Efficacy of pyrimethamine/sulfadoxine in the prevention of toxoplasmic encephalitis relapses andPneumocystis carinii pneumonia in HIV-infected patients

Ruf, B.; Schürmann, Dirk; Bergmann, Frank; Schüler-Maué, W; Grünewald, Thomas; Gottschalk, H. J.; Witt, Heiko; Pohle, H. D.

doi:10.1007/bf01964427

Cited by 28 publications

(19 citation statements)

References 20 publications

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“…There has been no evidence of treatment-induced resistance so far reported that have contributing to a relapse of CT. Few studies have arrived at a solution of how to prevent relapses. Pyrimethamine and sulfadoxine twice a week appears to give promising results for prevention of CT. Allergic reactions are usually mild and disappear on continuation, but may limit the value of this regimen (Ruf et al, 1993). Daily doses of pyrimethamine and sulfadiazine are more effective as maintenance therapy for preventing relapses of CT (4.4 compared to 19.5 per 100 patient-years; incidence rate ration, 4.36; p=0.024) than twice weekly administration (Podzamczer et al, 1995).…”

Section: Anti-toxoplasma Therapymentioning

confidence: 99%

Toxoplasmosis in HIV/AIDS Patients - A Living Legacy

Nissapatorn¹

2011

Microbes, Viruses and Parasites in AIDS Process

101

124

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Section: Anti-toxoplasma Therapymentioning

confidence: 99%

Toxoplasmosis in HIV/AIDS Patients - A Living Legacy

Nissapatorn¹

2011

Microbes, Viruses and Parasites in AIDS Process

101

124

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“…Standard treatment of toxoplasmosis, on the other hand, utilizes the combination pyrimethamine-sulfadiazine (24). Newer drug combinations which have shown promise for prophylaxis or treatment include pyrimethamine-sulfadoxine (42), trimethoprim-dapsone (23), clindamycin-primaquine (41), and pyrimethamine-clindamycin (19). Atovaquone (566C80), an antimalarial hydroxyquinone with a mechanism of action unlike that of any of the above drugs, has also recently been reported to have significant activity in laboratory animals (14) and humans (15).…”

mentioning

confidence: 99%

Structure-activity and structure-selectivity studies on diaminoquinazolines and other inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Rosowsky

Hynes

Queener

1995

Antimicrob Agents Chemother

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Twenty-eight 2,4-diaminoquinazolines with alkyl, halogen, or alkoxy groups at the 5-, 6-, and/or 7-position, eight 2,4-diaminopteridines with alkyl and aralkyl groups at the 6-and 7-positions, five 1,3-diamino-7,8,9,10-tetrahydropyrimido[4,5-c]isoquinolines with an alkyl, alkylthio, or aryl group at the 6-position, and nine 4,6-diamino-1,2-dihydro-s-triazines with one or two alkyl groups at the 2-position and a substituted phenyl or naphthyl group at the 1-position were evaluated as inhibitors of dihydrofolate reductase enzymes from Pneumocystis carinii, Toxoplasma gondii, and rat liver. Halogen substitution at the 5-or 6-position of 2,4-diaminoquinazoline favored selective binding to the P. carinii enzyme but not the T. gondii enzyme. For example, the 50% inhibitory concentrations of 2,4-diamino-6-chloroquinazoline as an inhibitor of P. carinii, T. gondii, and rat liver dihydrofolate reductase were 3.6, 14, and 29 M, respectively, corresponding to 12-fold selectivity for the P. carinii enzyme but only marginal selectivity for the T. gondii enzyme. Greater than fivefold selectivity for P. carinii but not T. gondii dihydrofolate reductase was also observed for the 2,4-diaminoquinazolines with 5-methyl, 5-fluoro, 5-and 6-bromo, 6-chloro, and 5-chloro-6-bromo substitution. In contrast, alkyl and aralkyl substitution at the 6-and 7-positions of 2,4-diaminopteridines was found to be a favorable feature for selective inhibition of the T. gondii enzyme and, in two cases, for both enzymes. Nine of the fifty-one compounds tested against P. carinii dihydrofolate reductase and four of the thirty compounds tested against T. gondii dihydrofolate reductase displayed fivefold or greater selectivity for the microbial enzyme versus the rat liver enzyme. The most selective against both enzymes was 2,4-diamino-6,7-bis(cyclohexylmethyl)pteridine, with a selectivity ratio 2 orders of magnitude greater than the value reported for trimetrexate and piritrexim. Since substitution at the 7-position is generally considered to be detrimental to the binding of 2,4-diaminopteridines and related compounds to mammalian dihydrofolate reductase, the selectivity observed in this study with the 6,7-bis(cyclohexylmethyl) analog may represent a useful approach to enhancing selective inhibition of the enzyme from nonmammalian species.

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“…Twenty reported findings from studies that were performed up to 1996 ( n = 1,228) (Table 1) [34−51], and six described results of studies performed after 1996 ( n = 368) (Table 2) [52−57]. …”

Section: Resultsmentioning

confidence: 99%

“…Most studies co-administered folinic acid (leucovorin) with pyrimethamine for acute therapy; only four did not report co-administering folinic acid with pyrimethamine – three in the pre-HAART group [35,58,59] and one in the post-HAART group [52]. Of the included studies, 11 did not report co-administering folinic acid with pyrimethamine during maintenance therapy [34,35,38,41,45,47,49,51,52,54,60]. …”

Section: Resultsmentioning

confidence: 99%

Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis

Connolly

Goodwin²,

Schey

et al. 2017

Pathogens and Global Health

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Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate of relapse associated with pyrimethamine-based maintenance therapy (i.e. secondary prophylaxis) in patients with human immunodeficiency virus (HIV) or AIDs treated prior to and after the common use (i.e. 1996) of highly active antiretroviral therapy (HAART) (pre-HAART and post-HAART, respectively). PubMed, Google Scholar, and Cochrane databases were searched to 6 June 2016 using search terms: pyrimethamine, Daraprim, Fansidar, Metakelfin, Fansimef, 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, encephalitis, cerebral, toxoplasmosis, toxoplasmic, and gondii. Single-arm cohort, retrospective, and randomized studies were included. Twenty-six studies with 1,596 patients were included in the analysis; twenty pre-HAART (n = 1,228) studies and six post-HAART (n = 368) were performed. Pooled proportions test for pyrimethamine-based therapy from pre-HAART studies indicated a relapse rate of 19.2% and 18.9% from the fixed-effects and random-effects models, respectively. The relapse rate in the post-HAART studies was 11.1% (fixed and random effects). Continuous therapy was suggestive of lower incidence of relapse compared with intermittent therapy in the pre-HAART era (range, 18.7 to 17.3% vs. 20.9 to 25.6%, respectively). These findings indicate that the likelihood of relapse associated with pyrimethamine-based therepy in patients with HIV and TE decreased after the introduction of HAART to approximately 11%. The findings have important implications as relapse may affect a patient’s disease severity and prognosis, increase utilization of health care resources, and result in additional health care expenditure.

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Efficacy of pyrimethamine/sulfadoxine in the prevention of toxoplasmic encephalitis relapses andPneumocystis carinii pneumonia in HIV-infected patients

Cited by 28 publications

References 20 publications

Toxoplasmosis in HIV/AIDS Patients - A Living Legacy

Toxoplasmosis in HIV/AIDS Patients - A Living Legacy

Structure-activity and structure-selectivity studies on diaminoquinazolines and other inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis

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