History of malaria
Encyclopedia
The history of malaria predates humanity, as this ancient disease evolved before humans did
. Malaria
, a widespread and potentially lethal infectious disease, has afflicted people for much of human history
, and has affected settlement patterns. The prevention and treatment of the disease have been investigated in science and medicine for hundreds of years, and, since the discovery of the parasite which causes it, attention has focused on its biology. These studies have continued up to the present day, since no effective Malaria vaccine
has yet been developed and many of the older antimalarial drug
s are losing effectiveness as the parasite evolves high levels of drug resistance
. As malaria remains a major public health problem, causing 250 million cases of fever and approximately one million deaths annually, understanding its history is key.
es and non-human primate
s. The first evidence of malaria parasites was found in mosquitoes preserved in amber
from the Palaeogene period
that are approximately 30 million years old. Malaria may have been a human pathogen
for the entire history of the species. Humans may have originally caught Plasmodium falciparum
from gorilla
s.
About 10,000 years ago malaria started having a major impact on human survival which coincides with the start of agriculture (Neolithic revolution
); a consequence was natural selection
for sickle-cell disease
, thalassaemias, glucose-6-phosphate dehydrogenase deficiency
, ovalocytosis
, elliptocytosis and loss of the Gerbich antigen (glycophorin C
) and the Duffy antigen
on the erythrocytes because such blood disorders confer a selective advantage against malaria infection (balancing selection
). The three major types of inherited genetic resistance
(sickle-cell disease, thalassaemias, and glucose-6-phosphate dehydrogenase deficiency) were present in the Mediterranean world by the time of the Roman Empire
, about 2000 years ago.
References to the unique periodic fevers of malaria are found throughout recorded history. According to legend, the Chinese emperor Huang Di (Yellow Emperor
, 2697–2590 BCE
) ordered the compilation of a canon of internal medicine. The Chinese Huangdi Neijing (The Inner Canon of the Yellow Emperor) apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrence – the earliest written report of malaria. In the Sushruta Samhita
, a Sanskrit medical treatise (6th century BCE), the symptoms of malarial fever were described and attributed to the bites of certain insects.
The term 'miasma' was coined by Hippocrates
of Kos
who used it to describe dangerous fumes from the ground that are transported by winds and can cause serious illnesses. The name malaria, derived from ‘mal’aria’ (bad air in Medieval Italian) was probably first used by Leonardo Bruni
in a publication of 1476. This idea came from the Ancient Romans who thought that this disease came from the horrible fumes from the swamps. The idea that the disease came from the foul gasses released from soil, water and air persisted throughout the nineteenth century.
Malaria was once common in most of Europe and North America, where it is now for all purposes non-existent. The coastal plains of southern Italy, for example, fell from international prominence (the Crusaders going by sea to the Holy Land
took ship at Bari
) when malaria expanded its reach in the sixteenth century. At roughly the same time, in the coastal marshes of England
, mortality from "marsh fever" or "tertian ague" ("the ague" from Latin "febris acuta") was comparable to that in sub-Saharan Africa
today. William Shakespeare
was born at the start of the especially cold period that climatologists call the "Little Ice Age
", yet he was aware enough of the ravages of the disease to mention it in eight of his plays. Throughout history the most critical factors in the spread or eradication of disease have been human behavior (shifting population centers, changing farming methods and the like) and living standards. Precise statistics do not exist because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented. Poverty
has been and remains a reason for the disease to remain while it has undergone a decline in other locations. Climate change
is likely to affect future trends in malaria transmission, but the severity and geographic distribution of such effects is currently uncertain, though attracting increasing scientific attention.
. The historian Herodotus
(484–425 BCE) wrote that the builders of the Egyptian pyramids were given large amount of garlic
, likely to protect them against malaria. Sneferu
, the founder of the Fourth dynasty of Egypt
, who reigned from around 2613 - 2589 BCE, used bed-nets as protection against mosquitoes, Cleopatra VII, the last Pharaoh
of Ancient Egypt
, also slept under a mosquito net
. Malaria became widely recognized in ancient Greece
by the 4th century BCE, and is implicated in the decline of many city-state
populations. Hippocrates (460–370 BCE), the "father of medicine", related the presence of intermittent fevers
with climatic
and environmental
conditions and classified the fever
according to periodicity: tritaios pyretos / febris tertiana, and tetrataios pyretos / febris quartana (every fourth day).
For thousands of years, traditional herbal remedies
have been used to treat malaria. Around 168 BCE the herbal remedy Qing-hao (Artemisia annua
) came into use in China
to treat female hemorrhoid
s (Recipes for 52 kinds of diseases
unearthed from the Mawangdui tombs).
Qinghao was first recommended for acute intermittent fever episodes by Ge Hong
as an effective medication in the 4th century Chinese manuscript Zhou hou bei ji fang, usually translated as "Emergency Prescriptions kept in one's Sleeve". His recommendation was to soak fresh plants of the artemisia herb in cold water, wring it out and ingest the expressed bitter juice in its raw state.
Medical accounts and ancient autopsy reports state that tertian malarial fevers caused the death of four members of the Medici
family of Florence
: Eleonora of Toledo (1522–1562), Cardinal Giovanni (1543–1562), Don Garzia (1547–1562) and Grand Duke Francesco I
(1531–1587). These claims have been reexamined with more modern methologies. These methods have confirmed the presence of P.falciparum in the remains confirming the original diagnosis.
Treatment of malaria was discussed in several European herbal texts during the Renaissance
including Otto Brunfels
(1532), Leonhart Fuchs
(1543), Adam Lonicer
(1560), Hieronymus Bock
(1577), Pietro Andrea Mattioli
(1590), and Theodor Zwinger
(1696).
European settlers and their West African slaves
likely brought malaria to the Americas in the 16th century. Spanish missionaries found that fever was treated by Amerindians near Loxa (Peru
) with powder from Peruvian bark
(Cinchona
succirubra). There are no references to malaria in the "medical books" of the Mayans or Aztecs. Quinine
(Kinine), a toxic plant alkaloid
, is an effective muscle relaxant, as the modern use for nocturnal leg cramps suggests, long used by the Quechua
Indians of Peru to reduce the shaking effects caused by severe chills in the Andes
. The Jesuit Brother Agostino Salumbrino (1561–1642), an apothecary
by training and who lived in Lima
, observed the Quechua using the quinine-containing bark of the cinchona
tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was entirely unrelated to its effect in controlling shivering from cold, it was nevertheless the correct medicine for malaria. The use of the “fever tree” bark was introduced into European medicine by Jesuit missionaries (Jesuit's bark
). Jesuit Barnabé de Cobo (1582–1657), who explored Mexico and Peru, is credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain
, and afterwards to Rome and other parts of Italy
, in 1632. Francesco Torti published in 1712 that only “intermittent fever” was amenable to the fever tree bark (“Therapeutice Specialis ad Febres Periodicas Perniciosas”, 1712 Modena). This work finally established the specific nature of cinchona bark and brought about its general use in medicine.
In 1717, the graphite pigmentation of a postmortem spleen
and brain was published by Giovanni Maria Lancisi
in his malaria text book “De noxiis paludum effluviis eorumque remediis”. He related the prevalence of malaria in swampy areas to the presence of flies
and recommended swamp
drainage
to prevent it.
Pierre Joseph Pelletier
and Joseph Bienaimé Caventou
separated in 1820 the alkaloids Cinchonine and Quinine from powdered fever tree bark, allowing for the creation of standardized doses of the active ingredients. Prior to 1820, the bark was first dried, ground to a fine powder and then mixed into a liquid (commonly wine) which was then drunk.
An English trader, Charles Ledger
, and his Amerindian servant, Manuel Incra Mamani, had spent four years collecting cinchona seeds in the Andes in Bolivia
, highly prized for their quinine but a prohibited export. Ledger managed to get some seeds out; in 1865 the Dutch government bought a small parcel, and 20,000 trees of the famous Cinchona ledgeriana
were successfully cultivated in Java
(Indonesia). By the end of the nineteenth century the Dutch had established a world monopoly in the supply of quinine.
'Warburg's Tincture'
In 1834, in British Guiana
(now Guyana
), a German physician, Carl Warburg
, invented an antipyretic
medicine: 'Warburg's Tincture
'. This secret, proprietary remedy contained quinine and a number of different other herbs
. Trials were made in Europe in the 1840s and 1850s, and it was officially adopted by the Austrian Empire
in 1847. Warburg's Tincture gained a high, international reputation. It was considered by many eminent medical professionals to be a more efficacious antimalarial drug than quinine. It was also more economical. The British Government supplied Warburg's Tincture to troops in India
and other colonies.
Synthetic drugs
William Henry Perkin, a student of August Wilhelm von Hofmann
at the Royal College of Chemistry
in London, tried in the 1850s to synthesize quinine in a commercially practicable process. The idea was to take two equivalents of N-allyltoluidine (C10H13N) and three atoms of oxygen to produce quinine (C20H24N2O2) and water. The experiments were unsuccessful. However, Perkin's Mauve
was produced when attempting quinine total synthesis
via the oxidation of N-allyltoluidine. Before Perkin's discovery all dye
s and pigments were derived from roots, leaves, insects, or, in the case of Tyrian purple
, molluscs
. Perkin's discovery of artificially synthesized dyes led to important advances in medicine, photography, and many other fields.
In 1891 Paul Guttmann
and Paul Ehrlich
noted that methylene blue
had a high affinity for some tissues and that this dye had a slight antimalarial property. MB and its congeners may act by preventing the biocrystallization
of heme. A mixture of eosin
Y, methylene blue and demethylated methylene blue (azure B) was later used for a number of different blood film
staining procedures (Malachowski stain, Romanowsky stain
, Giemsa stain
). Ehrlich, the founder of chemotherapy
, advocated a rational development of drugs by exploiting biochemical differences (“magic bullets”).
in the blood and spleen of a patient who had died in a hospital for insane people. Meckel was probably looking at the parasites
of malaria without realizing it; malaria was not mentioned in his report. He thought the pigment was melanin
. The causal relationship of pigment to the parasite was established in 1880, when the French physician Charles Louis Alphonse Laveran
, working in the military hospital of Constantine
Algeria
, observed pigmented parasites inside the red blood cell
s of people suffering from malaria. He also witnessed the events of exflagellation and became convinced that the moving flagella were parasitic microorganisms. He noted that quinine removed the parasites from the blood. Laveran called this microscopic organism Oscillaria malariae and proposed that malaria was caused by this protozoa
n. This discovery was not initially well received and remained controversial until the development of the oil immersion lens in 1884 and of superior staining methods in 1890-1891.
In 1885 Ettore Marchiafava
, Angelo Celli
and Camillo Golgi
studied the reproduction cycles in human blood (Golgi cycles). Golgi observed that all parasites present in the blood divided almost simultaneously at regular intervals and that division coincided with attacks of fever. Golgi also recognized that the three types of malaria are caused by different protozoan organisms. By 1890 Laveran's germ was generally accepted but most of Laveran's initial ideas had been discarded in favor of the taxonomic work and clinical pathology
of the Italian school. Marchiafava and Celli called the new microorganism Plasmodium
. Pel, presaging its discovery by over 50 years, proposed the first theory of the existence of a tissue stage of the malaria parasite in 1886. This suggestion was reiterated in 1893 when Golgi also suggested that the parasites might have an undiscovered tissue phase this time in endothelial cells. Pel in 1896 supported Gogli's latent phase theory. Also in 1886 Golgi described the morphological differences that are still used to distinguish two malaria parasite species Plasmodium vivax
and Plasmodium malariae
. Shortly after this Sakharov in 1889 and Marchiafava & Celli in 1890 independently identified Plasmodium falciparum
as a species distinct from P. vivax and P. malariae. In 1890, Grassi and Feletti reviewed the available information and named both P. malariae and P. vivax with the following statement: "C'est pour cela que nous distinguons, dans le genre Haemamoeba, trois espèces (H. malariae de la fièvre quarte, H. vivax de la fièvre tierce et H. praecox de la fièvre quotidienne avec coutres intermittences etc.)." H. vivax was soon renamed Plasmodium vivax. In 1892 Marchiafava and Bignami proved that the multiple forms seen by Laveran are a single species. This species was eventually named P. falciparum.
Laveran was awarded the 1907 Nobel Prize for Physiology or Medicine "in recognition of his work on the role played by protozoa in causing diseases". In 1897 the sexual stages of a related haematozoan, Haemoproteus columbae, in the blood were discovered by William MacCallum in infected birds.
Giovanni Maria Lancisi
, John Crawford, Patrick Manson
, Josiah C. Nott
, Albert Freeman Africanus King
, and Charles Louis Alphonse Laveran
developed theories that malaria may be caused by mosquito bites, but there was little evidence to support this idea. An early effort at malaria prevention occurred in 1896. An Uxbridge
malaria outbreak prompted health officer, Dr. Leonard White
, to write a report to the State Board of Health, which led to a study of mosquito-malaria links, and the first efforts for malaria prevention. Massachusetts
State pathologist, Theobald Smith, asked that White's son collect mosquito specimens for further analysis, and that citizens 1) add screens
to windows, and 2) drain
collections of water.
