Bloodletting to bark: Observations on how the Cinchona bark came to be used to
treat malaria
Sophia Colantonio, BSc
Faculty of Medicine,
University of Ottawa, Ontario, Canada;
Yale School of Public Health
New Haven, Connecticut, United States
Corresponding author:
Sophia Colantonio
Faculty of Medicine,
University of Ottawa,
451 Smyth Road,
Ottawa, Ontario
K1H 8M5
Phone: 613-863-6673
E-mail: [email protected]
Manuscript word count: 7,368
Table of Contents
Section
Acknowledgements
Introduction
Supernatural malaria beliefs in Antiquity
Page(s)
2
2-3
4
Rational and naturalistic malaria beliefs in
Antiquity
5-7
Empedocles of Agrigentum (504-433 BCE)
8-9
Hippocrates of Cos (460-379 BCE)
10-11
Galen of Pergamum (130 – 201 CE)
11-12
Jesuits and the discovery of Cinchona bark
13-22
Renaissance malaria treatments (1500 to
1800)
22-25
Contact dermatitis
25-28
Thomas Sydenham (1624-1689)
28-31
Robert Talbor (1642-1681)
31-32
Conclusion
33-34
References
35-37
1
Bloodletting to bark: Observations on how the Cinchona bark came to be used to
treat malaria
Acknowledgements
I am very grateful for Dr. Caroline Hetenyi for providing me this opportunity to
participate in the Geza Hetenyi Memorial Studentship for the Study of History of
Medicine. Thank you to my team of supervisors Jonathan Ferrier, Dr. Toby Gelfand, and
Dr. Robert Jackson who have been an invaluable source of mentorship and
encouragement throughout the entire process. Finally, I would like to thank my friends
and family for their support and kindness, especially my parents and the Vallee family.
This experience has piqued my curiosity in the history of medicine and its relevance to
contemporary practice. I have acquired a deeper appreciation for the context and
evolution of medical thought over time.
Introduction
Throughout the ages, infectious diseases have shaped and continue to shape
history. The ancient scourge of malaria has plagued man from Antiquity to the modern
day. The disease has strong political and economic associations. Epidemics of malaria
have been the constant companion to warfare and colonial conquests. Outbreaks were
the by-product of large movements of troops into malaria ecosystems. Conquerors
from Alexander the Great, Julius Caesar, to Oliver Cromwell were all victims of malaria.
The economic development of countries with the construction of railroads and canals
were also linked with malaria outbreaks (Ackerknecht, 1972). Thousands of lives were
lost in the construction of the Panama Canal and Ottawa’s Rideau. Currently, there are
an estimated 781, 000 deaths caused by malaria a year (WHO, 2010) and medicine is
2
still searching for effective treatments. Therapeutic regimens for malaria reflect the
evolution of our framework for understanding disease from a primitive supernatural
etiology to a modern microbiological etiology.
Only four of the approximately 200 species of malaria protozoa affect humans:
Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, and Plasmodium
ovale (Sallares, 2002). A mosquito vector, from Anopheles genus, is required to transmit
the protozoan disease to humans through a bite to the skin. The disease can be treated
with quinine or one of its synthetic forms. Quinine is the main active antimalarial
compound derived from the bark of Cinchona species of trees. Cinchona trees are native
to Peru, Ecuador, and Bolivia. There are over 20 species of Cinchona trees but only four
species and several hybrids contain therapeutic amounts of quinine. The four species of
Cinchona that can be optimized in antimalarial preparations are C. calisaya, C.
ledgeriana, C. succirubra and C. officinalis (Bruce-Chwatt, 1990). Depending on the
species, the quinine content of bark ranges between 4% to 13% (Lewis and ElvinLewis, 2003). Quinine’s mechanism of action is to destroy the Plasmodium parasite
harboured in the human’s red blood cells. It binds to double-stranded DNA resulting in
the inhibition DNA replication and RNA transcription and ultimately kills the malaria
parasite (Trevor et al., 2007). How Cinchona bark made its way from the Peruvian
forest and into Western medicine is an important part of medical history. The story of
Cinchona bark shows the evolution of medical thought on therapeutics over the ages.
3
Before Cinchona bark: Understanding of disease and therapeutic regimen from
Antiquity to up to the Renaissance
Supernatural malaria beliefs in Antiquity
The influence of primitive medicine survived into Antiquity as there were many
magico-religious beliefs regarding malaria fevers. Physicians and patients alike held
these primitive beliefs regarding supernatural powers inflicting malaria on man.
Consequently, some of the standard treatments were targeted at reversing the spells
cast upon them through a variety of superstitious methods consisting of magical elixirs,
incantations, charms, exorcisms and sacrifices (Neghina et al., 2010). Romans even had
cults that honoured a fever goddess and prayed for relief. Evidence is provided from
the writings of the Roman philosopher and statesman, Cicero (106 - 43 BCE), who
described “the old Fever Temple on the Palatine” (Russell, 1943). Interestingly,
‘abracadabra’ was initially recited in magic spells to try to break the curse of malaria
fevers in Rome (Sallares et al., 2004).
People ingested a variety of unpalatable
remedies from garlic in sour wine, cocktails of cucumber and camphor, to spiders all in
unsuccessful attempts to relieve malaria fevers (Schlagenhauf, 2004).
The
superstitious ritual of transference of disease from human to animal was performed to
cure malaria fevers by having livestock such as sheep brought into the room of the
feverish patient to absorb the human illness (Rocco, 2003).
