Doxycycline Prophylaxis for Falciparum Malaria

Pang, L; Boudreau, EllenF.; Limsomwong, Nipon; Singharaj, Pricha

doi:10.1016/s0140-6736(87)92141-6

Cited by 78 publications

(27 citation statements)

References 15 publications

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“…Doxycycline has been used in the prophylaxis of Plasmodium falciparum malaria and has been found to be effective and well tolerated (34). Doxycycline does not accumulate in the blood of patients with renal failure (37), does not produce a high rate of vestibular disturbances like those reported for minocycline (14), and is considered to be one of the safest tetracyclines for the treatment of extrarenal infections in patients with renal failure (37).…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo effects of doxycycline on Toxoplasma gondii

Chang

Comte

Péchère

1990

Antimicrob Agents Chemother

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We investigated the effects of doxycycline on Toxoplasma gondii infections in vitro and in vivo. Resident peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to doxycycline at different concentrations. The antitoxoplasmic activity of doxycycline was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. The concentration of doxycycline that inhibited 50% of the radioactive uptake was calculated to be 6.4 ,Ig/ml (95% confidence limits, 5.07 to 8.06 ,ug/ml); the concentration of doxycycline that inhibited 90% of the radioactive uptake was 14 pg/ml. Tetracycline was ineffective up to 40 ,ug/ml. Furthermore, microscopic examination of the infected macrophages after treatment with doxycycline confirmed the inhibition of intracellular growth of T. gondui. Mice acutely infected by the intraperitoneal route with 5 x 103 tachyzoites of T. gondii were protected against death with a dose of 300 mg of doxycycline per kg (body weight) administered by the oral route for 10 days, starting 24 h after challenge. When mice were infected with 105 tachyzoites of T. gondii and treated 12 days starting 2 h after challenge, the protection and the cure rates were, respectively, 100 and 0% after doxycycline alone (300 mg/kg per day), 0 and 0% after pyrimethamine alone (12.5 mg/kg per day), and 100 and 60% after the combination of these two drugs at the same dosages given above. These results suggest that doxycycline may prove to be useful in the treatment of toxoplasmic infections.Infection with Toxoplasma gondii is a potential hazard for immunocompromised patients, such as those suffering from the acquired immune deficiency syndrome (AIDS) (30). Currently, the treatment of choice for toxoplasmosis is the synergistic combination of pyrimethamine with sulfonamides (20,29,43). The treatment of patients with AIDS suffering from toxoplasmic encephalitis with this combination entails a significant mortality rate, usually associated with relapse after withdrawal of therapy for reasons of toxicity, mainly because of the sulfonamide component of the combination (27,30). Moreover, it has been proposed that patients with AIDS suffering from toxoplasmic encephalitis should be maintained on a chronic suppressive (clinical prophylactic) regimen to avoid relapses (23). Thus, the development of effective and safer compounds for treating this disease is critically needed. As alternative treatments, the experimental in vitro and in vivo activities of some new macrolides have been assessed (1,5,(7)(8)(9), but their efficacies in human toxoplasmosis, however, remain to be confirmed in clinical trials. Clindamycin has been shown to have activity in animal models of toxoplasmosis (2, 32, 41), and its use as an alternative drug in the treatment of patients who do not tolerate sulfonamides has been reported recently (12).Among the other possible therapies, the antitoxoplasmic activities of tetracyclines have been studied in animal models. The results of those studies with tetracycl...

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Section: Methodsmentioning

confidence: 99%

In vitro and in vivo effects of doxycycline on Toxoplasma gondii

Chang

Comte

Péchère

1990

Antimicrob Agents Chemother

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“…Both drugs are specific inhibitors of the enzyme dihydrofolate reductase (DHFR;5,6,7, DNA Extraction and Nucleotide Sequence Analysis. Parasites were obtained from infected erythrocytes by lysis in TSE buffer (100 mM NaCl/50 mM EDTA/20 mM Tris, pH 8.0) containing 0.15% saponin.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria.

Peterson

Milhous

Wellems

1990

Proc. Natl. Acad. Sci. U.S.A.

370

303

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Proguanil and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria. Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine, and vice versa. Analysis of the P. falciparum dihydrofolate reductase (DbFR) from different parasites reveals the-structural basis for differential susceptibility to these antifolate drugs. Parasites harboring a pair of point mutations from Ala-16 to Val-16 and from Ser-108 to Thr-108 are resistant to cycloguanil (the active metabolite of proguanil) but not to pyrimethamine. A single Asn-108 mutation, on the other hand, confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil. Significant crossresistance to both drugs occurs in parasites having mutations that include Ser-108lOS Asn-108 and Ile-164 -Leu-164. These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of DHFR. Alternative inhibitors, used alone or in combination, may be effective against some strains of cycloguanil-or pyrimethamine-resistant malaria.Proguanil and pyrimethamine, introduced nearly 40 years ago (1, 2), were powerful additions to the spectrum ofantimalarial agents. Both drugs are specific inhibitors of the enzyme dihydrofolate reductase (DHFR;5,6,7, DNA Extraction and Nucleotide Sequence Analysis. Parasites were obtained from infected erythrocytes by lysis in TSE buffer (100 mM NaCl/50 mM EDTA/20 mM Tris, pH 8.0) containing 0.15% saponin. After centrifugation at 5000 x g, the parasites were resuspended in TSE buffer and lysed by addition of sodium lauryl sulfate (SDS) to 1% and NaCI04 to 0.5 M. The lysate was gently mixed at room temperature for 1 hr, extracted twice with phenol equilibrated in TSE buffer (pH 8.0), and finally extracted twice with 1:1 (vol/vol) phenol/chloroform. The solution was brought 0.2 M in sodium acetate, 1.5 volumes of 95% EtOH were added, and the DNA was spooled out of solution.In P. falciparum the DHFR domain is part of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR/TS). Oligonucleotide primers were designed from the gene sequence (23) and used in the polymerase chain reaction to amplify the DHFR domain as described (7). Fifty nanograms of P. falciparum DNA (representing -1.5 X 106 copies of the genome) was used as the starting material. Both strands of amplified DNA were sequenced by a modification of the method reported by Innis et al. (24). Two microliters of the polymerase chain reaction product were used in a Abbreviations: DHFR, dihydrofolate reductase; PABA, p-aminobenzoic acid. 3018The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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“…From 2002 to 2006, 1,787 malaria cases were found among French soldiers expected to be taking DOX. A surge in the number of malaria cases within 3 weeks after discontinuing DOX prophylaxis is often observed (29,43). DOX failures soon after termination of drug therapy suggest that DOX serves primarily as a suppressive agent.…”

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confidence: 99%

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline

Briolant

Baragatti

Parola

et al. 2009

Antimicrob Agents Chemother

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The distribution and range of 50% inhibitory concentrations (ICAccording to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 M.

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Doxycycline Prophylaxis for Falciparum Malaria

Cited by 78 publications

References 15 publications

In vitro and in vivo effects of doxycycline on Toxoplasma gondii

In vitro and in vivo effects of doxycycline on Toxoplasma gondii

Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria.

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline

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