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Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria.^[3]^[4] It is often used together with chloroquine or atovaquone.^[4]^[3] When used with chloroquine the combination will treat mild chloroquine resistant malaria.^[3] It is taken by mouth.^[5]

Side effects include diarrhea, constipation, skin rashes, hair loss, and itchiness.^[3] Because malaria tends to be more severe in pregnancy, the benefit typically outweighs the risk.^[3] If used during pregnancy it should be taken with folate.^[3] It is likely safe for use during breastfeeding.^[3] Proguanil is converted by the liver to its active metabolite, cycloguanil.^[4]

Proguanil has been studied at least since 1945.^[6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[7] The wholesale cost in the developing world is about 0.10 to 0.50 USD per day.^[5] In the United States and Canada it is only available in combination as atovaquone/proguanil.^[8]

Medical uses

Proguanil is used for the prevention and treatment of malaria in both adults and children, particularly in areas where chloroquine-resistant P. falciparum malaria has been reported. It is usually taken in combination with atovaquone, another antimalarial drug.^[9]

It is also effective in the treatment of most other multi-drug resistant forms of P. falciparum; the success rate exceeds 93%.^[10]

Side effects

Proguanil is generally well-tolerated and most people do not experience side effects. However, common side effects include abdominal pain, nausea, headache, and fever. Taking proguanil with food may lessen these side effects.^[11] Proguanil should not be taken by people with severe renal impairment, pregnant women, or women who are breastfeeding children less than 5 kg.^[12] There have also been reports of increased levels of liver enzymes, which may remain high for up to 4 weeks after completion of treatment.^[13]

Mechanism

When used alone, proguanil functions as a prodrug. Its active metabolite, cycloguanil, is an inhibitor of dihydrofolate reductase (DHFR).^[14] Although both mammals and parasites produce DHFR, cycloguanil's inhibitory activity is specific for parasitic DHFR. This enzyme is a critical component of the folic acid cycle. Inhibition of DHFR prevents the parasite from recycling dihydrofolate back to tetrahydrofolate (THF). THF is required for DNA synthesis, amino acid synthesis, and methylation; thus, DHFR inhibition shuts down these processes.^[15]

Proguanil displays synergism when used in combination with the antimalarial atovaquone. This mechanism of action differs from when proguanil was used as a singular agent. In this case, it is not thought to function as a DHFR inhibitor. The addition of proguanil has shown to reduce resistance to atovaquone and increase the ability of atovaquone to trigger a mitochondrial apoptotic cascade.^[16] This is commonly referred to as “collapse of the mitochondrial membrane potential.”^[17] Proguanil lowers the effective concentration of atovaquone needed to increase permeability of the mitochondrial membrane.^[18]

References

^ Mehlhorn, Heinz (2008). Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 388. ISBN 9783540489948. Archived from the original on 2016-12-20.
^ "Malarone (atovaquone/proguanil) Tablets, Pediatric Tablets. Full Prescribing Information" (PDF). GlaxoSmithKline. Research Triangle Park, NC 27709. Archived (PDF) from the original on 20 September 2016. Retrieved 14 July 2016.
^ ^a ^b ^c ^d ^e ^f ^g WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 199, 203, 594. ISBN 9789241547659. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
^ ^a ^b ^c "Atovaquone and Proguanil Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
^ ^a ^b "Proguanil". International Drug Price Indicator Guide. Retrieved 8 December 2016.
^ Nzila, Alexis (2006-06-01). "The past, present and future of antifolates in the treatment of Plasmodium falciparum infection". Journal of Antimicrobial Chemotherapy. 57 (6): 1043–1054. doi:10.1093/jac/dkl104. ISSN 0305-7453. PMID 16617066.
^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
^ "Proguanil". www.medscape.com. Medscape. Archived from the original on 9 November 2016. Retrieved 8 November 2016.
^ "Malaria: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on 2016-11-17. Retrieved 2016-11-16.
^ Boggild, Andrea K.; Parise, Monica E.; Lewis, Linda S.; Kain, Kevin C. (2007-02-01). "Atovaquone-Proguanil: Report from the Cdc Expert Meeting on Malaria Chemoprophylaxis (ii)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. ISSN 0002-9637. PMID 17297027.
^ "Atovaquone And Proguanil (Oral Route) Side Effects - Mayo Clinic". www.mayoclinic.org. Archived from the original on 2016-11-09. Retrieved 2016-11-08.
^ Prevention, CDC - Centers for Disease Control and. "CDC - Malaria - Travelers - Choosing a Drug to Prevent Malaria". www.cdc.gov. Archived from the original on 2016-11-13. Retrieved 2016-11-08.
^ Looareesuwan, S.; Wilairatana, P.; Chalermarut, K.; Rattanapong, Y.; Canfield, C. J.; Hutchinson, D. B. (1999-04-01). "Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand". The American Journal of Tropical Medicine and Hygiene. 60 (4): 526–532. ISSN 0002-9637. PMID 10348224.
^ Pubchem. "proguanil | C11H16ClN5 - PubChem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2016-11-14. Retrieved 2016-11-13.
^ Boggild, Andrea K.; Parise, Monica E.; Lewis, Linda S.; Kain, Kevin C. (2007-02-01). "Atovaquone-Proguanil: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis (ii)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. ISSN 0002-9637. PMID 17297027.
^ Srivastava, Indresh K.; Vaidya, Akhil B. (1999-06-01). "A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil". Antimicrobial Agents and Chemotherapy. 43 (6): 1334–1339. ISSN 0066-4804. PMC 89274 . PMID 10348748.
^ Srivastava, Indresh K.; Rottenberg, Hagai; Vaidya, Akhil B. (1997-02-14). "Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite". Journal of Biological Chemistry. 272 (7): 3961–3966. doi:10.1074/jbc.272.7.3961. ISSN 0021-9258. Archived from the original on 2014-11-19.
^ Thapar, MM; Gupta, S; Spindler, C; Wernsdorfer, WH; Björkman, A (May 2003). "Pharmacodynamic Interactions Among Atovaquone, Proguanil and Cycloguanil against Plasmodium falciparum in vitro". Transactions of the Royal Society of Tropical Medicine and Hygiene. 97 (3): 331–7. doi:10.1016/S0035-9203(03)90162-3. PMID 15228254.