It was Britain's Sir Ronald Ross
, an army surgeon working in Secunderabad
India
, who proved in 1897 that malaria is transmitted by mosquitoes. He was able to find pigmented malaria parasites in a mosquito that he artificially fed on a malaria patient named Hussain Khan, who had crescents in his blood. He continued his research into malaria by showing that certain mosquito species (Culex
fatigans) transmit malaria to sparrows and isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. He reported this to the British Medical Association
in Edinburgh
, Scotland
in 1898 and was greeted with a standing ovation.
Giovanni Battista Grassi
, professor of Comparative Anatomy at Rome University, showed that human malaria could only be transmitted by Anopheles
(Greek "anofelís": good-for-nothing) mosquitoes. Grassi along with his coworkers Amico Bignami
, Giuseppe Bastianelli
and Ettore Marchiafava announced at the session of the Accademia dei Lincei
on December 4, 1898 that a healthy man in a non-malarial zone had contracted tertian malaria after being bitten by an experimentally infected Anopheles claviger.
In 1899 Bastianelli and Bignami were the first to observe the complete P. vivax transmission cycle from mosquito to human and back.
A bitter dispute broke out between the British and Italian schools of malariology over priority but Ross received the 1902 Nobel Prize for Physiology or Medicine for "his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it". In Cuba Carlos Finlay
found that yellow fever
is transmitted by another type of mosquito, now Aedes aegypti
. His observation was confirmed by a medical board headed by Walter Reed
. Yellow fever and malaria among workers had seriously delayed construction of the Panama Canal
. Mosquito control instituted by William C. Gorgas
dramatically reduced this problem.
Relapses were first noted in 1897 by Thayer who recounted the experiences of a physician who suffered a relapse of malaria twenty one months after leaving an endemic area. He proposed the existence of a tissue stage.
was synthesized by Heinrich Caro
at BASF
, a German chemical company. Robert Koch
in 1882 used this dye to discover the cause of tuberculosis - Mycobacterium tuberculosis
. Paul Ehrlich in 1880 described the use of "neutral" dyes - mixtures of acid
ic and basic
dye
s for the differentiation of cells in peripheral blood smears. In 1886 Bernthsen prepared a relatively pure dye, obtained by decomposition of methylene blue which he termed methylene azure. In 1891 Ernst Malachowski and Dmitri Leonidovich Romanowsky
independently developed techniques using a mixture of Eosin
Y and modified methylene blue (methylene azure) that produced a surprising hue
unattributable to either staining component: a beautiful, distinctive shade of purple. Malachowski used alkali-treated methylene blue solutions and Romanowsky used methylene blue solution which were moulded or aged. This new method differentiated blood cells and demonstrated the nuclei of malarial parasites. Jenner in 1899 introduced methanol
as a solvent for the dye precipitate.
Malachowski's staining technique is one of the most significant technical advances in the history of malaria.
Also in 1900 Amico Bignami and Giuseppe Bastianelli found that they could not infect an individual with blood containing only gametocytes. The possibility of the existence of a chronic blood stage infection was proposed by Ross and Thompson in 1910.
In 1903 Fritz Schaudinn
erroneously reported direct infection of erythrocytes by infective sporozoites of P. vivax. Schaudinn's error dominated scientific opinion for over forty years.
The existence of exoerythrocytic merogony of non-human malaria parasites in the internal organs was first demonstrated by Aragão in 1908.
In 1920 Félix Mesnil
and Émile Roubaud
achieve the first experimental infection of chimpanzee
s with P. vivax.
Three possible mechanisms of relapse were proposed by Marchoux in 1926 (i) parthenogenesis of macrogametocytes (ii) persistence of schizonts in small numbers in the blood where their multiplication is inhibited by immunity and this immunity disappears and/or (iii) reactivation of an encysted body in the blood. James in 1931 based on the lack of activity of quinine on the sporozoites proposed that after being injected by the mosquito, the sporozoites are carried to internal organs, where they enter the reticuloendothelial cells and undergo a cycle of development. Huff and Bloom in 1935 demonstrated the exoerythrocytic stages of avian malaria. In 1945 Fairley et al. reported that inoculation of blood from a patient with P. vivax may fail to induce malaria in a susceptible recipient although the donor may subsequently develop overt malaria. The sporozoites disappeared from the blood stream within one hour and reappeared eight days later. This suggested that persistent tissue forms existed. Using mosquitoes rather than blood Shute in 1946 described a similar phenomenon and proposes the existence of an 'x-body' or resting form. The following year Sapero proposed that a link existed between a tissue stage not yet discovered in patients with malaria and the phenomenon of relapse. Garnham in 1947 described exoerythrocytic schizogony in Hepatocystis (Plasmodium) kochi. In the following year Shortt and Garnham described the liver stages of P. cynomolgi in the monkey. In the same year a human volunteer consented to receive a massive dose of infected sporozoites of P. vivax and undergo a liver biopsy three months later thus allowing Shortt et al. to demonstrate the tissue stage of a human malarial parasite.
The tissue form of Plasmodium ovale
was described in 1954 and that of P. malariae in 1960 in experimentally infected chimpanzees.
The latent or dormant liver form of the parasite (hypnozoite), responsible for the late relapses characteristic of P. vivax and P. ovale infections, was observed in the 1980s. The term hypnozoite was coined by Miles B. Markus, a PhD student in Imperial College, London. In 1976, he speculated: "If sporozoites of Isospora
can behave in this fashion, then those of related Sporozoa, like malaria parasites, may have the ability to survive in the tissues in a similar way." He adopted the term "hypnozoite" for malaria in 1978 when he wrote in a little-known journal that this name would "... describe any dormant sporozoites or dormant, sporozoite-like stages in the life cycles of Plasmodium or other Haemosporina
".
In 1982 Krotoski et al report identification of P. vivax hypnozoites in liver cells of infected chimpanzees and in 1984 Mazier et al report in vitro cultivation of P. vivax liver stages in human hepatocytes. In 1989 chloroquine resistance in P. vivax is reported in Papua New Guinea.
were intentionally infected with malaria to create a fever. In the 1920s Julius Wagner-Jauregg
, a Viennese psychiatrist
, began to treat neurosyphilitics with induced P. vivax malaria. Three or four bouts of fever were enough to kill the temperature-sensitive syphilis bacteria (Spirochaeta pallida also known as Treponema pallidum
). P. vivax infections were terminated by quinine. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable to the almost-certain death from syphilis. Therapeutic malaria opened up a wide field of chemotherapeutic research and was practised until 1950. Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica.
Raymond Corbett Shannon
discovered disease-bearing Anopheles gambiae
mosquitoes living in Brazil
, likely brought there by plane or fast mail steamer. This species of mosquito is a particularly efficient vector for malaria and is native to Africa. In 1938, the introduction of this new mosquito vector caused the greatest epidemic of malaria ever seen in the New World
. However, complete eradication of A.gambiae from north-east Brazil and thus from the New World was achieved in 1940 by meticulous application of Paris Green
to breeding places and of Pyrethrum
spray-killing to adult resting places.
(Germany) about 12000 different compounds and succeeded in producing Resochin® as substitutes for quinine in the 1930s (Dtsch.-Reichs-Pat. 683692); it is chemically related to quinine through the possession of a quinoline nucleus and the dialkylaminoalkylamino side chain. Resochin (a RESOrcinate of a 4-aminoCHINoline) (7-chloro-4- 4- (diethylamino) - 1 - methylbutyl amino quinoline) and a similar compound Sontochin (3-methyl Resochin) were synthesized in 1934 in close cooperation with American companies. There were over 2,000 cartel agreements between IG Farben
and foreign firms — including Standard Oil of New Jersey
, DuPont
, Dow Chemical Company
, and others in the United States. In March 1946 the drug was officially named Chloroquine
. Chloroquine is an inhibitor of hemozoin
production through biocrystallization
and is one of the best antimicrobials ever developed. Quinine and chloroquine affect malarial parasites only at stages in their life cycle when the parasites are forming hematin-pigment (hemozoin) as a byproduct of hemoglobin
degradation.
The drug target of chloroquine is host-derived, which markedly delayed the emergence of resistance and it took P. falciparum 19 years to build resistance to chloroquine. The first chloroquine-resistant strains were detected around the Cambodia
‐Thailand
border and in Colombia
, in the 1950s. These resistant strains spread rapidly, resulting in a large increase in mortality from this disease, particularly in Africa during the 1990s.
Until the 1950s screening of anti malarial drugs was carried out on avian malaria. This was less than satisfactory as the avian malaria species differ in a number of ways from those that infect humans. The discovery in 1948 of Plasmodium berghei
in wild rodents in the Congo
and later other rodent species that could infect laboratory rats transformed the tests used for drug development. The short hepatic phase and life cycle of these parasites made them extremely useful as animal models, a status they still retain.
Plasmodium cynomolgi in Rhesus monkeys (Macaca mulatta) were used in the 1960s to test drugs active against P. vivax. This model is also still in use.
Genetically modified mice (non obese diabetic severe combined immunodeficient and BXN) can be engrafted with human stem cells and used as models for Plasmodium falciparum
. Although the model is of variable reproducibility it has been used in some experiments.
Growth of the liver stages in animal free systems has been difficult but was achieved in the 1980s when P. berghei pre-erythrocytic stages was grown in wI38,a human embryonic lung cell line. This was followed by their growth in the human hepatoma line HepG2. Both P. falciparum and P. vivax have been grown in human liver cells; partial development of P. ovale in human liver cells has also been achieved; and P. malariae has been grown in chimpanzee and Aotus
liver cells.
Systematic screening of traditional Chinese medical herbs was carried out by a number of Chinese research teams consisting of hundreds scientists in the 1960s and 1970s. Qinghaosu, later named artemisinin
, was cold extracted in a neutral milieu (pH 7.0) from the dried leaves of Artemisia annua
inspired by Ge Hong's recommendation.
Artemisinin was isolated by Tu Youyou, a Chinese pharmacologist. Tu headed a team of investigators who were tasked by the Chinese government with finding a treatment for choloroquine resistant malaria. Their work was known as Project 523 named after the date it was announced - May 23, 1967. The team investigated >2000 Chinese herb preparations and by 1971 had made 380 extracts from 200 herbs. An extract from qinghao (Artemisia annua
) was effective but the results were variable. Tu reviewed the literature including the 340 BC book Zhou hou bei ji fang (A handbook of prescriptions for emergencies) by the Chinese physician Ge Hong. This book contained the only useful reference to the herb: "A handful of qinghao immersed with two litres of water, wring out the juice and drink it all." After making a non-toxic, neutral extract, Tu and two team members volunteered to take the extract before antimalarial trials were done in patients. The first studies were published in Chinese with the first English language paper citing successful trials for artemisinin appeared in 1979. The authors of this paper were anonymous according to Chinese custom at the time. Tu presented her findings to a United Nations
scientific meeting in Beijing
in 1981. Since then artemisinin has become a standard treatment for malaria.
Artemisinin is a sesquiterpene lactone
containing a peroxide
group, which is believed to be essential for its anti-malarial activity. Its derivatives, artesunate and artemether, have been used in clinics since 1987 for the treatment of drug-resistant and drug-sensitive malaria, in especially, cerebral malaria. These drugs are characterized by fast action, high efficacy and good tolerance. They kill the asexual forms of P. berghei
and P. cynomolgi and have transmission-blocking activity. In 1985, Zhou Yiqing and his team combined artemether and lumefantrine into a single tablet, which was registered as a new medicine in China in 1992, and later it became known as “Coartem”. Artemisinin combination treatments (ACTs) are now widely used to treat uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries and only a minority of the patients who need artemisinin-based combination treatments actually receive them. Improved agricultural practices, selection of high-yielding hybrids, microbial
production, and the development of synthetic peroxides will lower prices.
is credited with first synthesis of DDT
(DichloroDiphenylTrichloroethane) in 1874. The insecticidal properties of DDT were identified in 1939 by the chemist Paul Hermann Müller
of the Swiss firm Geigy Pharmaceutical
. For his discovery of the high efficiency of DDT as a contact poison
against several arthropod
s he was awarded the Nobel Prize in Physiology or Medicine in 1948. In the fall of 1942, samples of the chemical were acquired by the United States, Britain, and Germany and laboratory tests demonstrated that it was highly effective against insects. As the Rockefeller studies showed in Mexico
, DDT remained effective for six to eight weeks if sprayed on the inside walls and ceilings of houses and other buildings.The first field test in which residual DDT was applied to the interior surfaces of all habitations and outbuildings was carried out in central Italy
in the spring of 1944. The objective was to determine the residual effect of the spray upon anopheline density in the absence of other control measures. Spraying began in Castel Volturno
and, after a few months, in the delta of the Tiber
. The unprecedented effectiveness of the chemical was confirmed: the new insecticide
was able to achieve the eradication of malaria through the eradication of mosquitoes. At the end of World War II a massive malaria control program based on DDT spraying was carried out in Italy. In Sardinia
- the second largest island in the Mediterranean - between 1946 and 1951, the Rockefeller Foundation
conducted a large-scale experiment to test the feasibility of the strategy of "species eradication" in an endemic malaria vector. Malaria was effectively eliminated in the United States by the use of DDT in the National Malaria Eradication Program
(1947–52). The concept of eradication prevailed in 1955 in the Eighth World Health Assembly
: DDT was adopted as a primary tool in the fight against malaria.
