Proguanil

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Proguanil
Proguanil.svg
Proguanil molecule spacefill.png
Clinical data
Trade names Paludrine, others
Other nameschlorguanide, chloroguanide [1]
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 75%
Metabolism By liver (CYP2C19)
Metabolites cycloguanil and 4-chlorophenylbiguanide
Elimination half-life 12–21 hours [2]
Identifiers
  • 1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.007.196 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H16ClN5
Molar mass 253.73 g·mol−1
3D model (JSmol)
Melting point 129 °C (264 °F)
  • Clc1ccc(NC(=N/C(=N/C(C)C)N)N)cc1
  • 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) Yes check.svgY
  • Key:SSOLNOMRVKKSON-UHFFFAOYSA-N Yes check.svgY
   (verify)

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. [4]

Contents

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]

It is on the World Health Organization's List of Essential Medicines. [5] In the United States and Canada it is only available in combination as atovaquone/proguanil. [6]

History

When the Japanese attack on Pearl Harbor started World War II in the Pacific, the US became very interested in antimalarial medications and funded a large joint US-UK program to find new non-toxic and easy to produce drugs of the type. [7] It was joined by a team led by Frank Rose at the Medical Chemicals Section of Imperial Chemical Industries (later Pharmaceuticals Division, which ended up demerged into Zeneca) at Blackley, which earlier developed a way to manufacture mepacrine, an antimalarial made exclusively in Germany before the war. [7]

Rose and his colleague Frank Curd decided to concentrate on pyrimidines as relatively simple to synthetise, even though the Advisory Panel recommended against that because most antimalarials by then were either quinolines or acridines. Checking prospective 2,4-diaminopyridine derivatives with a basic side chain and a benzenoid moiety one after another, they noticed a geometric pattern in the effective analogs and wondered if they could reproduce their interesting biologic activity with molecules even simpler, without the pyrimidine ring, and tried biguanides (then called diguanides) with which Rose was familiar due to his earlier sulphonamide research to great effect. [8] The drug was introduced by ICI in 1945.

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]

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.

<span class="mw-page-title-main">Mefloquine</span> Pharmaceutical drug

Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<span class="mw-page-title-main">Artemisinin</span> Group of drugs used against malaria

Artemisinin and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant.

<span class="mw-page-title-main">Travel medicine</span> Branch of medicine

Travel medicine or emporiatrics is the branch of medicine that deals with the prevention and management of health problems of international travelers.

<span class="mw-page-title-main">Artesunate</span> Chemical compound

Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of malaria. Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.

<span class="mw-page-title-main">Chloroquine</span> Medication used to treat malaria

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and the NIH does not recommend its use for this purpose. It is taken by mouth.

<span class="mw-page-title-main">Primaquine</span> Pharmaceutical drug

Primaquine is a medication used to treat and prevent malaria and to treat Pneumocystis pneumonia. Specifically it is used for malaria due to Plasmodium vivax and Plasmodium ovale along with other medications and for prevention if other options cannot be used. It is an alternative treatment for Pneumocystis pneumonia together with clindamycin. It is taken by mouth.

<i>Plasmodium vivax</i> Species of single-celled organism

Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than Plasmodium falciparum, the deadliest of the five human malaria parasites, P. vivax malaria infections can lead to severe disease and death, often due to splenomegaly. P. vivax is carried by the female Anopheles mosquito; the males do not bite.

<i>Plasmodium ovale</i> Species of single-celled organism

Plasmodium ovale is a species of parasitic protozoon that causes tertian malaria in humans. It is one of several species of Plasmodium parasites that infect humans, including Plasmodium falciparum and Plasmodium vivax which are responsible for most cases of malaria in the world. P. ovale is rare compared to these two parasites, and substantially less dangerous than P. falciparum.

<span class="mw-page-title-main">Atovaquone</span> Antimicrobial and antiprotozoan drug

Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP).

Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by Plasmodium falciparum that is not treatable with chloroquine. It is not typically used to prevent malaria. It is taken by mouth.

Malaria prophylaxis is the preventive treatment of malaria. Several malaria vaccines are under development.

<span class="mw-page-title-main">Amodiaquine</span> Chemical compound

Amodiaquine (ADQ) is a medication used to treat malaria, including Plasmodium falciparum malaria when uncomplicated. It is recommended to be given with artesunate to reduce the risk of resistance. Due to the risk of rare but serious side effects, it is not generally recommended to prevent malaria. Though, the World Health Organization (WHO) in 2013 recommended use for seasonal preventive in children at high risk in combination with sulfadoxine and pyrimethamine.

