1993

Zhao KC, Song ZY (1993)
Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu
Acta Pharma Sin 28:342–346

Article in Chinese non available

English Abstract

Qinghaosu (QHS), also known as artemisinin and arteannuin, is a novel type of sesquiterpene with a peroxide linkage isolated from the Chinese herb Artemisia annua L. Since its discovery as an antimalarial with low toxicity, hundreds of derivatives have been synthesized among them artesunate (ATS), artemether (ATM) and dihydroqinghaosu (DHQHS) were found to be more active than QHS itself. A suppository of QHS, a dual-pack dosage form of ATS (artesunic acid to be dissolved in sodium bicarbonate solution just before iv injection) and an oil solution of ATM for im injection had been approved by our Ministry of Health for clinical use. However, a preparation for oral administration is still not available. We have reported that when dogs were given QHS tablets orally at the dose of 70 mg/kg, no drug was detected in the serum using the RIA method, whereas appreciable serum concentration was found by the same method when dogs were given DHQHS tablets at a dose as low as 10 mg/kg. This paper reports the pharmacokinetics of DHQHS in man studied with the RIA method and compared with QHS. When DHQHS in tablet form was given to human volunteers at doses of 1.1-2.2 mg/kg, peak serum levels of 0.13-0.71 micrograms/ml were obtained in 1.33 h with MRT of 2.26-2.36 h. When QHS tablets were given at the dose as high as 15 mg/kg, however, the peak serum level found in 1.5 h was only 0.09 microgram/ml with MRT of 1.33 h. Therefore, the bioavailability of QHS tablets is only 1.62-10.08% that of DHQHS.

1996

Alin MH, Ashton M, Kihamia CM, Mtey GJ, Björkman A (1996)
Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria
Br J Clin Pharmacol 41:587–592

Abstract

Qinghaosu (QHS), also known as artemisinine and arteannuin, is isolated from the Chinese herb Artemisia annua L. It is highly active against both chloroquine-sensitive and chloroquine-resistant strains of P. berghei and has been approved by the Ministry of Health for the treatment of malaria. When QHS is treated with sodium borohydride, dihydroqinghaosu (DH QHS) is resulted with the antimalarial activity enhanced several fold. This paper reports the pharmacokinetics of DHQHS studied with the radioimmunoassay method. When the drug was given orally in tablet form to rabbits at doses of 10, 20 and 30 mg/kg, peak serum levels of 0.03, 0.05 and 0.13 micrograms/ml, respectively, were obtained in 1 to 2 h. The corresponding T1/2 of the drug were found to be 1.19, 1.00 and 1.10 h and the MRTs were 1.73, 1.36 and 1.53 h. No significant difference between dosages used was observed. When dogs were given DHQHS tablets at the dose of 20 mg/kg, a peak serum concentration of 0.13 micrograms/ml wes reached in about 2 h with a T1/2 of 2.10 h and an MRT of 3.04 h. However, when dogs were given QHS tablets at the dose of 70 mg/kg, no drug was detected in the serum. It would appear that the bioavailability of DHQHS tablets is much higher than that of QHS when given orally to the dog.

2004

Karin Räth, Katja Taxis, Gitta Walz, Christoph H. Gleiter, Shu-Ming Li, And Lutz Heide
Pharmacokinetic Study Of Artemisinin After Oral Intake Of A Traditional Preparation Of Artemisia annua L. (Annual Wormwood)
American Journal of Tropical Medicine and Hygiene, 70(2), 2004, pp. 128–132

Pharmacokinetic Study Of Artemisinin After Oral Intake Of A Traditional Preparation of Artemisia annua} L. (Annual Wormwood)

Abstract

Artemisia annua L. (annual wormwood) contains the antimalarial artemisinin. Aqueous preparations of the dried herb are included in the pharmacopoeia of the People’s Republic of China for treatment of fever and malaria. Fourteen healthy male volunteers received one liter of tea prepared from nine grams of Artemisia annua leaves. Blood samples were taken and artemisinin was detected by reversed phase high-performance liquid chromatography. The mean ± SD maximum plasma concentration of artemisinin was 240 ± 75 ng/mL and the mean ± SD area under the plasma concentration-time curve was 336 ± 71 ng/mL × hr. Artemisinin was absorbed faster from herbal tea preparations than from oral solid dosage forms, but bioavailability was similar. One liter of an aqueous preparation of nine grams of Artemisia annua contained 94.5 milligrams of artemisinin (approximately 19% of the usually recommended daily dose). Artemisinin plasma concentrations after intake of this herbal tea are sufficient for clinical effects, but insufficient to recommend such preparations as equivalent substitutes for modern artemisinin drugs in malaria therapy.