DDT was banned in the US in 1972, after the discussion opened by the book of the American biologist Rachel Carson
which launched the environmental
movement in the West. The book catalogued the environmental impacts of the indiscriminate spraying of DDT and suggested that DDT and other pesticide
s may cause cancer and that their agricultural use was a threat to wildlife
. Recently, the U.S. Congress
, Republicans and Democrats alike, supports indoor DDT spraying
as a vital component of any successful malaria control program, and the U.S. Agency for International Development
has initiated DDT and other insecticide spraying programs in some poor tropical countries.
A wide range of other insecticide
s is available for mosquito control in addition to the measures of draining of wetland
breeding grounds and provision of better sanitation
. Pyrethrum
(Chrysanthemum
[or Tanacetum
] cinerariaefolium) is an economically important source of natural insecticide. Pyrethrin
s attack the nervous system
s of all insects. A few minutes after application the insect cannot move or fly away and female mosquitoes are inhibited from biting. The use of pyrethrum in insecticide preparations dates back to Persia
, about 400 BCE
. Pyrethrins are non-persistent, being biodegradable
and also breaking down easily on exposure to light
. The majority of the world's supply of pyrethrin and Chrysanthemum cinerariaefolium comes from Kenya
. The flower was first introduced into Kenya and the highlands of Eastern Africa
during the late 1920s. The flowers of the plant are harvested shortly after blooming and are either dried and powdered or the oils within the flowers are extracted with solvent
s.
was established in 1976 by William Trager and James B. Jensen, which facilitated research into the molecular biology of the parasite and the development of new drugs substantially. By using increasing volumes of culture medium, one can grow P.falciparum to higher parasitemia (above 10%).
was pioneered in the 1980s. Giemsa
microscopy
and RDTs represent the two diagnostics
most likely to have the largest impact on malaria control today. Rapid diagnostic tests for malaria do not require any special equipment and offer the potential to extend accurate malaria diagnosis to areas when microscopy services are not available.
The application of genomics
to malaria research is now of central importance. With the sequencing of the three genome
s of the malaria parasite P.falciparum, one of its vector Anopheles gambiae, and the human genome
, the genetics of all three organisms in the malaria lifecycle can now be studied. This breakthrough is expected to produce advances in the understanding of the interactions between the parasite and its human host—such as between virulence factor
s and the human immune system
—as well as allowing the identification of the factors that restrict one species of parasite to one or a few species of mosquitoes. It is likely that these will eventually lead to new therapeutic approaches.
Another new application of genetic technology is the ability to produce genetically-modified
mosquitoes that are unable to transmit malaria, allowing biological control of malaria transmission.
The World Health Organization
(WHO) recommends Indoor residual spraying
as one of three primary means of malaria control, the others being use of insecticide-treated mosquito nets (ITNs)
and prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs). In 2000, only 1.7 million (1.8%) African children living in stable malaria-endemic conditions were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs by 2007, leaving 89.6 million children unprotected. An increased percentage of African households (31%) are estimated to own at least one ITN in 2008 (WHO World Malaria Report 2009). Most nets are impregnated with pyrethroid
s, a class of insecticides with particularly low toxicity
. Dow AgroSciences
developed a microencapsulated formulation of the organophosphate
chlorpyrifos methyl as a cost-effective, long-lasting alternative to DDT. As an Indoor residual spraying against pyrethroid resistant mosquitoes chlorpyrifos methyl outperformed DDT and lambdacyhalothrin
. Organizations such as the Clinton Foundation
continue to supply anti-malarial drugs to Africa and other affected areas; according to director Inder Singh
, in 2011 more than 12 million individuals will be supplied with subsidized anti-malarial drugs. Other organizations, such as Malaria No More
continue distribution of more broad-based prophylaxis.
Human evolution
Human evolution refers to the evolutionary history of the genus Homo, including the emergence of Homo sapiens as a distinct species and as a unique category of hominids and mammals...
. Malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
, a widespread and potentially lethal infectious disease, has afflicted people for much of human history
History of the world
The history of the world or human history is the history of humanity from the earliest times to the present, in all places on Earth, beginning with the Paleolithic Era. It excludes non-human natural history and geological history, except insofar as the natural world substantially affects human lives...
, and has affected settlement patterns. The prevention and treatment of the disease have been investigated in science and medicine for hundreds of years, and, since the discovery of the parasite which causes it, attention has focused on its biology. These studies have continued up to the present day, since no effective Malaria vaccine
Malaria vaccine
Malaria vaccines are an area of intensive research. However, there is no effective vaccine that has been introduced into clinical practice.The global burden of P. falciparum malaria increased through the 1990s due to drug-resistant parasites and insecticide-resistant mosquitoes; this is illustrated...
has yet been developed and many of the older antimalarial drug
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...
s are losing effectiveness as the parasite evolves high levels of drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
. As malaria remains a major public health problem, causing 250 million cases of fever and approximately one million deaths annually, understanding its history is key.
Origin and early history
Human malaria likely originated in Africa and has coevolved along with its hosts, mosquitoMosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...
es and non-human primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s. The first evidence of malaria parasites was found in mosquitoes preserved in amber
Amber
Amber is fossilized tree resin , which has been appreciated for its color and natural beauty since Neolithic times. Amber is used as an ingredient in perfumes, as a healing agent in folk medicine, and as jewelry. There are five classes of amber, defined on the basis of their chemical constituents...
from the Palaeogene period
Paleogene
The Paleogene is a geologic period and system that began 65.5 ± 0.3 and ended 23.03 ± 0.05 million years ago and comprises the first part of the Cenozoic Era...
that are approximately 30 million years old. Malaria may have been a human pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
for the entire history of the species. Humans may have originally caught Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
from gorilla
Gorilla
Gorillas are the largest extant species of primates. They are ground-dwelling, predominantly herbivorous apes that inhabit the forests of central Africa. Gorillas are divided into two species and either four or five subspecies...
s.
About 10,000 years ago malaria started having a major impact on human survival which coincides with the start of agriculture (Neolithic revolution
Neolithic Revolution
The Neolithic Revolution was the first agricultural revolution. It was the transition from hunting and gathering to agriculture and settlement. Archaeological data indicates that various forms of plants and animal domestication evolved independently in 6 separate locations worldwide circa...
); a consequence was natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
for sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
, thalassaemias, glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...
, ovalocytosis
Ovalocytosis
Southeast Asian ovalocytosis is a form of hereditary elliptocytosis common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria.-Southeast Asian ovalocytosis:...
, elliptocytosis and loss of the Gerbich antigen (glycophorin C
Glycophorin C
Glycophorin C plays a functionally important role in maintaining erythrocyte shape and regulating membrane material properties, possibly through its interaction with protein 4.1. Moreover, it has previously been shown that membranes deficient in protein 4.1 exhibit decreased content of glycophorin C...
) and the Duffy antigen
Duffy antigen system
Duffy antigen/chemokine receptor also known as Fy glycoprotein or CD234 is a protein that in humans is encoded by the DARC gene....
on the erythrocytes because such blood disorders confer a selective advantage against malaria infection (balancing selection
Balancing selection
Balancing selection refers to a number of selective processes by which multiple alleles are actively maintained in the gene pool of a population at frequencies above that of gene mutation. This usually happens when the heterozygotes for the alleles under consideration have a higher adaptive value...
). The three major types of inherited genetic resistance
Genetic resistance to malaria
Genetic resistance to malaria occurs through both modifications of the immune system that enhance immunity to this infection and also by changes in human red blood cells that hinder the malaria parasite's ability to invade and replicate within these cells...
(sickle-cell disease, thalassaemias, and glucose-6-phosphate dehydrogenase deficiency) were present in the Mediterranean world by the time of the Roman Empire
Roman Empire
The Roman Empire was the post-Republican period of the ancient Roman civilization, characterised by an autocratic form of government and large territorial holdings in Europe and around the Mediterranean....
, about 2000 years ago.
References to the unique periodic fevers of malaria are found throughout recorded history. According to legend, the Chinese emperor Huang Di (Yellow Emperor
Yellow Emperor
The Yellow Emperor or Huangdi1 is a legendary Chinese sovereign and culture hero, included among the Three Sovereigns and Five Emperors. Tradition holds that he reigned from 2697–2597 or 2696–2598 BC...
, 2697–2590 BCE
Common Era
Common Era ,abbreviated as CE, is an alternative designation for the calendar era originally introduced by Dionysius Exiguus in the 6th century, traditionally identified with Anno Domini .Dates before the year 1 CE are indicated by the usage of BCE, short for Before the Common Era Common Era...
) ordered the compilation of a canon of internal medicine. The Chinese Huangdi Neijing (The Inner Canon of the Yellow Emperor) apparently refers to repeated paroxysmal fevers associated with enlarged spleens and a tendency to epidemic occurrence – the earliest written report of malaria. In the Sushruta Samhita
Sushruta Samhita
The Sushruta Samhita is a Sanskrit text, attributed to one Sushruta, foundational to Ayurvedic medicine , with innovative chapters on surgery....
, a Sanskrit medical treatise (6th century BCE), the symptoms of malarial fever were described and attributed to the bites of certain insects.
The term 'miasma' was coined by Hippocrates
Hippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
of Kos
Kos
Kos or Cos is a Greek island in the south Sporades group of the Dodecanese, next to the Gulf of Gökova/Cos. It measures by , and is from the coast of Bodrum, Turkey and the ancient region of Caria. Administratively the island forms a separate municipality within the Kos peripheral unit, which is...
who used it to describe dangerous fumes from the ground that are transported by winds and can cause serious illnesses. The name malaria, derived from ‘mal’aria’ (bad air in Medieval Italian) was probably first used by Leonardo Bruni
Leonardo Bruni
Leonardo Bruni was an Italian humanist, historian and statesman. He has been called the first modern historian.-Biography:...
in a publication of 1476. This idea came from the Ancient Romans who thought that this disease came from the horrible fumes from the swamps. The idea that the disease came from the foul gasses released from soil, water and air persisted throughout the nineteenth century.
Malaria was once common in most of Europe and North America, where it is now for all purposes non-existent. The coastal plains of southern Italy, for example, fell from international prominence (the Crusaders going by sea to the Holy Land
Holy Land
The Holy Land is a term which in Judaism refers to the Kingdom of Israel as defined in the Tanakh. For Jews, the Land's identifiction of being Holy is defined in Judaism by its differentiation from other lands by virtue of the practice of Judaism often possible only in the Land of Israel...
took ship at Bari
Bari
Bari is the capital city of the province of Bari and of the Apulia region, on the Adriatic Sea, in Italy. It is the second most important economic centre of mainland Southern Italy after Naples, and is well known as a port and university city, as well as the city of Saint Nicholas...
) when malaria expanded its reach in the sixteenth century. At roughly the same time, in the coastal marshes of England
England
England is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
, mortality from "marsh fever" or "tertian ague" ("the ague" from Latin "febris acuta") was comparable to that in sub-Saharan Africa
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
today. William Shakespeare
William Shakespeare
William Shakespeare was an English poet and playwright, widely regarded as the greatest writer in the English language and the world's pre-eminent dramatist. He is often called England's national poet and the "Bard of Avon"...
was born at the start of the especially cold period that climatologists call the "Little Ice Age
Little Ice Age
The Little Ice Age was a period of cooling that occurred after the Medieval Warm Period . While not a true ice age, the term was introduced into the scientific literature by François E. Matthes in 1939...
", yet he was aware enough of the ravages of the disease to mention it in eight of his plays. Throughout history the most critical factors in the spread or eradication of disease have been human behavior (shifting population centers, changing farming methods and the like) and living standards. Precise statistics do not exist because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. As a consequence, the majority of cases are undocumented. Poverty
Poverty
Poverty is the lack of a certain amount of material possessions or money. Absolute poverty or destitution is inability to afford basic human needs, which commonly includes clean and fresh water, nutrition, health care, education, clothing and shelter. About 1.7 billion people are estimated to live...
has been and remains a reason for the disease to remain while it has undergone a decline in other locations. Climate change
Effects of climate change on humans
Climate change has brought about severe and possibly permanent alterations to our planets’ geological, biological and ecological systems. The Intergovernmental Panel on Climate Change now contends that “there is new and stronger evidence that most of the warming observed over the last 50 years is...
is likely to affect future trends in malaria transmission, but the severity and geographic distribution of such effects is currently uncertain, though attracting increasing scientific attention.
Early research and treatment
The introduction of molecular methods confirmed the high prevalence of P.falciparum malaria in ancient EgyptAncient Egypt
Ancient Egypt was an ancient civilization of Northeastern Africa, concentrated along the lower reaches of the Nile River in what is now the modern country of Egypt. Egyptian civilization coalesced around 3150 BC with the political unification of Upper and Lower Egypt under the first pharaoh...
. The historian Herodotus
Herodotus
Herodotus was an ancient Greek historian who was born in Halicarnassus, Caria and lived in the 5th century BC . He has been called the "Father of History", and was the first historian known to collect his materials systematically, test their accuracy to a certain extent and arrange them in a...
(484–425 BCE) wrote that the builders of the Egyptian pyramids were given large amount of garlic
Garlic
Allium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...
