Sweet Wormwood

Scientific Name(s): Artemisia annua L. Family: Asteraceae (daisies)

Common Name(s): Artemether , artemisinin , artemotil , artesunate , quinghao (Chinese, meaning “from the green herb”) , sweet annie , sweet wormwood , wormweed 1 , 2

Uses

Review of the medical literature supports the clinical efficacy of artemisinin and its derivatives against all forms of human malaria, particularly Plasmodium falciparum . Other reported pharmacological activities include cytotoxicity against cancer cells, and antibacterial and antifungal activity.

Dosing

Clinical trial and World Health Organization (WHO) documentation include oral and intravenous dosage forms of artesunate. Parenteral preparations are available for oil-soluble artemether and the newly marketed artemotil. Numerous dosage regimens are available, but WHO recently approved riamet ( Coartem ), lumefantrine 120 mg combined with artemether 20 mg. Treatment includes administering 4 tablets initially, repeating dosage in 8 hours, and then taking twice daily for the next 2 days. The combination has proven to be effective, with reported cure rates up to 98%.

Contraindications

Avoid use in women during first trimester of pregnancy because of potential teratogenicity.

Pregnancy/Lactation

Avoid use. Artemisinin derivatives, in particular artemether, have a toxic effect on embryos, but no teratogenicity was described in animal studies in mice, rats, or rabbits. Thus, teratogenicity potential may be limited to early pregnancy.

Interactions

Clinically important effects may occur in patients because of the potent inhibition of cytochrome P-450 1A2 (CYP1A2) enzyme by artemisinin. Caution may be warranted in diabetic patients because some artemether trial patients developed hypoglycemia. Clinical trial data document prolongation of the QT interval in patients treated with artesenate and artemether, which may increase the risk of serious arrhythmias in patients receiving other drugs that prolong the QT interval. Grapefruit juice may increase the bioavailability of artemether.

Adverse Reactions

Clinical trial data documents GI complaints such as abdominal pain, diarrhea, nausea, and vomiting. Pruritus, urticaria, and rash have been reported as well as pain and abscess development at the injection site. Cardiovascular changes include bradycardia and prolongation of the QT interval. Metabolic changes include hypoglycemia.

Toxicology

The risk of cumulative neurotoxicity may prohibit the prophylactic use of artemisinin-based drugs.

Botany

A. annua belongs to the Asteraceae family and is an annual herb native to China, commonly found in the northern parts of the Chahar and Suiyan provinces as part of the natural vegetation. However, the plant now grows in several countries, including Argentina, Australia, Bulgaria, France, Hungary, Italy, Spain, and the United States. The herb's dissected leaves measure 2 to 5 cm in length. It is single-stemmed and has alternate branches growing more than 2 m in height. 1 , 2

History

The herb A. annua has been used medicinally to treat fevers for more than 2,000 years and to treat malaria for more than 1,000 years in China. Quinghao, the Chinese term for the plant, means “from the green herb.” The current edition of the Pharmacopoeia of the People's Republic of China documents the therapeutic use of A. annua for treating fevers and malaria. The herb is prepared with hot water according to traditional Chinese medicine. 1 , 2

The earliest record of the herb's clinical use dates back at least 2,000 years to the Wu Shi Er Bing Fang (Prescriptions for Fifty-two Diseases) , which was unearthed from the Ma Wang Dui tomb at Changsha, Hunan in 1973. In the 4th century, the medicinal use of the herb for fevers was described in Chinese Handbook of Prescriptions for Emergency Treatments . 1

Artemisinin, the most studied derivative, and its semisynthetic derivatives, arteether, artemether, and artesunate, have been clinically evaluated and are the only antimalarial drugs to which clinical resistance has never been documented. Artemisinin was isolated from A. annua in 1972, and its structure was elucidated in 1979. In 2004, the Roll Back Malaria Partnership ( http://www.rbm.who.int ) issued a statement in response to antimalarial drug resistance, recommending that treatment policies for falciparum malaria in all countries experiencing resistance to monotherapies should be combination therapies, preferably those containing an artemisinin derivative. 3 , 4 , 5

Chemistry

Numerous and extensive phytochemical investigations have been conducted on the herb. In general, most studies examine the sesquiterpine artemisinin and its derivatives, arteether, artemether, artesunate, and dihydroartemisinin. Only selected studies will be discussed from the large amount of literature.

