Publisher Summary This chapter discusses a wide range of animal models available for laboratory studies requiring mosquito transmission of plasmodia. The malarial infections are normally initiated when an infected mosquito, in the act of feeding, injects sporozoites into a susceptible host. However, the majority of experimental studies start with infections initiated by the injection of infected blood. In Plasmodium vivax malaria in humans, characteristics of the infection such as length of the prepatent period, duration and severity of clinical attacks, tendency to relapse, and the latent period between relapses are determined by the number of sporozoites injected to initiate infection. The sporozoite-induced infections differ markedly from infections induced by the injection of infected blood. The total reliance on syringe-passed parasites gives misleading results and bears little relationship to mosquito-borne infections. Only mosquito-produced sporozoites can initiate an infection comparable to those experienced in nature. The sexual development of the parasite takes place in the mosquito gut, and studies on the genetics of the parasite require the establishment of a system of mosquito transmission to understand the mechanisms involved.

The Transmission by Mosquitoes of Plasmodia in the Laboratory

SUMMARY The technical genesis and practice of 8-aminoquinoline therapy of latent malaria offer singular scientific, clinical, and public health insights. The 8-aminoquinolines brought revolutionary scientific discoveries, dogmatic practices, benign neglect, and, finally, enduring promise against endemic malaria. The clinical use of plasmochin—the first rationally synthesized blood schizontocide and the first gametocytocide, tissue schizontocide, and hypnozoitocide of any kind—commenced in 1926. Plasmochin became known to sometimes provoke fatal hemolytic crises. World War II delivered a newer 8-aminoquinoline, primaquine, and the discovery of glucose-6-phosphate dehydrogenase (G6PD) deficiency as the basis of its hemolytic toxicity came in 1956. Primaquine nonetheless became the sole therapeutic option against latent malaria. After 40 years of fitful development, in 2018 the U.S. Food and Drug Administration registered the 8-aminoquinoline called tafenoquine for the prevention of all malarias and the treatment of those that relapse. Tafenoquine also cannot be used in G6PD-unknown or -deficient patients. The hemolytic toxicity of the 8-aminoquinolines impedes their great potential, but this problem has not been a research priority. This review explores the complex technical dimensions of the history of 8-aminoquinolines. The therapeutic principles thus examined may be leveraged in improved practice and in understanding the bright prospect of discovery of newer drugs that cannot harm G6PD-deficient patients.

https://cmr.asm.org/content/cmr/32/4/e00011-19.full-text.pdf

8-Aminoquinoline Therapy for Latent Malaria

Over the past three decades the emergence and geographical dissemination of drug resistance has hampered both the treatment of acute malaria and its prevention by chemoprophylaxis. The need to cure established infections in indigenous people in endemic areas continues to present a global challenge, but a particular difficulty arises at present from the exponentially increasing numbers of non-immune people who travel to malarious countries. Plasmodium falciparum, the parasite causing malignant tertian malaria, is the main cause of morbidity and mortality and is responsible for the great majority of deaths on the African continent, as well as in travellers returning to non-endemic countries. Between 0.43 and 0.86 million African infants up to four years of age die of malaria every year1. Drug resistance in this parasite first emerged in the early 1960s when chloroquine, until then the most widely used, safest and cheapest blood schizontocide, failed to cure acute infections. Since that time, a pattern of multidrug resistance has evolved and has now reached a critical point. P. vivax, which accounts for considerable morbidity though few deaths, is characterized by the development of relapses from the latent stage of the parasite in the liver, the hypnozoite (Figure 1). Radical cure by destroying the hypnozoites can be achieved only by administering a lengthy course of primaquine, an 8-aminoquinoline which can have serious side-effects. Moreover, chloroquine resistance has appeared in P. vivax in several countries. The need for new antimalarials is now acute, but until very recently most of the pharmaceutical industry has responded in lukewarm fashion at best. This paper focuses on the evolution of a novel 8-aminoquinoline that has emerged from the antimalarial drug programme first started by the Walter Reed Army Institute of Research (WRAIR) in the USA in 1963. Originally labelled WR 238,605 it was later called etaquine and has now been given the generic name tafenoquine. The potential role of this broad-spectrum compound is discussed from two points of view as a longacting chemoprophylactic for non-immune travellers, and as an agent for the treatment of established infection with multidrug-resistant P. falciparum or the radical cure of P. vivax.

The evolution of tafenoquine--antimalarial for a new millennium?

Following Ronald Ross' demonstration in 1897 that mosquitoes transmit malarial parasites, efforts to control malaria were naturally focussed on attacking the mosquito vector by various measures, mainly directed against the aquatic stages. Although the results were spectacular in some areas, there was a growing realisation that effective control of malaria depended on other factors, including the availability of better drugs than quinine and a greater understanding of the epidemiology of the disease under various environmental conditions. With the discovery of DDT, an all-out effort was made to eradicate malaria by attacking adult mosquitoes. Eradication was not achieved in many countries, mainly because of inadequate health infrastructures. With the emergence of chloroquine-resistant parasites, the search for more effective drug regimens intensified, various drugs and drug combinations were assessed, and methods were developed to monitor and assess degrees of resistance. Since resistance to drugs can develop very quickly, the use of drug combinations, especially those containing artemisinin derivatives, is now recommended. Insecticide-impregnated bednets have become the preferred method of vector control. Although the search for better tools must continue, the events of the past century emphasise the need to strengthen health systems to ensure that they are capable of delivering effective interventions and of assessing their effectiveness in controlling malaria.