Some of the common mythical explanations for malaria fevers were attributed
to the nefarious undertakings of both demons and dragons. Around 500 CE, John Lydus
correlated the frequency of fevers with the work of specific demons. Air, water and
earth demons were thought to cause intermittent fevers. In addition, the cold demon
4
that quarrelled with the other demons caused the reoccurrence of the fevers (Neghina
et al., 2010). The pagan beliefs about demons were even reflected in burials of
individuals stricken with malaria who had heavy weights placed on their hands and
feet to confine the deadly demons (Sallares et al., 2004). Another superstitious belief
held in ancient Roman times was that a dragon lived under Rome breathing “bad air”
that caused the disease (Neghina et al., 2010).
Rational and naturalistic malaria beliefs in Antiquity
In Antiquity, a rational and naturalistic framework for understanding malaria
began to emerge. Although there were primitive beliefs that existed, the evolution of
thinking among philosophers, doctors, and other scholars began to move away from
spirits and gods. Theories of disease now were viewed through an earthly lens or
naturalistic lens. Thus a rational and naturalistic view of malaria was developed.
Various scholars elucidated explanations of malaria in terms of natural phenomenon.
The naturalistic conceptualization of malaria is reflected in the miasmatic
theory of disease. Miasmas were unhealthy vapours that emanated from swamps and
caused the fevers. This naturalistic theory of malaria persisted for over 2500 years
until the Renaissance (Cox, 2010). The names ‘mal’ aria’ (spoiled air), ‘agues of the
marshes’, ‘marsh fever’, and ‘paludal poison’ reflect this medical understanding of the
swampy origin of disease in Antiquity (Cunha & Cunha, 2008; Mason-Bahr, 1938). It
was also referred to more simply as ‘fever’ and ‘ague’; however, it is important to note
that throughout history both of these terms were imprecisely used to describe fevers of
other etiologies. In particular, typhoid fever has a similar clinical presentation and was
often confused with malaria by Greek and Roman physicians (Packard, 2007).
5
The Romans recognized the temporal variation in malaria, as it was widely
known that summer and early fall were notorious for epidemics of the disease
sweeping through Roman cities. Yet they attributed the seasonal outbreaks of malaria
not to the peak in the mosquito-protozoa lifecycle but to the miasmas of stagnant
waters and swamp gases (Cunha & Cunha, 2008); there was some speculation at the
time that malaria was due to microorganisms and not noxious swamp gas; however,
these failed to gain traction and the theories of miasma prevailed up until the
Renaissance.
In 1st century BCE, agriculturalists and architects made several important
observations regarding malaria’s etiology and ecology. Marcus Terrentius Varro (116 –
28 BCE), a Roman agriculturalist in his publication Rerum Rusticarum raised health
concerns about marshy areas as he was convinced that ‘animaletti’, invisible minute
animals bred in swamps and through the inhalation infected humans with ‘diseases
that were difficult to be rid of’ (Russell, 1943). The architect Marcus Vitruvius Pollio
(90–20 BCE), commonly known as Vitruvius, also suspected minute organisms or
“insects” were implicated in malaria fevers. He furthered the ecological understanding
of malaria observing that salt-water swamps did not harbour malaria (Ackerknecht,
1972). The agriculturalist, Lucius Junius Moderatus Columella or Columella (116 BCE)
thought that mosquito bites transmitted the disease:
"marshes threw up noxious steams and bred insects, armed with mischievous
stings, and pestilent swimming and creeping things whereby hidden diseases
were often contracted, the causes of which even the physicians themselves
could not thoroughly understand." (Russell, 1943).
6
Today the theory of ‘animaletti’ being responsible for malaria would be
considered a microbiological explanation of the disease; however, at the time it was
unpopular and regarded as unusual (Rocco, 2003). This idea was not revisited until the
Renaissance when scientific discovery of bacteria by Antoni Van Leeuwenhoek in 1676
laid the foundation for further microbiological studies in the next two hundred years
(Cox, 2010). In 1717, Giovanni Maria Lancisi hypothesized that small organisms “bugs”
or “worms” entering the blood could be the causative agents of malaria (Neghina et al.,
2010). Lancisi also documented the Italian peasant belief mosquito bites caused
malaria fevers but it would not be until Ronald Ross’ experiments in 1890s that
definitively linked mosquitoes and malaria transmission (Mason-Bahr, 1938).
For centuries, the practice of bloodletting, purging, and the application of cool
cloths remained the foundation of malaria treatment (Kinsley-Scott and Norton, 2003).
The malaria treatment of bloodletting was based on the humoral theory of disease
developed through the work of the prominent Greek philosophers and physicians
Empedocles of Agrigentum (504-433 BCE), Hippocrates (460-379 BCE) and Galen (130
– 201 CE).
7
Empedocles of Agrigentum (504-433 BCE)
Empedocles of Agrigentum was a Greek philosopher who has been credited as
the most probable author of the theory of four elements, four qualities, and four
humors. The four elements consist of air, fire, water, and earth. These four elements in
turn correspond to for qualities: hot, dry, wet, and cold. Four organs (heart, liver,
spleen, and the brain) produced the four humours (blood, yellow bile, black bile, and
phlegm) (see Figure 1)(Ackerknecht, 1982).
Empedocles had a basic ecological
understanding of malaria as he built drainage canals in Selinus, Sicily to mitigate a local
epidemic around 550 BCE (Ackerknecht, 1972; Russel 1943).
8
(Liver)
Yellow bile
(Fire)
Hot
Dry
(Air)
Blood
(Heart)
(Earth)
Black Bile
(Spleen)
Wet
Cold
(Water)
Phlegm
(Brain)
Figure 1. Diagram illustrating the Greek theory of the four qualities, the four
elements and the four humours. The elements were regarded as being related to
qualities, and these in turn governed the respective humours. Imbalance in the
qualities and humours could be compensated by using drugs with the opposite
qualities. From Ackerknecht, 1982.
