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International Journal of Pharmaceutics, 69 (1991) 83-920 1991 Elsevier Science Publishers B.V. 0378-5173/91/$03.50ADONIiO378517391OO1187

8

IJP 02325

Invited ReviewFormulation and pharmacokinetics of artemisinin and itsderivatives

H.A.C. Titulaer , J. Zuidema and C.B. Lugt 2 Department of Pharmaceutics,roesestraat 79, 3522 AD Utrecht (The Netherlands) and ACF-Chemie SV;

&iaarssen (The Netherlandr)(Received 10 June 1990)

(Modified version received 20 October 19#)(Accepted 30 October 1990)

Key work Artemisinin; Qinghaosu; Artesunate; Artemether; Pharmacokinetics; Formulation; Malaria

Artemisinin, the leading compound of a completely deviant class of drugs, might be of incredible importance in the combat omalaria. Although the herb from which it is isolated has been known for more than 2000 years, and over 2000 patients have beesuccessfully treated in clinical studies, no phannacokinetic data are available, and thus empirical formulations are used. In this reviewthe available literature on formulation and kinetic aspects of artemisinin and its derivatives is reinterpreted and discussed in order tdetermine the kinetic reorients for a rational and optimal design of artemisinin formulations.

Introduction

Artemisinin (Chinese: Q~~aosu) (Fig. la) is asesquiterpene lactone with a characteristic per-oxide bridge. It is isolated from the herb Arfemisiaannua L. (Qinhao), a member of the Compositaefamily (Asteraceae). This herb has been in use inChina for more than 2000 years in the treatmentof fever. In the twentieth century it became clearthat its antipyretic activity is confined to the treat-ment of malaria. After the isolation of the activeprinciple artemisinin by Chinese scientists in 1972,this substance appeared to be a potent blood

Correspondence: H.A.C. Titulaer, Dept. of Pharmaceutics, Uni-versity of Utrecht, Croesestraat 79, 3522 AD Utrecht, TheNetherlands.

schizontocide, the peroxide group, unique in nature, being essential for its activity. Arte~si~n ithe leading compound of a completely deviant

i, HCH ,

I?a)R: 4) a~emisininb) -OH:I

dihydroartem~sinin4Sf;~)(CH2)&OONa sodium artesunateartemether;) -O-CH&H, arteether-O-CH,C,H,COONa sodium artelinatePig. 1. Structure of artemisinin and some of its derivatives,

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84

class of drugs, which might be of significant im-portance in the combat of malaria. A detailedreview on the history, isolation and structureelucidation was published by Klayman (1985).The parasite and fever clearance rates witharte~si~n and its derivatives are higher thanwith any other antimalarial drug (Qinghaosu anti-malaria coordinating research group, 1979; Jing-BoJian et al., 1982; Li et al., 1985). Excellent resultshave been reported in the treatment of Plasmodiumviuax and P. falciparum infections in patients,including the cerebral form, with both chloro-quine-sensitive and c~oroq~ne-resistant strains(Qinghaosu antimalaria coordinating researchgroup, 1979; Luo and Shen, 1987; Myint andShwe, 1987; Myint et al., 1989). Artemisinin resis-tance could be induced in vitro (Inselburg, 1985;Li et al., 1986). Until now no resistance has beendescribed in patients. Cross-resistance with other~tirnala~~s is limited.In this article the available literature on formu-lation and kinetic aspects of artemisinin and itsderivatives is reviewed, in many cases reinterpre-ted and discussed, These data are related to infor-mation on the fever and parasite clearances inorder to determine the kinetic requirements for anoptimal and rational ~te~si~n formulation de-sign.

Artemisinin DerivativesArtemisinin can be hydrogenated at the C-10keto group to the hemiacetal ~hydroarte~si~n(Fig. lb). The resulting hydroxy group can be usedfor further derivatisation. Many experimental de-rivatives have been prepared of which only a feware used in practice (Luo and Shen, 1987). Themost important derivatives are currently artesu-

nate, the water-soluble sodium salt of the succinicacid ester (Fig. lc), and the lipophilic estersartemether and arteether (Fig. Id and e).The usage of artesunate is limited by its hy-groscopy and poor stability in aqueous solution,due to hydrolysis of the ester linkage. It is there-fore distributed in a dual package, powder withsolvent. Recently, more stable water-soluble com-pounds have been developed, in which a carbo-

xylic acid chain is joined by an ether linkage (Linet al., 1987). The sodium salt of artelinic acid (FigIf) is the most promising of this class of drugs, buis not yet in use.

