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Am. J. Trop. Med. Hyg., 71(2), 2004, pp. 187-189
Copyright © 2004 by The American Society of Tropical Medicine and Hygiene

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SHORT REPORT: THE ACTIVITY OF PAMAQUINE, AN 8-AMINOQUINOLINE DRUG, AGAINST SPOROZOITE-INDUCED INFECTIONS OF PLASMODIUM VIVAX (NEW GUINEA STRAINS)

ANTHONY W. SWEENEY, CHARLES R. B. BLACKBURN, AND KARL H. RIECKMANN
Institute for the Biotechnology of Infectious Diseases, University of Technology Sydney, Gore Hill, New South Wales, Australia; Darling Point New South Wales, Australia; Army Malaria Institute, Enoggera, Queensland, Australia

 

ABSTRACT

It was reported in 1946 that the administration of pamaquine during the incubation period delayed but did not prevent primary attacks of a New Guinea strain of Plasmodium vivax malaria. The observation that none of the four test subjects in this study had relapses has not previously been published and may have important implications for the evaluation of other 8-aminoquinoline compounds against relapsing vivax malaria.

In 1926, pamaquine (plasmoquine) was the first drug to be synthesized with a marked activity against human malaria parasites.1 This 8-aminoquinoline drug, taken in combination with quinine, was able to cure many Plasmodium vivax infections when taken daily over a period of 2–3 weeks.2 Pamaquine also prevented primary attacks of P. vivax malaria when administered at a daily dose of 60 mg base from the day before until the sixth day after exposure to sporozoite-infected mosquitoes.3 Subsequent concerns about drug toxicity, including the sudden onset of severe hemolytic reactions, prompted the Malaria Commission of the League of Nations to advocate that the daily dose of pamaquine be reduced to 27 mg and that its administration be limited to seven days.4 Even when combined with quinine, this lower dose of pamaquine did not prevent relapses of P. vivax malaria.

During 1944, a reappraisal of pamaquine was undertaken in the United States under the auspices of the Board for the Coordination of Malarial Studies.5 A recent historical account of Australian malaria research during World War II indicates that the wartime American interest in pamaquine stimulated Fairley’s group of Australian Army researchers at the Land Headquarters Medical Research Unit in Cairns, Queensland to investigate the causal prophylactic potential of this drug against New Guinea strains of P. vivax in 1945.6 Although the results of this study were previously published,7 the data concerning subsequent relapses were only described in an internal report.8 The results contained in this report, which are published here for the first time, provide new information about the activity of 8-aminoquinoline compounds against the exoerythrocytic stages of P. vivax and should stimulate further discussion about the potential role of these compounds in the prevention and treatment of P. vivax malaria. This study was done when there were no accepted ethical guidelines and procedures for clinical trials. However, an independent review of these World War II experiments made by the Australian Repatriation Medical Authority in 1999 considered them "to be best practice setting for the time and by current standards, even by allowing for the substantial developments of research ethics in recent years, were well conducted."9

On 15 January 1945, 10 Australian Army volunteers, who had not previously been exposed to malaria, were each bitten by 20 Anopheles punctulatus mosquitoes infected with sporozoites of a New Guinea strain of P. vivax. Four volunteers received 80 mg of pamaquine base on the day prior to biting, on the day of biting, and for five days subsequent to biting, a total of 560 mg over a seven-day period (–1 to +5 regimen). The daily dose was divided and given as follows: 20 mg at 10:00 AM, 30 mg at 2:00 PM, and 30 mg at 6:00 PM. Another four volunteers received the same daily dose regimen of pamaquine on the sixth to tenth days (inclusive) after biting, a total of 400 mg over a five-day period (+6 to +10 regimen). The other two volunteers did not receive the drug and served as controls.

Thick blood films (not less than 1 µL) were collected from each volunteer at least once a day and examined for malaria parasites. All eight volunteers who had pamaquine developed overt P. vivax malaria requiring therapy as previously reported.10 In the four volunteers receiving the –1 to +5 pamaquine regimen, patent parasitemia and/or overt malaria were first observed between 17 and 21 days after exposure to mosquitoes. In the four volunteers receiving the +6 to +10 regimen, parasitemia and/or overt malaria appeared between 19 and 26 days. Both control volunteers developed patent parasitemia and fever > 38°C between 11 and 13 days after the mosquito bites.

