- Email: [email protected]
α, β-Arteether for the treatment of complicated falciparum malaria
TRANSACTIONS
OFTHE
a, P-Arteether
ROYAL
SOCIETY
OFTROPICAL
for the treatment
MEDICINE
AND
of complicated
HYGIENE
(1997) 91,328-330
falciparum
malaria
Sanjib Mohanty, S. K. Mishra, S. K. Satpathy, Sanghamitra Dash and Jayakrishna Internal Medicine and Pathology, Ispat General Hospital, Rourkela, India
Patnaik
Departments of
Abstract a, P-Arteether is an ethyl ether derivative of artemisinin which is an efficient schizontocidal drug in mild falciparum malaria. The present study reports the efficacy of the drug in severe falciparum malaria. Fifty patients with severe falciparum malaria were given intramuscular arteether, 150 mg, once daily on 3 consecutive days. The median fever clearance time was 72 h (range 12-120 h) and the median parasite clearance time was 2 d (range l-4 d). Rapid recovery from coma was observed in cerebral malaria patients (after a median of 18 h, range 6-72 h). The recovery from other complications was also faster and complete. Two patients died; both had cerebral malaria and haemolytic jaundice, one had respiratory distress needing ventilatory support and the other had severe anaemia. Recrudescence within 28 d was observed in 7 patients. Drug toxicity or significant side effects were not noticed in any patient. Keywords:
malaria, Plasmodiumfulciparum, chemotherapy, a, P-arteether
Introduction Resistance of Plasmodium falciparum to antimalarial drugs is now common, and even resistance to quinine has been reported in Thailand and Viet Nam (WHO, 1987). This has led to a search for an effective alternative antimalarial drug with minimal side effects. The compounds derived from the Chinese medicinal plant qinghaosu (artemisinin) are the most rapidly acting antimalarial drugs available to date (WHITE, 1994). Artesunate and artemether, 2 of the artemisinin derivatives with significant antimalarial activity, have been used in over a million people in Burma, Viet Nam, Thailand and The Gambia with impressive results (SHWE et al., 1988; ARNOLD et al., 1990; LOOAREESUWAN et al., 1992; WHITE et al., 1992). Reports suggest that artemisinin derivatives are very rapidly acting and have a broader stage specificity of antimalarial action, producing more rapid clinical and parasitological response than other antimalarial drugs (HIEN & WHITE, 1993). So far, no significant toxicity or drug resistance to these compounds has been reported (WHITE, 1994). The World Health Organization scientific working group on chemotherapy of malaria (WHO, 1986) has focused attention on the development of arteether, the ethyl derivative of artemisinin, for convenient parenteral use in the treatment of complicated falciparum malaria. Ethers have good storage stability and are highly soluble in oils and suitable for injectable formulation. Both artemether and arteether are more potent than artemisinin. The experimental and phase 1 trials of a, P-arteether have been completed by the Central Drug Research Institute (CDRI), Lucknow, India; a single dose of 300 mg and multiple doses of 150 mg for 3 d produced no significant side effect (A~THANA et al., 1994). Phase 2 trials in uncomplicated falciparum malaria patients have established its effectiveness as a schizontocidal drug (MISHRA et al., 1995). Armed with this experience, a phase 3 trial in patients with severe falciparum malaria was conducted at Ispat General Hospital, Rourkela, and is reported in this paper. Materials and Methods Fifty consecutive patients with severe falciparum malaria, as defined by the World Health Organization (WHO, 1990), admitted to the Internal Medicine Deuartment of Isuat General Hosoital. Rourkela. Orissa, India who we¬ excluded by ihe driteria given below; were included in the study. The presence of asexual l? Address for correspondence: Dr S. Mohanty, Consultant (Internal Medicine), Ispat General Hospital, Rourkela 769 005, Orissa, India. .- -
falciparum parasites in the peripheral blood was confirmed soon after admission. Patients who had received antimalarial drugs within the preceding 7 d, pregnant women, and children below 14 years of age were excluded. Written, informed consent was obtained from the patients or their relatives for the arteether therapy. Venous blood was collected in heparinized tubes for estimation of plasma glucose, urea, creatinine, bilirubin, alanine aminotransferase, and haemoglobin levels, and in ethylenediaminetetraacetic acid for total erythrocyte count, total and differential leucocyte counts, and parasite count. Parasite density was expressed as the percentage of parasitized erythrocytes after counting a minimum of 2000 cells. Parasite count, haemoglobin, total and differential leucocyte counts were repeated every day until day 7, and