Hippocrates of Cos (460-379 BCE)
9
Hippocrates is known in the popular vernacular as the “father of medicine”. The
personal life of this famous physician from the Greek Island of Cos remains a mystery.
Unbeknownst to the general public, the writings of Hippocrates have actually been
determined to belong to different collective groups of writers. Pieces of literature were
compiled in 3 BCE in Alexandria that generally reflected the thoughts of scholars from
the school of Cos from 480 to 380 BCE and were published under the moniker
Hippocrates. Other groups of scholars that contributed to Hippocratic publications
were from Cnidian scholars in the Near East (present day south western Turkey) and
Sicilian scholars. Hippocrates’ name was chosen to represent this movement because
he was the physician held in the highest esteem at the time. The following discussion
uses Hippocrates to denote this collective group of scholarly writings.
The Hippocratic view of health was both holistic and naturalistic focusing on the
entire individual and not the diseased body part in isolation. It emphasized harnessing
nature to restore health. The four humours governed well-being and illness. According
to the humoural theory, diseases were due to the imbalance of blood, phlegm, black bile
and yellow bile. Health or eucrasia was a balance of humours and illness or dyscrasia
was a disruption this humoural equilibrium. Nature resolved diseases through a
process of either crisis or lysis. Crisis occurred on a ‘critical day’ when a coction or
disease end-product was eliminated from the body. Lysis was the gradual attenuation
of the disease. Hippocratic physicians’ therapeutic rational was to target this imbalance
by channelling natures healing properties primarily through diet.
Second line
treatments of surgery, bloodletting, purging, and vomiting were less commonly
administered (Ackerknecht, 1982).
10
Hippocrates was focused on describing easily observable diseases. He astutely
described various diseases of infectious origin including measles, mumps, and malaria.
His contributions to the understanding of malaria ranged from the characterization of
the disease to the description of seasonal variation of outbreaks. The different types of
malaria fevers were first delineated in Hippocrates Epidemics (Volume 1) (Table 1).
The sequela of splenomegaly, the enlargement of the spleen, was also first described by
Hippocrates (Cunha & Cunha, 2008).
Galen of Pergamum (130 – 201 CE)
Galen was born in the ancient Greek city of Pergamum (present day Turkey) and
studied medicine and philosophy throughout the Greek empire in Smyrna, Corinth, and
Alexandria. Shortly after completing his studies he moved to Rome, where he
established his career in medicine.
Galen’s understanding of pathology was informed by Hippocrates doctrine of
the four humours. He explored the etiology of the different types of intermittent
malaria fevers in De differentiis febrium (On the kinds of fever). The three principal
intermittent fevers: quotidian fevers, tertian fevers, and quartan fevers were the result
of too much phlegm, bile, and black bile, respectively. Galen described how the fevers
associated with an excess of bile caused the blood to ‘ferment’ and yield a frothy
residue much like boiling milk (Jarcho, 1993).
Galen diverged from Hippocrates in his therapeutic approach. Unlike
Hippocrates, Galen pursued more active forms of treatment from polypharmacy to
evacuations of humours. Galen’s work popularized the practice of prescribed bleedings
for malaria patients. The pathological ‘frothy’ residue could be treated with its removal
11
through bloodletting or purging. This practice of bloodletting was a cornerstone of
malaria treatment until the Renaissance (Duran-Reynals, 1946).
It was not until the 17th century, that the shift from bloodletting and purging
towards Cinchona bark, the world’s first antimalarial pharmaceutical drug occurred
(Schlagenhauf, 2004). Cinchona bark would go on to ultimately revolutionize the
treatment of the disease and mark the beginning of the movement towards empirical
modern medicine from the centuries of dogmatic practices of Galenic medicine.
Malaria Species
Type of
malaria
Duration of
fever (hours)
Periodicity of
malaria
paroxysms
(hours)
Days from
initial fever
(onset) to
next fever
(crisis)
Age of
Preferred
human host
Age of
parasitized RBCs
P. malariae
P. vivax
Quartan
Mild
tertian
Ovale
tertian
Malignant
tertian*
9
11
72
48
4
3
All ages
Young adults
All RBCs
Young RBCs
11
48
3
Young adults
40
48
3
Mature adults
Young RBCs
(reticulocytes)
Young RBCs
(reticulocytes)
P.ovale
P.falciparum
Three parallel
Quotidian
6-12
24
2
generations of P.
malariae or two
parallel
generations of P.
vivax, P. ovale, or
P. falciparum
Mixed malaria
Continuous
Continuous
Continuous
1
species
Table 1. Greek classification of intermittent malaria fevers.
*Also known as pernicious or semitertian malaria.
Very young
children
All RBCs
All ages
All RBCs
From Cunha & Cunha, 2008.
Jesuits and the discovery of Cinchona bark
12
In the Renaissance, much of Europe was affected by the scourge of malaria. In
1557, the first record of a malaria pandemic in Europe was documented. In the 17th
century Europe, civil wars and wars created favourable conditions for malaria to thrive
(Ackerknecht, 1972) so much so that malaria was considered the greatest disease of
that century. Its devastating effects were exemplified by the English national worries of
1639 that feared the loss of crops because malaria fevers had caused a shortage of
healthy workers (Duran-Reynals, 1946). Not surprisingly, the spread of malaria
coincided with the rising wealth of the European nations who were matching their
strong interest with funding of explorations to distant lands in search of new
commercial enterprises and consequently new cures, such as Cinchona bark, were also
discovered in this process (Tulchinsky and Varavikova, 2009).
