Artemisinin Derivatives

Artemisinin Derivatives

Drug Nomenclature

Date of monograph revision: 10-Jul-1996; 01-Jun-1998; 24-Aug-1999; 30-Nov-2001; 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006

Artemether

Drug Nomenclature

Date of monograph revision: 10-Jul-1996; 01-Jun-1998; 24-Aug-1999; 30-Nov-2001; 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006
Synonyms: o-Methyldihydroartemisinin; Artemeetteri; Artemeter; Artemetherum; Dihydroartemisinin Methyl Ether; Dihydroqinghaosu Methyl Ether; SM-224
BAN: Artemether
INN: Artemether [rINN (en)]
INN: Artemetero [rINN (es)]
INN: Artéméther [rINN (fr)]
INN: Artemetherum [rINN (la)]
INN: Артеметер [rINN (ru)]
Chemical name: (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin
Molecular formula: C16H26O5 =298.4
CAS: 71963-77-4
ATC code: P01BE02
Chemical Structure of Artemether

Chemical Structure of Artemether

Pharmacopoeias:

In Chin. and Int.

Artemisinin

Drug Nomenclature

Date of monograph revision: 10-Jul-1996; 01-Jun-1998; 24-Aug-1999; 30-Nov-2001; 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006
Synonyms: Arteannuin; Artemisinina; Artemisinine; Artemisininum; Huanghuahaosu; Qinghaosu
INN: Artemisinin [rINN (en)]
INN: Artemisinina [rINN (es)]
INN: Artémisinine [rINN (fr)]
INN: Artemisininum [rINN (la)]
INN: Артемизинин [rINN (ru)]
Chemical name: (3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one
Molecular formula: C15H22O5 =282.3
CAS: 63968-64-9
ATC code: P01BE01
Chemical Structure of Artemisinin

Chemical Structure of Artemisinin

Pharmacopoeias:

In Chin., Int., and Viet.

Artemotil

Drug Nomenclature

Date of monograph revision: 11-Jul-1996; 01-Jun-1998; 24-Aug-1999; 30-Nov-2001; 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006
Synonyms: Arteether; Artemotilo; Artemotilum; Dihydroartemisinin Ethyl Ether; Dihydroqinghaosu Ethyl Ether; SM-227
INN: Artemotil [rINN (en)]
INN: Artemotilo [rINN (es)]
INN: Artémotil [rINN (fr)]
INN: Artemotilum [rINN (la)]
INN: Артемотил [rINN (ru)]
Chemical name: (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-ethoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin
Molecular formula: C17H28O5 =312.4
CAS: 75887-54-6
ATC code: P01BE04
Chemical Structure of Artemotil

Chemical Structure of Artemotil

Pharmacopoeias:

In Int.

Artesunate

Drug Nomenclature

Date of monograph revision: 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006
Synonyms: Artesunato; Artesunatum
USAN: Artesunate
INN: Artesunate [rINN (en)]
INN: Artesunato [rINN (es)]
INN: Artésunate [rINN (fr)]
INN: Artesunatum [rINN (la)]
INN: Артезунат [rINN (ru)]
Chemical name: (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano-[4,3-j]-1,2-benzodioxepin-10-ol hydrogen succinate
Molecular formula: C19H28O8 =384.4
CAS: 83507-69-1; 88495-63-0; 182824-33-5
ATC code: P01BE03
Chemical Structure of Artesunate

Chemical Structure of Artesunate

Pharmacopoeias:

In Int. and Viet.

Sodium Artesunate

Drug Nomenclature

Date of monograph revision: 10-Jul-1996; 01-Jun-1998; 24-Aug-1999; 30-Nov-2001; 19-Apr-2004; 29-Apr-2004; 05-Oct-2004; 28-Jul-2006
Synonyms: Artesunato sódico; Dihydroartemisinin Hemisuccinate Sodium; Dihydroqinghaosu Hemisuccinate Sodium; SM-804
INN: Sodium Artesunate [rINNM (en)]
INN: Artesunato sódico [rINNM (es)]
INN: Artésunate de Sodium [rINNM (fr)]
INN: Natrii Artesunatum [rINNM (la)]
INN: Натрий Артезунат [rINNM (ru)]
Chemical name: (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano-[4,3-j]-1,2-benzodioxepin-10-ol hydrogen succinate sodium
Molecular formula: C19H27O8Na =406.4

Adverse Effects and Precautions

Artemisinin and its derivatives appear to be generally well tolerated, although there have been reports of mild gastrointestinal disturbance (including nausea, vomiting, diarrhoea, and abdominal pain), dizziness, headache, tinnitus, neutropenia, elevated liver enzyme values, and ECG abnormalities including prolongation of the QT interval.

Evidence of severe neurotoxicity has been seen in animals given high doses.

General references to adverse effects associated with artemisinin derivatives.

  1. 1. Price R, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999; 60: 547–55. PubMed

Effects on the blood.

For a report of severe haemolytic anaemia occurring in patient after taking artemether-lumefantrine, see Go to Effects on the blood..

