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From methylene blue to chloroquine: A brief review of the development of an antimalarial therapy



Malarial treatment is widely and readily available today. However, there was a time in the not-so-distant past when malaria was a deadly disease with no known cause or cure. In this article, we trace the origins of an antimalarial therapy from the discovery of the nature of the malarial parasite through the development of chloroquine. We dedicate this article to Johann "Hans" Andersag, the scientist who developed chloroquine, on the 110th anniversary of his birth, 16 February 1902.
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From methylene blue to chloroquine: a brief review
of the development of an antimalarial therapy
Kristine Krafts &Ernst Hempelmann &
Agnieszka Skórska-Stania
Received: 16 February 2012 /Accepted: 27 February 2012 / Published online: 13 March 2012
#Springer-Verlag 2012
Abstract Malarial treatment is widely and readily avail-
able today. However, there was a time in the not-so-
distant past when malaria was a deadly disease with no
known cause or cure. In this article, we trace the origins
of an antimalarial therapy from the discovery of the
nature of the malarial parasite through the development
of chloroquine. We dedicate this article to Johann
HansAndersag, the scientist who developed chloro-
quine, on the 110th anniversary of his birth, 16 Febru-
ary 1902.
Elucidation of the cause of malaria
In 1887, the Polish pathologist Czesław Chęciński ap-
plied a combination of methylene blue and eosin to
blood smears and discovered the daisy-like and sickle-
shaped parasites we now know as Plasmodium malariae
and Plasmodium falciparum.Untilthistime,therewere
many hypotheses regarding the causative agent of this
disease, from poisonous air (a theory mentioned as early
as 1476 by Leonardo Bruni (Bruni 1476)) to bacteria
(Klebs and Tommasi-Crudeli 1879). Three years after
Chęcińskis stain was published, the German physician
Ernst Malachowski discovered a method of polychrom-
ing methylene blue that, when used in combination with
eosin, revealed not only a range of colors within leuko-
cytes, but also the elusive purple-red nucleus of the
malarial parasite (Krafts et al. 2011). The discovery of
the malarial nucleus provided definitive proof that the
malarial organism was a eukaryote. A search for an
effective antiparasitic malarial treatment could now be-
gin in earnest.
Paul Ehrlich (18541915)
Paul Ehrlich (Fig. 1), a highly renowned German physician
and scientist, developed a new and effective stain for blood
in 1880 which he termed the neutralen Farbkörper or neu-
tral stain.This stain incorporated methylene blue and acid
fuchsin and allowed differentiation between the different
types of white blood cells. Among his remarkable accom-
plishments was his discovery that certain dyes could be used
as drugs which would kill a specific organism while leaving
other tissues unharmed.
In 1891, Ehrlich discovered that methylene blue fell
into this category of magic bulletdrugs, in this case
targeting the malarial organism (Fig. 2). Until this point
in time, the primary treatment for malaria was quinine
(Fig. 3a), a natural substance derived from the cinchona
tree of South America and thus limited in supply. Ehr-
lichs introduction of methylene blue (Fig. 3b), a syn-
thetic compound, allowed large-scale production of
antimalarial therapy, unlimited by the supply or location
of natural resources.
K. Krafts (*)
Department of Pathology,
University of Minnesota School of Medicine,
Duluth, MN, USA
E. Hempelmann
Department of Pharmacology, Witwatersrand University,
Johannesburg, South Africa
A. Skórska-Stania
Department of Crystal Physics and Crystal Chemistry,
Faculty of Chemistry, Jagiellonian University,
Kraków, Poland
Parasitol Res (2012) 111:16
DOI 10.1007/s00436-012-2886-x
Author's personal copy
Fig. 1 Paul Ehrlich in 1910
Fig. 2 Figure from Guttmann and Ehrlichs1891 paper Ueber die Wirkung des Methylenblau bei Malaria(On the Action of Methylene Blue on
Malaria) showing the action of methylene blue on the organism in an infected patient (Guttmann and Ehrlich 1891)
Fig. 3 Structures of relevant antimalarial drugs. aQuinine. bMethy-
lene blue. cChloroquine
2 Parasitol Res (2012) 111:16
Author's personal copy
That same year, Gutmann and Ehrlich successfully
treated two patientsa domestic servant and a sailor
with methylene blue (Guttmann and Ehrlich 1891). Ehr-
lichs student, Röhl, continued antimalarial trials with
methylene blue at Bayer in Eberfield. However, methy-
lene blue was found to be insufficiently effective to
supplant quinine as an antimalarial drug. Röhl began
testing the companys antimalarial compounds in birds
(Figs. 4and 5) and devised a new compound in which
one methyl group was replaced by an aminoalkyl group.