Some 38 amorphane and cadinane sesquiterpenes have been isolated from A. annua . Most of the medicinal components of the plant are found in the leaves, stems, flowers, and seeds. The sesquiterpene trioxane lactone, artemisinin, which contains a peroxide bridge essential for its medicinal activity, is the main active compound in A. annua . Dihydroartemisinin is the reduced form and active metabolite of artemisinin. Artesunate is a water-soluble hemisuccinate derivative of artemisinin. Artemether is a lipid-soluble methyl ether derivative of artemisinin and is more active than artemisinin. Arteether is a lipid-soluble ethyl ether derivative of dihydroartemisinin. Some other important artemisinin derivatives include alpha-artelinic acid, arteanniun B, and 4-(P-Substituted Phenyl)-4(R or S)-(10 [alpha or beta]-dihydroartemisininoxy) butyric acids, which are dihydroartemisinin derivatives, as well as arteflene (a synthetic derivative) and semisynthetic artemisinin trioxanes (C-10 carbon-substituted and 10 deoxoartemisinin compounds). 1 , 6 , 7 , 8

The highest concentration of artemisinin is found in its leaves prior to flowering. Artemisinin concentrations from wild Artemisia range from 0.01% to 0.5% (w/w). An ethnopharmacology study showed that 40% of artemisinin may be extracted from the aerial parts of the plant by simple tea preparation methods. 4 , 9

Antiviral activity is associated with the sterols sitosterol and stigmaterol of A. annua . The plant's essential oil is composed of linalool, 1,8-cineol, p-cymene, thujone, and camphor. Camphor stimulates the CNS, while the other essential oils produce depression, reduce spontaneous activity, and increase the hypnotic action of pentobarbital. The lipids and essential oils also have been used in cosmetics and perfumes for skin prophylaxis and to treat inflammation. 10 , 11 , 12

In addition, 17 methoxylated flavones and 4 coumarins have been found in the plant. Flavones, such as casticin, chrysoplenetin, chrysosplenol-D, and cirsilineol in A. annua are thought to enhance the antimalarial activity of artemisinin. 13

Uses and Pharmacology

The clinical efficacy of artemisinin and its derivatives against all forms of human malaria, particularly Plasmodium falciparum , have been proven. Hundreds of studies have been published, most from Asia and Africa, but only selected investigations on this efficacy will be discussed, including use against uncomplicated and complicated malaria. Pharmacoeconomic studies support the cost-effectiveness of artemisinin-based combinations in combating malaria in developing countries. 14

Other reported pharmacological activity includes cytotoxic activity against cancer cells, the essential oil inhibition of the growth of the gram-positive bacterium Enterococcus hirae , and growth inhibition of several phytopathogenic fungi by extracts. 15 , 16

Malaria

Artemisinin and its derivatives are toxic to the malarial parasite at nanomolar concentrations, causing specific membrane structural changes in the erythrocyte stage that kill the parasite. In general, the mechanism of action involves 2 steps: activation followed by alkylation. Iron activates artemisinin into a free radical through an iron-mediated cleavage. The second step, alkylation, involves the formation of covalent bonds between the artemisinin-derived free radicals and the malarial proteins. 1 , 2 , 6 , 17

Cerebral malaria
Clinical data

A randomized, unblinded trial examined the efficacy of intramuscular (IM) artemether (3.2 mg/kg loading dose on day 1, followed by 1.6 mg/kg on days 2 through 4) or quinine (20 mg/kg loading dose on day 1, followed by 10 mg/kg every 12 hours for 4 days) in 576 children between 1 and 9 years of age with cerebral malaria. Primary end points of the study were mortality and residual neurologic sequelae during the dry season of the illness. Secondary end points were clearance rates of parasites and fever, time to recovery from coma, and neurologic sequelae at discharge and 1 month after admission. The mortality rate was 20.5% for artemether and 21.5% for quinine. Residual neurologic sequelae at approximately 5 months were 3.3% for artemether and 5.3% for quinine. Total clearance time of the parasite was 48 hours in the artemether group and 60 hours in the quinine group ( P < 0.001). Resolution of fever was 30 hours for artemether-treated patients and 33 hours for quinine-treated patients. Time to recovery from coma was 26 hours in the artemether group and 20 hours in the quinine group ( P  = 0.046). At the time of discharge, neurologic sequelae were present in 21% for artemether-treated patients and 25% for quinine-treated patients, and at 1 month 8% and 10%, respectively. Reported adverse reactions included abscess development by 1 patient in the artemether group and 5 patients in the quinine group, and 1 urticarial rash in the quinine group. 18