Formulation and Phar maeokinetics

ArtemisininIntravenous administration Concentration-timeprofiles of artemisinin in man after intravenous

injection are not available because of the lowsolubility in water and lack of a suitable solvenfor i.v. use. The pharmacokinetics after i.v. injec-tion have been determined in rats (Niu et al.1985), but information on the formulation is lacking. Probably, a micron&d aqueous suspensionwas used in that study.Each of the seven points in the curve waobtained from three rats, 21 in total. The distribu-tion and elimination are very rapid and the distribution volume is large. The parameters calculatedfrom these data were tl,*, a = 2.66 min, t1,2fi = 30 min and VP= 4.1 l/kg. These data can onlybe seen as rough estimates of the true populationmeans in rats, due to meth~olo~c~ and statisti-cal shortcomings of the study.

Intramuscular administration The intramuscu-lar route of administration is most frequently usedAbout 2000 patients were successfully treated inChina during the 1970s (Qinghaosu antimalariacoordinating research group, 1979; Li G.-Q. et al.1982). The i.m. formulation consisted of a suspen-sion in oil or water. The applied dosage scheme i800-1200 mg divided over 3 days, e.g. 600 mg onday 1 and 300 mg on days 2 and 3, administeredas a single daily dose. Precise data on the formula-tion such as suspension vehicle, concentration,viscosity, etc. have not been given or discussed.The pha~aco~netics in humans have beendetermined after i.m. ad~~stration of suspensions in oil and aqueous suspensions (Titulaer eal., 1990). Ten healthy male volunteers received400 mg artemisinin as a suspension in olive oil oin 0.5% HPMC and 0.9% NaCl. The i.m. injectionwas placed in the upper outer quadrant of thbuttock. In Fig. 2 the concentration-time profiles

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are shown. In Table la the calculated pharmaco- availability relative to the i.m. injection of a suskinetic parameters are summarized. pension in oil is only 32% (Titulaer et al., 1990).A striking difference was observed between theaqueous suspension and the suspension in oil. Themean peak concentration after i.m. administrationof the suspension in oil resembles that after oraladministration of the same dose, though maximaoccur at a later time. After i.m. injection of anaqueous suspension low and variable concentra-tions were observed. This is probably caused bythe fast aqueous solvent absorption and subse-quent particle aggregation, in contrast to the caseof oil as vehicle.The profiles of the suspension in oil show alarge variation in peak concentrations and thetime that zero concentrations are reached again.This obvious variation in absorption rate might becaused by differences in the shape of the depotand/or in the activity of the volunteer and subse-quent bloodflow in the muscle.

The study of Zhao (1987) had the character oa preliminary experiment, since the data wercollected from only one volunteer. The resultsdiffer considerably from the results of the study oTitulaer et al. (1990). The peak concentration wafound at about 4 h and the concentrations wermuch higher over the whole time period.Artemisinin was given in the study of Titulaer eal. after an overnight fasting period, but in thstudy of Zhao artemisinin was administered 3min after a light breakfast. An explanation mighbe therefore that the absorption of artemisinin iinfluenced by concomitant food intake. Drugs witha high first-pass metabolism, such as artemisinin,are often susceptible to the influence of food oabsorption and bioavailability (Beerman, 1979Merkus, 1984).