UpToDate Contents

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1. 抗マラリア剤：概要 antimalarial drugs an overview
2. 旅行者におけるマラリア感染の予防 prevention of malaria infection in travelers
3. 抗原虫治療 antiprotozoal therapies
4. 合併症のない熱帯熱マラリアの治療 treatment of uncomplicated falciparum malaria
5. 熱帯熱マラリア以外のマラリアの概要 overview of non falciparum malaria

English Journal

Formation of the diuretic chlorazanil from the antimalarial drug proguanil-Implications for sports drug testing.

Thevis M1, Geyer H2, Thomas A2, Tretzel L2, Bailloux I3, Buisson C3, Lasne F3, Schaefer MS4, Kienbaum P4, Mueller-Stoever I5, Schänzer W2.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2015 Nov 10;115:208-13. doi: 10.1016/j.jpba.2015.07.017. Epub 2015 Jul 22.
Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analyt
PMID 26226108

WITHDRAWN: Drugs for preventing malaria in travellers.

Jacquerioz FA1, Croft AM.
The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2015 Oct 5;10:CD006491. [Epub ahead of print]
BACKGROUND: Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti-mosquito measures and drug prophylaxis. However, antimalaria drugs have adverse effects which are sometimes serious.OBJECTIVES: To compare the effects of currently used antimalaria dru
PMID 26436859

[13-year old girl with fever 6 months after returning from sub-Saharan Africa].

Erhardt J1, Frank M1.
Deutsche medizinische Wochenschrift (1946).Dtsch Med Wochenschr.2015 Oct;140(21):1614. doi: 10.1055/s-0041-103556. Epub 2015 Oct 21.
HISTORY AND ADMISSION FINDINGS: A 13-year-old girl presented with regular fevers, 6 months after a prolonged trip through Africa. The patient reported relapsing fevers at 48 hour intervals. Each febrile episode was followed by pronounced fatigue and a subsequent recovery back to her usual state of h
PMID 26488102

Japanese Journal

Prolonged administration of proguanil induces reproductive toxicity in male rats

Akinsomisoye Olumide Stephen,Raji Yinusa
Journal of toxicological sciences 36(5), 587-599, 2011-10-01
… The toxicity of proguanil was studied on reproductive activities in male rats using in vivo and in vitro methods. … Groups of ten to twelve-week-old rats were administered proguanil (2.9 mg/kg body weight) daily for 5 days and 6 weeks respectively. … Sertoli cells obtained from sixteen to eighteen day-old-rats were cultured and treated with 0.3 μM to 10 μM of proguanil for 5 days after which Sertoli cell viability and nuclei integrity were determined. …
NAID 10029481335

Influence of the Genetic Polymorphisms in the 5' Flanking and Exonic Regions of CYP2C19 on Proguanil Oxidation

SATYANARAYANA Chakradhara Rao Uppugunduri,DEVENDRAN Anichavezhi,JAYARAMAN Muthukumaran,MANNU Jayakanthan,MATHUR Premendu P.,GOPAL Shewade Deepak,RAJAGOPAL Krishnamoorthy,CHANDRASEKARAN Adithan
Drug metabolism and pharmacokinetics 24(6), 537-548, 2009-12-25
NAID 10027119696

Efficacy and safety of atovaquone-proguanil compared with mefloquine in the treatment of nonimmune patients with uncomplicated P. falciparum malaria in Japan

HITANI Akihiro,NAKAMURA Tetsuya,OHTOMO Hiroshi,NAWA Yukifumi,KIMURA Mikio
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 12(5), 277-282, 2006-10-01
NAID 10018348283