Scientists at Bayer began synthesizing a large number
of compounds, the most successful of which was termed
quinacrine (subsequently marketed as mecaprine and
atabrine), which they synthesized in 1931.
Hans Andersag (19021955)
Johann HansAndersag (Fig. 6) was born February 16,
1902, in Lana (Meran) to Johann Andersag and Cre-
sienz Andersag (née Tribus) (Fig. 7). Johann, the short
form of the name Johannes, is derived from the Hebrew
name Yehochanan יוחנן meaning Yah weh (JH W H ) is
gracious.Popular in Northern Europe, especially in
Germany, the name Johannes has several variants in-
cluding, Hans (diminutized to Hänschen or Hänsel),
Hannes, Jens, and Jan. Later in his life, Andersag
changed his given name from Johann to the shortened
form Hans.
Andersag studied chemistry in Munich from 1921 to
1927 and worked at Bayer in Elberfeld until 1955 (Fig. 8).
He was married to Else Andersag née Nouvortne.
In July, 1934, Andersag modified atabrine by replac-
ing its acridine ring with a quinoline ring. The resulting
compound, which would later be termed chloroquine
(Fig. 3c), was found to have high antimalarial activity,
and unlike methylene blue or atabrine, did not discolor
skin and eyes.
Andersag began with two compounds: oxaloacetic acid
diethylester and m-chloroaniline (Fig. 9). His process con-
sisted of the following steps (Fig. 10):
1. Condensation of m-chloroaniline with oxaloacetic acid
2. Saponification and thermal decarboxylation
3. Reaction with phosphorus oxychloride (POCl
Fig. 4 Bayer laboratory (Pharmakologisches Labor) (courtesy, Bayer
AG Archiv)
Fig. 5 Testing antimalarial compounds using birds (Pharmakologisches
Labor) (Courtesy, Bayer AG Archiv)
Fig. 6 Hans Andersag (courtesy, Bayer AG Archiv)
Parasitol Res (2012) 111:16 3
Author's personal copy
4. Substitution by a diamino group
Andersag made a salt of the base using 2,4,-dihydroxy-
benzoic acid. This salt received the name resochin, being the
RESOrcinate of a 4-aminoCHINolin.
Resochin was tested in 1935 by Bayer against blood-
induced vivax malaria in four paretics at a psychiatric clinic
in Düsseldorf but was found to be too toxic for practical
use in humans(Coatney 1963). Subsequently, Bayer
shelved the drug for more than 10 years, a decision that
would come to be known as the resochin error.
Meanwhile, Andersag continued to modify the drug to
minimize the toxic effect, producing the compound 3-
methylresochin (Dünschede 1971). This compound was
named sontochinand was tested at the Institute for Trop-
ical Diseases in Hamburg. By the end of 1939, over 1,100
patients with malaria had been treated with sontochin.
Both drugs, resochin and sontochin, were patented in
November 1939 (Reichspatentamt, Patentschrift Nr
683692) and later issued to The Winthrop Chemical Com-
pany through their IG Farben cartel arrangement with Bayer
(US Patent 2 233 970). Clinical trials with sontochin were
also conducted jointly by French and German scientists in
Tunisia in 19411943, with very impressive results. In May,
1943, drug supplies and accompanying data were handed
over by the French authorities to the Allied Forces. During
the following years, resochin was rediscovered; it was given
the name chloroquineby EK Marshall in November 1945
(Coatney 1963).
Chloroquine was a first-line antimalarial therapy
for many years. As is the case for most antimicrobial
drugs, resistant strains of the target organism eventually
Fig. 7 Birth certificate of
Johann HansAndersag,
pages 1 and 2. (Courtesy, parish
register of Lana a.d.E.).
Translation: Parish of Lana: List
of the 1902 born and baptized
children. Name and first name:
ANDERSAG, Johann Josef.