Oral administration Concentration-time pro-files of artemisinin after oral administration, asdepicted in Fig. 3, have been determined by Zhao(1987) and Titulaer et al. (1990). In Table lb thecalculated pharmacokinetic parameters from thesecond study are summarized.Artemisinin is quickly absorbed with peak con-centrations occurring at about 1 h, but the bio-

Rectal administration Artemisinin, rectally administered in suppositories, is tested in large clinical trials in China (Li et al., 1985). Fig. 4b showan artemisinin concentration-time curve of a human volunteer after administration of 10 mg/kgas a suppository (Zhao, 1987). The peak concentration is much lower than after oral adminis-tration, being found at about 7-9 h after administration. Information about the formulation (sup

8

TABLE 1Pharmacokinetics after administration of 400 mg artemisinin (data from Titulaer et al., 1990)

c(lzh

(a) Suspension in oil, i.m.Min 91MaX 331Mean 209SD 97n 10

;;;,-

0.7573.42.0

10

AUC MAT(/-% h I-)

t,/,, abs h/2* el(h) (h) (h )

993 1.10 0.76 4.163945 3.56 2.47 15.962419 2.30 1.59 7.441055 0.20 0.51 3.83

10 8 8 8

k(l?)

0.070.170.110.048

MRT(h )

7.225.210.6

5.88

(b) Aqueous suspension, oralh4in 159 0.75 574 0.49 0.14 1.0 0.24 0.26MaX 440 2 1018 1.79 0.93 2.9 0.67 3.9Mean 260 1 819 0.78 0.54 1.9 0.41 3.4SD 94 0.5 190 0.41 0.29 0.6 0.14 0.7n 10 10 8 8 8 8 8 8

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86

IGIlL I.M. (suspension in oil)

cla

24 36 40Time (h)

25

C

I. M. (aqueous suspension)

I I I0 2 4 6

b Time (h)8Fig. 2. Artemisinin concentration-time curves after i.m. admin-istration of 400 mg artemisinin; (a) suspension in oil, (b)aqueous suspension (n = 10, bars indicate SE. From Titulaer et

al., 1990).

pository base and size, particle size) is lacking. Itmight be assumed that the suppositories availablein China containing micronized artemisinin and apolyethylene glycol-stearate base with poly-sorbate, were used. The above-mentioned studyhas the character of a pilot study.

Fig. 4a shows concentration-time profiles afterrectal administration of 400 mg artemisinin as amicro-clysma to 10 healthy volunteers (Titulaer etal., 1990). Artemisinin appears to be poorly ab-sorbed from this formulation. An explanationmight be that artemisinin is solubilized better inpolyethylene glycol derivatives than in water and

that the latter is not rectally absorbed, remainingavailable as solvent during the absorption processKinetics of artemisinin derivatives

Artesunate Sodium artesunate is in use inChina for i.v. and i.m. administration. Li G.Q. eal. (1982) reported the use of slowly i.v. injectedartesunate, 20 mg/ml 5% GNS or GS and i.minjections of artesunate, 100 mg/ml distilled waterA loading dose of 200 mg, followed by 100 mg ondays 2 and 3 was used.

Pharmacokinetic data in man are not available.Artesunate is rapidly distributed in rabbits, rats

Oral (400 mg aqueous suspension)

0 2 4 6a Time (h)

PcJ/L Oral (10 mg/kg p.o. capsule)

00 4 8 12 16 20 24

b Time (h)Fig. 3. Artemisinin concentration-time curves after oral admin-istration of artemisinin. (a) Aqueous suspension 4043 mg (n = 10bars indicate SE. From Titulaer et al., 1990). (b) Capsule 1

mg/kg (n = 1. Redrawn after Shishan Zhao, 1987).

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8

Pc!lLi

Rectal (400 mgaqueous suspension)

25 -

%OP

PcllL200

1 0 0

0

0 6 1 2 1 8 2 4a Time (h)

Rectal (70 mg/kg supp.)

0 8 1 6 2 4 3 2 4 0b Time (h)

Fig. 4. Artemisinin concentration-time curves after rectal ad-ministration of artemisinin. (a) 400 mg in a micro-clysma(n = 10, bars indicate SE. From Titulaer et al., 1990). (b) 10mg/kg in a suppository (n = 1. Redrawn after Shishan Zhao,

1987).

and dogs. It is hydrolyzed to dihydroartemisininby blood esterases with a half-life of about 1.7 min(Zhou et al., 1987) or 4 min (Edlund et al., 1984),respectively. The hydrolysis half-life in dogs isabout 0.45 h (Zhao et al., 1986). Artesunate cantherefore be conceived as being the prodrug ofdihydroartemisinin. Dihydroartemisinin is rapidlyeliminated with a half-life of about 2.5 h as de-termined from studies in dogs (Theoharides et al.,1988). The dihydroartemisinin concentration de-creases to the detection limit in about 2 h in rats(Edlund et al., 1984).