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Proguanil
Clinical data
Trade names	Paludrine, others
Synonyms	chlorguanide, chloroguanide
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of; administration	By mouth (tablets)
ATC code	P01BB01 (WHO);
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Protein binding	75%
Metabolism	By liver (CYP2C19)
Metabolites	cycloguanil and 4-chlorophenylbiguanide
Biological half-life	12–21 hours
Identifiers
	IUPAC name 1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine;
CAS Number	500-92-5 ;
PubChem CID	4923;
DrugBank	DB01131 ;
ChemSpider	4754 ;
UNII	S61K3P7B2V;
KEGG	D08428 ;
ChEBI	CHEBI:8455 ;
ChEMBL	CHEMBL1377 ;
ECHA InfoCard	100.007.196
Chemical and physical data
Formula	C11H16ClN5
Molar mass	253.731 g/mol
3D model (JSmol)	Interactive image;
Melting point	129 °C (264 °F)
	SMILES Clc1ccc(NC(=N/C(=N/C(C)C)N)N)cc1 ;
	InChI InChI=1S/C11H16ClN5/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17) ; Key:SSOLNOMRVKKSON-UHFFFAOYSA-N ;
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英: proguanil
商: マラロン配合
関: クロログアニド

[1] Mehlhorn, Heinz (2008). Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 388. ISBN 9783540489948. Archived from the original on 2016-12-20.

[2] "Malarone (atovaquone/proguanil) Tablets, Pediatric Tablets. Full Prescribing Information" (PDF). GlaxoSmithKline. Research Triangle Park, NC 27709. Archived (PDF) from the original on 20 September 2016. Retrieved 14 July 2016.

[WHO2008-3] ^ ^a ^b ^c ^d ^e ^f ^g WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 199, 203, 594. ISBN 9789241547659. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.

[AHFS2016-4] "Atovaquone and Proguanil Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.

[ERC2014-5] "Proguanil". International Drug Price Indicator Guide. Retrieved 8 December 2016.

[6] Nzila, Alexis (2006-06-01). "The past, present and future of antifolates in the treatment of Plasmodium falciparum infection". Journal of Antimicrobial Chemotherapy. 57 (6): 1043–1054. doi:10.1093/jac/dkl104. ISSN 0305-7453. PMID 16617066.

[WHO19th-7] "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.

[8] "Proguanil". www.medscape.com. Medscape. Archived from the original on 9 November 2016. Retrieved 8 November 2016.

[9] "Malaria: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on 2016-11-17. Retrieved 2016-11-16.

[10] Boggild, Andrea K.; Parise, Monica E.; Lewis, Linda S.; Kain, Kevin C. (2007-02-01). "Atovaquone-Proguanil: Report from the Cdc Expert Meeting on Malaria Chemoprophylaxis (ii)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. ISSN 0002-9637. PMID 17297027.

[11] "Atovaquone And Proguanil (Oral Route) Side Effects - Mayo Clinic". www.mayoclinic.org. Archived from the original on 2016-11-09. Retrieved 2016-11-08.

[12] Prevention, CDC - Centers for Disease Control and. "CDC - Malaria - Travelers - Choosing a Drug to Prevent Malaria". www.cdc.gov. Archived from the original on 2016-11-13. Retrieved 2016-11-08.

[13] Looareesuwan, S.; Wilairatana, P.; Chalermarut, K.; Rattanapong, Y.; Canfield, C. J.; Hutchinson, D. B. (1999-04-01). "Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand". The American Journal of Tropical Medicine and Hygiene. 60 (4): 526–532. ISSN 0002-9637. PMID 10348224.

[14] Pubchem. "proguanil | C11H16ClN5 - PubChem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2016-11-14. Retrieved 2016-11-13.

[15] Boggild, Andrea K.; Parise, Monica E.; Lewis, Linda S.; Kain, Kevin C. (2007-02-01). "Atovaquone-Proguanil: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis (ii)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. ISSN 0002-9637. PMID 17297027.

[16] Srivastava, Indresh K.; Vaidya, Akhil B. (1999-06-01). "A Mechanism for the Synergistic Antimalarial Action of Atovaquone and Proguanil". Antimicrobial Agents and Chemotherapy. 43 (6): 1334–1339. ISSN 0066-4804. PMC 89274 . PMID 10348748.

[17] Srivastava, Indresh K.; Rottenberg, Hagai; Vaidya, Akhil B. (1997-02-14). "Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite". Journal of Biological Chemistry. 272 (7): 3961–3966. doi:10.1074/jbc.272.7.3961. ISSN 0021-9258. Archived from the original on 2014-11-19.

[18] Thapar, MM; Gupta, S; Spindler, C; Wernsdorfer, WH; Björkman, A (May 2003). "Pharmacodynamic Interactions Among Atovaquone, Proguanil and Cycloguanil against Plasmodium falciparum in vitro". Transactions of the Royal Society of Tropical Medicine and Hygiene. 97 (3): 331–7. doi:10.1016/S0035-9203(03)90162-3. PMID 15228254.

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