Severe malaria
Clinical data

One open, paired, randomized trial examined the efficacy of artemether versus chloroquine in treating moderate and severe malaria. Thirty children (2 to 12 years of age) with moderate malaria received either IM artemether (4 mg/kg loading dose, then 2 mg/kg every 24 hours) or IM chloroquine (3.5 mg/kg every 4 hours). Primary end points included fever and parasite clearance times. Fever clearance time was 19.3 hours for artemether and 10.7 hours for chloroquine; parasite clearance time was 36.7 hours for artemether and 48.4 hours for chloroquine. In the second part of the study, 43 children with severe malaria received the same dosage regimen of artemether or quinine. Fever clearance time was 30 hours for both treatment groups. Parasite clearance time was 48 hours for artemether and 54 hours for chloroquine. Coma resolution time was 16 hours for artemether and 18 hours for chloroquine. 19

A randomized, double-blind study of 560 adults examined the efficacy of artemether versus quinine in treating severe malaria. The dosage regimens were for a minimum of 72 hours: 276 patients receiving a loading dose of IM artemether 4 mg/kg followed by 2 mg/kg every 8 hours and 284 patients receiving IM quinine 20 mg/kg followed by 10 mg/kg every 8 hours. Primary end points included fever and parasite clearance rates and recovery from coma. Fever resolution time was 127 hours for artemether and 90 hours for quinine. Parasite clearance time was 72 hours for artemether and 90 hours for quinine. Recovery from coma was 66 hours for artemether and 48 hours for quinine. Adverse effects included culture negative pyuria in the artemether group and hypoglycemia for the quinine group. The overall mortality rate was 15%, and there was no significant difference in mortality between groups. 20

According to the results from a study conducted in Thailand, artemether and artesunate may be effective in treating multidrug-resistant malaria. One hundred twenty men were randomized to receive either a single oral dose of artemether 300 mg followed by an oral dose of mefloquine 750 mg at 24 hours and 500 mg at 30 hours or a single oral dose of artesunate 300 mg followed by the same dosage regimen of mefloquine. Outcome measures included fever and parasite clearance rates, and overall cure rate. Within 24 hours, fever clearance was 62% for the artemether-treated patients versus 77% for artesunate-treated patients. Within 24 hours, parasite clearance was 91% for the artemether-treated patients versus 93% for the artesunate-treated patients. The cure rates were 98% for the artemether group and 97% for the artesunate group. Adverse reactions were similar for both therapeutic regimens and included loss of appetite, nausea, and vomiting. 21

Uncomplicated malaria
Clinical data

A randomized trial compared the efficacy of oral artemether and oral mefloquine in 46 adult men (15 to 50 years of age) diagnosed with acute uncomplicated malaria. Dosage regimens involved 12 patients receiving mefloquine (1,250 mg total daily dose) and 34 patients receiving artemether (700 mg total daily dose) for 5 days. Because the cure rate of mefloquine is well documented, more patients were randomized to the artemether group. Primary trial end points included fever and parasite clearance times and cure rate. Fever clearance time was 30 hours for artemether and 27 hours for mefloquine. Mean parasite clearance time was 34 hours for artemether and 54 hours for mefloquine. Cure rate at 28 days was 97% for artemether and 73% for mefloquine. Adverse reactions were similar for the 2 therapeutic regimens and included abdominal pain, bradycardia, diarrhea, dizziness, and nausea. 22

A randomized, double-blind, controlled efficacy trial compared CGP56697 (combination of artemether and benflumetol) with pyrimethamine/sulfadoxine (P/S) in treating 287 children (1 to 5 years of age) diagnosed with uncomplicated malaria. The trial was conducted in Gambia at 2 centers. In accordance with guidelines from the Gambian government, 144 children received 1 tablet of CGP56697 (artemether 20 mg and benflumetol 120 mg) at 0, 8, 24, and 48 hours if they weighed less than 33 pounds or 2 tablets at 0, 8, 24, and 48 hours if they weighed 33 pounds or more, and 143 children received half a tablet of P/S (pyrimethamine 12.5 mg and sulfadoxine 250 mg) once if they weighed less than 33 pounds and 1 tablet once if they weighed 33 pounds or more. Primary trial end point was the number of children with no detectable P. falciparum by day 4. Secondary end points were parasite clearance times, day 15 cure rate, and the number of repeat episodes of malaria within 29 days. Three days after treatment, 133 (100%) of the evaluable patients in the CGP56697 group and 128 (93%) of the evaluable children in the P/S group were free of parasites. The day 15 cure rate was 93% for CGP56697 and 98% for P/S. Within 29 days, 20 patients treated with CGP56697 and 1 patient from the P/S-treated group returned with second malarial episodes. Adverse reactions were similar for the 2 therapeutic regimens. 23