After Francisco Pizarro’s conquest of Peru in 1532, the doors to this country
were opened to religious missionaries including the Jesuit priests who were seeking to
spread their faith. In 1568, the Jesuit priests arrived in Peru and within several decades
of their settling they unlocked the cure for malaria from the heart of Peruvian forests
(Rocco, 2003). According to Jesuit doctrine they were forbidden to study medicine, as it
could detract from their primary focus of spiritual matters. However, the study of
pharmacy and herbalism were acceptable in their faith. In their studies of medical
botany, the Jesuits priests undertook numerous field expeditions to describe and
characterize the flora of remote forests in this newly discovered land.
During an
expedition to Loxa in the Southern district of Peru (Figure 2), the natural habitat of
Cinchona trees, the Jesuit’s observed that the Incans, the indigenous people, were
making teas out of the bark of the tree to treat shivers from exposure to the cold.
13
Having observed the bark’s effects of ceasing shivering, the Jesuits then hypothesized
that it might be an effective remedy to treat the chills associated with malaria. In the
1630s, the medicinal properties of Cinchona bark were first documented in two
separate publications. Around 1630, Antonio de la Calancha, an Augustianian friar,
described:
“A tree grows which they call ‘the fever tree’ [arbol de calenturas] in the country
of Loxa, whose bark, of the colour of cinnamon, made into powder amounting to
the weight of two small silver coins and given as a beverage, cures the fevers
and tertianas; it has produced miraculous results in Lima.” (Duran-Reynals,
1946) (Figure 3-5)
In 1639, Bernabé Cobó, a Jesuit priest gave a remarkably similar description to
Calancha’s:
“In the district of the city of Loxa, a diocese of Quito, grow certain kind of large
trees, which have bark like cinnamon, a bit coarse and very bitter; which,
ground to powder, is given to those who have the ague and with only this
remedy it is gone. These powders must be taken to the weigh of two reals of
silver in wine or any other liquor just before the chill starts. These powders are
now so well known and esteemed, not only in all the Indies, but in Europe, that
with insistence they are sent for from Rome.” (Rocco, 2003)
In 1642, doctor Pedro Barba a professor of medicine at the Royal Academy of
Valladolid, Spain published Vera praxis ad curationem Tertianae, etc. (Seville).
Historians consider this to be the first publication written in Europe about Cinchona
bark used to treat intermittent fevers (Waring, 1878).
14
Figure 2. The distribution of five 'species' of the cinchona tree along the west coast of South
America (shaded areas). From Bruce-Chwatt, 1990.
15
Figure 3. Cinchona offiicianilis bark. From Zell, 2009.
Bag for cinchona bark, Peru, 1777-1785
Figure 4. Rawhide ‘seron’, a bag used for storage and transportation of Cinchona bark, Peru,
1777-1785. This bag was collected on the 1777 Peruvian expedition of Hipolito Ruiz Lopez
and Antonio Pavon y Jimienz that was commissioned by Spanish King Charles III to explore
the region. From Science Museum, 2011.
Bag for cinchona bark, Peru, 1777-1785
16
Figure 5. One of the earliest illustrations of the Cinchona tree, published
1662. From Schlagenhauf, 2004.
17
There has been lengthy debate regarding whether the Incans already knew of the
antimalarial properties of Cinchona bark before the Jesuits. Scholars in favour of prior
Incan knowledge argue that the indigenous people harboured great disdain for the
Spanish occupants. This view is supported by the accounts of the Italian merchant
Antonius Bollus who resided in Peru, who stated:
“The bark was known to the Indians and that they used it upon themselves in
disease; but that they always tried with all means in their power to prevent the
remedy becoming known to the Spaniards, who of all Europeans particularly
aroused their ire’ (Jaramillo-Arango, 1949).
Additional arguments include that Incans extensive medical botanical knowledge of
thousands of uses of plants would have surely included Cinchona bark (Honigsbaum,
2002). Some historians contend that the Incans had knowledge of the remedy but the
bitterness of quinine deterred them from taking it when suffering from malaria fevers
(Jaramillo-Arango, 1949).
Although it cannot be known definitively, there is more convincing evidence to
support the modern view that the Incans were not aware of the antimalarial properties
of Cinchona bark. First, genetic evidence supports that malaria was introduced in South
America in the 16th century from Spanish conquistadors and their African slave trade. It
is hypothesized that through the enterprises undertaken by the Spanish conquistadors
in the New World, that they were responsible for first importing malaria to Hispaniola
Island and then subsequently spreading the disease to the mainland (Schlagenhauf,
2004). Second, archaeological evidence supports that Pre-Columbian South Americans
were a healthy group of people suffering from a small number of diseases.
Archaeological evidence in the form of portraits of illnesses depicted on pots, in
addition to mummies and skeletons preserved at high altitudes of the Andes have
18
substantiated the existence of various infectious diseases such as tuberculosis,
leishmaniasis, treponematoses, and hookworms, but have failed to provide evidence to
support the Pre-Columbian existence of malaria (Kiple, 1993). If malaria were a new
disease introduced by the Europeans, then it would be logically impossible for the
Incans to have an herbal remedy for a disease that they had never encountered.
Despite the Incans having a broad botanical knowledge, there is lack of
hieroglyphics or archaeological evidence to support that they knew of this remedy.
There are some limitations to this counter-argument as during the European conquests
many Incan populations were eradicated along with their traditional medicinal
knowledge (Honigsbaum, 2002).
Ecologic plausibility must also be taken into consideration. Malaria is endemic at
low altitudes in South America, whereas the Cinchona trees are most abundant at
higher altitudes, growing between 1,500 and 3,000 meters, where malaria is not an
issue (Rocco, 2003; Lee, 2002).