Born: 16 February 1902, 10 ½
at night. Baptized 17 February
1902, 1 in the afternoon. Name
of the father: Johann Andersag,
born in Lana 24. Aug 1861, son
of Johann and Anna. Position of
the father: Tenant. Name of the
mother: Cresienz nee Tribus,
born in Tisens 27. Aug. 1866,
daughter of Michael and Josefa
Fig. 8 Andersag (left) at Pharmazeutisch-wissenschaftliches Labor,
Elberfeld, 6 December 1953 (courtesy, Bayer AG Archiv)
4 Parasitol Res (2012) 111:16
Author's personal copy
developed. However, since the mechanism of the drug
(inhibition of hemozoin biocrystallization) involves a
host-derived drug target (which cannot be modified by
the malarial parasite), it took over 20 years for resistant
forms of malaria to develop (Hempelmann 2007). For
those 20 years, Andersags drug saved countless lives
Fig. 9 a,bPages from Andersags laboratory notebook detailing his method for the synthesis of chloroquine. (courtesy, Bayer AG Archiv)
Fig. 10 Synthesis of
chloroquine by Andersag
Parasitol Res (2012) 111:16 5
Author's personal copy
and it continues to be an effective antimalarial treatment
nearly 80 years later.
Bruni L (1476) History of the Florentine people, Edited and translated
by James Hankins, 2004. Harvard University Press, Harvard
Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloro-
quine. AmJTrop Med Hyg 12:121128
Dünschede H-B (1971) Tropenmedizinische Forschung bei Bayer.
Michael Triltsch Verlag, Düsseldorf
Guttmann P, Ehrlich P (1891) Ueber die Wirkung des Methylenblau
bei Malaria. Berliner Klinische Wochenschrift 28:953956
Hempelmann E (2007) Hemozoin biocrystallization in Plasmodium
falciparum and the antimalarial activity of crystallization inhib-
itors. Parasitol Res 100:671676
Klebs E, Tommasi-Crudeli C (1879) Studi Sulla Natura della Malaria,
Rome, Italy. Translated by Drummond E, On the nature of ma-
laria. Lond Sel Monogr New Sydenham Soc 1888(121):156
Krafts KP, Hempelmann E, Oleksyn BJ (2011) The color purple: from
royalty to laboratory, with apologies to Malachowski. Biotech
Histochem 86:735
6 Parasitol Res (2012) 111:16
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... The formation of hemzoin occurs during both the blood and sexual stages of the life cycle and is an essential process for the parasites survival, and inhibition of these processes swiftly kills it. [17] The antifolates ...
... Additionally, by using drugs in combination, the probability that the parasites will become resistant to two drugs with different MoA will be exponentially reduced. [26] Some frequently used ACTs consists of dihydroartemisinin (12) and piperaquine (17), as well as arthemether (13) and lumefantrine (18) (Figures 1.5 and 1.6). [2] 6 Figure 1.6: Piperaquine (17) and lumefantrine (18), drugs commonly used in combination therapies. ...
... [26] Some frequently used ACTs consists of dihydroartemisinin (12) and piperaquine (17), as well as arthemether (13) and lumefantrine (18) (Figures 1.5 and 1.6). [2] 6 Figure 1.6: Piperaquine (17) and lumefantrine (18), drugs commonly used in combination therapies. ...
Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More- over, several functionalized derivatives of these compounds have shown great promise as an- tiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first devel- oped by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further inves- tigating alternative protocols for the construction of indoloquinolines, a regiodivergent inter- mediate was discovered, which allowed for the synthesis of both novel pyridophenanthridine and pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido- carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal com- plex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Oki- nawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amina- tion. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being re- gioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction and intramolecular nucleophilic C-N bond formation. The scope and limitations for the novel pro- tocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally su- perior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino- lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, in- stallation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate func- tionalizations than the neocryptolepine approach, with no apparent trend concerning electron- withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru- bicin against human prostate cancer (IC50 = 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dual anticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar- bazole was found to contain any significant activity against the evaluated Plasmodium falci- parum strain. The antimicrobial assays revealed the importance of the inclusion of a methyl group for activity, but not strictly in the form of an N-methyl unit, which is the general con- census in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial cell lines.
... Chloroquine was synthesized in Germany in the 1930s as resochin and a wartime American effort saw it registered in 1946 as a less expensive, safer, and better tolerated therapy of acute malaria. Plantationdependent quinine subsequently declined significantly because of a lack of demand [49]. ...