<span class="mw-page-title-main">Cycloguanil</span> Chemical compound

Cycloguanil is a dihydrofolate reductase inhibitor, and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil. However, more recent work has indicated that, while proguanil is synergistic with the drug atovaquone, cycloguanil is in fact antagonistic to the effects of atovaquone, suggesting that, unlike cycloguanil, proguanil may have an alternative mechanism of antimalarial action besides dihydrofolate reductase inhibition.

<span class="mw-page-title-main">History of malaria</span> History of malaria infections

The history of malaria extends from its prehistoric origin as a zoonotic disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak malaria infested every continent except Antarctica. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the Plasmodium parasites which cause it, research attention has focused on their biology as well as that of the mosquitoes which transmit the parasites.

<span class="mw-page-title-main">Dihydrofolate reductase inhibitor</span> Cellular enzyme inhibitor

A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.

<span class="mw-page-title-main">Mass drug administration</span>

The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA) or mass dispensing.

<span class="mw-page-title-main">Piperaquine</span> Chemical compound

Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement for the structurally similar antimalarial drug chloroquine. Due to widespread parasite resistance to piperaquine, the drug fell out of use as a monotherapy, and is instead used as a partner drug for artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host heme.

Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommended for severe or complicated malaria. It is taken by mouth.

References

  1. ↑ Mehlhorn H (2008). "Proguanil". Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 388. ISBN   9783540489948. Archived from the original on 20 December 2016.
  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.
  3. 1 2 3 4 5 6 7 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 199, 203. hdl:10665/44053. ISBN   9789241547659.
  4. 1 2 3 4 "Atovaquone and Proguanil Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ↑ "Proguanil". www.medscape.com. Medscape. Archived from the original on 9 November 2016. Retrieved 8 November 2016.
  7. 1 2 Quirke VM (2004). "War and Change in the Pharmaceutical Industry: A Comparative Study of Britain and France in the Twentieth Century". Entreprises et Histoire. 36 (2): 64. doi:10.3917/eh.036.0064.
  8. ↑ Suckling CW, Langley BW (1990). "Francis Leslie Rose: 27 June 1909-3 March 1988". Biographical Memoirs of Fellows of the Royal Society. Royal Society (Great Britain). 36: 491–524 (503-505). doi:10.1098/rsbm.1990.0041. PMID   11616178. S2CID   40302178.
  9. ↑ "Malaria". MedlinePlus Medical Encyclopedia. U.S. National Library of Medicine. Archived from the original on 17 November 2016. Retrieved 16 November 2016.
  10. ↑ Boggild AK, Parise ME, Lewis LS, Kain KC (February 2007). "Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. doi: 10.4269/ajtmh.2007.76.208 . PMID   17297027.
  11. ↑ "Atovaquone And Proguanil (Oral Route) Side Effects". Mayo Clinic. Archived from the original on 9 November 2016. Retrieved 8 November 2016.
  12. ↑ "CDC - Malaria - Travelers - Choosing a Drug to Prevent Malaria". U.S. Centers for Disease Control and Prevention (CDC). Archived from the original on 13 November 2016. Retrieved 8 November 2016.
  13. ↑ Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB (April 1999). "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. doi:10.4269/ajtmh.1999.60.526. PMID   10348224. S2CID   32365159.
  14. ↑ "Proguanil | C11H16ClN5". PubChem. U.S. National Library of Medine. Archived from the original on 14 November 2016. Retrieved 13 November 2016.
  15. ↑ Boggild AK, Parise ME, Lewis LS, Kain KC (February 2007). "Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II)". The American Journal of Tropical Medicine and Hygiene. 76 (2): 208–223. doi: 10.4269/ajtmh.2007.76.208 . PMID   17297027.
  16. ↑ Srivastava IK, Vaidya AB (June 1999). "A mechanism for the synergistic antimalarial action of atovaquone and proguanil". Antimicrobial Agents and Chemotherapy. 43 (6): 1334–1339. doi:10.1128/AAC.43.6.1334. PMC   89274 . PMID   10348748.
  17. ↑ Srivastava IK, Rottenberg H, Vaidya AB (February 1997). "Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite". The Journal of Biological Chemistry. 272 (7): 3961–3966. doi: 10.1074/jbc.272.7.3961 . PMID   9020100.
  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): 331–337. doi:10.1016/S0035-9203(03)90162-3. PMID   15228254.
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