Transfusion of 200 mL of whole blood from the volunteers to uninfected recipients were made 9 or 10 days after exposure to mosquitoes. All of the recipients of blood from the two control volunteers and the four volunteers in the +6 to +10 group developed malaria, thereby demonstrating that the volunteers had submicroscopic levels of parasites in their circulation 9 or 10 days after infection. However, none of the recipients of blood from the four volunteers in the –1 to +5 group developed overt attacks of malaria, indicating that pamaquine had delayed the release of pre-erythrocytic stages into the bloodstream.10

Although pamaquine delayed the onset of primary attacks of malaria, it did not prevent them. Incomplete protection was also observed during other studies with maximum tolerated doses of pamaquine using the same drug regimen.11,12 This is in contrast to the earliest prophylactic study reported in 1931 in which complete protection was observed, even at somewhat lower doses of pamaquine.3

After developing malaria, the volunteers at Cairns received a 13-day treatment regimen of quinine, atebrin, and pamaquine: quinine, 2,000 mg/day on days 1–3; atebrin, 600 mg on day 4, 500 mg on day 5, 400 mg on day 6, 300 mg on day 7, and 200 mg on day 8; quinine, 1,000 mg/day; and pamaquine, 30 mg base/day on days 9–13. Each person then received suppressive doses of 100 mg of atebrin daily for 42 days. After completing this 55-day drug regimen, all volunteers were monitored until January 29, 1946, 380 days after being bitten by infected mosquitoes.

All four volunteers who were in the +6 to +10 group had relapses between 43 and 118 days after the end of treatment. The two control volunteers also relapsed 39 and 82 days after treatment. In contrast, none of the four volunteers in the –1 to +5 group had any further attacks of P. vivax malaria during the 380 day observation period (Table 1Go).


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TABLE 1
First relapse in volunteers on two different prophylactic regimens of pamaquine who were exposed to the bites of mosquitoes infected with New Guinea strains of Plasmodium vivax*
 
The wartime research at Cairns demonstrated that in contrast to European strains of P. vivax, which are characterized by an interval of 6–12 months between the primary attack and the first relapse, New Guinea strains of the parasite usually relapse within a few weeks or months after treatment of the primary attack or cessation of suppressive drug therapy.13 Thus, relapses occurred between 6 and 17 weeks after the end of drug suppression in the six volunteers who did not receive pamaquine during the first six days after mosquito exposure. However, no relapses were observed among the four volunteers who received pamaquine from –1 to +5 days after exposure to infected mosquitoes. Even though the period of observation after completing treatment of the first attack did not exceed 10 months and the numbers were small, the short-term relapse pattern (so characteristic of New Guinea strains of P. vivax) and the homogeneity of results indicate real differences between the two test groups. The unpublished report prepared by one of us (CRBB) noted: "It would appear not unlikely that radical cure has been effected."8 Confirmation of radical cure in the four volunteers who received pamaquine during the first week after mosquito exposure was provided in a tabulated analysis of P. vivax malaria relapses among the volunteers in the Cairns experiments compiled on February 28, 1947, more than 22 months after they completed treatment of their first attack.14 This states explicitly that the four individuals did not relapse.

Thus, high doses of pamaquine during the first five days after mosquito exposure had two separate effects on the exoerythrocytic stages of P. vivax. 1) The incubation period was prolonged because subinoculations from the four volunteers were negative on the 9th or 10th day after biting when erythrocytic parasites were expected to be present. 2) Relapses did not occur after treatment. This implies that the drug slowed, but did not prevent, the development of the pre-erythrocytic stages that are responsible for the primary attack, whereas it did prevent the development of the exoerythrocytic stages that cause relapses. These findings are consistent with the hypnozoite theory of malaria relapses,15 and they are in agreement with the results obtained during prophylactic studies with the Chesson strain of P. vivax.12

The 58-year-old observations presented in this report are the first indication that a drug taken during the first week of the incubation period provides better protection against relapses than against primary attacks of P. vivax malaria. In other words, liver stages eventually producing relapses were apparently more susceptible to drug action than those responsible for the initial attack of malaria. The observed dichotomy in the response of exoerythrocytic schizonts to pamaquine may apply to other 8-aminoquinoline drugs and should be borne in mind during current efforts to improve the prevention and treatment of P. vivax malaria.16

Received December 11, 2003. Accepted for publication February 8, 2004.