, likely to protect them against malaria. Sneferu
Sneferu
Sneferu, also spelled as Snephru, Snefru or Snofru , was the founder of the Fourth dynasty of Egypt. Estimates of his reign vary, with for instance The Oxford History of Ancient Egypt suggesting a reign from around 2613 BC to 2589 BC, a reign of 24 years, while Rolf Krauss suggests a 30-year reign...
, the founder of the Fourth dynasty of Egypt
Fourth dynasty of Egypt
The fourth dynasty of ancient Egypt is characterized as a "golden age" of the Old Kingdom. Dynasty IV lasted from ca. 2613 to 2494 BC...
, who reigned from around 2613 - 2589 BCE, used bed-nets as protection against mosquitoes, Cleopatra VII, the last Pharaoh
Pharaoh
Pharaoh is a title used in many modern discussions of the ancient Egyptian rulers of all periods. The title originates in the term "pr-aa" which means "great house" and describes the royal palace...
of Ancient Egypt
Ancient Egypt
Ancient Egypt was an ancient civilization of Northeastern Africa, concentrated along the lower reaches of the Nile River in what is now the modern country of Egypt. Egyptian civilization coalesced around 3150 BC with the political unification of Upper and Lower Egypt under the first pharaoh...
, also slept under a mosquito net
Mosquito net
A mosquito net offers protection against mosquitos, flies, and other insects, and thus against diseases such as malaria, dengue fever, yellow fever, and various forms of encephalitis, including the West Nile virus, if used properly and especially if treated with an insecticide, which can double...
. Malaria became widely recognized in ancient Greece
Ancient Greece
Ancient Greece is a civilization belonging to a period of Greek history that lasted from the Archaic period of the 8th to 6th centuries BC to the end of antiquity. Immediately following this period was the beginning of the Early Middle Ages and the Byzantine era. Included in Ancient Greece is the...
by the 4th century BCE, and is implicated in the decline of many city-state
City-state
A city-state is an independent or autonomous entity whose territory consists of a city which is not administered as a part of another local government.-Historical city-states:...
populations. Hippocrates (460–370 BCE), the "father of medicine", related the presence of intermittent fevers
Fevers
Fevers are a five-piece band formed in 2010 in Ottawa, Ontario. The band consists of Colin MacDougall , Jim Hopkins , Martin Charbonneau , Sarah Bradley and Mike Stauffer . Theirs is a fresh take on a classic genre, combining indie rock and electronic music...
with climatic
Climate
Climate encompasses the statistics of temperature, humidity, atmospheric pressure, wind, rainfall, atmospheric particle count and other meteorological elemental measurements in a given region over long periods...
and environmental
Natural environment
The natural environment encompasses all living and non-living things occurring naturally on Earth or some region thereof. It is an environment that encompasses the interaction of all living species....
conditions and classified the fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
according to periodicity: tritaios pyretos / febris tertiana, and tetrataios pyretos / febris quartana (every fourth day).
For thousands of years, traditional herbal remedies
Herbalism
Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, herblore, and phytotherapy...
have been used to treat malaria. Around 168 BCE the herbal remedy Qing-hao (Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...
) came into use in China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
to treat female hemorrhoid
Hemorrhoid
Hemorrhoids or haemorrhoids , are vascular structures in the anal canal which help with stool control. They become pathological or piles when swollen or inflamed. In their physiological state they act as a cushion composed of arterio-venous channels and connective tissue that aid the passage of...
s (Recipes for 52 kinds of diseases
Wushi'er Bingfang
The Wushi'er Bingfang , or Recipes for Fifty-Two Ailments, is an ancient Chinese medical text that was discovered in 1973 in Mawangdui in a tomb that was sealed in 168 BCE under the Han Dynasty. The text was copied in seal script on sheets of silk around 215 BCE, under the Qin Dynasty, but might...
unearthed from the Mawangdui tombs).
Qinghao was first recommended for acute intermittent fever episodes by Ge Hong
Ge Hong
Ge Hong , courtesy name Zhichuan , was a minor southern official during the Jìn Dynasty of China, best known for his interest in Daoism, alchemy, and techniques of longevity...
as an effective medication in the 4th century Chinese manuscript Zhou hou bei ji fang, usually translated as "Emergency Prescriptions kept in one's Sleeve". His recommendation was to soak fresh plants of the artemisia herb in cold water, wring it out and ingest the expressed bitter juice in its raw state.
Medical accounts and ancient autopsy reports state that tertian malarial fevers caused the death of four members of the Medici
Medici
The House of Medici or Famiglia de' Medici was a political dynasty, banking family and later royal house that first began to gather prominence under Cosimo de' Medici in the Republic of Florence during the late 14th century. The family originated in the Mugello region of the Tuscan countryside,...
family of Florence
Florence
Florence is the capital city of the Italian region of Tuscany and of the province of Florence. It is the most populous city in Tuscany, with approximately 370,000 inhabitants, expanding to over 1.5 million in the metropolitan area....
: Eleonora of Toledo (1522–1562), Cardinal Giovanni (1543–1562), Don Garzia (1547–1562) and Grand Duke Francesco I
Ferdinando I de' Medici, Grand Duke of Tuscany
Ferdinando I de' Medici, Grand Duke of Tuscany was Grand Duke of Tuscany from 1587 to 1609, having succeeded his older brother Francesco I.-Biography:...
(1531–1587). These claims have been reexamined with more modern methologies. These methods have confirmed the presence of P.falciparum in the remains confirming the original diagnosis.
Treatment of malaria was discussed in several European herbal texts during the Renaissance
Renaissance
The Renaissance was a cultural movement that spanned roughly the 14th to the 17th century, beginning in Italy in the Late Middle Ages and later spreading to the rest of Europe. The term is also used more loosely to refer to the historical era, but since the changes of the Renaissance were not...
including Otto Brunfels
Otto Brunfels
Otto Brunfels was a German theologian and botanist...
(1532), Leonhart Fuchs
Leonhart Fuchs
Leonhart Fuchs , sometimes spelled Leonhard Fuchs, was a German physician and one of the three founding fathers of botany, along with Otto Brunfels and Hieronymus Bock .-Biography:...
(1543), Adam Lonicer
Adam Lonicer
Adam Lonicer, Adam Lonitzer or Adamus Lonicerus was a German botanist, noted for his 1557 revised version of Eucharius Rösslin’s herbal....
(1560), Hieronymus Bock
Hieronymus Bock
Hieronymus Bock was a German botanist, physician, and Lutheran minister who began the transition from medieval botany to the modern scientific worldview by arranging plants by their relation or resemblance....
(1577), Pietro Andrea Mattioli
Pietro Andrea Mattioli
Pietro Andrea Gregorio Mattioli was a doctor and naturalist born in Siena.He received his MD at the University of Padua in 1523, and subsequently practiced the profession in Siena, Rome, Trento and Gorizia, becoming personal physician of Ferdinand II, Archduke of Austria in Prague and Ambras...
(1590), and Theodor Zwinger
Theodor Zwinger
Theodor Zwinger the Elder was a Swiss physician and humanist scholar. He made significant contributions to the emerging genres of reference and travel literature...
(1696).
European settlers and their West African slaves
Atlantic slave trade
The Atlantic slave trade, also known as the trans-atlantic slave trade, refers to the trade in slaves that took place across the Atlantic ocean from the sixteenth through to the nineteenth centuries...
likely brought malaria to the Americas in the 16th century. Spanish missionaries found that fever was treated by Amerindians near Loxa (Peru
Peru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....
) with powder from Peruvian bark
Jesuit's bark
Jesuit's Bark, also called Peruvian Bark, is the historical name of the most celebrated specific remedy for all forms of malaria. It is so named because it was obtained from the bark of several species of the genus Cinchona, of the order Rubiaceae, that have been discovered at different times and...
(Cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
succirubra). There are no references to malaria in the "medical books" of the Mayans or Aztecs. Quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
(Kinine), a toxic plant alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
, is an effective muscle relaxant, as the modern use for nocturnal leg cramps suggests, long used by the Quechua
Quechuas
Quechuas is the collective term for several indigenous ethnic groups in South America who speak a Quechua language , belonging to several ethnic groups in South America, especially in Peru, Ecuador, Bolivia, Chile, Colombia and Argentina.The Quechuas of Ecuador call themselves as well as their...
Indians of Peru to reduce the shaking effects caused by severe chills in the Andes
Andes
The Andes is the world's longest continental mountain range. It is a continual range of highlands along the western coast of South America. This range is about long, about to wide , and of an average height of about .Along its length, the Andes is split into several ranges, which are separated...
. The Jesuit Brother Agostino Salumbrino (1561–1642), an apothecary
Apothecary
Apothecary is a historical name for a medical professional who formulates and dispenses materia medica to physicians, surgeons and patients — a role now served by a pharmacist and some caregivers....
by training and who lived in Lima
Lima
Lima is the capital and the largest city of Peru. It is located in the valleys of the Chillón, Rímac and Lurín rivers, in the central part of the country, on a desert coast overlooking the Pacific Ocean. Together with the seaport of Callao, it forms a contiguous urban area known as the Lima...
, observed the Quechua using the quinine-containing bark of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...
tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was entirely unrelated to its effect in controlling shivering from cold, it was nevertheless the correct medicine for malaria. The use of the “fever tree” bark was introduced into European medicine by Jesuit missionaries (Jesuit's bark
Jesuit's bark
Jesuit's Bark, also called Peruvian Bark, is the historical name of the most celebrated specific remedy for all forms of malaria. It is so named because it was obtained from the bark of several species of the genus Cinchona, of the order Rubiaceae, that have been discovered at different times and...
). Jesuit Barnabé de Cobo (1582–1657), who explored Mexico and Peru, is credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain
Spain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
, and afterwards to Rome and other parts of Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, in 1632. Francesco Torti published in 1712 that only “intermittent fever” was amenable to the fever tree bark (“Therapeutice Specialis ad Febres Periodicas Perniciosas”, 1712 Modena). This work finally established the specific nature of cinchona bark and brought about its general use in medicine.
In 1717, the graphite pigmentation of a postmortem spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
and brain was published by Giovanni Maria Lancisi
Giovanni Maria Lancisi
Giovanni Maria Lancisi was an Italian physician, epidemiologist and anatomist who made a correlation between the presence of mosquitoes and the prevalence of malaria...
in his malaria text book “De noxiis paludum effluviis eorumque remediis”. He related the prevalence of malaria in swampy areas to the presence of flies
Fließ
Fließ is a municipality in the Landeck district and is located5 km south of Landeck on the upper course of the Inn River. It has 9 hamlets and was already populated at the roman age; the village itself was founded around the 6th century. After a conflagration in 1933 Fließ was restored more...
and recommended swamp
Swamp
A swamp is a wetland with some flooding of large areas of land by shallow bodies of water. A swamp generally has a large number of hammocks, or dry-land protrusions, covered by aquatic vegetation, or vegetation that tolerates periodical inundation. The two main types of swamp are "true" or swamp...
drainage
Drainage
Drainage is the natural or artificial removal of surface and sub-surface water from an area. Many agricultural soils need drainage to improve production or to manage water supplies.-Early history:...
to prevent it.
Antimalarial drugs
QuininePierre Joseph Pelletier
Pierre Joseph Pelletier
Pierre-Joseph Pelletier was a French chemist who did notable research on vegetable alkaloids, and was the co-discoverer of quinine and strychnine.- Further reading :...
and Joseph Bienaimé Caventou
Joseph Bienaimé Caventou
Joseph Bienaimé Caventou was a French chemist.He was a professor at the École de Pharmacie in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an apothecary. He was a pioneer in the use of mild solvents to isolate a number of active ingredients from...
separated in 1820 the alkaloids Cinchonine and Quinine from powdered fever tree bark, allowing for the creation of standardized doses of the active ingredients. Prior to 1820, the bark was first dried, ground to a fine powder and then mixed into a liquid (commonly wine) which was then drunk.
An English trader, Charles Ledger
Charles Ledger
Charles Ledger was an alpaca farmer and noted for his work in connection with quinine, a treatment for malaria.Ledger belonged to a huguenot family that emigrated to England in the 18th century; he was born at London, the son of George Ledger, a mercantile broker, and his wife Charlotte, née Warren...
, and his Amerindian servant, Manuel Incra Mamani, had spent four years collecting cinchona seeds in the Andes in Bolivia
Bolivia
Bolivia officially known as Plurinational State of Bolivia , is a landlocked country in central South America. It is the poorest country in South America...
, highly prized for their quinine but a prohibited export. Ledger managed to get some seeds out; in 1865 the Dutch government bought a small parcel, and 20,000 trees of the famous Cinchona ledgeriana
Cinchona ledgeriana
Cinchona ledgeriana is a plant indigenous to the eastern slopes of the Andes, where they grow from in elevation in Colombia and Bolivia. Specimens grow in height and have large glossy leaves....
were successfully cultivated in Java
Java
Java is an island of Indonesia. With a population of 135 million , it is the world's most populous island, and one of the most densely populated regions in the world. It is home to 60% of Indonesia's population. The Indonesian capital city, Jakarta, is in west Java...
(Indonesia). By the end of the nineteenth century the Dutch had established a world monopoly in the supply of quinine.