Effects on the heart.

Bradycardia was reported in 10 of 34 patients who received artemether orally for 4 days.1

  1. 1. Karbwang J, et al. Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria. Lancet 1992; 340: 1245–8. PubMed

Effects on the nervous system.

Neurotoxicity has been reported in animals given artemotil or artemether.1 An in-vitro study2 has shown that dihydroartemisinin, the metabolite common to all artemisinin derivatives currently used, is neurotoxic. There has been a report3 of acute cerebellar dysfunction manifesting as ataxia and slurred speech in a patient who took a 5-day course of artesunate by mouth.

  1. 1. Brewer TG, et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 1994; 88 (suppl 1): 33–6. PubMed
  2. 2. Wesche DL, et al. Neurotoxicity of artemisinin analogs in vitro. Antimicrob Agents Chemother 1994; 38: 1813–19. PubMed
  3. 3. Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997; 336: 1328. PubMed

Pregnancy.

Artesunate or artemether was used to treat multidrug-resistant falciparum malaria in 83 pregnant women in Thailand; of 73 pregnancies resulting in live births none showed evidence of any congenital abnormality.1 Sixteen of the women were given artesunate during the first trimester; of these, 12 had normal deliveries, 1 was lost to study, and 3 had spontaneous abortions.

No undue adverse effects on the neonates occurred in a study2 involving 45 women treated for multidrug-resistant malaria during their second or third trimester of pregnancy with either artemether or artemether plus mefloquine.

WHO3 recommends that, where available, artesunate is the first option, and artemether is the second, for the parenteral treatment of severe falciparum malaria during the second and third trimesters. In the first trimester, until more evidence becomes available, artesunate may be considered as an option.

  1. 1. McGready R, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998; 92: 430–3. PubMed
  2. 2. Sowunmi A, et al. Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine[sic]-pyrimethamine-resistant falciparum malaria during pregnancy. J Obstet Gynaecol 1998; 18: 322–7.
  3. 3. . WHO. Guidelines for the treatment of malaria. Geneva: WHO, 2006. Also available at: online (accessed 21/06/06)

Interactions

Use of artemisinin derivatives with drugs that prolong the QT interval should be avoided if possible; caution is advised when artemisinin derivatives are given with other antimalarials that have this propensity.

Grapefruit juice.

The oral bioavailability of artemether may be increased if taken with grapefruit juice.

  1. 1. van Agtmael MA, et al. The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther 1999; 66: 408–14. PubMed

Pharmacokinetics

Peak plasma concentrations have been achieved in about 3 hours after oral doses of artemether, in about 6 hours after intramuscular injection of artemether, and in about 11 hours after rectal artemisinin. Artemisinin and its derivatives are all rapidly hydrolysed to the active metabolite dihydroartemisinin. Reported elimination half-lives have been about 45 minutes after intravenous doses of artesunate, about 4 hours after rectal artemisinin, and about 4 to 11 hours after intramuscular or oral artemether. There are very few published data on the pharmacokinetics of artemotil, but its elimination half-life appears to be longer than that of artemether.

Reviews.

  1. 1. White NJ, et al. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 1999; 37: 105–25. PubMed
  2. 2. Navaratnam V, et al. Pharmacokinetics of artemisinin-type compounds. Clin Pharmacokinet 2000; 39: 255–70. PubMed

Uses and Administration

Artemisinin is a sesquiterpene lactone isolated from Artemisia annua, a herb that has traditionally been used in China for the treatment of malaria. It is a potent and rapidly acting blood schizontocide active against Plasmodium vivax and against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.

Artemisinin has been given orally or rectally in the treatment of malaria; regimens were often empirical with typical oral doses ranging from 10 to 25 mg/kg daily over a variable number of days.? However, it has largely been replaced in practice by its derivatives artemether and artesunate.

The following doses are recommended by WHO for the treatment of uncomplicated falciparum malaria.

Artesunate, when used with other antimalarials (amodiaquine, mefloquine, or pyrimethamine-sulfadoxine), is given orally to adults and children in a dose of 4 mg/kg daily, as a single dose, for 3 days.

Artemether is given orally with lumefantrine; 6 doses in total are given, the first at diagnosis and repeated after 8, 24, 36, 48, and 60 hours. Each dose is:

adults and children weighing over 34 kg, artemether 80 mg with lumefantrine 480 mg

children 5 to 14 kg, artemether 20 mg with lumefantrine 120 mg

children 15 to 24 kg, artemether 40 mg with lumefantrine 240 mg

children 25 to 34 kg, artemether 60 mg with lumefantrine 360 mg

For parenteral use in severe malaria, WHO recommends:

for adults or children, artesunate 2.4 mg/kg intravenously or intramuscularly, repeated after 12 and 24 hours and then once daily thereafter

as an alternative in children, artemether 3.2 mg/kg intramuscularly, followed by 1.6 mg/kg daily thereafter. For both drugs the patient should be transferred to oral therapy as soon as possible

Other derivatives of artemisinin, such as artemotil, are under investigation or commercial development (see Administration of Artemisinin Derivatives, Go to Administration of artemisinin derivatives.).