Authors’ addresses: Anthony W. Sweeney, Institute for the Biotechnology of Infectious Diseases, University of Technology Sydney, Westbourne Street, Gore Hill, New South Wales 2065, Australia, Telephone: 61-2-4385-8774, Fax: 61-2-9514-4003, E-mail: tony. sweeney{at}uts.edu.au. Charles R. B. Blackburn, 64/10 Etham Avenue, Darling Point, New South Wales 2027, Australia, Telephone: 61-2-9363-4816, E-mail: ruthven{at}nd3d.com. Karl H. Rieckmann, Army Malaria Institute, Gallipoli Barracks, Enoggera, Queensland 4052, Australia, Telephone: 61-7-3332-4931, E-mail: Karl.Rieckmann{at}defence.gov.au.

Reprint requests: Anthony W. Sweeney, Institute for the Biotechnology of Infectious Diseases, University of Technology Sydney, West-bourne Street, Gore Hill, New South Wales 2065, Australia.

 

REFERENCES

  1. Muehlens P, 1926. Die Behandlung der natuerlichen menschli\chen Malaria-infektionen mit Plasmochin. Arch Schiffs-u Tropenhyg 30: 25–32.
  2. Sinton JA, Smith S, Pottinger S, 1930. Studies in malaria, with special reference to treatment. Part XII. Further research into the treatment of chronic benign tertian malaria with plasmoquine and quinine. Indian J Med Research 17: 793–814.
  3. James SP, Nicol MB, Shute PG, 1931. On the prevention of malaria with plasmoquine. Lancet ii: 341–342.
  4. Malaria Commission, 1933. Third General Report, Therapeutics of Malaria. Bull Health Org League of Nations 2: 185–285.
  5. Shannon JA, 1946. Rationale underlying the clinical evaluation of antimalarial drugs. Wiselogle, FY ed. A Survey of Antimalarial Drugs, 1941–1945. Washington, DC: Board for the Co-ordination of Malarial Studies, 177–220.
  6. Sweeney T, 2003. Malaria Frontline. Melbourne: Melbourne University Press, 152–155.
  7. Fairley NH, 1946. The chemotherapeutic control of malaria. Schweiz Med Wochenschr 76: 925–932.
  8. LHQ Medical Research Unit, 1946. The Antimalarial Activity of Plasmoquine in Volunteers Exposed to Experimental Mosquito-Transmitted Malaria (New Guinea strains). Fairley Papers 65/9/35. Canberra: Basser Library, Australian Academy of Science.
  9. Sweeney T, 2003. Malaria Frontline. Melbourne: Melbourne University Press, 306.
  10. Fairley NH, Blackburn CR, Andrew RR, Mackerras MJ, Roberts FHS, Allmann SLW, Gregory TS, Backhouse TC, Tonge JI, Black RH, Pope KG, Dunn SR, Swan MSA, Akhurst TAF, Roberts EM, 1947. Sidelights on malaria in man obtained by subinoculation experiments. Trans R Soc Trop Med Hyg 40: 621–676.
  11. Feldman HR, Packer H, Murphy FD, Watson RB, 1946. Pamaquine naphthoate as a prophylactic for malarial infections. Fed Proc 5: 224.
  12. Jones R, Craige B, Alving AS, Whorton M, Pullman TN, Eichelberger L, 1948. A study of the prophylactic effectiveness of several 8-aminoquinolines in sporozoite-induced vivax malaria (Chesson strain). J Clin Invest 27 (Suppl): 6–11.[Medline]
  13. Fairley NH, 1945. Chemotherapeutic suppression and prophylaxis in malaria: an experimental investigation undertaken by medical research teams in Australia. Trans R Soc Trop Med Hyg 38: 311–365.
  14. Anonymous, 1947. Cairns Experimental Group – Relapse Experience. Notes dated February 28, 1947. Fairley Papers 65/32/13. Canberra: Basser Library, Australian Academy of Science.
  15. Krotoski WA, Collins WE, Bray RS, Garnham PCC, Cogswell FB, Gwadz RW, Killick-Kendrick R, Wolf R, Sinden R, Koontz LC, Stanfill PS, 1982. Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection. Am J Trop Med Hyg 31: 1291–1293.
  16. Baird JK, Rieckmann KH, 2003. Vivax series: can primaquine therapy for vivax malaria be improved? Trends Parasitol 19: 115–120.[ISI][Medline]



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