The chequered history of malaria control: are new and better tools the ultimate answer?

In 1902, Sir Ronald Ross was awarded the Nobel Prize in Medicine for his discovery of the mosquito transmission of malaria. This finding was achieved working with avian malaria and its vector, giving him a control over his experimental subjects difficult to attain with human models. Since then, malaria parasites of birds have played an essential role as a model in human malaria studies. Important advances in medical parasitology such of the study of the life cycle, development of chemotherapy, and cultivation in vitro have initially been developed using bird haemosporidian models. Significant anti-malarial compounds such as plasmochin, primaquine and atebrin were evaluated in bird model. In the same way bird parasites were used for drug testing and for further malaria-associated experiments. Nowadays, research on bird malaria is at the very peak since scientists have realized the benefits of using studies on avian malaria to answer ecological, behavioural and evolutionary questions. This review will highlight the importance of studies on avian malaria, showing the results of some recent investigations on this topic and describing new applications of avian malaria researches that could be useful for conservation and health policies in 21th century.

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Recent Advances in Studies on Avian Malaria Parasites

anderen Infektionskrankheiten nm die tViitarbeit der Chemie auf dem Gebiet der h6chsten Menschheitsprobleme handelt, was ieh in diesem Kreis nicht n~iher darzulegen brauche. Ich m6chte zum SchluB noch einige Worte fiber die Entwicklungsgeschichte des Plasmochins hinzuffigen. Auch dieses Produkt verdankt ebenso wie das Bayer 2o5 seine Existenz der gleichberechtigten und in meinen Angen auch gleichwertigen Zusammenarbeit zwischen chemischem und chemotherapeutischem Laboratorium im Rahmen unserer Fabrik. Im Falle der Malaria war yon seiten des chemotherapentischen Laboratoriums noch eine besondere Voraussetzung zu erftillen, n~imlich die Ausaxbeitung einer Methode, die einen qnantitat iven Vergleich verschiedener Pr~parate auf die Erreger der Malaria zul~iBt. Herr Dr. ROEHL, yon dem diese Grundlage geschaffen wurde, hat nachher die M6glichkeit, Ihnen fiber diese Arbeiten selbst zu berichten. Es bleibt mir also nur fibrig, die Namen derjenigen Herren zu nennen, denen der chemische Teil der Erfindung zu verdanken ist. Es sind dies die Herren Dr. SCHUL~MA~N, Dr. SCH6N~6~E:a und Dr. WlNGLER, welche auf einem neuen, yon dem bisher bekannten v611ig abweichenden chemischen Wege die gegen Malaria wirksame Reihe yon Verbindungen einschlieBlieh des Plasmochins synthetisiert haben. Herr Dr. SCHULEMANN hat sich auBerdem auch an der praktischen Erprobnng des Mittels im Herbst 1925 und 1926 in Grosseto in Toskana beteiligt, wo ihm yon den Leitern der dortigen Krankenh~iuser in der Klinik des Herrn Prof. MEM~I in entgegenkommendster Weise eine Arbeitsm6glichkeit geschaffen wurde, ~hnlich wie unserem Herrn Dr. IRo~L seitens der spanischen Regierung in Talavera de la Reina. Um die Ausarbeitung des Herstellungsverfahrens haben sich die Herren Dr. MI~TZSCI~ und Dr. SCHRANZ verdient gemacht, um die pharmakologische Analyse der Plasmochinwirknng auf den I4reislauf der Letter nnseres pharmakologischen Laboratoriums, Herr Dr. EicHHoL'rz. Der besondere Dank unserer Firma gilt abet den Herren, die nach Abschlul3 der Laboratoriumsarbeit ihr K6nnen und die in ihren Kliniken gebotenen M6glichkeiten zur Auswertung des Plasmochins am malariainfizierten Pat ienten zur Verffigung stellten. Herr Prof. SIOLI machte die ersten Versuche bezfiglich Vertr~glichkeit und heilender Wirkung am malariageimpften Paralytiker, w~ihrend die Herren des Hamburger Tropeninstitnts, vor allem Herr Obermedizinalrat Prof. Noc~T und Herr Prof. M~3ttL~s ihre internationalen Beziehungen und die in ihre Behandlung gekommenen F~ille yon Mfickenstichmalaria fiir die Erprobung des Mittels eingesetzt haben. Herr Prof. MO~LENS hatte dieses Jahr kaum die Folgen ether schweren Blinddarmoperation fiberstanden, als er sich entschloB, nach Jugoslavien, Griechenland und Bulgarien zu gehen, um seine in Hamburg gesammelten Erfahrungen an der mazedonischen Malaria zu erweitern und zu vertiefen, was wir nm so dankbarer begriigt haben, als uns die Prfifungsm6glichkeit in eigenen I(olonien fehlt, fiber die jedes andere europ~ische Knltur land verfiig±. Trotz aller Schwierigkeiten konnte auf diese Weise durch das Zusammenwif~:en yon dentscher medizinischer Wissenschaft und chemischer Indnstrie ein neues Produkt geschaffen werden, yon dem wir die Hoffnnng haben, dab es sich in den H~nden der Jkrzteschaft der ganzen Welt als eine fiberlegene Waffe gegen eine der verbreitetsten und verheerendsten Krankhei~cen auszuwirken berufen isL

W. Roehl

Papers

Die Wirkung des Plasmochins auf die Vogelmalaria