P.O. Box 144345, Austin, TX 78714-4345
Phone: (512) 926-4900 x129 Fax: (512) 926-2345
Contact: Public Relations
Website: www.herbalgram.org
MEMBER ADVISORY
A Brief History of Chloroquine
FDA fast-tracks the drug, modeled after the natural substance quinine in cinchona bark, for use in COVID-19 clinical trials
Editor’s note: The nonprofit American Botanical Council (ABC) is disseminating this information to its members and other stakeholders in the medicinal plant community to provide historical insight into the ethnobotanical approach to drug discovery with respect to chloroquine and its derivative hydroxychloroquine. ABC is not recommending the use of chloroquine or hydroxychloroquine, or any of the quinoline alkaloids on which these drugs are modeled, as treatments or for the prevention of COVID-19. This includes any naturally occurring botanicals with similar or related chemistries. Such recommendations must come from appropriate medical and regulatory authorities after appropriate testing is done. ABC emphasizes that the use of these drugs carries a substantial risk of adverse side effects. ABC has always supported the process of modern drug development from medicinal plant and fungal sources, insofar as many modern conventional pharmaceutical drugs are derived directly or indirectly from medicinal plants and fungi.
By Stefan Gafner, PhD
On March 16, 2020, US President Donald Trump announced during a press conference that chloroquine and hydroxychloroquine have shown “encouraging early results [against the coronavirus],” and that “we’re going to be able to make that drug available almost immediately.” The statement was later clarified by US Food and Drug Administration (FDA) Commissioner Stephen Hahn, MD, who said that chloroquine was “already approved for the treatment of malaria, as well as an arthritis condition. That’s a drug that the president has directed us to take a closer look at, as to whether an expanded use approach to that could be done to actually see if that benefits patients. And again, we want to do that in the setting of a clinical trial, a large pragmatic clinical trial to actually gather that information and answer the question that needs to be answered.”1
The idea to look into the effectiveness of chloroquine-derivatives is likely based on reports of in vitro activities of chloroquine against the severe acute respiratory syndrome coronavirus (SARS-CoV) after the SARS pandemic in 2002-2003. However, there was no follow-up with suitable animal and clinical testing after the pandemic subsided.2 Clinical data on the efficacy of both drugs in the treatment of COVID-19 are preliminary, but results from these trials are reportedly encouraging, and not less than 20 clinical trials with chloroquine or hydroxychloroquine are under way in China.3 Early results from a clinical study in France showed that of 20 patients with coronavirus disease 2019 (COVID-19) receiving 200 mg hydroxychloroquine (Plaquenil®; Sanofi-Aventis; Paris, France) three times per day for 10 days, alone or in combination with the antibiotic azithromycin (manufacturer name not provided), 500 mg on the first day, followed by 250 mg for the next 4 days, 75% were no longer contagious after six days, compared to 0% of patients (n = 16) not receiving treatment.4
Neither chloroquine nor its hydroxy-derivative is a natural botanical ingredient. However, their discovery is based on the same compound, the alkaloid quinine. Quinine is extracted from the bark of several species of Cinchona (Cinchona spp., Rubiaceae) trees that are native to the Andean regions of South America. Of note, cinchona bark contains several other alkaloids (e.g., quinidine, cinchonidine, and cinchonine), all with prominent antimalarial effects.5 According to historical accounts, the tree was used by curanderos in the Andes mountains prior to the arrival of the Spanish conquerors.6,7 It is believed that the indigenous population already used cinchona bark to treat malaria and other types of fever before its use was known to the Europeans.8
Cinchona bark was eventually brought to Europe by Spanish Jesuits (hence one of the common names, “Jesuit bark”) in 1632.9,10 The powdered bark of the tree was the first effective treatment for malaria, which, until the 19th century, was common in many parts of Europe, particularly in countries bordering the Mediterranean Sea. In 1820, French scientists Pierre Pelletier and Joseph Caventou developed a process to extract quinine from cinchona bark, which helped to provide a more consistent dosage to malaria patients.8,10
This discovery proved very useful for the major European empires, as they were expanding their reach into parts of the world where malaria was widespread. It was crucial to have enough cinchona bark to supply their armed forces with quinine. However, several of the South American countries gained independence in the early 19th century, and, therefore controlled the access to the trees. Since the sale of the bark provided substantial profits to countries like Bolivia, Columbia, Ecuador, and Peru, they imposed strict restrictions on seeds and plants. With the goal to get broader (and less costly) access to the tree, colonial powers such as France, Great Britain, and the Netherlands sent out several expeditions to procure seeds and plants. This was often done illegally by smuggling out the seeds for use in colonial plantations. A number of attempts to get seeds out of South America were successful, most prominently by British trader Charles Ledger who managed to send several pounds of seeds of a high quinine-producing Cinchona species (later named Cinchona ledgeriana) to his brother in 1865. However, to Ledger’s dismay, the British government showed little interest in them. They were eventually sold to the Dutch, who cultivated cinchona in their colony of Java (now Indonesia) and, by the 1930s, controlled 97% of the world quinine market.11 Due to the bitterness of quinine, English soldiers started to mix quinine with sugar and soda, which eventually led to the creation of commercial tonic water in 1858.12 Due to toxicity concerns, the FDA has limited the content of quinine to 83 ppm (83 mg/L) when used as a flavor in carbonated beverages.13
With the advancement in chemical synthesis towards the end of the 19th century, a number of prominent researchers started to work on synthetic antimalarial drugs. The antimalarial properties of the first such drug, methylene blue, was discovered by prominent German physician Paul Ehrlich.14 Subsequent variations of antimalarial compounds were structurally much more similar to quinine. In 1931, scientists at Bayer I.G. Farbenindustrie (Eberfeld, Germany) synthesized mepacrine (quinacrine), which was followed in 1934 by chloroquine. The original chloroquine synthesis was performed by Hans Andersag, but the compound, named resochin, was deemed too toxic by the Germans to be used for medicinal purposes. In attempt to protect their discovery, Bayer shared the data with the Winthrop Chemical Company (New York, NY), which patented resochin as SN-7618 in 1941.15
Intense efforts by the United States during World War II to find new synthetic antimalarial drugs in order to decrease dependency on the natural alkaloid quinine led to another look at 4-aminoquinolone derivatives, and by 1944, SN-7618 was shown to have the most favorable therapeutic outcome based on animal and human studies. In 1946, the compound was named chloroquine.15 Hydroxychloroquine, which is a slight modification of chloroquine, was first synthesized in 1950, as the effort continued to find new antimalarial drugs.16
Besides the treatment and prophylaxis of malaria, chloroquine and hydroxychloroquine have both been prescribed generically for decades around the world for the treatment of certain autoimmune diseases, such as lupus erythematosus and rheumatoid arthritis. In 2014, the European Medicines Agency granted Orphan Drug Designation to the Netherlands drug company, DualTPharma, B.V., for the use of chloroquine to treat glioma, a form of brain cancer.17 Although the drug is routinely used for these conditions, it carries significant risk of adverse side effects, and patients must adhere to strict treatment protocols supervised by their physicians and pharmacists.