Furthermore, despite the extensive contact between the Incans and the Spanish, the
Jesuits documented the first accounts of Cinchona bark used in malaria treatment
almost one century after Pizarro’s conquest of Peru. During Pizarro’s conquest of Peru,
his soldiers often sought treatment by local traditional healers. Subsequently, many of
the plants used in the soldiers’ healing were documented and shipped back to Spain,
yet Cinchona bark was never mentioned (Honigsbaum, 2002). This significant omission
would be improbable given the need for a malaria cure in Europe. In addition, the
Jesuits were dutiful historians and deeply integrated with the Incans, who did not make
any mention of the remedy for nearly hundred years of living in Peru. If the Incans had
19
already known of a cure, it is likely the Jesuits would have also known about it much
earlier. The balance of evidence supports the case that the Jesuits deserve the credit
for the use of Cinchona bark to treat malaria.
Because of the association of the Catholic religion and Jesuits with Cinchona bark,
there was a backlash from Protestants in Europe who sought to discredit the validity of
the remedy. There were allegations that this remedy was the ‘Devil’s powder’ and part
of an elaborate ‘Popish plot’ (Lee, 2002). These insinuations along with ancient Galenic
practice of bloodletting were part of the resistance that constantly challenged Cinchona
bark’s medicinal legitimacy. The stigma surrounding this new cure began to decrease
after the secret ingredient in the successful treatment of King Charles II in 1672 was
revealed a decade later to be Cinchona bark (Bruce-Chwatt, 1990). Robert Talbor was
the apothecarist and self-proclaimed ‘feverologist’ who oversaw the treatment of King
Charles II. He recognized the magnitude of the stigma surrounding Cinchona bark and
took careful measures to disguise bark masking it in wine when administering it to the
king (Rocco, 2003). In 1677, Cinchona bark was formally introduced into Western
medicine with it first appearance in the London Pharmacopoeia as Peruvian bark (or
cortex Peruvianus) (Keeble, 1997).
In 1682 after the secret ingredient was revealed, Cinchona bark became an accepted
treatment for malaria and was the first and only drug available on market for this
disease. The overwhelming demand for the Cinchona bark soon outpaced the meagre
supply, the scarcity of Cinchona bark in Europe was a major driver for New World
explorations.
20
In 1735, the French Academy of Science funded Charles Marie de la Condamine’s
exploration of South America. His mission’s objectives were first to, settle the ongoing
dispute of the shape of the Earth and second, to locate and import the Cinchona tree
(Lee, 2002). Soon after Condamine’s arrival in Ecuador, he received news that the rival
French team had recently achieved this non-medical goal in Lapland (Honigsbaum,
2002). With the first objective resolved, Condamine spent his time in South America
pursuing the illusive Cinchona tree. Two years later, he arrived in Loxa, Peru and found
the Cinchona tree, which he imprecisely referred to the tree using the indigenous
language, Quechua, as quina quina (or quinaquina or kinakina). The local indigenous
people referred to Peruvian balsam trees (Myroxylon peruiferum) as quina quina that
translates to “bark of barks”. The Peruvian balsam unlike the Cinchona species has no
antimalarial properties but was mainly used for treating wounds. However, the main
active compound of Cinchona bark, quinine, would later take it etymological roots from
quina quina the wrong tree (Keeble, 1997).
Beyond the lack of precision in naming, Condamine made several important
contributions to advancing the medicinal knowledge of the cure. First, he astutely
correlated the different varieties of Cinchona trees based on their colour of bark with
their febrifugal content. In descending order of their febrifugal effects, he ranked red
bark as the most effective, then yellow, and lastly white bark being of negligible
therapeutic benefit. Condamine determined this order based on the bitterness of the
different colours of bark, which was later realized to be due to their quinine content.
Red bark would turn out to be the only bark of therapeutic value. Second, the
specimens of Cinchona that he collected he sent to Carl Linnaeus that became the basis
21
of the taxonomic classification of that species. In 1742, Carl Linnaeus in published
Genera Plantarum naming the genera of trees Cinchona to honour the Lady Chinchon,
the wife of Viceroy of Peru who had supposedly been cured by this remedy around the
late 1620s to early 1630s (Lee, 2002). Both the spelling and the story turned out to be
inaccurate. Linnaeus misspelled Lady Chinchon’s name and the historical attempts to
correct the scientific name proved unsuccessful. The colourful story about Lady
Chinchon also turned out to be little more than a myth (Bruce-Chwatt, 1988; BruceChwatt, 1990). Historical examination has revealed that it is more plausible that Lady
Chinchon’s husband was the victim of malaria.
Renaissance malaria treatments (1500 to 1800)
Renaissance medicine was the foundation of modern medicine but was also
beholden to intense superstitions (Ackerknecht, 1982). Malaria remedies reflected this
tension between rational and mythical approaches to treatment. The Renaissance was
also the first time that the word ‘malaria’ appeared in the English language in Horace
Walpole’s writings in 1740 (Sallares, 2002).
The supernaturalistic approach to treating malaria included: astrology; witchhunting; and a variety of quack medicines. Quack medicine was widely practiced by
individual’s lacking any formal medical education. These charlatans marketed
themselves as “ague curers” and typically would treat malaria fevers with a variety of
absurd and ineffective cures including charms, incantations, and worthless medicine.
For instance, the ‘tried and true’ malaria remedy of the 16th century Roman healer
Tralliano consisted of getting a patient to wear an orange with peach pit stuck inside
around his neck (Rocco, 2003).
A frightening bogus Renaissance remedy called Dr.
22
Goddard’s Drops was allegedly made from human skulls (Duran-Reynals, 1946).