2010

Ferreira JF, Luthria DL, Sasaki T, Heyerick A.
Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer
Molecules. 2010 Apr 29;15(5):3135-70. doi: 10.3390/molecules15053135. PMID: 20657468; PMCID: PMC6263261.

Review

Abstract

Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea), leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT), instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria) and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases.

2011

Philippe Rasoanaivo, Colin W Wright, Merlin L Willcox, Ben Gilbert
Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions
Malaria Journal 2011, 10 (Suppl 1): S4

Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions

Abstract

Background: In traditional medicine whole plants or mixtures of plants are used rather than isolated compounds. There is evidence that crude plant extracts often have greater in vitro or/and in vivo antiplasmodial activity than isolated constituents at an equivalent dose. The aim of this paper is to review positive interactions between components of whole plant extracts, which may explain this.

Methods: Narrative review.

Results: There is evidence for several different types of positive interactions between different components of medicinal plants used in the treatment of malaria. Pharmacodynamic synergy has been demonstrated between the Cinchona alkaloids and between various plant extracts traditionally combined. Pharmacokinetic interactions occur, for example between constituents of Artemisia annua tea so that its artemisinin is more rapidly absorbed than the pure drug. Some plant extracts may have an immunomodulatory effect as well as a direct antiplasmodial effect. Several extracts contain multidrug resistance inhibitors, although none of these has been tested clinically in malaria. Some plant constituents are added mainly to attenuate the side-effects of others, for example ginger to prevent nausea.

Conclusions: More clinical research is needed on all types of interaction between plant constituents. This could include clinical trials of combinations of pure compounds (such as artemisinin + curcumin + piperine) and of combinations of herbal remedies (such as Artemisia annua leaves + Curcuma longa root + Piper nigum seeds). The former may enhance the activity of existing pharmaceutical preparations, and the latter may improve the effectiveness of existing herbal remedies for use in remote areas where modern drugs are unavailable.

2014

Mostafa A. Elfawala, Melissa J. Towler, Nicholas G. Reich, Pamela J. Weathers, and Stephen M. Rich
Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin
Francisco J. Ayala, University of California, Irvine, 2014 (received for review July 10, 2014)

Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin

Abstract

Pharmaceutical monotherapies against human malaria have proven effective, although ephemeral, owing to the inevitable evolution of resistant parasites. Resistance to two or more drugs delivered in combination will evolve more slowly; hence combination therapies have become the preferred norm in the fight against malaria. At the forefront of these efforts has been the promotion of Artemisinin Combination Therapy, but despite these efforts, resistance to artemisinin has begun to emerge. In 2012, we demonstrated the efficacy of the whole plant (WP)—not a tea, not an infusion—as a malaria therapy and found it to be more effective than a comparable dose of pure artemisinin in a rodent malaria model. Here we show that WP overcomes existing resistance to pure artemisinin in the rodent malaria Plasmodium yoelii. Moreover, in a long-term artificial selection for resistance in Plasmodium chabaudi, we tested resilience of WP against drug resistance in comparison with pure artemisinin (AN). Stable resistance to WP was achieved three times more slowly than stable resistance to AN. WP treatment proved even more resilient than the double dose of AN. The resilience of WP may be attributable to the evolutionary refinement of the plant’s secondary metabolic products into a redundant, multicomponent defense system. Efficacy and resilience of WP treatment against rodent malaria provides compelling reasons to further explore the role of nonpharmaceutical forms of AN to treat human malaria.