Also noteworthy is the fact that acute and/or chronic ingestion of these antimalarials can result in poisoning cataloged in the International Classification of Disease as either “cinchonism” or “quinism.” Symptoms of cinchonism include gastrointestinal disturbances, vasodilatation, sweating, and headache, and are mostly reversible after discontinuing drug intake.18 While historically the terms quinism and cinchinism were used interchangeably,19 quinism now refers to a chronic encephalopathy (brain disease) leading to brain dysfunction that is associated with the intake of drugs with a quinoline structure.20
While cinchona bark and quinine are no longer the antimalarial therapies of choice, the history of chloroquine provides a good example of the importance of research into the efficacy of plant-based ingredients and natural products (e.g., phytochemicals) as scaffolds for the development of effective conventional pharmaceutical drugs. The potential usefulness of chloroquine and hydroxychloroquine in the treatment of COVID-19 still needs to be established, but, independent of the outcome of such research, it is worth a moment to reflect on where these drugs have been coming from, and what can be gained from knowledge of the ethnopharmacological use of plants.
References
1. Etherington D. FDA testing coronavirus treatments, including chloroquine, plasma from COVID-19 patients. Tech Crunch. March 19, 2020.
2. Fong IW. Emerging animal coronaviruses: First SARS and now MERS. Emerging Zoonoses: A Worldwide Perspective. Cham, Switzerland: Springer International Publishing; 2017:63-80.
3. Colson P, Rolain J-M, Lagier J-C, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrobial Agents. 2020:105932.
4. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. Int J Antimicrobial Agents. 2020;[In Press] March 17, 2020. DOI : 10.1016/j.ijantimicag.2020.105949.
5. Seeler AO, Dusenberry E, Malanga C. The comparative activity of quinine, quinidine, cinchonine, cinchonidine, and quinodine against Plasmodium lophurae infections of Peking ducklings. J Pharmacol Exper Ther. 1943;78(2):159-163.
6. Bruce-Chwatt LJ. Three hundred and fifty years of the Peruvian fever bark. Br Med J. 1988;296(6635):1486-1487.
7. Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malaria J. 2011;10(1):144.
8. Kaufman TS, Rúveda EA. The quest for quinine: Those who won the battles and those who won the war. Angew Chem Int Ed 2005;44(6):854-885.
9. Harrison N. In celebration of the Jesuit’s powder: a history of malaria treatment. Lancet Inf Dis. 2015;15:1143.
10. Eyal S. The fever tree: from malaria to neurological diseases. Toxins. 2018;10(12):491.
11. Honigsbaum M. The Fever Trail. London, United Kingdom: Macmillan; 2003.
12. Raustiala K. The imperial cocktail - how the gin and tonic became the British Empire's secret weapon. Slate [online].2013.
13. Code of Federal Regulations, Title 21, Section 172.575. Washington, DC: US Department of Health and Human Services; 2019.
14. Al-Bari MAA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicr Chemother. 2015;70(6):1608-1621.
15. Coatney GR. Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg. 1963;12:121-128.
16. Surrey AR, Hammer HF. The preparation of 7-chloro-4-(4-(N-ethyl-N-β-hydroxyethylamino)-1-methylbutylamino)-quinoline and related compounds. J Am Chem Soc. 1950;72(4):1814-1815.
17. Public summary of opinion on orphan designation: Chloroquine for the treatment of glioma. Amsterdam, Netherlands: European Medicines Agency; 2015:1-4.
18. Bateman D, Dyson E. Quinine toxicity. Adverse Drug React Acute Poisoning Rev. 1986;5(4):215-233.
19. Luedke M, Massey EW. Bark's bite: did 18th century pharmacopeia complicate Thomas Jefferson's headaches? Neurosci Hist. 2015;3(3):96-100.
20. Nevin RL. Neuropsychiatric quinism: Chronic encephalopathy caused by poisoning by mefloquine and related quinoline drugs. In: Ritchie EC, Llorente MD, eds. Veteran Psychiatry in the US: Optimizing Clinical Outcomes. Cham, Switzerland: Springer International Publishing; 2019:315-331.