Artesunate penetrated the blood cells of ratwith a low distribution rate. Dihydroartemisinin,however, is preferentially accumulated in thPlasmodium falciparum infected erythrocyte ivitro, showing a 2-fold concentration in the unin-fected erythrocyte as compared to 300-fold in thinfected red cell (Gu et al., 1984). This is probablyconnected with the altered membrane structure oinfected erythrocytes (Ye et al., 1986) and/or extensive binding to parasite substrates. The proteinbinding of artesunate is reported to reach an extent of 59% and, more relevantly, that of dihydro-artemisinin 43% (Luo and Shen, 1987).

Artesunate has been reported to be percuta-neously absorbed and to clear the parasitaemiaafter administration in an ointment to hairlessmice (Xuan et al., 1988). At this moment threlevance of this finding is not easy to interpret.

Artemether Artemether is in use in China solution in oil for i.m. administration in humansLi G.-Q. et al. (1982) reported the following dosing scheme: artemether oil preparation, 80 mg/ml:day 1, 320 mg; days 2 and 3, 160 mg.Fig. 5 shows mean concentrations of artemetherin plasma after a dose of 6 and 10 mg/kg, respectively, to three volunteers (Zhou et al., 1988). Thet maxis found at about 6 h. The half-life of absorp-tion was 2-2.6 h.The half-life of elimination cannot be calculated with enough accuracy from this study, due t

300P!JiL n* Artemether i-m.* 6 mg / k g

_ 1 0 mg l k g

I I I0 1 0 20 30 4Time (h)

Fig. 5. Artemether concentration-time curve after the intramuscular administration of 6 mg/kg and 10 mg/kg (n =

Redrawn after Zhou et al., 1988).

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88

the sustained absorption. The authors suggestedemanation half-lives from about 7 to 11 h. Theperiod during which the concentrations are higherthan the effective concentration is claimed to beabout 50 h after a dose of 6 mg/kg. This meansthat the artemether injection is a long-acting pre-paration and should allow once daily dosing.However, the power of a study with three volun-teers is low. An estimation of the risk of unpro-tected intervals between two dosages needs a largerscale study.The bioavailability of artemether intramuscu-larly injected as a solution in oil is reported to be37-50% (China cooperative research group onqinghaosu and its derivatives as antimalarials,1982). However, these results might be biased bythe limited observation time of 72 h. If this find-ing is true, this is a serious drawback compared tothe artemisinin suspension injection in oil (Titu-laer et al., 1990).Artemether is strongly bound to plasma pro-teins (76%) and distributes rapidly over the bloodcells and brain (Li et al., 1982; Luo and Shen,1987). In contrast to artesunate the biotransforma-tion into d~ydro~e~si~n is slow.Artemether has, as artesunate, been reported tobe percutaneously absorbed after administrationin an ointment to hairless mice (Klayman, 1985).Fundamental pharmacokinetic properties of arte-misinin

Absorption Artemisinin is rapidly but incom-pletely absorbed after oral administration (Titu-laer et al., 1990). The mean absorption time (MAT)is 0.78 h and the bioavailability relative to the i.m.injected suspension in oil 32%. Because no i.v.formulation of artemisinin is available yet, futurestudies must reveal the absolute bioav~lability.The low bioavailability after oral administrationcould be explained from the results of former invitro studies and pharmacokinetic experiments inrats and dogs (Niu et al., 1985; Zhao et al., 1986).After in vitro incubation of arte~si~ in stomachand ileum preparations of the rat, artemisininappeared to be stable, but a high metabolicclearance was demonstrated in rat liver slices (Niuet al., 1985), indicating that the incomplete ab-sorption after oral ad~stration can at least par-

tially be ascribed to a high first-pass clearance inthe liver.Distribution and protein binding The tissue distribution was determined after iv. administration

of 150 mg/kg artemisinin in rats (Niu et al1985). The highest concentrations are found in thelungs, also quite high in the kidneys, lower iheart, brain and liver and low in muscles, fatspleen and fetus. After oral administration of 90mg/kg the highest concentrations are found in theliver. The dist~bution is very rapid. The distribu-tion (a-) phase ends within 20 min. The con-centrations are much higher at 5 min than at 3min after injection. From the high concentrationsin the brain it appears that arternisinin passes thblood-brain barrier in rats.

