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Information on level of drugs into breastmilk
Published in Wendy Jones, Breastfeeding and Medication, 2018
Proguanil is metabolised in the body to the active anti-malarial drug cycloguanil. Its use is becoming limited due to the development of resistance. It is licenced in paediatric formulations with babies under 6.0 kg (0 to 12 weeks of age) being recommended to be given one-eighth the adult dose. The BNF states that although it is present in breastmilk the risk to the infant is minimal. Although all anti-malarials are present in breastmilk the amounts reached are inadequate to provide adequate prophylaxis and the infant should receive its own medication.
Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
The biguanides proguanil and chlorproguanil are metabolized in vivo to the triazine compounds cycloguanil and chlorcycloguanil, respectively, which are structurally similar to the diamino-pyrimidine pyrimethamine. Triazines are known as type 2 antifolate drugs because they specifically inhibit parasite DHFR, an enzyme that regenerates folate cofactors, which are essential for 2-carbon transfer reactions and the synthesis of parasite nucleic acids (Canfield et al., 1995). Both triazines are competitive inhibitors of DHFR. Because they inhibit all growing stages of the malaria parasite, both proguanil and chlorproguanil have been used as causal prophylactics, and are effective in preventing the growth of sporogonic stages in the mosquito. Like pyrimethamine, triazines synergize with type 1 antifolate drugs (sulphonamides and sulphones). The biguanide pro-drugs, but not triazine metabolites, have a secondary site of action, independent of their effect on the parasite folate pathway (Kaneko et al., 1999). Proguanil, but not cycloguanil, is synergistic in combination with atovaquone, a drug that inhibits parasite mitochondrial electron transport (see above). Proguanil-atovaquone synergy in vitro is independent of the extent of proguanil metabolism (see below).
Proguanil and Chlorproguanil
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Because the metabolism of proguanil to cycloguanil and chlorproguanil to chlorcycloguanil is mediated principally by CYP2C19, co-administered drugs that inhibit the activity of this enzyme may attenuate anti-malarial activity. Consistent with this substrate interaction, cimetidine (Kolawole et al., 1999) and fluvoxamine (Jeppesen et al., 1997) impair the metabolism of proguanil to cycloguanil and 4-chlorophenylbiguanide. A further example is provided by the proton pump inhibitor omeprazole, which approximately halves proguanil bioactivation to cycloguanil (Funck-Brentano et al., 1997). Data relating to antiretroviral therapies appear inconsistent. For example, in vitro evidence (Xu and Desta, 2013) and some in vivo data (Soyinka and Onyeji, 2010) suggest that the anti-retroviral efavirenz should also inhibit CYP2C19 activity and reduce cycloguanil formation, but several studies in humans have shown that it is, to the contrary, an inducer (Michaud et al., 2012; van Luin et al., 2010). Between-study differences in factors such as dose regimens and frequencies of polymorphisms in CYP2C19 could un-derlie these apparent discrepancies, suggesting that carefully conducted local studies should be performed if proguanil is to be administered with other drugs that have potential clinically significant effects on CYP450 enzyme activity.
Histopathological and ultrastructural assessment of atovaquone-proguanil hydrochloride combination in chronic murine toxoplasmosis
Published in Ultrastructural Pathology, 2021
Manar S. Elmehankar, Abeer A. Elhenawy, Wafaa A. Aboukamar, Manal A. Elzoheiry, Nairmen Nabih
The synergetic effect of combined ATV/PROG could be attributed to the chemical properties of proguanil in the form of its high bioavailability and high intracellular concentration.33 After hepatic metabolism, proguanil is transformed to active cycloguanil metabolite with inhibition of dihydrofolate reductase enzyme that is essential for folate production involved in parasite DNA synthesis.6,33 Alternatively, proguanil was suggested to enhance the effect of ATV as a biguanide rather than as cycloguanil.34 In the present study, the higher reduction in brain tissue T. gondii cyst count of ATV/PROG-treated group could be partially attributed to a change in ATV pharmacokinetics when combined with proguanil in malarone drug therapy that resulted in enhancement of its efficacy. Additional research is needed to confirm these results.
Antimalarial drugs for treating and preventing malaria in pregnant and lactating women
Published in Expert Opinion on Drug Safety, 2018
Makoto Saito, Mary Ellen Gilder, Rose McGready, François Nosten
No teratogenic or embryotoxic effects were shown in rats and rabbits [126]. However, a theoretical concern on its use in the first trimester remains as cycloguanil, the active metabolite of proguanil, is an anti-folate. Co-administration of folic acid supplements at least during the first trimester should thus be considered [23]. In total 327 women were reported to be exposed to AP in the first trimester either as treatment or prophylaxis [123,127–129]. In the cohort of Danish travelers receiving AP as prophylaxis in their first trimester, the prevalence of congenital abnormality was 1.3% (2/149) and risk was not increased in comparison to that of the background population (2.5%, 13,993/570,728, odds ratio 0.55, 95% CI 0.14 to 2.21) [127]. Another cohort of travelers in Europe including 165 women exposed to AP either as prophylaxis or treatment in the first trimester reported 13% (12/165) of miscarriage and 4% (4/162) of congenital malformation [128]. The other 13 women exposed to AP in the first trimester delivered live-born babies without congenital abnormality [6,123,129].
A systems biology approach to antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Wilian Augusto Cortopassi, Tanos Celmar Costa Franca, Antoniana Ursine Krettli
The search for inhibitors of a specific protein, known as target-based method, is not necessarily classified as a systems biology approach, but it is an important part of the process, by allowing the more efficient search for new promising antimalarial drugs (Figure 1). Nevertheless, in most cases, the understanding of small molecules–protein interactions may require assistance of computational models, for instance when there is no structural data or the protein targets have dramatic conformational changes in solution. In these cases, homology modeling, docking, and molecular dynamics approaches can be of great help for uncovering these interactions. As soon as a drug target for a promising drug is identified, these in silico approaches become very important for designing more powerful inhibitors with greater affinities and lower toxicity. In addition, knowing the mechanism of action of these potential antimalarial drugs is a powerful tool for uncovering the cell function of Plasmodium. This deeper knowledge allows the development of more effective predictive algorithms for emergence of parasite resistance. In a recent study, for example Hartl and coworkers studied the correlation between resistance caused by P. falciparum dihydrofolate reductase mutations and the drug environment – defined as type of drug, pyrimethamine or cycloguanil, as well as their concentration. By knowing the mechanism of action of these two compounds, it was possible to build a model showing that the evolutionary aspects of resistance to pyrimethamine and cycloguanil are highly dependent on the environment, an algorithm that can be easily adapted to other antimalarials, and therefore inform new therapeutic strategies [56].