subsequently on days 14, 21 and 28. Biochemical tests of liver and renal function were carried out on days 4 and 7, and more frequently if necessary. a, P-Arteether, provided by CDRI in ampoules of 150 mg injectable solution, was administered by deep intramuscular injection once daily on 3 consecutive days. No other antimalarial drug was given during the trial. Supportive measures such as blood transfusion, intravenous fluids, electrolytes, dialysis, and respiratory support were provided according to need. Clinical assessment was performed every 4 h or more frequently if required in critically ill patients. The Glasgow coma score was used for objective assessment of cerebral malaria cases. Patients were evaluated with special attention to the fever clearance time, parasite clearance time, and recovery from complications. Fever clearance time was the period from the administration of the first dose of arteether until the buccal temuerature fell to 37°C and remained at or below 37°C for $2 h. Parasite clearance time was the time from the administration of the first dose until parasites were undetectable in a peripheral blood film, and remained so for 7 d. Recovery from coma was considered to have occurred when the patient became conscious, responded to verbal commands, and did not deteriorate further. All patients were kept in hospital for 7 d and more if so needed. On being discharged, they were asked to return for follow-up examination on days 14, 2 1 and 28. Cure was recorded if the patient recovered and did not have a recrudescence during this 28 d period. The study was approved by the ethical committees of Ispat General Hospital, Rourkela and CDRI, Lucknow. Results Fifteen patients had cerebral malaria, 13 had haemolytic jaundice, 3 had severe anaemia, and the remaining 19 had more than one complication-18 had cerebral
329
IX,8-ARTEETHER FOR MALARIA
malaria, 17 had haemolytic jaundice, 2 had severe anaemia, 5 had acute renal failure, and one had acute lung injury. All except 2 patients recovered completely; the 2 exceptions, who died during the course of the study, both had cerebral malaria and haemolytic jaundice; one also had acute lung injury and the other had severe anaemia. The median fever clearance time was 72 h (range 12-120 h). After 24, 48, 72 and 96 h, 6.4%, 38.3%, 55.5% and 93.6% of the patients, respectively, had become afebrile. The median parasite clearance time was 2 d (range l-4 d). Peripheral parasitaemia was undetectable in 31.9%. 89.4% and 93.6% of the natients 24 h after receiving the first, second and third doses of arteether, respectively. Thirty-three patients had cerebral malaria, including 18 with more than one complication. The median Glasgow coma score was 6 (range 3-l 1); 24 patients had a score of less than 8. Two patients had seizures before admission, and 2 died during their hospital stay. Five patients had features of decerebration, of whom 4 survived. Early papilloedema was observed in 2 patients on initial fundus examination, but it became normal by day 7. Seven patients deteriorated within the first 24 h after initiation of therapy; 5 recovered and 2 died. The median recovery time from coma was 18 h (range 6-72 h). The patients who recovered did not have any neurological deficit. Patients with haemolytic jaundice, acute renal failure, and severe anaemia recovered completely after arteether treatment and other supportive measures including blood transfusion and peritoneal dialysis, as required. Thirty-five patients could be followed-up for 4 weeks. Recrudescence was observed in 7 patients. l? falciparum parasites were detected in the peripheral blood film on day 17 in 2 patients, day 2 1 in one, day 26 in 2, and day 28 in 2 patients; none of them had any complication. The cure rate was thus 80% among the followed-up cases. No adverse side effect or toxicity was observed, except for excessive salivation in 3 patients. I
Discussion
This is the first report on the use of a, P-arteether in patients with severe falciparum malaria. Both parasite clearance and fever disappearance, 2 common indicators of recovery from malaria infection, were rapid after arteether therapy. We have previously reported that rapid parasite clearance was directly related to recovery in patients with uncomplicated malaria (MISHRA et al., 1995). However, in the present study, many of our severe malaria patients remained in a critical state even after they had become afebrile and their peripheral blood films were free of malaria parasites. So fever resolution and parasite clearance were not hallmarks of total cure of complicated and severe malaria. There was complete recovery from all the complications in 96% of our patients within 14 d. The mortal& rate of 2 of 50 severe malaria cases was less than that among