By combining the data on oral and intramuscu-lar administration in oil from the study of Titulaeret al. (1990) and supposing that the absorptionfrom the latter is complete, a volume of distribu-tion of about 5 l/kg can be estimated. From manyantimalarial drugs it is known that the volume odistribution and other kinetic parameters are altered in patients. Information on artemisinin withrespect to these parameters is currently lacking.Artemisinin passes the rat placenta but moreslowly than the distribution processes over thother organs. The concentrations in the rat fetuwere higher at 30 min as compared to 5 min afteinjection. No information is available onartemisinin excretion into breast milk.Protein binding of 64% has been reported (Luoand Shen, 1987). Artemisinin is excreted in humansaliva (Zhao, 1987). The plasma/saliva ratio wafairly constant, being about 8.0 + 2.7 (mean i SD)Normally, the reciprocal value, saliva/plasmaratio, is given in the literature. In this case, this about equal to 0.12, which is less than the frefraction in serum and is indicative of an intermediate salivary clearance rate (Zuidema and VaGinneken, 1983).

Metabolism and excretion In rat experimentsthe liver appears to be the main site of metabo~sm(Niu et al., 1985). Reduction of the peroxide bridgeis the most important step in the metabolic pathway. Four metabolites were extracted from urinafter an oral dose of artemisinin to volunteers.The metabolites all lack the peroxide moiety an

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8are therefore devoid of antimalarial activity. Thekidneys and the lungs contribute to the metabo-lism to a much lesser degree.

The half-life of elimination in humans is veryshort, of the order of magnitude of l-2 h afteroral administration (Titulaer et al., 1990). Theapparent elimination half-life after i.m. adminis-tration is much longer due to interference with thenow low absorption rate.

Only a very small fraction of the administereddose is excreted in unchanged form in fetes andurine, regardless of the route of administration.

Implications of Phar macokinetic Pr operties forTherapeutic UseDose and therapeutic range

The mechanism of action of artemisinin is notfully understood but differs from that of otherantimalarials. No folic acid antagonism has beendemonstrated. It has been suggested thatartemisinin or a peroxy metabolite acts as aninitiator in a free radical chain process (Ames etal., 1985; Krungkrai and Yuthavong, 1987). Someeffects on nucleic acid and protein synthesis havebeen reported (Ellis et al., 1985; Luo and Shen,1987; Xuan Wenyi et al., 1988) and an effect onpolyamine biotransformation has been described(Whaun et al., 1985). The primary target of attackis possibly protein synthesis. A minimal inhibitoryconcentration of 10e7 M is estimated forartemisinin (Luo and Shen, 1987). A membrane-stabilizing effect of Plasmodium-infected erythro-cytes and some modulating effects on red cellimmunity have been reported for artemether (Li etal., 1986).

Table 2 summarizes the most frequently usedroutes of administration, i.e. dosing schemes. Use-ful treatments of patients appeared to be anartemisinin aqueous or oily suspension of 1.2 g,intramuscularly injected over 3 days (e.g. 600, 300and 300 mg). As an oral dose 10 mg/kg bodyweight per day is mostly recommended. Rectally,2.8 g (600 mg at t = 0 and 4 h; 2 x 400 mg ondays 2 and 3) in 3 days has been used in clinicaltrials. From studies in mice it appears that theintramuscular injection of artemisinin in oil is

TABLE 2Formulation and clinical aspects

Formulation Clearance of Recrudescence Numberrate (1 month) ofF)ver r$rasites (w) patients

p.0. = 21-46 18-61 31-85 241i.m. (oil) b 21-36 28-48 13-21 212i.m. (aqueous) 31-46 30-73 9-28 369Rectal d 21 53 47 100Majority of infections, P. falciparum; others, P. oioax.a Tablets or suspension (nasal feeding), total 2-3.2 g in 3 daysc Suspension, total 0.8-1.2 g in 3 days.d Suppository, total 2.8 g divided in 3 days, twice daily. (Datfrom: Qinghaosu antimalaria coordinating research group1979; Li G.-Q. et al., 1982, 1985).

more active than in water (China cooperative research group on qinghaosu and its derivatives aantimalarials, 1982).

