Synergistic anti-malarial formulation

Details Synergistic anti-malarial formulation Synergistic anti-malarial formulation

2000-03-28

2001-12-04

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S456000, C424S455000, C424S452000, C514S783000, C514S966000

Reexamination Certificate

active

06326023

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel synergistic formulation comprising &agr;,&bgr;-arteether together with vegetable oil, said formulation useful in the treatment of comatose and cerebral malarial cases. The formulation specifically useful for rectal route treatment of highly multi-drug resistant
P. falciparum
and
P. vivar
cases and which can be used for emergency treatment of comatose and cerebral malaria. The invention also provides methods of treatment of malaria affecting the brain employing the novel formulation. The invention also provides process for preparation of the said novel formulation.
BACKGROUND OF THE INVENTION
According to WHO
P. falciparum
malaria is becoming increasing resistant to chloroquine, sulfadoxine-pyrimethamine and mefloquine (Eyles et al. 1963, Am. J. Torp. Med. Hyg. 12, 840-835; WHO Tech. Report Series No. 711, 1984; Boudreau et al. 1982 Lancet II, 1335; Noreen et al. 1991, Lancet 337, 1140-1143; Hurwitz et al. 1981, Lancet I, 1068-1070; Timmermanns et al 1982, Lancet I 11181).
Although quinine resistance is also emerging along Thailand-Myanmar border, still the quinine and tetracycline combinations remains over 80% effective in practice (Vanijanonta et al. 1992, Lancet 339,369). Besides, seven day regimen of quinine and tetracycline was found to be effective in treating
P. falciparum
cases which were resistant to artesunate, arteether and mefloquine combined therapy.
Mefloquine was reported to produce neuropsychiatric side-effects in adults who developed tonic clonic fits. Besides psychosis, delusions and hallucinations, anxiety sleep disturbances were also reported after mefloquine (Drugs 1990, 39, 160-169).
Multi-drug-resistance in
P. falciparum
malaria and high level of
P. vivax
resistant strains are posing a major threat to countries in South-east Asia. Africa and Southern America. Most seriously affected areas include Thai-Myanmar Burmese border, where resistance to nearly all available drugs (Chlorquine, sulfadoxine-pyrimethamine, mefloquine, quinine) has already got established, (WHO Report on Infectious Diseases, 1999, WHO/CDS/99.1).
Halofantrine is more effective but rather high doses of the drug are now required to control resistant
P. falciparum
Brasseur et al. 1993. Lancet 341, 901-2) which could lead to increased risk of cardiotoxicity of this new antimalarial including sinus bradycardia, sinus arrhythmia, tall peak T. waves, QT interval prolongation, ectopic beats (Karbwang et al. 1993, Lancet, 342, 501; Wildling et al. 1993. Lancet, 342, 55; Kremsner el al. Am. J. Trop. Med. Hyg. 50, 790-795) which has imposed great limitation on the antimalarial potential of this drug. Several reports have recently appeared which document emergence of chloroquine resistance by
P. viva
(Schwartz et al. 1991. New England J. Med. 324, 927; Schuurkamp et al. 1992. Trans. R. Soc. Trop. Med. Hyg. 86, 121-2; Murphy el al., 1993. Lancet, 341, 96-100; Garg et al. 1995. Trans. R. Soc. Trop. Med. Hyg. 89, 656-7; Than et al. 1995. Trans. R. Soc. Trop. Med. Hyg. 89, 307-8; Baird et al., 1996. Trans. R. Soc. Trop. Med. Hyg. 90, 409-410, Baird et al., Am. J. Trop. Med. Hyg. 56, 627-631. The World Health Organization (1984) had accorded high priority to the development of fast acting artemisinin derivatives as blood schizontocides for the emergency treatment of cerebral malaria as well as for the control of multiple drug resistant cases of
Plasmodium falcipanum.
&agr;,&bgr;-arteether is an ethylether derivative of qinghaosu (artemisinine), which is extracted from
Artemisia annua,
a plant long known in traditional Chinese medicine for its antimalarial properties. &agr;,&bgr;-Arteether (30:70) (intramuscular) is one of the artemisinin derivatives that has been developed in India and shows antimalarial activity against chloroquine, mefloquine and quinine resistant
P. yoelii nigeriensis