In contrast, the rational approach to treating malaria consisted of bleeding and
purging. These treatments were based on the humoural theory of illness developed by
Hippocrates and Galen that had survived into the Renaissance. Therapeutics were still
classified under the broad categories of cathartics, emetics, diuretics, and bleedings.
These treatments were general treatments designed at treating the whole body as
every part was considered inter-related. The interconnections of body implied that no
disease was isolated to a specific part and treatment should be focused on general
symptoms.
Many Renaissance physicians ascribed to the humoural theory of medicine that
viewed the body as a dynamic system fluctuating between equilibrium (health) and
disequilibrium (disease). The physician’s role was to act as a manager of an ill patient’s
secretions through a series procedures in order to re-establish well-being. Therapeutic
regimes consisted of extracting blood, inducing perspiration, urination, and defecation.
In addition, dietary regimes were a cornerstone of treatment. Drugs were administered
to alter the body’s equilibrium and their efficacy and the patient’s prognosis was
judged on their ability to produce visible proof of these desired alterations. In the
context of malaria fevers, bloodletting would be seen by both the patient and the
physician as an effective remedy as it would produce readily observable clinical signs
of its efficacy such decreasing the patient’s pulse, temperature and agitation. A patient’s
prognosis was based on the degree of their observable responses to therapy. The more
dramatic a physiological effect, the better the prospects of a patients recovery.
23
Reactions to treatments, even severe reactions, reassured patients and their families
that their illnesses were being managed competently.
The innate human fascination with health and well-being was alive in the
Renaissance. Information about how patients viewed diseases such as malaria can be
gleaned from the famous diarist of the seventeenth century such as Evelyn, Pepys,
Saint-Simon, and Mme. de Sevigne. Their writings provide insight of life in Europe
during a notoriously malarial time and the ubiquitous nature of the disease. These
recorders discuss their friends who have fallen ill, effective remedies and their
experiences with famous physicians. Laymen would speculate about their friends’
health conditions, guessing what type of fever they were afflicted with: tertian, quartan,
or quotidian (Duran-Reynals, 1946).
Over the course of the Renaissance time period a shift away from Galenic
medicine occurred and towards modern medicine occurred.
A new paradigm of
therapeutics emerged; specific drugs for the treatment of specific illness went from the
realm of quack physicians to mainstream practitioners. With this new shift in
paradigm, old Galen traditions were not immediately abandoned, more so a gradual
phasing out occurred. Often a combination of new and old therapies would be
administered. For instance, even after the discovery of utility of quinine for treating the
“intermittent fevers” of malaria, it was still prescribed in combination with cathartics.
Calomel, a mercury chloride salt, was a popular purgative administered with quinine.
The general reluctance to fully embrace a new philosophy of medicine stemmed from
physicians education in the older Galenic belief system that provided a rational
understanding of medicine for centuries. The earlier adopters of the new paradigm in
24
therapeutics depended on intellectual, economic, and regional variables. Much as today
academic institutes, wealthier patients and physicians, in urban settings were more
open to novel therapeutics. By the 1860s, the practice of bloodletting had virtually gone
extinct as it was viewed as an outdated practice. For instance, the 1861 records from
the Massachusetts General Hospital and the Bellevue hospital in New York show that
bloodletting was “almost obsolete” (Rosenberg, 1992).
Contact dermatitis
There is a long list of adverse side effects of Cinchona bark that have been well
documented especially in the 20th century. They are systematically grouped according
to cardiovascular, central nervous system, dermatologic, endocrine, hematological,
hepatic, neuromuscular, otic, ocular, renal, and respiratory systems.
Today the more common dermatologic side effects include: irritant and allergic
contact dermatitis, photosensitivity, and pruritus. Rare dermatologic side effects
include: acral necrosis, bullous dermatitis, bruising, cutaneous rashes (urticaria,
papular, scarlatinal), cutaneous vasculitis, exfoliative dermatitis, erythema multiforme,
petechiae, Stevens-Johnson syndrome, and toxic epidermal necrolysis (UpToDate,
2011). One of the first records of allergic contact dermatitis was recorded in Chevalier’s
1852 “Essay upon the health of workers who prepare sulphate of quinine” published in
the Annales d'Hygiene (Mitchell and Rook, 1979).
It is worth considering the impact of the dermatologic consequences of Cinchona
bark. The practice of dermatology finds its origins in the primitive medicine of
traditional cultures as it is concerned with the manifestations disease processes that
are readily visible. Traditional South American cultures have a long history of treating
25
dermatologic diseases. Indigenous healers have been engaged in treating common skin
problems including wounds, sores, infections, bites, rashes, and burns. Not much
attention has been given to the ability of Cinchona bark to elicit irritant and allergic
contact dermatitis and how this may have influenced Cinchona bark’s utilization by
indigenous healers. Both topical and systemic administration of quinine can cause
irritant and allergic contact dermatitis, as well as photocontact dermatitis and druginduced photodermatitis. Irritant contact dermatitis has been documented in workers
involved in all aspects of the preparation quinine from the stripping the Cinchona bark,
handling of powdered bark, and the extraction of quinine (Mitchell and Rook, 1979).
Allergic contact dermatitis is often associated with chemical contraceptives and hair
preparations (Ferguson et al., 1987).
Irritant contact dermatitis is a nonspecific inflammatory response of the skin
elicited by chemical exposure to quinine. Allergic contact requires sensitization to
quinine and then subsequent re-exposure to quinine produces a painful skin eruption.
Photocontact dermatitis has a similar sensitization mechanism but additionally
requires exposure to sunlight or another source of long wave radiation (Hickey et al.,
2007; Calnan, 1978). Drug-induced phototoxicity is not an immunologically mediated
process but requires long wave radiation activation of quinine to produce an adverse
skin reaction (Kerr, 2010).