Another randomized, open-label clinical trial examined the efficacy of 3 oral antimalarial combinations in 330 patients (average age: 15 years) diagnosed with uncomplicated malaria. Patients were evaluated over 42 days and randomized to receive chloroquine plus sulfadoxine-pyrimethamine (CQ + SP, n = 110), artesunate plus mefloquine (MAS3, n = 110), or artemether-lumefantrine (LAM3, n = 110). Primary trial end point was the 42-day cure rate. Secondary trial end points included parasite and fever clearance rates. The 42-day cure rates were 93%, 100%, and 97% for patients receiving CQ + SP, MAS3, and LAM3, respectively. Parasite clearance rates were approximately 3, 2, and 2 days for patients receiving CQ + SP, MAS3, and LAM3, respectively. The mean fever clearance time was 40, 25, and 23 hours for patients receiving CQ + SP, MAS3, and LAM3, respectively. Drug-related adverse reactions were similar among the therapeutic regimens. 24

The efficacy of 3 antimalarial combinations was assessed in 4 districts in Uganda in a total of 2,061 patients younger than 5 years of age, diagnosed with uncomplicated malaria, in a single-blind, randomized clinical trial. Patients were evaluated for approximately 1 month and received chloroquine plus sulfadoxine-pyrimethamine (CQ + SP, n = 677), amodiaquine plus sulfadoxine-pyrimethamine (AQ + SP, n = 690), or amodiaquine plus artesunate (AQ + AS, n = 694). Primary trial end point was the cure rate at 28 days. All 3 regimens proved ineffective, perhaps because of the high endemicity of malaria in this region of Africa. 25

Anticancer activity

The endoperoxide bridge is required for the anticancer activity of artemisinin and its derivatives through formation of a free radical, which causes molecular damage and cell death.

In vitro data

Of 9 terpenoids and flavonoids from wormwood, only artemisinin exhibited cytotoxicity toward the human tumor cell lines P-388, A-549, HT-29, MCF-7, and KB. 1 , 26

Artemisinin inhibited the growth of Ehrlich ascites and HeLa tumor cells with an IC 50 of 0.98 mcmol/L, unlike deoxyartemisinin, which lacks the endoperoxide bridge. 27

Dimers of dihydroartemisinin were cytotoxic to Ehrlich ascites and HeLa tumor cells, as well as to normal murine bone marrow progenitor cells. The endoperoxide bridge and an ether linkage played a role in cytotoxicity. Artemisinin derivatives were subjected to the National Cancer Institute 60-cell screening program. 28

Artemisinin derivatives may be effective in treating cancers that overexpress transferrin receptors. This mechanism of action involves the influx of iron in tumor cells, which then causes the formation of free radicals from artemisinin that cause molecular damage leading to cell death. A combination of dihydroartemisinin and halotransferrin resulted in rapid cell death in a human leukemia cell line with little effect on normal cells. When compared with controls, dihydroartemisinin 200 mcmol decreased MOLT-4 lymphocyte growth 50% in 8 hours. Cell death reached 100% in 8 hours when cells were exposed to the combination of dihydroartemisinin 200 mcmol and halotransferrin 12 mcmol. Dihydroartemisinin alone and in combination with halotransferrin had a similar effect on lymphocytes or normal cells, but the addition of halotransferrin did not enhance cell death in normal cells. 29

Artesunate, the semisynthetic derivative of artemisinin, induced apoptosis in human umbilical vein endothelial cells. Overexpression of the bcl-2 protein protects cells from apotosis, whereas activation of Bax drives apoptosis. Artesunate activated Bax, causing cell apoptosis and inhibiting the expression of the bcl-2 protein in a concentration- and dose-dependent manner. 30