and cures experimental cerebral malaria infections (
P. knowlesi/P. fragile
in rhesus monkey model). Dutta et al. 1989. Pharmacol. Res. 21, 415-19; Dutta and Tripathi, 1996, Japn. J. Trop. Med. Hyg. 24, 65-69; Tripathi et al. 1997, Exp. Parasitol. 87, 290-292; Bajpai et al. 1989 Trans. R. Soc. Trop. Med. Hyg. 83, 484).
&agr;,&bgr;-Arteether is relatively safer and its LD
50
dose is 1250 mg/kg in Swiss mice as compared to artemether (LD
50
263 mg/kg (im) and artesunate (LD
50
475 mg/kg, im)(J. Trad. Chinese Med. 1982,2(1) 31-38). Clinical trials of intramuscular injection of this compound have been completed and marketed. Data on clinical trials with injectible preparation of &agr;,&bgr; arteether (30:70 mixtures of isomers amongst
P.falciparum
cases has been published (Mohapatra et al 1996. Indian J. Med. Res. 104, 284-7, Valecha et al. 1997, Int. J. Clin. Pharm. Res. XVII (1)11-15. Mohanty et al. 1997. Trans , R. Soc. Trop. Med. Hyg. 91, 328-330; Mishra et al. 1995, Trans. R. Soc. Trop. Med. Hyg. 89, 299-301).
STATUS OF RECTAL SUPPOSITORIES OF ARTEMISININ DERIVATIVES
Several reports have been published which support the observation that rectal suppository preparations of artemisinin can exert antimalaral effect in reducing the
P. falciparum
parasitaemia in critically sick and and severe cases including cerebral complications (Li et al., Trans.R.Soc.Trop.Med.Hyg. 88(Suppl 1), 1994, 5-6; Arnold et al., Trans. R.Soc. Trop. Med.Hyg. 84, 1990, 499-502; Hien et al., Trans. R.Soc.Trop.Med. Hyg. 85, 1991, 202-211; Hien et al., Trans. R. Soc. Trop. Med. Hyg. 86, 1992, 582-583; Lie et al., J. Trad. Chinese Med. 5, 1985, 159-161; Cao et al., 1997, Trans.R.Soc.Trop.Med.Hyg. 91, 335-342). The suppository treatment was found satisfactory for parasite clearance and for fever clearance in patients. However, a very high dose of artemisinin (2800 mg in 48-56 h) is needed to be administered to produce complete parasite clearance. Besides the high dose of artemisinin administered may approach the toxicity level and there are frequent problems of recrudescence with this drug in children.
Artesunate suppositories have also been used for control of severe
P. falciparum
cases. Although they produce fast parasite clearance and fever clearance, the recrudescence rate is high. Artesunate suppositories were given at a total dose of 1600 mg (in 8 doses) over 3 day course and in order to prevent recrudescence a long-acting antimalarial mefloquine (1250 mg) was administered to reduce recrudescence rate (92%) [(Looareesuwan et al., Ann.Trop.Med.Parasitol. 89, 1995, 469-475; Looareesuwan et al., Jpn. O. Trop. Med Hyg. 24(suppl 1) 1996, 13-15]. Looareesuwan also administered 1600 mg artesunate suppository which was followed by mefloquine (1250 mg) which produced 96% cure rate and Bhatt et al., [Jpn. J. Trop. Med. Hyg. 24(suppl. 1), 1996, 59-63] also used 1600 mg artesunate suppositories followed by 1000 mg mefloquine. In spite of double treatment 13.6% mortality was recorded (cure rate 86.4%). Gomez [Gomez Landires, Jpn. J. Trop. Med. Hyg. 24 (suppl. 1) 1996, 16-24] employed 1400 mg artesunate suppository which was followed by 750 mg mefloquine. They [Thwe et al., Jpn. J. Trop. Med. Hyg. 24 (suppl. 1) 1996, 25-32] administered 1200 mg artesunate suppositories (in 3 days) followed by 1250 mg mefloquine for treatment of severe malaria and achieved a cure rate of 92.3%. Halpaap et al., (1998, Am. J. Trop. Med. Hyg. 58, 365-368) administered two 50 mg artesunate suppositories at 4 h interval in children followed by sulfadoxin/pyrimethamine, and Sabchareon et al., (1998) administered 200 mg artesunate suppository (×3 days) followed by mefloquine (2 doses).
Most of the trials recommend the administration of a second antimalarial like mefloquine or sulfadoxin/pyrimethamine with artesunate suppository. Wilairatana et al., (1997, Ann. J. Trop.Med. Med.Parasitol 91, 891-896) also reported that artesunate suppository was usefull in reducing and clearing parasitaemia in severe
P. falciparum
cases. Kyaw et al., (1996 Jpn. J. Trop.Med. Hyg. 24 suppl. 1, 55-58) compared the efficacy of artesunate suppositories (200 mg ×3 day

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