Reviews.

  1. 1. McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 1999 (accessed 17/05/05). PubMed
  2. 2. McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2000 (accessed 17/05/05). PubMed
  3. 3. Omari AAA, et al. Artemether-lumefantrine for treating uncomplicated falciparum malaria. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 2003 (accessed 17/05/05). PubMed
  4. 4. Olliaro PL, Taylor WR. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: a review. J Postgrad Med 2004; 50: 40–4. PubMed
  5. 5. Ashley EA, White NJ. Artemisinin-based combinations. Curr Opin Infect Dis 2005; 18: 531–6. PubMed
  6. 6. Bukirwa H, Critchley J. Sulfadoxine-pyrimethamine plus artesunate versus sulfadoxine-pyrimethamine plus amodiaquine for treating uncomplicated malaria. Available in The Cochrane Database of Systematic Reviews; Issue 1. Chichester: John Wiley; 2006 (accessed 18/07/06). PubMed

Administration of artemisinin derivatives.

To overcome the poor solubility of artemisinin in water a number of dosage forms and routes have been tried. Also, several more potent derivatives with more suitable pharmaceutical properties have been developed, notably the methyl ether derivative, artemether, and the ethyl ether derivative, artemotil, which are more lipid soluble; the sodium salt of the hemisuccinate ester, sodium artesunate, which is soluble in water but appears to have poor stability in aqueous solutions; and sodium artelinate, which is both soluble and stable in water. Other derivatives that have been studied include arteflene.

Several preparations of artemisinin derivatives are available either commercially or for studies organised by bodies such as WHO. These include oral formulations of artemether, artesunate, artemisinin itself, and dihydroartemisinin; intramuscular formulations of artemotil, artemether, and artesunate; intravenous formulations of artelinic acid and artesunate; and suppositories of artemisinin, artesunate, and dihydroartemisinin.

Malaria.

The overall management of malaria and the place of artemisinin derivatives in current recommendations are discussed on Go to Malaria. In an attempt to delay the development of resistance to these compounds, WHO at one time recommended that their use be restricted to the treatment of malaria in areas of documented multidrug resistance and that they should not be used at all for prophylaxis. However, the development of resistance to conventional treatment has now led WHO to recommend the use in such circumstances of combination therapies containing artemisinin derivatives (artemisinin-based combination therapies, also known as ACTs). The following combination therapies are recommended:

artemether-lumefantrine

artesunate plus amodiaquine

artesunate plus pyrimethamine-sulfadoxine (Fansidar)

artesunate plus mefloquine

Artemether-lumefantrine is now also recommended in the UK as an alternative to quinine-based therapy for uncomplicated falciparum malaria.

In acute uncomplicated malaria artemisinin derivatives are usually given by mouth. Those used have been artemisinin, artemether, or artesunate. Parenteral therapy is generally necessary in severe malaria and WHO recommends1 artesunate intravenously or intramuscularly in adults and children, or artemether intramuscularly in children, as alternatives to quinine for severe malaria. Rectal artesunate has been successful and is recommended by WHO1 if parenteral therapy is not possible.

  1. 1. . WHO. Guidelines for the treatment of malaria. Geneva: WHO, 2006. Also available at: online (accessed 21/06/06)

Schistosomiasis.

Findings of a reduced intensity of Schistosoma mansoni infection in patients treated with sodium artesunate for malaria1 prompted further investigation into the use of artemisinin derivatives for the control of schistosomiasis (Go to Schistosomiasis). A double-blind placebo-controlled study2 in children negative for S. mansoni found a significantly lower incidence of infection in those given artemether orally. There was also a significant reduction in the prevalence of Plasmodium falciparum infection. A number of studies in China have confirmed the benefits of artemether or artesunate, often with praziquantel, against S. japonicum.3

  1. 1. De Clercq D, et al. Efficacy of artesunate against Schistosoma mansoni infections in Richard Toll, Senegal. Trans R Soc Trop Med Hyg 2000; 94: 90–1. PubMed
  2. 2. Utzinger J, et al. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet 2000; 355: 1320–5. PubMed
  3. 3. Xiao S-H. Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins. Acta Trop 2005; 96: 153–67. PubMed

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Belgium: Arinate; Artesiane; Brazil: Paluther; Plasmotrim; France: Paluther¤; India: Betamotil; E Mal; Falcigo; Falcinil; Larinate; Larither; Mosether; Rapither-AB; Thailand: Plasmotrim;

Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Australia: Riamet; Austria: Riamet; Belgium: Amonate; Co-Arinate; Co-Artesiane; Czech Republic: Riamet; France: Riamet; Germany: Riamet; Greece: Riamet; Hong Kong: Riamet¤; India: Artemal; Larimal; Norway: Riamet; South Africa: Coartem; Sweden: Riamet; Switzerland: Riamet; Thailand: Coartem; United Kingdom: Riamet;



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