Full-text available
Kalimantan is a part of Indonesia, which occupies the southern three-quarters of the island of Borneo, sharing a border with the Malaysian states of Sabah and Sarawak. Although most areas of Kalimantan have low and stable transmission of Plasmodium falciparum and Plasmodium vivax, there are relatively high case numbers in the province of East Kalimantan. Two aspects of malaria endemicity in Kalimantan differentiate it from the rest of Indonesia, namely recent deforestation and potential exposure to the zoonotic malaria caused by Plasmodium knowlesi that occurs in relatively large numbers in adjacent Malaysian Borneo. In the present review, the history of malaria and its current epidemiology in Kalimantan are examined, including control and eradication efforts over the past two centuries, mosquito vector prevalence, anti-malarial use and parasite resistance, and the available data from case reports of knowlesi malaria and the presence of conditions which would support transmission of this zoonotic infection.
... In its new formulation, sontochin was renamed chloroquine (Figure 1). 27 However, in 1944, analysis of chloroquine revealed that its chemical composition was identical to the resochin previously synthesized by Hans Andersag in 1934 and analyzed by Winthrop. 28 In general, chloroquine has been used for malaria treatment, chemoprophylaxis, and the prevention of reinfection in treated patients. ...
... Chloroquine is a well-known drug, which has been used for decades in the treatment of malaria (Krafts et al., 2012). Shortly after the global outbreak of Covid-19, chloroquine generated a wave of excitement and was identified by some political leaders as a way of preventing infection and treating the disease. ...
As supporters of Brazilian President Jair Bolsonaro, the Bolsonarism movement has promoted the drug chloroquine for treating Covid-19 in Brazil, despite it being mostly rejected by mainstream health institutions as an effective treatment. This situation can be investigated through the lens of Science and Technology Studies (STS) and ignorance studies supported by methods from digital sociology. Bolsonarist discourse does not contest scientific authority tout court, but rather constructs boundaries between what supporters of the president see as legitimate and illegitimate science. This institutionalised ignorance is produced and maintained through Telegram messenger, a backbone of the multi-platform media ecosystem of Bolsonarism. It is accomplished through boundary work: the exclusion or inclusion of knowledge via two complementary practices – pejorative accusations against mainstream science and the crafting of affective bonds with the chloroquine alternative. While the former aims to invalidate knowledge held by experts opposed to the use of chloroquine, the latter focuses on mobilising trust in an alternative model of science, which we refer to as patriotic science. This model of science is demarcated from mainstream science, framed as corrupt and ill-equipped for the needs of Brazilians. This case study advances STS resources for examining the epistemic demarcation between science/non-science, relevant to other polities and publics that use such boundary work to institutionalise ignorance.
... CQ and more HCQ are generally safe, they are widely used worldwide, they have a low cost and wide availability, they have been helpful with prophylaxis as well as treatment of other infections. Discovered in 1934 [59], CQ become popular after WWII. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria [60] and it has been widely used since then. ...
Treatments do not replace vaccinations or restrictions, but are practical, effective, and safe means to help to reduce the fatality associated with COVID-19 infection. While no treatment is available and effective for all the current and future variants of COVID-19, treatments reduce the risk of COVID-19 becoming endemic and reduce mortality and collateral damages. The use of Zinc (Zn) for COVID-19 infection is here reviewed. Zn supplementation may help in prevention as well as during the administration of therapies. Zn supplementation reduces the risks of serious outcomes from Covid19 infection. Evidence also suggests that Zn helps in treatments of COVID-19 infection if taken in conjunction with antiviral drugs. The literature supports the use of Zn, with improvements towards a lower risk ranging from 37% in late treatment, RR 0.63 CI [0.53-0.74], to 78% in sufficiency, RR 0.22 CI [0.05-0.96].
The methods for the synthesis of quinoline and its hydrogenated derivatives from α,β-unsaturated aldehydes have been summarized for the first time. The review highlights the advances in this area over the past 15 years. Particular attention is focused on the use of catalytic systems, synthetic advantages, and mechanistic aspects of the reactions.
