Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war

Abstract

Malaria has had an enormous impact on human history, not least in times of war. The disease has been treatable by a natural remedy, quinine, since the 17th century, but the production of synthetic antimalarial agents was first achieved in Germany in the wake of the Great War of 1914-1918, in which malaria had caused immense problems. In the 1920s research workers in the Bayer laboratories of the IG Farbenindustrie consortium developed the 8-aminoquinoline plasmoquine (the forerunner of primaquine). They went on to develop the acridine dye, atebrin (mepacrine) and the 4-aminoquinolines, Resochin (developed at the end of the Second World War in America as chloroquine) and Sontochin. British attempts to match the advances achieved by the Germans were at first unproductive, partly because collaboration between academic and industrial organizations in the UK was beset by concerns over patent rights. However, with the outbreak of World War II, when supplies of antimalarials were scarce, ICI succeeded in the large-scale production of mepacrine (essential to prosecution of the war, particularly in the Far East) and also initiated a programme of collaborative research that eventually led to the discovery of proguanil (Paludrine); this, in its turn led to the diaminopyrimidine, pyrimethamine. A massive cooperative screening programme in the USA during World War II eventually bore fruit in the realization of the therapeutic potential of chloroquine, and in the later development of amodiaquine and primaquine. Some of this work also influenced the subsequent discovery of mefloquine and halofantrine at the Walter Reed Army Institute of Research.

Biological and haematological safety profile of oral amodiaquine and chloroquine in healthy volunteers with or without <i>Plasmodium falciparum</i> infection in northeast Tanzania

“…Although total serum bilirubin was elevated, in none of the cases had jaundice (the main characteristic presentation) (Larrey et al, 1986). The level of increase was mild and jaundice clinical presentation was unexpected based upon pre-clinical studies and previous experience with amodiaquine (Greenwood, 1995). A non-serious de-cline in neutrophils counts in 12.5% of volunteers was observed.…”

“…Since its discovery in 1940's (Greenwood, 1995), AQ established a good safety reputation and was used extensively for chemotherapy in malaria as an alternative to chloroquine (CQ) or to treat CQ failures as well as for chemoprophylaxis in non-immune travellers visiting malarious endemic countries (Hatton et al, 1986). Amodiaquine when used for prophylaxis in non-immune travellers may induce toxic hepatic and potential lethal agranulocytosis (Hatton et al, 1986, Larrey et al, 1986, CDC, 1986.…”

The DNA Virus White Spot Syndrome Virus Uses an Internal Ribosome Entry Site for Translation of the Highly Expressed Nonstructural Protein ICP35

“…QC was originally developed as an antimalarial and antigiardiasis treatment (68,69), but it is now thought to have many other potential uses. Recently, QC was shown to induce an anticancer effect by simultaneously suppressing NF-B and activating p53 signaling (70)(71)(72), and it also acts against prions by inhibiting the formation of PrP Sc (73,74).…”

Ética e investigación en la historia de la malaria

“…Y una vez más, como en los tiempos de Celli y Marchiafava, los enfermos mentales fueron usados como cobayos, como ocurrió con la experimentación conducida por Franz Sioli, director del Hospital Psiquiátrico de Dusseldorf. También en Italia, en los años transcurridos entre las dos guerras mundiales, los ensayos de los fármacos antimaláricos y sus protocolos terapéuticos se efectuaban sobre este tipo de pacientes 14 . El estallido de la II Guerra Mundial indujo en los dos bandos enfrentados una febril actividad de investigación, para poner a punto fármacos y protocolos terapéuticos idóneos para proteger a las tropas de la malaria y de las enfermedades infecciosas en general.…”