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Chloroquine: an Old Drug with New Perspective Against Giardiasis

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Chloroquine: an Old Drug with New Perspective Against Giardiasis See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/281780591 Chloroquine: An Old Drug With New Perspective Against Giardiasis Article · September 2015 DOI: 10.2174/1574891X10666150914122118 CITATIONS READS 0 211 7 authors, including: Angel A Escobedo Pedro Almirall Academic Paediatric Hospital "Pedro Borrás" Centro Municipal de Higiene, Epidemiología … 73 PUBLICATIONS 752 CITATIONS 33 PUBLICATIONS 305 CITATIONS SEE PROFILE SEE PROFILE Sergio Cimerman Marco Lalle Instituto de Infectologia Emílio Ribas Istituto Superiore di Sanità 44 PUBLICATIONS 549 CITATIONS 33 PUBLICATIONS 992 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: VI International Giardia & Cryptosporidium Conference. April 26-28, 2017. Havana City, Cuba http://www.giardiacrypto2017.sld.cu View project VI International Giardia & Cryptosporidium Conference. April 26-28, 2017. Havana City, Cuba http://www.giardiacrypto2017.sld.cu View project All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Angel A Escobedo letting you access and read them immediately. Retrieved on: 26 September 2016 Send Orders for Reprints to [email protected] Recent Patents on Anti-Infective Drug Discovery, 2015, 10, 000-000 1 Chloroquine: An Old Drug with New Perspective Against Giardiasis Angel A. Escobedoa,b,c*, Pedro Almirallc,d, Sérgio Cimermanc,e, Marco Lallef, Frank Pachecog, Carlos Z. Acandah and Niurka Sánchezh aAcademic Paediatric Hospital “Pedro Borrás”, Calle F No. 616 esquina 27, Plaza, La Habana, CP 10400, Cuba; bWorking Group on Zoonoses, International Society for Chemotherapy, Aberdeen, United Kingdom; cCommittee on Clinical Parasitol- ogy, Panamerican Association of Infectology; dMunicipal Centre of Hygiene, Epide- miology and Microbiology “Plaza”, Calle 8 No. 406 esquina a 19, Plaza, La Ha- bana, CP 10400, Cuba; eInstitute of Infectious Diseases “Emilio Ribas”, Rua Zaca- rias de Gois, 966/41, 04610-002, SP, São Paulo, Brazil; fDepartment of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Angel A. Escobedo Italy; gPolyclinic Cerro, Calzada del Cerro No. 1813 esquina a Arzobispo, Cerro, La Habana, CP 10600, Cuba; hCuban Institute of Gastro-enterology, Calle 25 No. 503 esquina a I, Plaza, La Ha- bana, CP 10400, Cuba Received: July 14, 2015; Revised: September 11, 2015; Accepted: September 11, 2015 Abstract: The occurrence of treatment failures to first-line treatment for giardiasis, one of the most wide- spread although neglected parasitic disease, has long been recognised. Nowadays, it starts to represent a great challenge to clinicians, especially in endemic countries. This requires the introduction of new drug interven- tions, but the development of novel drugs is a time and money consuming effort with most of the compounds never reaching the market. Consequently, alternative strategies are needed, especially for the treatment of giardiasis. Chloroquine (CQ), a synthetic drug developed as antimalarial agent, has been shown to also exert antigiardial activity. Here, we present a minireview summarizing results on the treatment of human clinical cases with CQ, going through in vitro research, case report, and case series to human clinical trials, highlight- ing the benefits and mentioning possible adverse effects. Keywords: Chloroquine, Giardia, treatment. INTRODUCTION Africa, and Latin America about 200 million peo- Giardia lamblia (synonymous G. duodenalis or ple have symptomatic giardiasis, with some G. intestinalis), the aetiological agent of human 500,000 new cases reported each year [2] The pub- giardiasis, is one of the commonest intestinal pro- lic health impact of this parasitic protozoan infec- tozoa worldwide, both in developed as well as in tion is due to: a) its high prevalence, being one of developing countries, although the largest impact the main causes of diarrhoea among young chil- of giardiasis can be found in the latter, with South dren in day care centres [3] and among travellers Asia, the Middle East, and South America from non-endemic countries [1]; b) its propensity considered areas of high endemicity [1]. In Asia, to cause water- and (less frequently) food-borne outbreaks [3]; and c) its impact on community of *Address correspondence to this author at the Angel A. Escobedo, men who have sex with men [4]. Department of Microbiology, Paediatric Academic Hospital “Pedro Borrás”. 