Since a lot of drugs that were used for the treatment of malaria has shown resistance to the Plasmodium species. Even the ACT (Artemisia combination therapy) is not effective in certain cases. There is a need to look for some alternatives, which are effective in the clinical treatment of malaria and affordable for the general population. A therapy called Artemisia annua dry leaf antimalarial therapy (ALT) has been shown to be effective against artemisinin-resistant malarial infections and its treatment is resilient to resistance development in animal model systems. This proves to be an effective alternative to presently available antimalarials. This review defines the characteristics of different species of malaria-causing parasites, their vectors, endemicity, and features of the disease development, followed by properties of currently used (approved) antimalarials. The choices and methodologies of administration of antimalarials to adult, child, pregnant, and lactating women patients with acute and complicated malaria are described, followed by strategies to combat drug-resistant malaria, especially artemisinin resistance. A special emphasis on the origin, empirical basis, evidence on clinical efficacy, and cost aspects of ALT is given, along with the focus on the possibilities of repurposing ALT as a treatment for a variety of autoimmune, metabolic, and cancerous diseases.
Ziel dieser Arbeit war es, den Einfluss von CQ- und HCQ-Einnahme auf die quantitative Fundusautofluoreszenz (QAF) zu untersuchen. Untersucht wurde, ob sich die QAF als Screening Methode in der Früherkennung von CQ/HCQ induzierten retinalen Veränderungen eignet. Dazu wurden erstmalig in einer prospektiven Querschnittsstudie 38 Patienten unter CQ/HCQ Therapie eingeschlossen und mittels multimodaler Bildgebung (FAF, QAF, SD-OCT) sowie weiteren funktionellen Test (mfERG und Perimetrie) untersucht. QAF Aufnahmen wurden mittels FIJI Plug-Ins analysiert und gegen eine alters- und geschlechtsadaptierte Kontrollgruppe verglichen. Bei 5 der 38 Patienten zeigten sich für die CQ/HCQ Makulopathie typische Veränderungen in allen Modalitäten. Aufgrund der kontrovers diskutierten Aussagekraft der QAF im Alter über 60 Jahren formten wir eine Subpopulation der Patienten bis 60 Jahre, bei denen in 4 von 29 Fällen CQ/HCQ induzierte Veränderungen sichtbar waren. Unabhängig vom Alter zeigt sich bei Patienten ohne BEM, verglichen zur Kontrollgruppe, signifikant erhöhte QAF Werte. Diese fallen bereits nach kurzer Einnahmedauer auf und bleiben Jahre nach Absetzen der Therapie bestehen. Die erhöhten QAF Werte treten, mit Ausnahme der Patientin mit ausgeprägter BEM, in Abwesenheit von Pathologien in den anderen Untersuchungsmethoden und Veränderungen der äußeren Netzhaut in der SD-OCT auf. Bei Patienten mit BEM sind in den QAF Aufnahmen das typische parafoveale Autofluoreszenzmuster, sowie hohe QAF Werte außerhalb der Atrophiezone in der Perifovea zu erkennen. Erhöhte QAF Werte, bereits nach kurzer Einnahme, könnten auf Einlagerungen von CQ/HCQ oder deren Metaboliten zurückzuführen sein. Inwieweit sich Intensitäten und Muster der QAF im Verlauf der Medikamenteneinnahme verändern und so Hinweise auf mögliche frühe Netzhautschäden durch die Medikamente geben können, ist durch diese Arbeit nicht geklärt. Ob die QAF ein mögliches Screening Instrument zur frühen Detektion einer BEM sein kann, muss in weiteren Verlaufsstudien untersucht werden.
A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 μM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 μM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.
