Tags

Type your tag names separated by a space and hit enter

Atovaquone and proguanil hydrochloride: a review of nonclinical studies.
J Travel Med. 1999 May; 6 Suppl 1:S8-12.JT

Abstract

BACKGROUND

Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries.

METHODS

Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride.

RESULTS

Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 microM), and its effectiveness depends on the active metabolite cycloguanil (IC50 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone.

CONCLUSION

Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria.

Authors+Show Affiliations

Systems Biology Unit, Glaxo Wellcome Research & Development, Medicines Research Centre, Stevenage, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

23573546

Citation

Pudney, M, et al. "Atovaquone and Proguanil Hydrochloride: a Review of Nonclinical Studies." Journal of Travel Medicine, vol. 6 Suppl 1, 1999, pp. S8-12.
Pudney M, Gutteridge W, Zeman A, et al. Atovaquone and proguanil hydrochloride: a review of nonclinical studies. J Travel Med. 1999;6 Suppl 1:S8-12.
Pudney, M., Gutteridge, W., Zeman, A., Dickins, M., & Woolley, J. L. (1999). Atovaquone and proguanil hydrochloride: a review of nonclinical studies. Journal of Travel Medicine, 6 Suppl 1, S8-12.
Pudney M, et al. Atovaquone and Proguanil Hydrochloride: a Review of Nonclinical Studies. J Travel Med. 1999;6 Suppl 1:S8-12. PubMed PMID: 23573546.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atovaquone and proguanil hydrochloride: a review of nonclinical studies. AU - Pudney,M, AU - Gutteridge,W, AU - Zeman,A, AU - Dickins,M, AU - Woolley,J L, PY - 2013/4/11/entrez PY - 1999/5/1/pubmed PY - 2013/6/29/medline SP - S8 EP - 12 JF - Journal of travel medicine JO - J Travel Med VL - 6 Suppl 1 N2 - BACKGROUND: Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries. METHODS: Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride. RESULTS: Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 microM), and its effectiveness depends on the active metabolite cycloguanil (IC50 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone. CONCLUSION: Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria. SN - 1195-1982 UR - https://www.unboundmedicine.com/medline/citation/23573546/Atovaquone_and_proguanil_hydrochloride:_a_review_of_nonclinical_studies_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1195-1982&date=1999&volume=6&issue=&spage=S8 DB - PRIME DP - Unbound Medicine ER -