quinine-treated patients in our hospital (unpublished observations). In the present study, 22 of 24 patients with a Glasgow coma score less than 8 recovered. Five patients had signs of decerebration, but only one of them died. This indicated that arteether is not only schizontocidal but could also check the progressive pathology in severe malaria. KAREWANG et al. (1995) have renorted excellent survival rates. together with rapid parasite clearance, using another artemisinin derivative, artemether. Arteether is an a, P-ethyl ether derivative suspended in ground-nut oil, with slow absorption and elimination. This permits a convenient, once daily dosing schedule. The problem of recrudescence after treatment with artemisinin compounds is troublesome in endemic areas. Seven (20%) of our patients who were followed-up had recrudescences (3 before day 21 and 4 after 21 d). As
the patients returned to an endemic area, it is impossible to tell whether the reappearance of malaria after 21 d was due to reinfection or recrudescence. Even if one assumes that all of them had recrudescences, it is important to note that none of them had any complication. However, considering their speed of action rather than the period of morbidity, artemisinin and related compounds may be preferred for the treatment of severe malaria, rather than other antimalarial compounds. There was no evidence of cardiotoxicity, neutropenia, drug fever, or allergic manifestation. With other artemisinin compounds, some side effects have been reported in experimental animals, namely neurotoxicity, conduction abnormality, and neutropenia (BREWER et aZ., 1994). Except for excessive salivation in 3 patients, no side effect or adverse reaction was noted in our patients. Safety and ease of intramuscular injection of IX, parteether could be advantageous in its use in peripheral hospitals, where facilities for intravenous administration and patient monitoring for drug toxicity do not exist. Quinine is at present the mainstay of therapy for severe falciparum malaria in most rural parts of the world; arteether may be a suitable alternative because of its efficacy, safety, and easy administration, particularly for patients with severe falciparum malaria. Acknowledgements
We express our sincere gratitude to Dr V. P. Sharma, Director, Malaria Research Centre, New Delhi; Dr B Dash, Director (Medical and Health Services), Rourkela Steel Plant, Rourkela; Dr V. I’. Kamboj, Director, and Dr 0. I’. Asthana, Head, Clinical and Exnerimental Medicine. at the Central Drug Research 1nstitute;Lucknow; and to Dr’DI N. Mohapatra and Dr D. Mohanty, Senior Deputy Directors, Ispat General Hospital, Rourkela, for their interest in the project: References Arnold K., Hien, T. T., Chinh, N. T., Phu, N. H. & Mai, I? I? (1990). A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,499-502. Asthana, 0. I’., Gaur, S. I? S., Srivastava, J. S., Ghatak, A., Gupta, K. C. & Srimal, R. C. (1994). Clinical studies with alpha-beta arteether in healthy human volunteers. In: Proceedings of the CSIR Golden Jubilee Symposium, Kumar, S., Sen, A. K., Khanna, R. N. & Dutta, G. B. (editors). New Delhi: Central Drug Research Institute, pp. 3 18-324. Brewer,T. G., Peggins, J. O., Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., Swearengen, J., Heiffer, M. H. & Schuster, B. G. (1994). Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, supplement 1, S1/33-Sll36. Hien, T. T. & White, N. J. (1993). Qinghaosu. Lancet, 341, 603-608. Karbwang, J., Tin, T., Rimchala, W., Sukontason, K., Namsiripongpun, V., Thanavibul, A., Na-Bangchang, K., Laothavorn, P., Bunnag, D. & Harinasuta,T. (1995). Comparison of artemether and quinine in the treatment of severe falciparum malaria in south-east Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89,668-67 1. Looareesuwan, S.,Viravan, C.,Vanijanonta, S., Wilairatana, P., Suntharasamai, P., Charoenlarp, P., Arnold, K., Kyle, D., Canfield, C. &Webster, K. (1992). A randomized trial of mefloquine, artesunate, and artesunate followed by mefloquine in acute uncomplicated falciparum malaria. Lancet, 339,821-824. Mishra, S. K., Asthana, 0. P., Mohanty, S., Patnaik, J. K., Das, B. S., Srivastava, J. S., Satpathy, S. K., Dash, S., Rath, P. K. & Varghese, K. (1995). Effectiveness of CL,fl-arteether in acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89, 299-30 1. Shwe, T., Myint, P. T., Htut, Y., Myint, W. & Soe, L. (1988). The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 82, 665-666. White, N. J. (1994). Artemisinin: current status. Transactions of the Royal Society of Tropical Medicine and Hveiene, 88, supplement 1, S113-Sll4. White, N. J., Waller, D., Crawley, J., Nosten, F., Chapman, D., Brewster, D. & Greenwood, B. M. (1992). Comparison of -I
330
SANJIBMOHANTYETAL.