'Warburg's Tincture'
In 1834, in British Guiana
British Guiana
British Guiana was the name of the British colony on the northern coast of South America, now the independent nation of Guyana.The area was originally settled by the Dutch at the start of the 17th century as the colonies of Essequibo, Demerara, and Berbice...
(now Guyana
Guyana
Guyana , officially the Co-operative Republic of Guyana, previously the colony of British Guiana, is a sovereign state on the northern coast of South America that is culturally part of the Anglophone Caribbean. Guyana was a former colony of the Dutch and of the British...
), a German physician, Carl Warburg
Carl Warburg
Carl Warburg, also known as Charles Warburg, was a physician, clinical pharmacologist, pharmaceutical chemist, botanist and manufacturer...
, invented an antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...
medicine: 'Warburg's Tincture
Warburg's Tincture
Warburg's tincture was a pharmaceutical drug, now obsolete. It was invented in 1834 by Dr Carl Warburg.Warburg's tincture was well known in the Victorian era as a medicine for fevers, especially tropical fevers, including malaria. It was considered, by some, to be superior to quinine.Warburg's...
'. This secret, proprietary remedy contained quinine and a number of different other herbs
Herbalism
Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, herblore, and phytotherapy...
. Trials were made in Europe in the 1840s and 1850s, and it was officially adopted by the Austrian Empire
Austrian Empire
The Austrian Empire was a modern era successor empire, which was centered on what is today's Austria and which officially lasted from 1804 to 1867. It was followed by the Empire of Austria-Hungary, whose proclamation was a diplomatic move that elevated Hungary's status within the Austrian Empire...
in 1847. Warburg's Tincture gained a high, international reputation. It was considered by many eminent medical professionals to be a more efficacious antimalarial drug than quinine. It was also more economical. The British Government supplied Warburg's Tincture to troops in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
and other colonies.
Synthetic drugs
William Henry Perkin, a student of August Wilhelm von Hofmann
August Wilhelm von Hofmann
August Wilhelm von Hofmann was a German chemist.-Biography:Hofmann was born at Gießen, Grand Duchy of Hesse. Not intending originally to devote himself to physical science, he first took up the study of law and philology at Göttingen. But he then turned to chemistry, and studied under Justus von...
at the Royal College of Chemistry
Royal College of Chemistry
The Royal College of Chemistry was a college originally based on Oxford Street in central London, England. It operated between 1845 and 1872....
in London, tried in the 1850s to synthesize quinine in a commercially practicable process. The idea was to take two equivalents of N-allyltoluidine (C10H13N) and three atoms of oxygen to produce quinine (C20H24N2O2) and water. The experiments were unsuccessful. However, Perkin's Mauve
Mauve
Mauve is a pale lavender-lilac color, one of many in the range of purples. The color mauve is named after the mallow flower....
was produced when attempting quinine total synthesis
Quinine total synthesis
In total synthesis, the Quinine total synthesis describes the efforts in synthesis of quinine over a 150 year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine...
via the oxidation of N-allyltoluidine. Before Perkin's discovery all dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
s and pigments were derived from roots, leaves, insects, or, in the case of Tyrian purple
Tyrian purple
Tyrian purple , also known as royal purple, imperial purple or imperial dye, is a purple-red natural dye, which is extracted from sea snails, and which was possibly first produced by the ancient Phoenicians...
, molluscs
Mollusca
The Mollusca , common name molluscs or mollusksSpelled mollusks in the USA, see reasons given in Rosenberg's ; for the spelling mollusc see the reasons given by , is a large phylum of invertebrate animals. There are around 85,000 recognized extant species of molluscs. Mollusca is the largest...
. Perkin's discovery of artificially synthesized dyes led to important advances in medicine, photography, and many other fields.
In 1891 Paul Guttmann
Paul Guttmann
Paul Guttmann was a German pathologist who practiced medicine in Berlin. He is remembered for work with neurologist Albert Eulenburg involving the sympathetic nervous system...
and Paul Ehrlich
Paul Ehrlich
Paul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...
noted that methylene blue
Methylene blue
Methylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
had a high affinity for some tissues and that this dye had a slight antimalarial property. MB and its congeners may act by preventing the biocrystallization
Biocrystallization
Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro...
of heme. A mixture of eosin
Eosin
Eosin is a fluorescent red dye resulting from the action of bromine on fluorescein. It can be used to stain cytoplasm, collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic....
Y, methylene blue and demethylated methylene blue (azure B) was later used for a number of different blood film
Blood film
A blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
staining procedures (Malachowski stain, Romanowsky stain
Romanowsky stain
Romanowsky staining is a prototypical staining technique that was the forerunner of several distinct but similar methods, including Giemsa, Jenner, Wright, Field, and Leishman stains, which are used to differentiate cells in pathologic specimens....
, Giemsa stain
Giemsa stain
Giemsa stain, named after Gustav Giemsa, an early German microbiologist, is used in cytogenetics and for the histopathological diagnosis of malaria and other parasites.-Uses:...
). Ehrlich, the founder of chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, advocated a rational development of drugs by exploiting biochemical differences (“magic bullets”).
Life cycle
Johann Heinrich Meckel recorded in 1848 innumerable black-brown pigment granulesHemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...
in the blood and spleen of a patient who had died in a hospital for insane people. Meckel was probably looking at the parasites
Parasitism
Parasitism is a type of symbiotic relationship between organisms of different species where one organism, the parasite, benefits at the expense of the other, the host. Traditionally parasite referred to organisms with lifestages that needed more than one host . These are now called macroparasites...
of malaria without realizing it; malaria was not mentioned in his report. He thought the pigment was melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
. The causal relationship of pigment to the parasite was established in 1880, when the French physician Charles Louis Alphonse Laveran
Charles Louis Alphonse Laveran
Charles Louis Alphonse Laveran was a French physician.In 1880, while working in the military hospital in Constantine, Algeria, he discovered that the cause of malaria is a protozoan, after observing the parasites in a blood smear taken from a patient who had just died of malaria.He also helped...
, working in the military hospital of Constantine
Constantine, Algeria
Constantine is the capital of Constantine Province in north-eastern Algeria. It was the capital of the same-named French département until 1962. Slightly inland, it is about 80 kilometres from the Mediterranean coast, on the banks of Rhumel river...
Algeria
Algeria
Algeria , officially the People's Democratic Republic of Algeria , also formally referred to as the Democratic and Popular Republic of Algeria, is a country in the Maghreb region of Northwest Africa with Algiers as its capital.In terms of land area, it is the largest country in Africa and the Arab...
, observed pigmented parasites inside the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s of people suffering from malaria. He also witnessed the events of exflagellation and became convinced that the moving flagella were parasitic microorganisms. He noted that quinine removed the parasites from the blood. Laveran called this microscopic organism Oscillaria malariae and proposed that malaria was caused by this protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
n. This discovery was not initially well received and remained controversial until the development of the oil immersion lens in 1884 and of superior staining methods in 1890-1891.
In 1885 Ettore Marchiafava
Ettore Marchiafava
Ettore Marchiafava was an Italian physician and zoologist who worked on malariaEttore Marchiafava , was the personal doctor of three popes and the Royal House of Savoy, a senator and professor of Pathological Anatomy at the Sapienza University of Rome...
, Angelo Celli
Angelo Celli
Angelo Celli was an Italian physician and zoologist who studied malaria.Celli graduated in medicine in 1878 at the Sapienza University of Rome, where he became hygiene professor. In 1880 with Ettore Marchiafava he studied a new protozoan discovered by Alphonse Laveran and which they called...
and Camillo Golgi
Camillo Golgi
Camillo Golgi was an Italian physician, pathologist, scientist, and Nobel laureate.-Biography:Camillo Golgi was born in the village of Corteno, Lombardy, then part of the Austrian Empire. The village is now named Corteno Golgi in his honour. His father was a physician and district medical officer...
studied the reproduction cycles in human blood (Golgi cycles). Golgi observed that all parasites present in the blood divided almost simultaneously at regular intervals and that division coincided with attacks of fever. Golgi also recognized that the three types of malaria are caused by different protozoan organisms. By 1890 Laveran's germ was generally accepted but most of Laveran's initial ideas had been discarded in favor of the taxonomic work and clinical pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
of the Italian school. Marchiafava and Celli called the new microorganism Plasmodium
Plasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
. Pel, presaging its discovery by over 50 years, proposed the first theory of the existence of a tissue stage of the malaria parasite in 1886. This suggestion was reiterated in 1893 when Golgi also suggested that the parasites might have an undiscovered tissue phase this time in endothelial cells. Pel in 1896 supported Gogli's latent phase theory. Also in 1886 Golgi described the morphological differences that are still used to distinguish two malaria parasite species Plasmodium vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
and Plasmodium malariae
Plasmodium malariae
Plasmodium malariae is a parasitic protozoa that causes malaria in humans. It is closely related to Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial infection. While found worldwide, it is a so-called "benign malaria" and is not nearly as dangerous as that...
. Shortly after this Sakharov in 1889 and Marchiafava & Celli in 1890 independently identified Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
as a species distinct from P. vivax and P. malariae. In 1890, Grassi and Feletti reviewed the available information and named both P. malariae and P. vivax with the following statement: "C'est pour cela que nous distinguons, dans le genre Haemamoeba, trois espèces (H. malariae de la fièvre quarte, H. vivax de la fièvre tierce et H. praecox de la fièvre quotidienne avec coutres intermittences etc.)." H. vivax was soon renamed Plasmodium vivax. In 1892 Marchiafava and Bignami proved that the multiple forms seen by Laveran are a single species. This species was eventually named P. falciparum.
Laveran was awarded the 1907 Nobel Prize for Physiology or Medicine "in recognition of his work on the role played by protozoa in causing diseases". In 1897 the sexual stages of a related haematozoan, Haemoproteus columbae, in the blood were discovered by William MacCallum in infected birds.
Giovanni Maria Lancisi
Giovanni Maria Lancisi
Giovanni Maria Lancisi was an Italian physician, epidemiologist and anatomist who made a correlation between the presence of mosquitoes and the prevalence of malaria...
, John Crawford, Patrick Manson
Patrick Manson
Sir Patrick Manson was a Scottish physician who made important discoveries in parasitology and was the founder of the tropical medicine field....
, Josiah C. Nott
Josiah C. Nott
Josiah Clark Nott was an American physician and surgeon. He was also an author of surgical, yellow fever, and race theories.-Biography:...
, Albert Freeman Africanus King
Albert Freeman Africanus King
Albert Freeman Africanus King was a bystander physician who was pressed into service during the assassination of Abraham Lincoln. In addition, King was one of the earliest to suggest the connection between mosquitos and malaria....
, and Charles Louis Alphonse Laveran
Charles Louis Alphonse Laveran
Charles Louis Alphonse Laveran was a French physician.In 1880, while working in the military hospital in Constantine, Algeria, he discovered that the cause of malaria is a protozoan, after observing the parasites in a blood smear taken from a patient who had just died of malaria.He also helped...
developed theories that malaria may be caused by mosquito bites, but there was little evidence to support this idea. An early effort at malaria prevention occurred in 1896. An Uxbridge
Uxbridge, Massachusetts
Uxbridge is a town in Worcester County, Massachusetts, in the United States. It was first settled in 1662, incorporated in 1727 at Suffolk County, and named for the Earl of Uxbridge. Uxbridge is south-southeast of Worcester, north-northwest of Providence, and southwest of Boston. It is part of...
malaria outbreak prompted health officer, Dr. Leonard White
Leonard White (physician)
Leonard D. White, MD was a late 19th century physician and one of the Health Officers in Massachusetts who was involved with the earliest study of mosquitoes and malaria and efforts for community prevention of malaria.-Early life:...
, to write a report to the State Board of Health, which led to a study of mosquito-malaria links, and the first efforts for malaria prevention. Massachusetts
Massachusetts
The Commonwealth of Massachusetts is a state in the New England region of the northeastern United States of America. It is bordered by Rhode Island and Connecticut to the south, New York to the west, and Vermont and New Hampshire to the north; at its east lies the Atlantic Ocean. As of the 2010...
State pathologist, Theobald Smith, asked that White's son collect mosquito specimens for further analysis, and that citizens 1) add screens
Window screen
A window screen, insect screen or bug screen is a metal wire, fiberglass, or other synthetic fiber mesh, stretched in a frame of wood or metal, designed to cover the opening of an open window. Its primary purpose is to keep leaves, debris, insects, birds, and other animals from entering a building...
to windows, and 2) drain
Drainage
Drainage is the natural or artificial removal of surface and sub-surface water from an area. Many agricultural soils need drainage to improve production or to manage water supplies.-Early history:...
collections of water.
It was Britain's Sir Ronald Ross
Ronald Ross
Sir Ronald Ross KCB FRS was a British doctor who received the Nobel Prize for Physiology or Medicine in 1902 for his work on malaria. He was the first Indian-born person to win a Nobel Prize...
, an army surgeon working in Secunderabad
Secunderabad
Secunderabad popularly known as the twin city of Hyderabad is located in the Indian state of Andhra Pradesh north of Hyderabad. Named after Sikandar Jah, the third Nizam of the Asaf Jahi dynasty, Secunderabad was founded in 1806 AD as a British cantonment...