As can be derived from Table 2, fever andparasite clearance rates are higher with i.m. suspensions in oil than with the i.m. aqueous suspen-sion. The rates after oral and rectal administrationare comparable with that of i.m. artemisinin suspension in oil. These facts are easily understoodfrom the artemisinin bioavailability data of theseformulations and their pharmacokinetic profilesdescribed above (Niu et al., 1985; Titulaer et al.1990).Recrudescence rate

The recrudescence rate with artemisinin andrelated compounds is relatively high and depen-dent on the formulation, dosing scheme and dura-tion of therapy (Jiang et al., 1982; Li et al., 1984)Oral and rectal formulations, the formulationswith a short mean residence time, are afflictedwith a higher recrudescence rate than parenteralformulations (Luo and Shen, 1987), as shown iTable 2.

The high recrudescence rate is probably causedby two factors. The activity of artemisinin and itderivatives is confined to the blood schizonts (theplasmodia in the erythrocytic phase, especially intheir early stage, the rings) and the rather shortelimination half-life. It is obviously important thatbetween two dosage times artemisinin remains

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90present in sufficiently high concentrations. It canbe supposed that newly formed erythrocytes, thereticulocytes, are sensitive to infection when theyare not rapidly protected by sufficient drug de-livery, especially since the younger population ismore susceptible to an attack of P. fulciparum(Boonpucknavig et al., 1984).

DiscussionImportant aspects for therapy are a rapid onsetof action and a relatively long duration of action.

From Table 2, it can be concluded that the feverand parasite clearances are low following the veryslowly absorbed i.m. aqueous suspension but thatabsorption rates as found for the oral and i-m.suspension in oil do not differ markedly. Fromrecent Chinese data it can be seen that the in-travenous administration of artesunate also doesnot result in a more rapid fever and/or parasiteclearance.It appears, however, to be very important thatartemisinin is dosed in such a frequency that aconstant supply of sufficient drug is guaranteed toprevent an excessively high recrudescence rate.This means that a sustained release formulationwith a sufficiently high initial release has thehighest potential for recrudescence prevention.

Moreover, formulations with a high bioavaila-bility and low production costs are essential asStetson is costly and available on the marketin limited quantities only.

At present, only the intr~us~ular suspensionin oil meets all the requirements. A disadvantage,however, is the high variability in absorption rateMore research is needed (and is now in progress)to determine the optimal manner of administra-tion and most appropriate formula.The once daily dosage schemes as currentlyapplied with the available preparations and amentioned in this article are sensitive to recrudes-cence. All preparations run the considerable riskof much shorter durations of active protectionthan 24 h. Experimental therapy with parenteraldepot formulations and longer duration of therapyare needed for adapting dosage forms and dosageschemes in a close relationship to an optimumtherapy and prevention of recrudescence. At thistime it is still necessary to use other antimalarialdrugs after fever and parasitemia have subsided tprevent the residual recrudescence.Toxicity of artemisinin seems to be negligibleeven at high doses. A slight reticulocytopenia anda reversible pyrogenic reaction have been observed(Anonymous, 1987). Artemisinin and its derivatives are embryotoxic in laboratory animals (Chinacooperative research group on qinghaosu and itderivatives as antimalarials, 1982).Titulaer et al. (1990) reported the absence opain at the site of injection with i.m. formulationsand the absence of other side-effects after oral andrectal administration in their experiments.