artemether and chloroauine for severe malaria in Gambian children. Lancet, 339,3 i 7-32 1. WHO (1986). The development of artemisinine and in derivatives. Report of a meeting of the scientt$ic group on chemotherapy of mal&z. Geneva: World Health Oraanization. mimeoeraohed document CHEMAIJ86.3. . - WHO (1987). The epidemiology of drug resistance of malaria parasites. Bulletin of the World Health Organization, 65,
) Announcements
797-816. WHO (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2.
Received 3 June 1996; revised 9 October 1996; accepted for publication 12 November 1996
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OFTHE
a, P-Arteether
ROYAL
SOCIETY
OFTROPICAL
for the treatment
MEDICINE
AND
of complicated
HYGIENE
(1997) 91,328-330
falciparum
malaria
Sanjib Mohanty, S. K. Mishra, S. K. Satpathy, Sanghamitra Dash and Jayakrishna Internal Medicine and Pathology, Ispat General Hospital, Rourkela, India
Patnaik
Departments of
Abstract a, P-Arteether is an ethyl ether derivative of artemisinin which is an efficient schizontocidal drug in mild falciparum malaria. The present study reports the efficacy of the drug in severe falciparum malaria. Fifty patients with severe falciparum malaria were given intramuscular arteether, 150 mg, once daily on 3 consecutive days. The median fever clearance time was 72 h (range 12-120 h) and the median parasite clearance time was 2 d (range l-4 d). Rapid recovery from coma was observed in cerebral malaria patients (after a median of 18 h, range 6-72 h). The recovery from other complications was also faster and complete. Two patients died; both had cerebral malaria and haemolytic jaundice, one had respiratory distress needing ventilatory support and the other had severe anaemia. Recrudescence within 28 d was observed in 7 patients. Drug toxicity or significant side effects were not noticed in any patient. Keywords:
malaria, Plasmodiumfulciparum, chemotherapy, a, P-arteether
Introduction Resistance of Plasmodium falciparum to antimalarial drugs is now common, and even resistance to quinine has been reported in Thailand and Viet Nam (WHO, 1987). This has led to a search for an effective alternative antimalarial drug with minimal side effects. The compounds derived from the Chinese medicinal plant qinghaosu (artemisinin) are the most rapidly acting antimalarial drugs available to date (WHITE, 1994). Artesunate and artemether, 2 of the artemisinin derivatives with significant antimalarial activity, have been used in over a million people in Burma, Viet Nam, Thailand and The Gambia with impressive results (SHWE et al., 1988; ARNOLD et al., 1990; LOOAREESUWAN et al., 1992; WHITE et al., 1992). Reports suggest that artemisinin derivatives are very rapidly acting and have a broader stage specificity of antimalarial action, producing more rapid clinical and parasitological response than other antimalarial drugs (HIEN & WHITE, 1993). So far, no significant toxicity or drug resistance to these compounds has been reported (WHITE, 1994). The World Health Organization scientific working group on chemotherapy of malaria (WHO, 1986) has focused attention on the development of arteether, the ethyl derivative of artemisinin, for convenient parenteral use in the treatment of complicated falciparum malaria. Ethers have good storage stability and are highly soluble in oils and suitable for injectable formulation. Both artemether and arteether are more potent than artemisinin. The experimental and phase 1 trials of a, P-arteether have been completed by the Central Drug Research Institute (CDRI), Lucknow, India; a single dose of 300 mg and multiple doses of 150 mg for 3 d produced no significant side effect (A~THANA et al., 1994). Phase 2 trials in uncomplicated falciparum malaria patients have established its effectiveness as a schizontocidal drug (MISHRA et al., 1995). Armed with this experience, a phase 3 trial in patients with severe falciparum malaria was conducted at Ispat General Hospital, Rourkela, and is reported in this paper. Materials and Methods Fifty consecutive patients with severe falciparum malaria, as defined by the World Health Organization (WHO, 1990), admitted to the Internal Medicine Deuartment of Isuat General Hosoital. Rourkela. Orissa, India who we¬ excluded by ihe driteria given below; were included in the study. The presence of asexual l? Address for correspondence: Dr S. Mohanty, Consultant (Internal Medicine), Ispat General Hospital, Rourkela 769 005, Orissa, India. .- -