Irritant contact dermatitis is the most common form of dermatitis associated
with quinine. In the 20th century industrial processing has been the source of numerous
cases irritant contact dermatitis. Therefore, it is biologically plausible that indigenous
people could have also suffered from irritant contact dermatitis when handling
26
Cinchona bark. Any irritant contact dermatitis in indigenous peoples exposed to the
bark while handling it would dissuade their further use. Analogously, if poison ivy had
beneficial therapeutic effects these healing properties would likely go unnoticed
because of its unpleasant cutaneous reactions. Similarly irritant contact dermatitis
could have prevented the Incans from discovering the antimalarial effects of Cinchona
bark.
A large number of people are exposed to quinine but only a small percentage
exhibit an allergic reaction (Calnan & Caron, 1961). Allergic contact dermatitis is less
common would have been less likely to affect the discovery of Cinchona due to it lower
incidence. However, the initial experimentation the simple handling of the bark could
have sensitized indigenous healers and its administration either topically or orally
could have produced a range of symptoms from generalized scarlatiniform rash, or
more serious side effects including acute intravascular haemolysis and purpura
(Calnan & Caron, 1961).
There is sufficient evidence to support that irritant contact dermatitis could
have affected indigenous peoples and healers based on its frequency; however, it is
more difficult to evaluate the role of allergic contact dermatitis. Some limits of
determining the influence of allergic contact dermatitis with more confidence include
that indigenous healers transmitted knowledge of plants between generations orally
and therefore no historical documents of a prejudice against Cinchona bark because of
its unpleasant allergic contact dermatitis side effects would exist. In addition, skeletal
biology would not reflect epidermal conditions such as allergic contact dermatitis.
Definitively ascertaining causality would not be possible; however, it is possible to have
27
a reasonable degree of suspicion that allergic contact dermatitis could have influenced
its historical usage.
Thomas Sydenham (1624-1689)
Thomas Sydenham’s sobriquet as the “English Hippocrates” denotes his
importance in medical history. He emphasized the value of clinical observation and
experience in determining treatment that drew comparisons to Hippocrates. The
individualization of disease was paramount to his practice and he began to entertain
previously taboo ideas of specific remedies for specific diseases. Over his career he
made valuable contributions to clinical medicine and epidemiology (Ackerknecht,
1982).
His medical education was scant. Just two months after beginning his medical
studies the age of 18 at Oxford University, his studies were interrupted by the Civil
War. He resumed his studies five years later in 1647 and graduated with Bachelor’s in
Medicine one year later. It is unlikely that Sydenham found his medical studies
stimulating as he was interested in the clinical aspects of medicine, which were not
part of the medical education. During that period, the medical curriculum at Oxford was
entirely theoretical based on the works of Hippocrates and Galen. Sydenham’s opinion
of his medical education was recorded in the diary of a classmate Reverend John Ward
who wrote:
“Physick, says Sydenham, is not to bee learned by going to Universities,
but hee is for taking apprentices; and says one had as good send a man to
Oxford to learn shoemaking as practising physick.” (Dewhurst, 1962)
28
Sydenham made important contributions to the study of malaria that are not
without controversy. Some historians view him as an innovator in malaria treatment
(Dewhurst, 1962; Ackerknecht, 1982) while others have the opposite view of him as a
steward of tradition in malaria treatment (Duran-Reynals, 1946). Initially, Sydenham
objected to the use of Peruvian bark. This rejection has been interpreted by historians
who view him as innovator, as a thoughtful physician who was open to new ideas but
also balanced their risks. At the time, Peruvian bark was an expensive and rare
commodity. Consequently, the market proliferated with adulterated and bogus
remedies. Adulterated products were made of mixtures of species Cinchona barks with
negligible amounts quinine in combination with those that had therapeutic levels of
quinine. A common counterfeit remedy was cherry bark treated with aloe extracts to
give it the same bitter taste as Cinchona bark. Both adulterated and bogus remedies
were ineffective at treating malaria. It is understandable given these issues with the
quality control of quinine could have deterred his clinical use of a treatment that he
theoretically believed had value but was not available at a standard for clinical use.
Later on Sydenham promoted Cinchona bark as his preferred treatment for malaria and
as a general tonic to promote good health. One can surmise that his embrace of
Peruvian bark coincided with his ability to procure a reliable source of Cinchona bark
of superior quality.
Historians who see Sydenham a defender of the old Hippocratic and Galenic
guard of medicine interpret his reluctance to use Cinchona bark as being based in fear
of undermining the validity of the traditional medical education system. Evidence to
support this argument comes from his first edition of Methodus curandi febres (Method
29
for Curing Fevers) in 1666 that espouses the beliefs of Galen and Hippocrates that
malaria fevers were due to corrupt humours and opted for therapeutic evacuations
with bloodletting to restore balance.
There was a two year gap between the
publication of first and second edition, during which time Sydenham grew acquainted
with Peruvian bark. These historians contend that Sydenham experimented with
Cinchona bark cautiously and only administered the remedy as the malaria fever
declined. Quinine contradicted the tradition theory for curing fevers as it lowered the
temperature of a fever and did not expel the ‘corrupt’ humour from the body by either
catharsis or emesis. Traditional Galenic medical beliefs held at the time were that a
lowering the temperature would stop the elimination process of the ‘corrupt’ humour
and could jeopardize the patient’s life. It was important to wait for the fever to break to
ensure the humour had eliminated before starting a patient on Peruvian bark (DuranReynals, 1946).