Cisplatin (CP) is used to treat various types of cancer. However, its usage is limited due to nephrotoxicity. This study aims to examine the applicability of methylene blue (MB) against CP-induced kidney injuries. In this study, twenty-eight male rats were divided into four groups. Following administration of a single dose of CP (5 mg/kg), animals received intraperitoneal injections (IP) of MB (4 mg/kg) for seven days. In the final phase of the experiment, serum was collected from rats, with blood urea nitrogen (BUN) and creatinine (Cr) levels measured. Hematoxylin-Eosin (H&E) and Masson's trichrome staining were performed to examine histological changes. Immuno-histological staining was used to evaluate caspase-3 protein expression. The results showed that the MB (4 mg/kg) + CP treated rats underwent a lesser weight loss compared to the CP group (p < 0.05 and p < 0.001, respectively). The kidney weight decreased significantly in the CP + MB group compared to the CP group (p < 0.05 and p < 001, respectively). BUN and Cr levels that were increased significantly in the serum of the CP group (p < 0.001) compared to the control group showed no significant increase in the MB + CP group compared to the control group (p = 0.842 and p = 0.989, respectively). There was a significant decrease in kidney tissue injuries in the CP + MB compared to the CP group (p < 0.001). The glomerular size was recovered in the CP + MB group compared to the CP (p < 0.05). The significant increase in the capsular space of the CP group compared to the control group (p < 0.001) was attenuated in the CP + MB. MB restored the histological alterations in the kidneys. Treatment with 4 mg/kg of MB reduced the expression levels of Caspase-3. In conclusion, this study provides evidence concerning the anti-apoptotic roles of MB in CP-induced kidney damage. In conclusion, MB has a positive impact on kidney function.
Full-text available
The components of the blood stain, eosin and methylene blue, were introduced by Baeyer and Caro, respectively. Methylene blue was used primarily for detecting Mycobacterium tuberculosis until Ehrlich in 1880 mixed methylene blue with acid fuchsin to produce what he termed a "neutral stain," which allowed differentiation of blood cells. Eight years later, Chęciń ski changed the acidic component of the dye to eosin. Plehn subsequently altered the proportions of eosin and methylene blue to produce a greater range of red and blue hues. In 1891, Malachowski and Romanowsky independently developed stains composed of eosin and "ripened" methylene blue that not only differentiated blood cells, but also demonstrated the nuclei of malarial parasites. A number of "ripening" or "polychroming" techniques were investigated by different groups, but the aqueous dye solutions produced were unstable and precipitated rapidly. Subsequently, methanol was introduced as a solvent for the dye precipitate and techniques were developed that utilized the fixative properties of the methanolic solution prior to aqueous dilution for staining. This avoided the troublesome process of heat fixation of blood films. Giemsa further improved these techniques by using more controlled methods of methylene blue demethylation. In addition, he used measured amounts of known dyes and increased dye stability by adding glycerol to the methanol solvent. With the outbreak of World War I, it became difficult to obtain German dyes outside of Germany; during the World War II, it became impossible. In their effort to improve the inferior American versions of Giemsa's stain, Lillie, Roe, and Wilcox discovered that the best staining results were obtained using pure methylene blue, one of its breakdown products (azure B) and eosin. These three substituents remain the major components of the stain to this day.
It is traditional in this Society that the President deliver an address at the annual banquet. In line with that tradition, I have chosen to discuss one facet of that patriarch of human disease—malaria. The facet I have selected is the chronicle of the antimalarial drug, chloroquine—a true story tinged with an element midway between romance and intrigue. In view of the recent public interest in drugs for human consumption, this story is timely; it has not been recounted before. Practically all of the world's regular supply of quinine was denied to the Allies following the Japanese invasion of Pearl Harbor in December 1941. This was a most serious loss for it was apparent that a long war lay ahead and that much of it would have to be fought in highly malarious areas. This country moved immediately to meet the emergency. The War Production Board (on April 4, 1942) issued Conversation Order M-131 which took quinine off the market and restricted its use almost completely to the treatment of malaria. At the same time, an appeal was made to those who held supplies of the alkaloid to deposit them with the War Production Board.
History of the Florentine people, Edited and translated by James Hankins Pitfalls in a discovery: the chronicle of chloro-quine
  • Bruni
Bruni L (1476) History of the Florentine people, Edited and translated by James Hankins, 2004. Harvard University Press, Harvard Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloro-quine. AmJTrop Med Hyg 12:121–128 Dünschede H-B (1971) Tropenmedizinische Forschung bei Bayer
Studi Sulla Natura della Malaria Translated by Drummond E, On the nature of malaria
  • E Klebs
  • Tommasi
  • Crudeli
Tropenmedizinische Forschung bei Bayer
  • H-B Dünschede
Dünschede H-B (1971) Tropenmedizinische Forschung bei Bayer. Michael Triltsch Verlag, Düsseldorf
Pitfalls in a discovery: the chronicle of chloroquine
  • L Bruni
Bruni L (1476) History of the Florentine people, Edited and translated by James Hankins, 2004. Harvard University Press, Harvard Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloroquine. AmJTrop Med Hyg 12:121-128