falciparum parasites in the peripheral blood was confirmed soon after admission. Patients who had received antimalarial drugs within the preceding 7 d, pregnant women, and children below 14 years of age were excluded. Written, informed consent was obtained from the patients or their relatives for the arteether therapy. Venous blood was collected in heparinized tubes for estimation of plasma glucose, urea, creatinine, bilirubin, alanine aminotransferase, and haemoglobin levels, and in ethylenediaminetetraacetic acid for total erythrocyte count, total and differential leucocyte counts, and parasite count. Parasite density was expressed as the percentage of parasitized erythrocytes after counting a minimum of 2000 cells. Parasite count, haemoglobin, total and differential leucocyte counts were repeated every day until day 7, and subsequently on days 14, 21 and 28. Biochemical tests of liver and renal function were carried out on days 4 and 7, and more frequently if necessary. a, P-Arteether, provided by CDRI in ampoules of 150 mg injectable solution, was administered by deep intramuscular injection once daily on 3 consecutive days. No other antimalarial drug was given during the trial. Supportive measures such as blood transfusion, intravenous fluids, electrolytes, dialysis, and respiratory support were provided according to need. Clinical assessment was performed every 4 h or more frequently if required in critically ill patients. The Glasgow coma score was used for objective assessment of cerebral malaria cases. Patients were evaluated with special attention to the fever clearance time, parasite clearance time, and recovery from complications. Fever clearance time was the period from the administration of the first dose of arteether until the buccal temuerature fell to 37°C and remained at or below 37°C for $2 h. Parasite clearance time was the time from the administration of the first dose until parasites were undetectable in a peripheral blood film, and remained so for 7 d. Recovery from coma was considered to have occurred when the patient became conscious, responded to verbal commands, and did not deteriorate further. All patients were kept in hospital for 7 d and more if so needed. On being discharged, they were asked to return for follow-up examination on days 14, 2 1 and 28. Cure was recorded if the patient recovered and did not have a recrudescence during this 28 d period. The study was approved by the ethical committees of Ispat General Hospital, Rourkela and CDRI, Lucknow. Results Fifteen patients had cerebral malaria, 13 had haemolytic jaundice, 3 had severe anaemia, and the remaining 19 had more than one complication-18 had cerebral
329
IX,8-ARTEETHER FOR MALARIA
malaria, 17 had haemolytic jaundice, 2 had severe anaemia, 5 had acute renal failure, and one had acute lung injury. All except 2 patients recovered completely; the 2 exceptions, who died during the course of the study, both had cerebral malaria and haemolytic jaundice; one also had acute lung injury and the other had severe anaemia. The median fever clearance time was 72 h (range 12-120 h). After 24, 48, 72 and 96 h, 6.4%, 38.3%, 55.5% and 93.6% of the patients, respectively, had become afebrile. The median parasite clearance time was 2 d (range l-4 d). Peripheral parasitaemia was undetectable in 31.9%. 89.4% and 93.6% of the natients 24 h after receiving the first, second and third doses of arteether, respectively. Thirty-three patients had cerebral malaria, including 18 with more than one complication. The median Glasgow coma score was 6 (range 3-l 1); 24 patients had a score of less than 8. Two patients had seizures before admission, and 2 died during their hospital stay. Five patients had features of decerebration, of whom 4 survived. Early papilloedema was observed in 2 patients on initial fundus examination, but it became normal by day 7. Seven patients deteriorated within the first 24 h after initiation of therapy; 5 recovered and 2 died. The median recovery time from coma was 18 h (range 6-72 h). The patients who recovered did not have any neurological deficit. Patients with haemolytic jaundice, acute renal failure, and severe anaemia recovered completely after arteether treatment and other supportive measures including blood transfusion and peritoneal dialysis, as required. Thirty-five patients could be followed-up for 4 weeks. Recrudescence was observed in 7 patients. l? falciparum parasites were detected in the peripheral blood film on day 17 in 2 patients, day 2 1 in one, day 26 in 2, and day 28 in 2 patients; none of them had any complication. The cure rate was thus 80% among the followed-up cases. No adverse side effect or toxicity was observed, except for excessive salivation in 3 patients. I