Keyword: malaria, drug resistance, artemisinin, Plasmodium, evolution

2015

Antoinette Carmela, Ariel Shaunna Garnet, Kirsten Noel Reed
Measuring changes in bioavailability of artemisinin
A Major Qualifying Project Report Submitted to the faculty of Worcester Polytechnic Institute In partial fulfilment of the requirements for the Degree of Bachelor of Science in Biology & Biotechnology, 4/30/2015

Measuring changes in bioavailability of artemisinin

Abstract

Malaria, the fifth leading cause of disease by infectious agents, has claimed the lives of approximately 584,000 people while posing a risk to 3.2 billion more worldwide, according to latest global estimates (World Health Organization, 2014). Artemisinin is a potent antimalarial found in Artemisia annua and is currently used in combination with other antimalarial drugs (artemisinin combination therapy; ACT), mainly against the infectious Plasmodium parasites. The use of artemisinin and its derivatives in ACT is currently the WHO recommended treatment for malaria, but is relatively expensive to many endemic regions. Artemisinin resistance in the Plasmodium parasite has recently developed, decreasing the potency of ACT, and initiated the search for alternative treatments. A. annua dried leaves taken orally has been found to be more efficacious than ACT, perhaps due to increased bioavailability of artemisinin. In this current project, a Caco-2 intestinal model was used to test changes in the bioavailability of artemisinin. The experiments were performed to simulate the effects of specific phytochemicals (at various concentrations) on artemisinin transport from the intestinal lumen into the serum. Sixty minute transport studies were analyzed across the monolayer at fifteen minute intervals, comparing artemisinin transport in combination with two flavonoids (quercetin and rutin), two phenolic acids (chlorogenic and rosmarinic acid), and one monoterpene (camphor). Of all the performed transports, only camphor (at a 1:10 molar ratio to artemisinin) showed a significant increase in artemisinin transport compared to the transport of artemisinin alone. Additionally, artemisinin transport across Caco-2 monolayers was found to vary with artemisinin concentration.

2016

Matthew R. Desrosiers, Pamela J. Weathers
Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria
Journal of Ethnopharmacology 190 (2016) 313–318

Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria

Abstract

Ethnopharmacological relevance: Artemisia annua L. produces the antimalarial sesquiterpene lactone, artemisinin (AN), and was traditionally used by the Chinese to treat fever, which was often caused by malaria.

Aim of the study: To measure effects of plant-based and dietary components on release of artemisinin and flavonoids from A. annua dried leaves (DLA) after simulated digestion.

Materials and Methods: Simulated digestion was performed on DLA in four types of capsules, or in conjunction with protein, and protein-based foods: dry milk, casein, bovine serum albumin, peanuts, peanut butter, Plumpy’nut(®), and A. annua essential oils. Artemisinin and total flavonoids were measured in the liquid phase of the intestinal stage of digestion.

Results: After simulated digestion, peanuts and Plumpy’nut(®) lowered AN and flavonoids, respectively, recovered from the liquid digestate fraction. None of the compositions of the tested capsules altered AN or flavonoid release. Surprisingly, bovine serum albumin (BSA) increased both AN and flavonoids recovered from liquid simulated digestate fractions while casein had no effect. AN delivered as DLA was about 4 times more soluble in digestates than AN delivered as pure drug. Addition of a volume of essential oil equivalent to that found in a high essential oil producing A. annua cultivar also significantly increased AN solubility in simulated digestates.
Conclusion: These results indicate encapsulating DLA may provide a way to mask the taste of A. annua without altering bioavailability. Similarly, many peanut-based products can be used to mask the flavor with appropriate dosing. Finally, the essential oil fraction of A. annua contributes to the increased AN solubility in DLA after simulated digestion. Our results suggest that use of DLA in the treatment of malaria and other artemisinin-susceptible diseases should be further tested in animals and humans.

Keywords: Artemisinin; Bioavailability; Digestion; Essential oils; Flavonoids; Malaria; Sesquiterpenoids; pACT

2018

Matthew R. Desrosiers, Pamela J. Weathers
Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves
Journal of Ethnopharmacology 210 (2018) 254–259

Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves

Abstract

Ethnopharmacological relevance: Artemisia annua has been used for>2000 yrs to treat fever and is more recently known for producing the important antimalarial drug, artemisinin.

Aim of the study: Artemisinin combination therapies (ACTs) are effective for treating malaria, but are often unavailable to those in need. Dried leaves of A. annua (DLA) have recently been studied as a cost effective alternative to traditional ACTs. DLA was shown to dramatically increase oral bioavailability compared to pure artemisinin, so more investigation into the mechanisms causing this increased bioavailability is needed.