India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
, who proved in 1897 that malaria is transmitted by mosquitoes. He was able to find pigmented malaria parasites in a mosquito that he artificially fed on a malaria patient named Hussain Khan, who had crescents in his blood. He continued his research into malaria by showing that certain mosquito species (Culex
Culex
Culex is a genus of mosquito, and is important in that several species serve as vectors of important diseases, such as West Nile virus, filariasis, Japanese encephalitis, St. Louis encephalitis and avian malaria....
fatigans) transmit malaria to sparrows and isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. He reported this to the British Medical Association
British Medical Association
The British Medical Association is the professional association and registered trade union for doctors in the United Kingdom. The association does not regulate or certify doctors, a responsibility which lies with the General Medical Council. The association’s headquarters are located in BMA House,...
in Edinburgh
Edinburgh
Edinburgh is the capital city of Scotland, the second largest city in Scotland, and the eighth most populous in the United Kingdom. The City of Edinburgh Council governs one of Scotland's 32 local government council areas. The council area includes urban Edinburgh and a rural area...
, Scotland
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...
in 1898 and was greeted with a standing ovation.
Giovanni Battista Grassi
Giovanni Battista Grassi
Giovanni Battista Grassi was an Italian zoologist, known for work demonstrating that mosquitos carry the malaria parasite Plasmodium in their digestive tract, on the embryological development of honey bees, on parasites, particularly the vine parasite phylloxera, migrations and metamorphosis in...
, professor of Comparative Anatomy at Rome University, showed that human malaria could only be transmitted by Anopheles
Anopheles
Anopheles is a genus of mosquito. There are approximately 460 recognized species: while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus Plasmodium, which cause malaria in humans in endemic areas...
(Greek "anofelís": good-for-nothing) mosquitoes. Grassi along with his coworkers Amico Bignami
Amico Bignami
Amico Bignami was an Italian physician and entomologistHe was born in Bologna and graduated as a doctor in Rome in 1882. In 1883, he became extraordinary professor of pathology and in 1906, full-time professor at the University of Rome. In 1917, he became professor of medicine, a post he occupied...
, Giuseppe Bastianelli
Giuseppe Bastianelli
Giuseppe Bastianelli was an Italian physician and zoologist who worked on malaria.Born in Rome, Bastianelli was initially interested in chemistry, physiology and neurology; subsequently he became interested in the study of malaria...
and Ettore Marchiafava announced at the session of the Accademia dei Lincei
Accademia dei Lincei
The Accademia dei Lincei, , is an Italian science academy, located at the Palazzo Corsini on the Via della Lungara in Rome, Italy....
on December 4, 1898 that a healthy man in a non-malarial zone had contracted tertian malaria after being bitten by an experimentally infected Anopheles claviger.
In 1899 Bastianelli and Bignami were the first to observe the complete P. vivax transmission cycle from mosquito to human and back.
A bitter dispute broke out between the British and Italian schools of malariology over priority but Ross received the 1902 Nobel Prize for Physiology or Medicine for "his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it". In Cuba Carlos Finlay
Carlos Finlay
Carlos Juan Finlay was a Cuban physician and scientist recognized as a pioneer in yellow fever research.- Early life and education :...
found that yellow fever
Yellow fever
Yellow fever is an acute viral hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the Flaviviridae family....
is transmitted by another type of mosquito, now Aedes aegypti
Aedes aegypti
The yellow fever mosquito, Aedes aegypti is a mosquito that can spread the dengue fever, Chikungunya and yellow fever viruses, and other diseases. The mosquito can be recognized by white markings on legs and a marking in the form of a lyre on the thorax...
. His observation was confirmed by a medical board headed by Walter Reed
Walter Reed
Major Walter Reed, M.D., was a U.S. Army physician who in 1900 led the team that postulated and confirmed the theory that yellow fever is transmitted by a particular mosquito species, rather than by direct contact...
. Yellow fever and malaria among workers had seriously delayed construction of the Panama Canal
Panama Canal
The Panama Canal is a ship canal in Panama that joins the Atlantic Ocean and the Pacific Ocean and is a key conduit for international maritime trade. Built from 1904 to 1914, the canal has seen annual traffic rise from about 1,000 ships early on to 14,702 vessels measuring a total of 309.6...
. Mosquito control instituted by William C. Gorgas
William C. Gorgas
William Crawford Gorgas KCMG was a United States Army physician and 22nd Surgeon General of the U.S. Army...
dramatically reduced this problem.
Relapses were first noted in 1897 by Thayer who recounted the experiences of a physician who suffered a relapse of malaria twenty one months after leaving an endemic area. He proposed the existence of a tissue stage.
Microscopic examination of stained blood films
In 1876 methylene blueMethylene blue
Methylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
was synthesized by Heinrich Caro
Heinrich Caro
Heinrich Caro , was a German chemist.He started his study of chemistry at the Friedrich Wilhelms University and later chemistry and dyeing in Berlin at the Royal Trades Institute...
at BASF
BASF
BASF SE is the largest chemical company in the world and is headquartered in Germany. BASF originally stood for Badische Anilin- und Soda-Fabrik . Today, the four letters are a registered trademark and the company is listed on the Frankfurt Stock Exchange, London Stock Exchange, and Zurich Stock...
, a German chemical company. Robert Koch
Robert Koch
Heinrich Hermann Robert Koch was a German physician. He became famous for isolating Bacillus anthracis , the Tuberculosis bacillus and the Vibrio cholerae and for his development of Koch's postulates....
in 1882 used this dye to discover the cause of tuberculosis - Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
. Paul Ehrlich in 1880 described the use of "neutral" dyes - mixtures of acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic and basic
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
s for the differentiation of cells in peripheral blood smears. In 1886 Bernthsen prepared a relatively pure dye, obtained by decomposition of methylene blue which he termed methylene azure. In 1891 Ernst Malachowski and Dmitri Leonidovich Romanowsky
Romanowsky stain
Romanowsky staining is a prototypical staining technique that was the forerunner of several distinct but similar methods, including Giemsa, Jenner, Wright, Field, and Leishman stains, which are used to differentiate cells in pathologic specimens....
independently developed techniques using a mixture of Eosin
Eosin
Eosin is a fluorescent red dye resulting from the action of bromine on fluorescein. It can be used to stain cytoplasm, collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic....
Y and modified methylene blue (methylene azure) that produced a surprising hue
Hue
Hue is one of the main properties of a color, defined technically , as "the degree to which a stimulus can be describedas similar to or different from stimuli that are described as red, green, blue, and yellow,"...
unattributable to either staining component: a beautiful, distinctive shade of purple. Malachowski used alkali-treated methylene blue solutions and Romanowsky used methylene blue solution which were moulded or aged. This new method differentiated blood cells and demonstrated the nuclei of malarial parasites. Jenner in 1899 introduced methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
as a solvent for the dye precipitate.
Malachowski's staining technique is one of the most significant technical advances in the history of malaria.
Life cycle
The existence of relapses was confirmed by Patrick Manson who allowed infected Anopheles mosquitoes to feed on his eldest son - Patrick Thurburn Manson. The younger Manson then described a relapse nine months later after his apparent cure with quinine.Also in 1900 Amico Bignami and Giuseppe Bastianelli found that they could not infect an individual with blood containing only gametocytes. The possibility of the existence of a chronic blood stage infection was proposed by Ross and Thompson in 1910.
In 1903 Fritz Schaudinn
Fritz Schaudinn
Fritz Richard Schaudinn was a German zoologistBorn in Röseningken, East Prussia, he co-discovered, with Erich Hoffmann in 1905, the causative agent of syphilis, Spirochaeta pallida...
erroneously reported direct infection of erythrocytes by infective sporozoites of P. vivax. Schaudinn's error dominated scientific opinion for over forty years.
The existence of exoerythrocytic merogony of non-human malaria parasites in the internal organs was first demonstrated by Aragão in 1908.
In 1920 Félix Mesnil
Félix Mesnil
Félix Étienne Pierre Mesnil was a French zoologist, biologist, botanist, mycologist and algologist....
and Émile Roubaud
Émile Roubaud
Émile Roubaud was a French biologist and entomologist known for his work on paludism, yellow fever and sleeping sickness. In 1920, he and Félix Mesnil achieved the first experimental infection of chimpanzees with Plasmodium vivax.He made his career at Pasteur Institute...
achieve the first experimental infection of chimpanzee
Chimpanzee
Chimpanzee, sometimes colloquially chimp, is the common name for the two extant species of ape in the genus Pan. The Congo River forms the boundary between the native habitat of the two species:...
s with P. vivax.
Three possible mechanisms of relapse were proposed by Marchoux in 1926 (i) parthenogenesis of macrogametocytes (ii) persistence of schizonts in small numbers in the blood where their multiplication is inhibited by immunity and this immunity disappears and/or (iii) reactivation of an encysted body in the blood. James in 1931 based on the lack of activity of quinine on the sporozoites proposed that after being injected by the mosquito, the sporozoites are carried to internal organs, where they enter the reticuloendothelial cells and undergo a cycle of development. Huff and Bloom in 1935 demonstrated the exoerythrocytic stages of avian malaria. In 1945 Fairley et al. reported that inoculation of blood from a patient with P. vivax may fail to induce malaria in a susceptible recipient although the donor may subsequently develop overt malaria. The sporozoites disappeared from the blood stream within one hour and reappeared eight days later. This suggested that persistent tissue forms existed. Using mosquitoes rather than blood Shute in 1946 described a similar phenomenon and proposes the existence of an 'x-body' or resting form. The following year Sapero proposed that a link existed between a tissue stage not yet discovered in patients with malaria and the phenomenon of relapse. Garnham in 1947 described exoerythrocytic schizogony in Hepatocystis (Plasmodium) kochi. In the following year Shortt and Garnham described the liver stages of P. cynomolgi in the monkey. In the same year a human volunteer consented to receive a massive dose of infected sporozoites of P. vivax and undergo a liver biopsy three months later thus allowing Shortt et al. to demonstrate the tissue stage of a human malarial parasite.
The tissue form of Plasmodium ovale
Plasmodium ovale
Plasmodium ovale is a species of parasitic protozoa that causes tertian malaria in humans. It is closely related to Plasmodium falciparum and Plasmodium vivax, which are responsible for most malaria. It is rare compared to these two parasites, and substantially less dangerous than P...
was described in 1954 and that of P. malariae in 1960 in experimentally infected chimpanzees.
The latent or dormant liver form of the parasite (hypnozoite), responsible for the late relapses characteristic of P. vivax and P. ovale infections, was observed in the 1980s. The term hypnozoite was coined by Miles B. Markus, a PhD student in Imperial College, London. In 1976, he speculated: "If sporozoites of Isospora
Isospora
Isospora is a genus of internal parasites classified under Coccidia.It is responsible for the condition isosporiasis.At least 248 species have been described in this genus, but most of them are little studied and it is doubtful whether all should be recognized as distinct species...
can behave in this fashion, then those of related Sporozoa, like malaria parasites, may have the ability to survive in the tissues in a similar way." He adopted the term "hypnozoite" for malaria in 1978 when he wrote in a little-known journal that this name would "... describe any dormant sporozoites or dormant, sporozoite-like stages in the life cycles of Plasmodium or other Haemosporina
Plasmodiidae
The Plasmodiidae are a family of apicomplexan parasites, including the type genus Plasmodium, which is responsible for malaria. This genus was created in 1903 by Mesnil.They are one of the four families in the order Haemosporida....
".
In 1982 Krotoski et al report identification of P. vivax hypnozoites in liver cells of infected chimpanzees and in 1984 Mazier et al report in vitro cultivation of P. vivax liver stages in human hepatocytes. In 1989 chloroquine resistance in P. vivax is reported in Papua New Guinea.
Therapeutic uses
In the early twentieth century, before antibiotics, patients with syphilisSyphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
were intentionally infected with malaria to create a fever. In the 1920s Julius Wagner-Jauregg
Julius Wagner-Jauregg
Julius Wagner-Jauregg was an Austrian physician, Nobel Laureate, and Nazi supporter.-Early life:...
, a Viennese psychiatrist
Psychiatrist
A psychiatrist is a physician who specializes in the diagnosis and treatment of mental disorders. All psychiatrists are trained in diagnostic evaluation and in psychotherapy...
, began to treat neurosyphilitics with induced P. vivax malaria. Three or four bouts of fever were enough to kill the temperature-sensitive syphilis bacteria (Spirochaeta pallida also known as Treponema pallidum
Treponema pallidum
Treponema pallidum is a species of spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis, bejel, pinta and yaws. The treponemes have a cytoplasmic and outer membrane...
). P. vivax infections were terminated by quinine. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable to the almost-certain death from syphilis. Therapeutic malaria opened up a wide field of chemotherapeutic research and was practised until 1950. Wagner-Jauregg was awarded the 1927 Nobel Prize in Physiology or Medicine for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica.
Control efforts
Efforts to control the spread of malaria suffered a major setback in 1930. EntomologistEntomology
Entomology is the scientific study of insects, a branch of arthropodology...