616, F. Plaza. Havana City, 10400, Cuba; Giardia infection occurs after ingestion of Tel:/Fax: +53 7 8301042; E-mail: [email protected] water or food contaminated with parasite cysts or 1574-891X/15 $100.00+.00 © 2015 Bentham Science Publishers 2 Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 Escobedo et al. directly between hosts by faecal-oral route. The trophozoite stage of the parasite replicates and colonizes the upper small intestine of the host attaching to the surface of enterocytes. Giardiasis may be asymptomatic or responsible for a broad clinical spectrum, including acute or chronic diar- rhoea which may be with or without dehydration and malabsorption syndrome. Nausea, vomiting, abdominal pain, flatulence and weight loss are also commonly reported [5]. In addition, giardiasis may have long term consequences on the growth and cognitive functions of infected children [6]. Fur- thermore, extra-intestinal manifestations and post- infectious sequelae can also occur [7, 8]. Current treatments rely on 5-nitroimidazole (5- NI) compounds that, although not ideal, are suc- Fig. (1). Chemical structures of quinacrine and chloroquine. cessful in a high percentage of patients. However, an increasing number of treatment failures have been reported in the literature [9-22]. Undesirable at the psychiatric hospital in Düsseldorf using para- side-effects, poor patient compliance and “drug lytic patients, who had been inoculated with Plas- resistance” are associated to treatment failures and modium vivax. The reported efficacy of CQ was with contraindications of these drugs for some pa- similar to that of atabrine although, due to its con- tients. Other compounds belonging to different troversial adverse effect (it was too toxic for human pharmacological classes have already been studied use), it was not subjected to any further clinical in the giardiasis context [23, 24]; one of them is study [26]. Thus, the recognition of the value of CQ chloroquine (CQ). This paper reviews published was delayed, and it was not brought forward until it data on the use of this drug as a treatment for was re-evaluated in the United States of America Giardia infections. and designated as the drug of choice against malaria near the end of World War II [27]. For many dec- MATERIAL & METHODS ades, CQ was the first line drug for the treatment of non-severe or uncomplicated malaria, until the A PubMed online data base search was com- emergence of drug resistance that greatly reduced pleted for articles published in the English, French, its usefulness [28]. To date, it is still used in many Italian and Spanish languages using the keywords regions of the world as a reliable treatment against “giardiasis,” “giardia,” “chloroquine,” “case se- simpler forms of malaria. ries,” “case reports,” and “clinical trials” and the reference lists of the retrieved articles. The search Beyond its well-known antimalarial effect, CQ included articles that were published as of May is currently recommended as second-line therapy 2015. in the treatment of other infectious and non- infectious diseases including extraintestinal amoe- CQ HISTORY biasis [29], HIV [30, 31], sarcoidosis [32, 33], rheumatoid arthritis [34], lupus erythematosus CQ is a synthetic agent of the 4-aminoquinoline [35], porphyria cutanea tarda [36], and cancer, series (Fig. 1). This drug was first synthesized by with evidence suggesting that this compound sen- Johann “Hans” Andersag at the Bayer laboratories in Elberfeld in 1934, when he modified quinacrine sitizes cancer cells to radiation and chemothera- (also known as atabrine) by replacing its acridine peutic agents [37, 38]. ring with a quinoline ring (Fig. 1) [25]. The first Although quinacrine was firstly reported at the human trials as anti-malaria agent were carried out end of the 30s as effective drug against clinical Chloroquine in Giardiasis Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 3 cases of giardiasis [39, 40], evidences of the effect to the plasma membranes, binds to DNA, although of CQ in the treatment of giardiasis dates only few it does not accumulate within the nuclei [55], and years later in Cuba. This novel use had been ini- decreases encystation rate from both in vitro- and tially described in the late 1940s [41, 42]; and patient-derived Giardia cysts [56, 57]. various studies have been subsequently carried out [43, 44]. Owing to the low experience, the appar- SUMMARY OF ISOLATED CASE RE- ent modest activity reported, the recognized activ- PORT/CASE SERIES OF CQ USE IN ity of quinacrine, its prioritized activity for malaria GIARDIASIS cases, and the introduction in the earliest 1960s of Parasitological outcome for CQ in the treatment more potent antigiardial drugs, such as metronida- of giardiasis is summarized in Table 1. The oldest zole (MTZ) [45-47], CQ was long forgotten for the studies show considerable variation in design, treatment against Giardia infections. reported detail, size, recruitment
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