Materials and Methods: In this study, we used a simulated digestion system coupled with Caco-2 cell permeability assays to investigate the intestinal permeability of DLA compared to pure artemisinin. We also determined the effects of different phytochemicals (7 flavonoids, 3 monoterpenes, 2 phenolic acids, scopoletin and inulin) and the cytochrome P450 isoform CYP3A4 on artemisinin intestinal permeability. Results: Artemisinin permeability, when delivered as digested DLA, significantly increased by 37% (Papp = 8.03 × 10−5 cm s−1) compared to pure artemisinin (Papp = 5.03 × 10−5 cm s−1). However, none of the phytochemicals tested or CYP3A4 had any significant effect on the intestinal permeability of artemisinin. We also showed that essential oil derived from A. annua negatively affected the intestinal permeability of artemisinin, but only after simulated digestion. Finally, we showed that A. annua essential oil reduced the transepithelial electrical resistance of Caco-2 monolayers, but only in the presence of bile. Although also reduced by essential oils, artemisinin Papp subsequently recovered in the presence of plant matrix. Conclusions: These results shed light on the mechanisms by which DLA enhances the oral bioavailability of artemisinin.

Keywords: Antiprotozoal, Drug transport, Essential oils, Flavonoids, Malaria, Terpenes

Jing Li, Chao Zhang, Muxin Gong, Manyuan Wang
Combination of artemisinin‐based natural compounds from Artemisia annua L. for the treatment of malaria: Pharmacodynamic and pharmacokinetic studies
Phytotherapy Research 32(8) · April 2018

Full text submitted to request

Abstract

Currently, the most effective antimalarial is artemisinin, which is extracted from the leaves of medicinal herb Artemisia annua L. (A. annua). Previous studies showed that the complex chemical matrix of A. annua could enhance both the bioavailability and efficacy of artemisinin. The present study aims to evaluate the efficacy and pharmacokinetic properties of a combination therapy based on artemisinin and 3 components from A. annua with high content (arteannuin B, arteannuic acid, and scopoletin). In vivo antimalarial activity was assessed following a 4‐day treatment in murine malaria models (Plasmodium yoelii and Plasmodium berghei). Results showed that a much sharper reduction in parasitemia ( 93%) was found in combination therapy compared with pure artemisinin ( 31%), indicating pharmacodynamic synergism occurring between artemisinin and arteannuin B, arteannuic acid, and scopoletin. Multiple‐dose pharmacokinetics further demonstrated that combination therapy results in increased area under the curve (AUC0→∞), Cmax, and t1/2 by 3.78‐, 3.47‐, and 1.13‐fold in healthy mice, respectively, and by 2.62‐, 1.82‐, and 1.22‐fold in P. yoelii‐infected mice, respectively. The calculated oral clearance of combination therapy in healthy and P. yoelii infected mice was also reduced. These findings imply that specific components in A. annua might offer a possibility to develop new artemisinin‐based natural combination therapy for malaria treatment.

Keyword: ACTs, Artemisia annua L, artemisinin, nature component, pharmacokinetics

2019

Pamela Weathers and Melissa Towler
Artemisinin estimated in malaria tea trial patient blood
May 25, 2019

Abstract

Objective: To measure amount of artemisinin the serum of a healthy human adult after consumption of dried leaf Artemisia annua (DLA). This was important for determining the amount of artemisinin in the blood after artemisinin was delivered as DLA and to measure length of persistence. The results were used to estimate the amount of artemisinin in the serum of adult humans who were treated with A. annua and A. afra in the Munyangi et al. malaria clinical trial.

Method: One adult human female subject (age 71, 140 lb [63.6 kg]) consumed 3 g powdered, encapsulated DLA (A. annua SAM, 2018 garden crop) had 3 blood draws: just prior to consumption of DLA; at 2 hr post consumption of DLA; and at 5 hr post consumption of DLA (taken on a different day at least a week later). Serum was isolated from the blood and analyzed for artemisinin using GCMS per the standard method.

Results: In a healthy human subject: Artemisinin (MW = 282.33) amount in the DLA was about 1.5% (15mg/g), so amount consumed (delivered) was 45 mg artemisinin. Estimating this human subject had about 4.13 L blood (https://reference.medscape.com/calculator/estimated-blood-volume), the amount of delivered artemisinin/mL blood could not exceed 10.90 mg/L, or 10.90 µg/mL. Human serum is 50-70% red blood cells (solids), so for this human subject, we estimated 55% serum (2.3 L), so the highest serum concentration of artemisinin would actually be about 20 mg/L or 20 µg/mL.