Raymond Corbett Shannon
Raymond Corbett Shannon
Raymond Corbett Shannon was an American entomologist who specialised in Diptera and medical entomology. His studies at Cornell University were interrupted by World War I, but he received his B.S. from there in 1923. He was employed by the U.S...
discovered disease-bearing Anopheles gambiae
Anopheles gambiae
Anopheles gambiae is a complex of at least seven morphologically distinguishable species of mosquitoes in the genus Anopheles. This complex was recognised in the 1960s and includes the most important vectors of malaria in sub-Saharan Africa and the most efficient malaria vectors known.This species...
mosquitoes living in Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
, likely brought there by plane or fast mail steamer. This species of mosquito is a particularly efficient vector for malaria and is native to Africa. In 1938, the introduction of this new mosquito vector caused the greatest epidemic of malaria ever seen in the New World
New World
The New World is one of the names used for the Western Hemisphere, specifically America and sometimes Oceania . The term originated in the late 15th century, when America had been recently discovered by European explorers, expanding the geographical horizon of the people of the European middle...
. However, complete eradication of A.gambiae from north-east Brazil and thus from the New World was achieved in 1940 by meticulous application of Paris Green
Paris Green
Paris Green is an inorganic compound more precisely known as copper acetoarsenite. It is a highly toxic emerald-green crystalline powder that has been used as a rodenticide and insecticide, and also as a pigment, despite its toxicity. It is also used as a blue colorant for fireworks...
to breeding places and of Pyrethrum
Pyrethrum
Pyrethrum refers to several Old World plants of the genus Chrysanthemum which are cultivated as ornamentals for their showy flower heads. Pyrethrum is also the name of a natural insecticide made from the dried flower heads of C. cinerariifolium and C...
spray-killing to adult resting places.
Antimalarial drugs
Hans Andersag and colleagues synthesized and tested at the Elberfeld laboratories of the IG FarbenIG Farben
I.G. Farbenindustrie AG was a German chemical industry conglomerate. Its name is taken from Interessen-Gemeinschaft Farbenindustrie AG . The company was formed in 1925 from a number of major companies that had been working together closely since World War I...
(Germany) about 12000 different compounds and succeeded in producing Resochin® as substitutes for quinine in the 1930s (Dtsch.-Reichs-Pat. 683692); it is chemically related to quinine through the possession of a quinoline nucleus and the dialkylaminoalkylamino side chain. Resochin (a RESOrcinate of a 4-aminoCHINoline) (7-chloro-4- 4- (diethylamino) - 1 - methylbutyl amino quinoline) and a similar compound Sontochin (3-methyl Resochin) were synthesized in 1934 in close cooperation with American companies. There were over 2,000 cartel agreements between IG Farben
IG Farben
I.G. Farbenindustrie AG was a German chemical industry conglomerate. Its name is taken from Interessen-Gemeinschaft Farbenindustrie AG . The company was formed in 1925 from a number of major companies that had been working together closely since World War I...
and foreign firms — including Standard Oil of New Jersey
Esso
Esso is an international trade name for ExxonMobil and its related companies. Pronounced , it is derived from the initials of the pre-1911 Standard Oil, and as such became the focus of much litigation and regulatory restriction in the United States. In 1972, it was largely replaced in the U.S. by...
, DuPont
DuPont
E. I. du Pont de Nemours and Company , commonly referred to as DuPont, is an American chemical company that was founded in July 1802 as a gunpowder mill by Eleuthère Irénée du Pont. DuPont was the world's third largest chemical company based on market capitalization and ninth based on revenue in 2009...
, Dow Chemical Company
Dow Chemical Company
The Dow Chemical Company is a multinational corporation headquartered in Midland, Michigan, United States. As of 2007, it is the second largest chemical manufacturer in the world by revenue and as of February 2009, the third-largest chemical company in the world by market capitalization .Dow...
, and others in the United States. In March 1946 the drug was officially named Chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
. Chloroquine is an inhibitor of hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...
production through biocrystallization
Biocrystallization
Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro...
and is one of the best antimicrobials ever developed. Quinine and chloroquine affect malarial parasites only at stages in their life cycle when the parasites are forming hematin-pigment (hemozoin) as a byproduct of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
degradation.
The drug target of chloroquine is host-derived, which markedly delayed the emergence of resistance and it took P. falciparum 19 years to build resistance to chloroquine. The first chloroquine-resistant strains were detected around the Cambodia
Cambodia
Cambodia , officially known as the Kingdom of Cambodia, is a country located in the southern portion of the Indochina Peninsula in Southeast Asia...
‐Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
border and in Colombia
Colombia
Colombia, officially the Republic of Colombia , is a unitary constitutional republic comprising thirty-two departments. The country is located in northwestern South America, bordered to the east by Venezuela and Brazil; to the south by Ecuador and Peru; to the north by the Caribbean Sea; to the...
, in the 1950s. These resistant strains spread rapidly, resulting in a large increase in mortality from this disease, particularly in Africa during the 1990s.
Until the 1950s screening of anti malarial drugs was carried out on avian malaria. This was less than satisfactory as the avian malaria species differ in a number of ways from those that infect humans. The discovery in 1948 of Plasmodium berghei
Plasmodium berghei
Plasmodium berghei is a unicellular parasite and it infects mammals other than humans.P. berghei is one of the four Plasmodium species that have been described in African murine rodents....
in wild rodents in the Congo
Belgian Congo
The Belgian Congo was the formal title of present-day Democratic Republic of the Congo between King Leopold II's formal relinquishment of his personal control over the state to Belgium on 15 November 1908, and Congolese independence on 30 June 1960.-Congo Free State, 1884–1908:Until the latter...
and later other rodent species that could infect laboratory rats transformed the tests used for drug development. The short hepatic phase and life cycle of these parasites made them extremely useful as animal models, a status they still retain.
Plasmodium cynomolgi in Rhesus monkeys (Macaca mulatta) were used in the 1960s to test drugs active against P. vivax. This model is also still in use.
Genetically modified mice (non obese diabetic severe combined immunodeficient and BXN) can be engrafted with human stem cells and used as models for Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
. Although the model is of variable reproducibility it has been used in some experiments.
Growth of the liver stages in animal free systems has been difficult but was achieved in the 1980s when P. berghei pre-erythrocytic stages was grown in wI38,a human embryonic lung cell line. This was followed by their growth in the human hepatoma line HepG2. Both P. falciparum and P. vivax have been grown in human liver cells; partial development of P. ovale in human liver cells has also been achieved; and P. malariae has been grown in chimpanzee and Aotus
Night monkey
The night monkeys, also known as the owl monkeys or douroucoulis, are the members of the genus Aotus of New World monkeys . They are widely distributed in the forests of Central and South America, from Panama south to Paraguay and northern Argentina...
liver cells.
Systematic screening of traditional Chinese medical herbs was carried out by a number of Chinese research teams consisting of hundreds scientists in the 1960s and 1970s. Qinghaosu, later named artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
, was cold extracted in a neutral milieu (pH 7.0) from the dried leaves of Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...
inspired by Ge Hong's recommendation.
Artemisinin was isolated by Tu Youyou, a Chinese pharmacologist. Tu headed a team of investigators who were tasked by the Chinese government with finding a treatment for choloroquine resistant malaria. Their work was known as Project 523 named after the date it was announced - May 23, 1967. The team investigated >2000 Chinese herb preparations and by 1971 had made 380 extracts from 200 herbs. An extract from qinghao (Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...
) was effective but the results were variable. Tu reviewed the literature including the 340 BC book Zhou hou bei ji fang (A handbook of prescriptions for emergencies) by the Chinese physician Ge Hong. This book contained the only useful reference to the herb: "A handful of qinghao immersed with two litres of water, wring out the juice and drink it all." After making a non-toxic, neutral extract, Tu and two team members volunteered to take the extract before antimalarial trials were done in patients. The first studies were published in Chinese with the first English language paper citing successful trials for artemisinin appeared in 1979. The authors of this paper were anonymous according to Chinese custom at the time. Tu presented her findings to a United Nations
United Nations
The United Nations is an international organization whose stated aims are facilitating cooperation in international law, international security, economic development, social progress, human rights, and achievement of world peace...
scientific meeting in Beijing
Beijing
Beijing , also known as Peking , is the capital of the People's Republic of China and one of the most populous cities in the world, with a population of 19,612,368 as of 2010. The city is the country's political, cultural, and educational center, and home to the headquarters for most of China's...
in 1981. Since then artemisinin has become a standard treatment for malaria.
Artemisinin is a sesquiterpene lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
containing a peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
group, which is believed to be essential for its anti-malarial activity. Its derivatives, artesunate and artemether, have been used in clinics since 1987 for the treatment of drug-resistant and drug-sensitive malaria, in especially, cerebral malaria. These drugs are characterized by fast action, high efficacy and good tolerance. They kill the asexual forms of P. berghei
Plasmodium berghei
Plasmodium berghei is a unicellular parasite and it infects mammals other than humans.P. berghei is one of the four Plasmodium species that have been described in African murine rodents....
and P. cynomolgi and have transmission-blocking activity. In 1985, Zhou Yiqing and his team combined artemether and lumefantrine into a single tablet, which was registered as a new medicine in China in 1992, and later it became known as “Coartem”. Artemisinin combination treatments (ACTs) are now widely used to treat uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries and only a minority of the patients who need artemisinin-based combination treatments actually receive them. Improved agricultural practices, selection of high-yielding hybrids, microbial
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...
production, and the development of synthetic peroxides will lower prices.
Insecticides
Othmar ZeidlerOthmar Zeidler
Othmar Zeidler was an Austrian chemist credited with the first synthesis of DDT.He was a son of the Viennese pharmacist Franz Zeidler. Othmar's brother, Franz Zeidler Jr. , also became a chemist and would collaborate with him on several projects...
is credited with first synthesis of DDT
DDT
DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....
(DichloroDiphenylTrichloroethane) in 1874. The insecticidal properties of DDT were identified in 1939 by the chemist Paul Hermann Müller
Paul Hermann Müller
Paul Hermann Müller also known as Pauly Mueller was a Swiss chemist and Nobel laureate. In 1948 he received the Nobel Prize in Physiology or Medicine for his 1939 discovery of insecticidal qualities and use of DDT in the control of vector diseases such as malaria and yellow fever.Müller was born...
of the Swiss firm Geigy Pharmaceutical
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
. For his discovery of the high efficiency of DDT as a contact poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
against several arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...
s he was awarded the Nobel Prize in Physiology or Medicine in 1948. In the fall of 1942, samples of the chemical were acquired by the United States, Britain, and Germany and laboratory tests demonstrated that it was highly effective against insects. As the Rockefeller studies showed in Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
, DDT remained effective for six to eight weeks if sprayed on the inside walls and ceilings of houses and other buildings.The first field test in which residual DDT was applied to the interior surfaces of all habitations and outbuildings was carried out in central Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
in the spring of 1944. The objective was to determine the residual effect of the spray upon anopheline density in the absence of other control measures. Spraying began in Castel Volturno
Castel Volturno
Castel Volturno is a comune in the Province of Caserta in the Italian region Campania, located about 35 km northwest of Naples and about 35 km west of Caserta on the Volturno river.-History:...
and, after a few months, in the delta of the Tiber
Tiber
The Tiber is the third-longest river in Italy, rising in the Apennine Mountains in Emilia-Romagna and flowing through Umbria and Lazio to the Tyrrhenian Sea. It drains a basin estimated at...
. The unprecedented effectiveness of the chemical was confirmed: the new insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...
was able to achieve the eradication of malaria through the eradication of mosquitoes. At the end of World War II a massive malaria control program based on DDT spraying was carried out in Italy. In Sardinia
Sardinia
Sardinia is the second-largest island in the Mediterranean Sea . It is an autonomous region of Italy, and the nearest land masses are the French island of Corsica, the Italian Peninsula, Sicily, Tunisia and the Spanish Balearic Islands.The name Sardinia is from the pre-Roman noun *sard[],...
- the second largest island in the Mediterranean - between 1946 and 1951, the Rockefeller Foundation
Rockefeller Foundation
The Rockefeller Foundation is a prominent philanthropic organization and private foundation based at 420 Fifth Avenue, New York City. The preeminent institution established by the six-generation Rockefeller family, it was founded by John D. Rockefeller , along with his son John D. Rockefeller, Jr...
conducted a large-scale experiment to test the feasibility of the strategy of "species eradication" in an endemic malaria vector. Malaria was effectively eliminated in the United States by the use of DDT in the National Malaria Eradication Program
National Malaria Eradication Program
In the United States, the National Malaria Eradication Program was launched on 1 July 1947. This federal program — with state and local participation — had succeeded in eradicating malaria in the United States by 1951.-History:...
(1947–52). The concept of eradication prevailed in 1955 in the Eighth World Health Assembly
World Health Assembly
The World Health Assembly is the forum through which the World Health Organization is governed by its 194 member states. It is the world's highest health policy setting body and is composed of health ministers from member states....
: DDT was adopted as a primary tool in the fight against malaria.
DDT was banned in the US in 1972, after the discussion opened by the book of the American biologist Rachel Carson
Rachel Carson
Rachel Louise Carson was an American marine biologist and conservationist whose writings are credited with advancing the global environmental movement....
which launched the environmental
Environmental science
Environmental science is an interdisciplinary academic field that integrates physical and biological sciences, to the study of the environment, and the solution of environmental problems...
movement in the West. The book catalogued the environmental impacts of the indiscriminate spraying of DDT and suggested that DDT and other pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s may cause cancer and that their agricultural use was a threat to wildlife
Wildlife
Wildlife includes all non-domesticated plants, animals and other organisms. Domesticating wild plant and animal species for human benefit has occurred many times all over the planet, and has a major impact on the environment, both positive and negative....