Animal data

Oral administration of ferrous sulfate enhanced dihydroartemisinin cytotoxicity in fibrosarcoma in rats. Fibrosarcoma tissue was implanted into the right flank of 50 female Fisher rats. Eight days after implantation, rats were randomized to receive 1 of 4 treatments: (1) ferrous sulfate 20 mg/kg in distilled water plus dihydroartemisinin 2 mg/kg in peanut oil; (2) distilled water and dihydroartemisinin; (3) ferrous sulfate in distilled water and peanut oil; (4) distilled water and peanut oil. Body weight and tumor size were measured daily for 11 days. Ferrous sulfate was first administered, followed by dihydroartemisinin 6 hours later. On day 4, treatment was increased to dihydroartemisinin 5 mg/kg until treatment ended on day 10. The combination of dihydroartemisinin with ferrous sulfate decreased tumor size by 30% ( P < 0.025). 3

The efficacy of artemisinin in preventing breast cancer development was examined for 40 weeks in rats treated with a single oral dose (50 mg/kg) of 7,12-dimethylbenz[a]anthracene (DMBA). The experimental group (n = 12) of rats was fed a powdered rat chow containing 0.02% artemisinin and the control group (n = 22) received plain, powdered food. Artemisinin delayed ( P < 0.002), and in some rats prevented (57% of artemisinin-fed versus 96% of the controls, P < 0.01), breast cancer development. In the artemisinin-fed rats that developed a tumor, tumor size was smaller ( P  < 0.05), and there was a longer duration of time for tumor development  (29.4 vs 15.3 weeks) when compared with controls. 31

Dosage

Clinical trial and WHO documentation support the efficacy of oral and IV dosage forms of artesunate for malaria. Parenteral preparations are available for oil-soluble artemether and the newly marketed artemotil. Numerous dosage regimens are available, but WHO has approved riamet ( Coartem ), a combination of lumefantrine 120 mg and artemether 20 mg. Treatment includes administering 4 tablets initially, repeating dosage in 8 hours, and then taking twice daily for the next 2 days. The combination's efficacy has been displayed by cure rates of up to 98%. 32

Pregnancy/Lactation

Artemisinin derivatives, in particular artemether, have a toxic effect on embryos, but no teratogenicity was described in animal studies in mice, rats, or rabbits. Thus, teratogenicity may be limited to early pregnancy. No abnormalities were found in children of mothers treated with artemisinin or artemether during the second or third trimester of pregnancy. In a 2004 report, 28 pregnant women from eastern Sudan were treated with IM artemether and 1 perinatal death was documented following premature delivery. The remaining women delivered full-term healthy infants. In another case, 4 accidental pregnancy exposures to artemether/lumefantrine and 2 to dihydroartemisinin/piperaquine resulted in favorable pregnancy outcomes. In Thailand, 81 women in their second and third trimesters of pregnancy received 3 days of artesunate/atovaquone/proguanil, and no differences were seen in newborns or in their growth and development studied over 12 months. 2 , 5 , 6 , 33

Interactions

Clinically significant effects may occur in patients because of the potent inhibition of cytochrome P-450 1A2 (CYP1A2) enzyme. 34 , 35

Antidiabetic agents

Caution may be warranted in diabetic patients because some artemether trial patients developed hypoglycemia.

Antiarrhythmic agents

Clinical trial data document prolongation of the QT interval in patients treated with artesenate and artemether, which may increase the risk of serious arrhythmias in patients receiving other drugs that prolong the QT interval. 34

Grapefruit juice

In healthy men, grapefruit juice has been shown to increase the bioavailability of artemether. 36

Adverse Reactions

Clinical trial data document GI complaints such as abdominal pain, diarrhea, nausea, and vomiting. Pruritus, rash, and urticaria have been reported as well as pain and abscess development at the injection site. Cardiovascular changes include bradycardia and prolongation of the QT interval. Metabolic changes include hypoglycemia. 35

Toxicology

The risk of cumulative neurotoxicity may prohibit the prophylactic use of artemisinin-based drugs. Animal studies in rats and dogs using 5 to 7 times the usual dose of artemether or arteether resulted in a high fatality rate because of neurotoxicity to cerebellar and brain-stem nuclei. However, primates were not as susceptible to the neurotoxicity. Neuropathology studies also found damage to auditory and vestibular nuclei. Dihydroartemisinin was the most toxic compound tested, while artelinic acid and artemisinin were the least toxic. 1 , 2

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