Discussion
This is the first report on the use of a, P-arteether in patients with severe falciparum malaria. Both parasite clearance and fever disappearance, 2 common indicators of recovery from malaria infection, were rapid after arteether therapy. We have previously reported that rapid parasite clearance was directly related to recovery in patients with uncomplicated malaria (MISHRA et al., 1995). However, in the present study, many of our severe malaria patients remained in a critical state even after they had become afebrile and their peripheral blood films were free of malaria parasites. So fever resolution and parasite clearance were not hallmarks of total cure of complicated and severe malaria. There was complete recovery from all the complications in 96% of our patients within 14 d. The mortal& rate of 2 of 50 severe malaria cases was less than that among quinine-treated patients in our hospital (unpublished observations). In the present study, 22 of 24 patients with a Glasgow coma score less than 8 recovered. Five patients had signs of decerebration, but only one of them died. This indicated that arteether is not only schizontocidal but could also check the progressive pathology in severe malaria. KAREWANG et al. (1995) have renorted excellent survival rates. together with rapid parasite clearance, using another artemisinin derivative, artemether. Arteether is an a, P-ethyl ether derivative suspended in ground-nut oil, with slow absorption and elimination. This permits a convenient, once daily dosing schedule. The problem of recrudescence after treatment with artemisinin compounds is troublesome in endemic areas. Seven (20%) of our patients who were followed-up had recrudescences (3 before day 21 and 4 after 21 d). As
the patients returned to an endemic area, it is impossible to tell whether the reappearance of malaria after 21 d was due to reinfection or recrudescence. Even if one assumes that all of them had recrudescences, it is important to note that none of them had any complication. However, considering their speed of action rather than the period of morbidity, artemisinin and related compounds may be preferred for the treatment of severe malaria, rather than other antimalarial compounds. There was no evidence of cardiotoxicity, neutropenia, drug fever, or allergic manifestation. With other artemisinin compounds, some side effects have been reported in experimental animals, namely neurotoxicity, conduction abnormality, and neutropenia (BREWER et aZ., 1994). Except for excessive salivation in 3 patients, no side effect or adverse reaction was noted in our patients. Safety and ease of intramuscular injection of IX, parteether could be advantageous in its use in peripheral hospitals, where facilities for intravenous administration and patient monitoring for drug toxicity do not exist. Quinine is at present the mainstay of therapy for severe falciparum malaria in most rural parts of the world; arteether may be a suitable alternative because of its efficacy, safety, and easy administration, particularly for patients with severe falciparum malaria. Acknowledgements
We express our sincere gratitude to Dr V. P. Sharma, Director, Malaria Research Centre, New Delhi; Dr B Dash, Director (Medical and Health Services), Rourkela Steel Plant, Rourkela; Dr V. I’. Kamboj, Director, and Dr 0. I’. Asthana, Head, Clinical and Exnerimental Medicine. at the Central Drug Research 1nstitute;Lucknow; and to Dr’DI N. Mohapatra and Dr D. Mohanty, Senior Deputy Directors, Ispat General Hospital, Rourkela, for their interest in the project: References Arnold K., Hien, T. T., Chinh, N. T., Phu, N. H. & Mai, I? I? (1990). A randomized comparative study of artemisinine (qinghaosu) suppositories and oral quinine in acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,499-502. Asthana, 0. I’., Gaur, S. I? S., Srivastava, J. S., Ghatak, A., Gupta, K. C. & Srimal, R. C. (1994). Clinical studies with alpha-beta arteether in healthy human volunteers. In: Proceedings of the CSIR Golden Jubilee Symposium, Kumar, S., Sen, A. K., Khanna, R. N. & Dutta, G. B. (editors). New Delhi: Central Drug Research Institute, pp. 3 18-324. Brewer,T. G., Peggins, J. O., Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., Swearengen, J., Heiffer, M. H. & Schuster, B. G. (1994). Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, supplement 1, S1/33-Sll36. Hien, T. T. & White, N. J. (1993). Qinghaosu. Lancet, 341, 603-608. Karbwang, J., Tin, T., Rimchala, W., Sukontason, K., Namsiripongpun, V., Thanavibul, A., Na-Bangchang, K., Laothavorn, P., Bunnag, D. & Harinasuta,T. (1995). Comparison of artemether and quinine in the treatment of severe falciparum malaria in south-east Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89,668-67 1. Looareesuwan, S.,Viravan, C.,Vanijanonta, S., Wilairatana, P., Suntharasamai, P., Charoenlarp, P., Arnold, K., Kyle, D., Canfield, C. &Webster, K. (1992). A randomized trial of mefloquine, artesunate, and artesunate followed by mefloquine in acute uncomplicated falciparum malaria. Lancet, 339,821-824. Mishra, S. K., Asthana, 0. P., Mohanty, S., Patnaik, J. K., Das, B. S., Srivastava, J. S., Satpathy, S. K., Dash, S., Rath, P. K. & Varghese, K. (1995). Effectiveness of CL,fl-arteether in acute falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89, 299-30 1. Shwe, T., Myint, P. T., Htut, Y., Myint, W. & Soe, L. (1988). The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 82, 665-666. White, N. J. (1994). Artemisinin: current status. Transactions of the Royal Society of Tropical Medicine and Hveiene, 88, supplement 1, S113-Sll4. White, N. J., Waller, D., Crawley, J., Nosten, F., Chapman, D., Brewster, D. & Greenwood, B. M. (1992). Comparison of -I
330
SANJIBMOHANTYETAL.
artemether and chloroauine for severe malaria in Gambian children. Lancet, 339,3 i 7-32 1. WHO (1986). The development of artemisinine and in derivatives. Report of a meeting of the scientt$ic group on chemotherapy of mal&z. Geneva: World Health Oraanization. mimeoeraohed document CHEMAIJ86.3. . - WHO (1987). The epidemiology of drug resistance of malaria parasites. Bulletin of the World Health Organization, 65,
) Announcements
797-816. WHO (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2.
Received 3 June 1996; revised 9 October 1996; accepted for publication 12 November 1996
/
An International
African Index Medicus (AIM) Project Index to African health literature and information
sources
In order to give access to information published in or related to Africa and to encourage local publishing, the Association for Health Information and Libraries in Africa (AHILA), with the technical support of the World Health Organization, has initiated a project to create an international index to African Health literature and information sources-the African Index Medicus. The creation of the regional index is a collaborative, participatory process. Firstly, national databases are being built, using a common methodology, in African countries. From them, local information services and products will be provided for national health professionals. National production should ensure self-sufficiency and sustainability at country level and the tailoring of services according to local needs. The various national databases are then merged into a regional data base to which are added bibliographic MEDLINE, records relating to health in Africa from other international existing sources such as WHO’s~OLIS, POPLINE etc. to produce the African Index Medicus in printed or electronic form, eventually CD-ROM. It is distributed to African countries as part of an affiliated membership to AHILA for institutions outside the region. At this stage, AHILA, with support from WHO, is looking for further sponsoring partners at bilateral level with African countries not yet participating in the Project. Sponsorship comprises equipment and training of staff and could be part of an information component of a health related project in the country, which may also include use of communications and CD-ROM. Further information can be obtained from Mrs Lucilda Hunter, WHO Regional Office for Africa, Library, P.O. Box 6, Brazzaville, Congo; fax +242 83 94 00, e-mail [email protected]
Low Priced
Publications
Corn Tropical
Health Technology
Students and medical workers from developing countries can purchase medical books and laboratory learning aids from Tropical Health Technology at reduced prices, including the new editions of: Manson’s Tropical Diseases, 20th edition Color Atlas of Tropical Medicine and Parasitology 4th edition Lecture Notes on Tropical Medicine, 4th edition. Also available are other up to date textbooks covering tropical paediatrics, epidemiology, cardiology, nursing, midwifery, laboratory sciences, and solar energy.Training materials include laminated colour photomicrographs with text covering the microscopical diagnosis of tropical disease. A publications list with prices (inclusive of postage) and order form can be obtained from Tropical Health Technology, 14 Bevills Close, Doddington, March, PE15 OTT, UK; fax: +44 (0) 1354 740 013, phone: +44 (0) 1354 740 825.