. Recently, the U.S. Congress
United States Congress
The United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....
, Republicans and Democrats alike, supports indoor DDT spraying
Indoor residual spraying
Indoor residual spraying or IRS is the process of spraying the inside of dwellings with an insecticide to kill mosquitoes that spread malaria. A dilute solution of insecticide is sprayed on the inside walls of certain types of dwellings—those with walls made from porous materials such as mud or...
as a vital component of any successful malaria control program, and the U.S. Agency for International Development
United States Agency for International Development
The United States Agency for International Development is the United States federal government agency primarily responsible for administering civilian foreign aid. President John F. Kennedy created USAID in 1961 by executive order to implement development assistance programs in the areas...
has initiated DDT and other insecticide spraying programs in some poor tropical countries.
A wide range of other insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...
s is available for mosquito control in addition to the measures of draining of wetland
Wetland
A wetland is an area of land whose soil is saturated with water either permanently or seasonally. Wetlands are categorised by their characteristic vegetation, which is adapted to these unique soil conditions....
breeding grounds and provision of better sanitation
Sanitation
Sanitation is the hygienic means of promoting health through prevention of human contact with the hazards of wastes. Hazards can be either physical, microbiological, biological or chemical agents of disease. Wastes that can cause health problems are human and animal feces, solid wastes, domestic...
. Pyrethrum
Pyrethrum
Pyrethrum refers to several Old World plants of the genus Chrysanthemum which are cultivated as ornamentals for their showy flower heads. Pyrethrum is also the name of a natural insecticide made from the dried flower heads of C. cinerariifolium and C...
(Chrysanthemum
Chrysanthemum
Chrysanthemums, often called mums or chrysanths, are of the genus constituting approximately 30 species of perennial flowering plants in the family Asteraceae which is native to Asia and northeastern Europe.-Etymology:...
[or Tanacetum
Tanacetum
Tanacetum is a genus of about 160 species of flowering plant in the family Asteraceae, native to many regions of the Northern Hemisphere.Common names include Tansy , Costmary , and Feverfew ; several other species are also known as tansies.Tanacetum species...
] cinerariaefolium) is an economically important source of natural insecticide. Pyrethrin
Pyrethrin
The pyrethrins are a pair of natural organic compounds that have potent insecticidal activity. Pyrethrins are neurotoxins that attack the nervous systems of all insects. When present in amounts not fatal to insects, they still appear to have an insect repellent effect. Pyrethrins are gradually...
s attack the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
s of all insects. A few minutes after application the insect cannot move or fly away and female mosquitoes are inhibited from biting. The use of pyrethrum in insecticide preparations dates back to Persia
Iran
Iran , officially the Islamic Republic of Iran , is a country in Southern and Western Asia. The name "Iran" has been in use natively since the Sassanian era and came into use internationally in 1935, before which the country was known to the Western world as Persia...
, about 400 BCE
Common Era
Common Era ,abbreviated as CE, is an alternative designation for the calendar era originally introduced by Dionysius Exiguus in the 6th century, traditionally identified with Anno Domini .Dates before the year 1 CE are indicated by the usage of BCE, short for Before the Common Era Common Era...
. Pyrethrins are non-persistent, being biodegradable
Biodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
and also breaking down easily on exposure to light
Light
Light or visible light is electromagnetic radiation that is visible to the human eye, and is responsible for the sense of sight. Visible light has wavelength in a range from about 380 nanometres to about 740 nm, with a frequency range of about 405 THz to 790 THz...
. The majority of the world's supply of pyrethrin and Chrysanthemum cinerariaefolium comes from Kenya
Kenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
. The flower was first introduced into Kenya and the highlands of Eastern Africa
East Africa
East Africa or Eastern Africa is the easterly region of the African continent, variably defined by geography or geopolitics. In the UN scheme of geographic regions, 19 territories constitute Eastern Africa:...
during the late 1920s. The flowers of the plant are harvested shortly after blooming and are either dried and powdered or the oils within the flowers are extracted with solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
s.
Cell culture
The first successful continuous malaria cultureMalaria culture
Malaria culture is the method to grow malaria parasites outside the body i.e. in an ex vivo environment.Plasmodium falciparum is currently the only human malaria parasite that has been successfully cultured continuously ex vivo...
was established in 1976 by William Trager and James B. Jensen, which facilitated research into the molecular biology of the parasite and the development of new drugs substantially. By using increasing volumes of culture medium, one can grow P.falciparum to higher parasitemia (above 10%).
Rapid diagnostic tests
The use of antigen-based malaria rapid diagnostic tests (RDTs)Malaria antigen detection tests
Malaria antigen detection tests are a group of commercially available tests that allow the rapid diagnosis of malaria by people who are not otherwise skilled in traditional laboratory techniques for diagnosing malaria or in situations where such equipment is not available. There are currently over...
was pioneered in the 1980s. Giemsa
Giemsa stain
Giemsa stain, named after Gustav Giemsa, an early German microbiologist, is used in cytogenetics and for the histopathological diagnosis of malaria and other parasites.-Uses:...
microscopy
Microscopy
Microscopy is the technical field of using microscopes to view samples and objects that cannot be seen with the unaided eye...
and RDTs represent the two diagnostics
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
most likely to have the largest impact on malaria control today. Rapid diagnostic tests for malaria do not require any special equipment and offer the potential to extend accurate malaria diagnosis to areas when microscopy services are not available.
21st century
Drug resistance poses a growing problem in the treatment of malaria in the 21st century, since resistance is now common against all classes of antimalarial drugs, with the exception of the artemisinins. This situation has resulted in the treatment of resistant strains becoming increasingly dependent on this class of drugs. However, the artemisinins are expensive, which limits their use in the developing world. Worrisome evidence is now emerging of malaria on the Cambodia-Thailand border that are resistant to combination therapies that include artemisinins, which raises the possibility that strains of malaria may have evolved that are untreatable with currently-available drugs. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinins, have probably been the main driving force in the selection of the resistant phenotype in the region.The application of genomics
Genomics
Genomics is a discipline in genetics concerning the study of the genomes of organisms. The field includes intensive efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping efforts. The field also includes studies of intragenomic phenomena such as heterosis,...
to malaria research is now of central importance. With the sequencing of the three genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s of the malaria parasite P.falciparum, one of its vector Anopheles gambiae, and the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
, the genetics of all three organisms in the malaria lifecycle can now be studied. This breakthrough is expected to produce advances in the understanding of the interactions between the parasite and its human host—such as between virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
s and the human immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
—as well as allowing the identification of the factors that restrict one species of parasite to one or a few species of mosquitoes. It is likely that these will eventually lead to new therapeutic approaches.
Another new application of genetic technology is the ability to produce genetically-modified
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
mosquitoes that are unable to transmit malaria, allowing biological control of malaria transmission.
The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) recommends Indoor residual spraying
Indoor residual spraying
Indoor residual spraying or IRS is the process of spraying the inside of dwellings with an insecticide to kill mosquitoes that spread malaria. A dilute solution of insecticide is sprayed on the inside walls of certain types of dwellings—those with walls made from porous materials such as mud or...
as one of three primary means of malaria control, the others being use of insecticide-treated mosquito nets (ITNs)
Mosquito net
A mosquito net offers protection against mosquitos, flies, and other insects, and thus against diseases such as malaria, dengue fever, yellow fever, and various forms of encephalitis, including the West Nile virus, if used properly and especially if treated with an insecticide, which can double...
and prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs). In 2000, only 1.7 million (1.8%) African children living in stable malaria-endemic conditions were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs by 2007, leaving 89.6 million children unprotected. An increased percentage of African households (31%) are estimated to own at least one ITN in 2008 (WHO World Malaria Report 2009). Most nets are impregnated with pyrethroid
Pyrethroid
A pyrethroid is an organic compound similar to the natural pyrethrins produced by the flowers of pyrethrums . Pyrethroids now constitute a major commercial household insecticides...
s, a class of insecticides with particularly low toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
. Dow AgroSciences
Dow AgroSciences
Dow AgroSciences LLC is a wholly owned subsidiary of the Dow Chemical Company specializing in not only agricultural chemicals such as pesticides, but also seeds and biotechnology solutions. The company is based in Indianapolis, Indiana, in the United States...
developed a microencapsulated formulation of the organophosphate
Organophosphate
An organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
chlorpyrifos methyl as a cost-effective, long-lasting alternative to DDT. As an Indoor residual spraying against pyrethroid resistant mosquitoes chlorpyrifos methyl outperformed DDT and lambdacyhalothrin
Cyhalothrin
Cyhalothrin is a pyrethroid insecticide, an ingredient in the Karate brand of pesticides sold by Syngenta.Cyhalothrin is a fluorinated pyrethrin analog.Lambda-cyhalothrin is a mixture of highly active isomers of cyhalothrin...
. Organizations such as the Clinton Foundation
Clinton Foundation
The William J. Clinton Foundation is a foundation established by former President of the United States Bill Clinton with the stated mission to "strengthen the capacity of people throughout the world to meet the challenges of global interdependence." The Foundation focuses on four critical areas:...
continue to supply anti-malarial drugs to Africa and other affected areas; according to director Inder Singh
Inder Singh (philanthropist)
Inder Singh is Executive Vice President of the multi-national Clinton Health Access Initiative, a global not-for-profit organization fighting malaria and other diseases. Mr. Singh has become known for his worldwide presence actions for global health, particularly regarding malaria eradication. He...
, in 2011 more than 12 million individuals will be supplied with subsidized anti-malarial drugs. Other organizations, such as Malaria No More
Malaria No More
Malaria No More is a nonprofit organization that aims to end death caused by malaria in Africa by 2015. Malaria No More is known for its participation in the Idol Gives Back charity specials.- History :...
continue distribution of more broad-based prophylaxis.
Further reading
- Robert Sallares (2002) Malaria and Rome: A History of Malaria in Ancient Italy, New York, N.Y.: Oxford University Press, ISBN 0199248508 / ISBN 978-0199248506
- Frank M. Snowden (2005) The Conquest of Malaria: Italy, 1900-1962, Yale Univ Press; illustrated edition, ISBN 0300108990 / ISBN 978-0300108996
- Randall M. Packard (2007) The Making of a Tropical Disease, The Johns Hopkins University Press; Baltimore, ISBN 0801887127 / ISBN 978-0801887123
- Irwin W. Sherman (2009) The Elusive Malaria Vaccine: Miracle or Mirage?, ASM Press, ISBN 978-1555815158
- Yip, Ka-Che (editor) (2009) Disease, Colonialism, and the State: Malaria in Modern East Asian History, Hong Kong University Press, ISBN 9622095879 / ISBN 978-9622095878
- Leo B. Slater (2009) War and Disease: Biomedical Research on Malaria in the Twentieth Century , Rutgers University Press, ISBN 0813544386 / ISBN 978-0813544380
- James L. A. Webb, Jr. (2009) Humanity’s Burden: A Global History of Malaria, Cambridge University Press, ISBN 978-0521670128
- Irwin W. Sherman (2010) Magic Bullets to Conquer Malaria. From Quinine to Qinghaosu, ASM Press, ISBN 978-1555815431
- Elisabeth Hsu, Stephen Harris (editors) (2010) Plants, Health and Healing: On the Interface of Ethnobotany and Medical Anthropology, Berghahn Books, ISBN 978-1845450601
External links
- Alphonse Laveran Nobel Lecture
- Grassi versus Ross
- Julius Wagner-Jauregg Nobel Lecture
- Malaria and the Fall of Rome
- Malaria Around the North Sea Malaria may have been introduced into the North Sea Basin in late Antiquity. It has been endemic at least since the 7th century, but its high-days were the Little Ice Age. After 1750 the disease retreated until it disappeared in the 1950s.
- Malariasite
- Malaria Website
- Medicines for Malaria Venture
- Medline Plus - Malaria
- Paul H Müller Nobel Lecture
- Ronald Ross Nobel Lecture
- The Global Fund to Fight AIDS, Tuberculosis and MalariaThe Global Fund to Fight AIDS, Tuberculosis and MalariaThe Global Fund to Fight AIDS, Tuberculosis and Malaria is an international financing organization that aims to "[a]ttract and disburse additional resources to prevent and treat HIV and AIDS, tuberculosis and malaria." A public–private partnership, the organization has its secretariat in Geneva,...
- The malaria genome
- Treatment of Malaria in the United States
- UK malaria treatment guidelines
- Wellcome images 2000 years of human culture, images from the Wellcome LibraryWellcome LibraryThe Wellcome Library is founded on the collection formed by Sir Henry Wellcome , whose personal wealth allowed him to create one of the most ambitious collections of the 20th century. Henry Wellcome's interest was the history of medicine in a broad sense and included subjects like alchemy or...
- WHO Malaria Control
- World Health Organisation (2006) Guidelines for the Treatment of Malaria
- World Malaria Map: Plasmodium falciparum Endemicity in 2007
- World Malaria Report 2009 Malaria is on the decline in various parts of the world, more than one-third of the 108 malarious countries documented reduction in malaria cases of app 50% in 2008 compared to 2000