Pharmaco~ne~c drug ~teractions have nobeen reported but are likely to occur, as artemisinin

RouteOrali.m. oili.m. aqueousRectal

Dose10 mg/kg

4C@mg4OOmgmm810 mg/kg10 mg/kg4OOmg

No. ofsubjects1

1010101610

c(F& trM% AUC(h) Mhl-)1150 4 8103260 1 819209 3.4 2419a B a

115 8 106210 6.65 -B a a

h,2,el(h-l)2.4 b1.9 =7.44 =ac6.5 bd_ac

a Not determined due to large variability and poor absorption. b Zhao (1987). Titulaer et al. (1989). d Shen (1986).

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9is a high clearance drug. More research is neededon this aspect.Potentiation and additive effects have been re-ported for many arte~si~n combinations withantimalarial drugs (Chawira and Warhurst, 1987;Chawira et al., 1986a,b, 1987). Antagonism, how-ever, may occur with pyrimethamine and withchloroquine in combination with artemisininagainst P. faic~pa~~ in the field.

SummaryArtemisinin is a sesquiterpene lactone with aunique peroxide moiety in its structure. It is the

leading compound of a new class of antimalarials.Besides artemisinin, its derivatives sodiumartesunate and artemether are experimentally ap-plied in the clinic. Artemisinin and derivatives arevery fast acting blood schizontocides, especiallysuited for the treatment of severely ill patients.Artemisinin has been dosed most frequently byintramuscular injection. The suspension in oil re-sults in a rapid absorption and relatively highpeak concentrations. An aqueous suspension re-sults in a more sustained release with a low onsetand low concentrations. Arte~si~n is completelyabsorbed, in the strict sense, after oral administra-tion, but a high first pass metabolism results inrelatively low bioavailability. Absorption afterrectal administration as an aqueous suspension orin suppositories is incomplete. Artemisinin israpidly distributed over the tissues, passes theerytbrocyte wall, the blood brain barrier, thesalivary glands and the placenta. It is rapidlyexcreted by biotransformation, mainly in the liver.Artemisinin shows a relatively high recrudescencerate, probably dependent on formulation char-acteristics which might be partially prevented bybetter products and better dosage schemes. Thetoxicity is low, however teratogenicity was ob-served in laboratory animals. Kinetic drug interac-tions are not reported but dynamic interactionsoccur with several antimala~~s.

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Quinones, dapsone metabolites, metal complexes, iminiumions and peroxides. J. Free Radicals Biol. Med., 1 (1985353-361.Anon~ous, Progress in tropical disease drug developmentScrip, 24 (1987) 1244.Beerman, B., Effects of food and drink on drug absorption iman. In Prescott, L.F. and Nimmo, W.S. (I%&), DruAbsorption, MTP Press, Edinburgh, 1979, pp. 238-252.Boonpucknavig, V., Srichakul, T. and Punyagupta, S., Clinicapathology. In Peters, W. and Richards, W.H.G. (E&sAntimaiaria~ Drugs I, Chap. 4, Springer, Berlin, 1984, pp127-168.

Chawira, A.N. and Warhurst, D.C., The effect of artemisinincombined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodiumfalciparum in vitro. J. Trop. Med. Hyg., 90 (1987) 1-8.Chawira, A.N., Warhurst, D.C. and Peters, W., Drug combination studies with qinghaosu (arte~sinin) against sensitivand resistant strains of rodent malaria. Trans. R. Sot. TropMed., 80 (1986a) 334-335.

Chawira, A.N., Warhurst, D.C. and Peters, W., Artemisinin(qinghaosu) combinations against chloroquine-sensitive anresistant Plasmodium falciparum in vitro. Trans. R. SoTrop. Med., 80 (1986b) 335.Chawira, A.N., Warhurst, DC., Robinson, W.L. and PetersW., The effect of combinations of qinghaosu (artemisinin)with standard antimalarial drugs in the suppressive treatment of malaria in mice. Trans. R. Sot. Trop. Med., 8(1987) 554-558.

China cooperative research group on qinghaosu and its derivatives as antimalarials. Studies on the toxicity of qinghaosuand its derivatives. J. Trad. Chin. Med., 2 (1982) 31-38.Edlund, P.O., Westerlund, D., Carlqvist, J., Wu, B.L. and JinJ.H., Determination of artesunate and dihydroartemisininein plasma by liquid chromatography with post-column derivatization and UV detection. Acta Phurm. Suet., 21 (1984223-234.

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