation afforded an increase in potency of up to 770-fold (compound 15 NH vs 21 N-CH3) compared to the corresponding N9-H analogue. In contrast to pcDHFR, several analogues had a greater selectivity ratio for tgDHFR compared to trimetrexate (TMQ) or PTX, most notably 2, 4-diamino-6-[(3',4'- dimethoxyphenyl)thio]pyrido[3,2-d]pyrimidine (4), 2,4-diamino-6-[(2'-methoxyphenyl)sulfonyl]pyrido[3, 2-d]pyrimidine (7), and 2,4-diamino-6-(2', 5'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (14) which combined relatively high potency at 10(-7)-10(-8) M along with selectivity ratios of 3.97, 6.67, and 4.93, respectively. Several analogues synthesized had better selectivity ratios than TMQ or PTX for both pcDHFR and tgDHFR, and the potencies of the N9-methylated compounds were comparable to or greater than that of TMQ or PTX. Selected compounds were evaluated as inhibitors of the growth of a variety of tumor cells in culture. The N9-CH3 analogues were, in general, highly potent with GI50 values in the nanomolar range. The N9-H and S9 analogues were less potent with GI50 values in the millimolar to micromolar range.
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PMID:6-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents. 980 92

The objective of this study was to determine the pharmacokinetics of trimetrexate and dapsone in AIDS patients with moderate to severe pneumocystis pneumonia. Trimetrexate, leucovorin, and dapsone were administered for 21 +/- 3 days in the following doses: trimetrexate glucuronate, 45 mg/m2; leucovorin, 20 mg/m2; and dapsone, 100 mg daily. The pharmacokinetics of trimetrexate, dapsone, and dapsone's metabolite, monoacetyldapsone, were determined at three separate periods over the course of treatment. Serial blood samples were obtained over 24 hours after dosing and analyzed for trimetrexate, dapsone, and monoacetyldapsone, and pharmacokinetic parameters were determined. The mean parameters obtained for the early, mid-, and late collection periods were the following: trimetrexate: t1/2 = 8.29, 9.15, 10.00 hr; AUC = 16.85, 22.38, 24.49 mg.hr/l; CI = 5.58, 4.14, 3.96 l/hr, respectively. DDS: t1/2 = 14.99, 16.59, 15.13 hr; AUC = 30.60, 35.29, 36.08 mg.hr/l; CI = 3.82, 3.49, 3.01 l/hr, respectively. Monoacetyldapsone: t1/2 = 20.25, 18.66, 16.32 hr; AUC = 24.05, 24.06, 23.86 mg.hr/l, respectively. No statistically significant changes in pharmacokinetics for trimetrexate or dapsone were observed over the 21 +/- 3 day course of treatment. The results suggest that there are no major interactions between trimetrexate and dapsone when administered together in acutely ill patients.
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PMID:Pharmacokinetics of trimetrexate and dapsone in AIDS patients with Pneumocystis carinii pneumonia. 1007 26

Trypanosoma cruzi, a protozoan parasite, is the causative agent for Chagas' disease, which poses serious public health problem in Latin America. The two drugs available for the treatment of this disease are effective only against recent infections and are toxic. Dihydrofolate reductase (DHFR) has a proven track record as a drug target. The lipophilic antifolate trimetrexate (TMQ), which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients, is a potent inhibitor of T. cruzi DHFR activity, with an inhibitory constant of 6.6 nM. The compound is also highly effective in killing T. cruzi parasites. The 50 and 90% lethal dose values against the trypomastigote are 19 and 36 nM, and the corresponding values for the amastigote form are 26 and 72 nM, respectively. However, as TMQ is also a good inhibitor of human DHFR, further improvement of the selectivity of this drug would be preferable. Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas' disease.
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PMID:Lipophilic antifolate trimetrexate is a potent inhibitor of Trypanosoma cruzi: prospect for chemotherapy of Chagas' disease. 1604 31

The best management strategy for HIV patients who fail to respond to first-line therapy for Pneumocystis jirovecii pneumonia is currently unclear. We identified all patients who were treated with trimetrexate and folinic acid who failed 7 or more days of cotrimoxazole, clindamycin-primaquine or dapsone-trimethoprim between 1996 and 2006. Trimetrexate was tolerated in 100% of cases with no treatment termination secondary to adverse drug reactions. Despite severe disease, 71% of patients were alive after 12 weeks.
AIDS 2009 Jun 19
PMID:Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia. 1942 49


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