In the second edition of Methodus curandi febres (Method for Curing Fevers) in
1668, Sydenham did not update the treatment of malaria fevers to include new remedy
of Peruvian bark. Historians who criticize Sydenham as standing in the way of
innovation, argue that this important omission was borne out fear to protect the
established medical tradition. The endorsement of Peruvian bark through its inclusion
in the updated edition would have undermined much of pharmacological theory of the
time. Effectively treating malaria fevers without eliminating the ‘corrupt humour
would directly challenge the medical doctrine. (Duran-Reynals, 1946).
30
The contradicting views of medical historians on Sydenham’s contribution to
Cinchona barks can be reconciled on middle ground. It appears he was willing to
promote its use in his clinical practice but perhaps he was not willing to risk
professional ostracism by championing its use more widely. Advocating the broader
use of Cinchona bark could have risked labelling him a quack at the time, something a
distinguished rational physician such as Sydenham may have felt the stakes were
simply too high.
Robert Talbor (1642-1681)
Robert Talbor (Tabor) was an iconoclast went who went against established
medical orthodoxy that was heavily based on Hippocrates and Galen. He was born in
Cambridgeshire and his personal ties to Cambridge University bestowed some
academic credibility; however, he did not have any formal medical education. Before
his university studies he had apprenticed at a local apothecary shop in Cambridge and
had developed a keen interest in remedies for ‘agues’. He began studies as at St. John’s
College at Cambridge University. Instead of completing his university degree, he moved
to Essex pursue his interests in developing a cure for agues. Essex was an ideal
location as the marshy seaside town was riddled with malaria. He soon rose to
prominence with his ability to cure fevers and often travelled to London to share his
expertise. His London consultations were shrouded under a vale of secrecy (DuranReynals, 1946; Keeble, 1997).
Around 1668, he saw the potential to expand his practice and moved to London.
He was labelled with the derisive epithet the “Quack from Essex” because he adopted
an empiric approach to the treatment of malaria (Duran-Reynals, 1946). Instead of
31
focusing on the medical standard of purgatives and bloodletting to treat malaria, he
administered ‘a preparation of four vegetables, whereof two are foreign and the other
domestick’. The active ingredient in his malaria remedy turned out to be Cinchona bark.
He rarely prescribed emetics and did not employ bloodletting. In 1672 he published his
first book on curing agues Pyretologia, a rational account of the cause and cure of Agues
he warns the readers:
“And let me advise the world to beware of all palliative Cures and especially that
known by the name of Jesuits' Powder, as it is given by unskillful hands for I
have seen most dangerous effects follow the taking of the Medicine uncorrected
and unprepared ...; and such as do take it have only a cessation for a time, the
ague returning in a fortnight or three weeks generally. Yet is this Powder not
altogether to be condemned; for it is a noble and safe medicine, if rightly
prepared and corrected, and administered by a skilful hand; otherwise as
pernicious a medicine as can be taken.” (Keeble, 1997)
Talbor’s caution of Jesuit’s powder has been interpreted as well-crafted attempt
to protect his secret remedy. The emphasis on the risks of the treatment would have
discouraged others from taking up the practice and protect his vested interest in the
cure.
History remembers Talbor kindly as physician who successfully cured King
Charles II and the Dauphin; however at the time his colleagues regarded him little more
a quack. It was King Charles II who appointed Talbor to the Royal College of Physicians
to show his appreciation.
32
Conclusion
From Antiquity to the Renaissance malaria was a scourge that touched the daily
life of individuals across the world. It was responsible for many devastating epidemics
and physicians and laymen alike had varying opinions of what could be an effective
cure that reflected the understanding of the etiology of the disease. Before the isolation
of quinine, many alternatives to Cinchona bark were posited in the Renaissance and
early 19th century including: chamomile, mineral water, bark from ash trees, unroasted
coffee, the rinds of pomegranates, or a combination of opium, camphor, and aloe
(Waring 1878). Using Cinchona bark to treat malaria was generally approached with
caution; however, some physicians appreciated its therapeutic value. The polymath
Benjamin Franklin (January 17, 1706 – April 17, 1790) was widely known for his
scientific, political, and philosophical contributions and also practised medicine. He
expressed the need to continue administering Cinchona bark for malaria fevers in a
letter to John Adams in 1781:
“I hope your health is fully established. I doubt not but you have the advice of
skilful physicians, otherwise I should presume to offer mine, which would be,
though you find yourself well, to take a few doses of bark, by way of fortifying
your constitution, and preventing a return of your fever.”
Benjamin Franklin encouraged his grandson to continue taking Cinchona bark in a
letter (1784) that “an ounce of prevention is worth a pound of cure adding particularly
true with regard to the bark and an intermittent” (Gelfand, 2006).
The French chemists Pelletier and Caventou isolated the main active compound
quinine from Cinchona bark in 1820 that brought “us nearer to the actual pure
proximate principles composing a complicated substance” (Waring, 1878) (Figure 6).
Quinine is a truly complicated substance stemming from its origins in Cinchona bark.
33
The controversy surrounding Cinchona bark reflects religious, political, and economic
motivations of the time. From the sacrosanct Galenic circles that dismissed it as
remedy for quacks, its crossover into modern medicine did not occur overnight.
Instead Cinchona bark crept into the mainstream as ‘secret remedy’ or remedy to be
used prudently. In contrast, today quinine and derivative antimalarial treatments are
liberally used across the world to prevent malaria among both travellers and residents.
Figure 6. French postage stamp from 1970 commemorating the sesquicentennary of
the discovery of quinine, the most active of the 20 or so alkaloids in Cinchona bark. The
chemical structure of quinine is depicted. Stamp image from Kinsley-Scott & Norton,
2003 and quinine image from Wikipedia, 2011.
34
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