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 widespread 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 diarrhoea 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 and the proportion and definition of evaluable patients, therapy dura- ANTIGIARDIAL IN VITRO ACTIVITY tion and dosing. The treatment efficacy in these In 1985, Gordts et al. evaluated the in vitro ac- reports is largely an estimate based on the eradica- tivity of different antiprotozoal drugs against more tion of the parasite and the improvements in symp- than 25 isolates of G. lamblia trophozoites ob- toms associated with giardiasis. Similarly, the tained by routine culture from the duodenal fluid level of detail in reporting adverse effects is vari- of children attending to the paediatric gastroen- able, thus it is difficult to assess the overall safety terology department. It was demonstrated that of CQ. more than half of the isolates were extremely sus- Based on the literature, Basnuevo and So- ceptible to CQ (MIC<1 g/ml) [48]. In vitro, CQ tolongo firstly described the use of CQ in the was shown to be more effective (IC50 = 0.4μM) treatment of giardiasis, by reporting a successful than MTZ (IC50 = 5.3μM) on G. lamblia tropho- cure rate among 2 patients in Cuba [41]. Later, the zoites, strain IMSS:0696:1 [49]. Although the same authors also reported a case series of 15 pa- mode of action of CQ is not fully understood, the tients, of whom 12 were successfully cured [42]. drug efficacy was linked to a reduced ability of Soon after, following these initial reports several Giardia trophozoite in vitro to attach to surface, studies were published confirming the antigiardial thus suggesting that a similar effect may occur efficacy of CQ, Table 1. Noteworthy, the com- in vivo [50]. CQ has been proven to be a lysoso- bined use of CQ and quinacrine (combined in a 3:1 motropic agent, so that it accumulates into proportion), increased the cure rate to more than lysosome, acidic cellular compartments involved 90% [58]. Other authors also reported the use of in endocytosis, where it prevents endosomal acidi- CQ in a number of patients infected with Giardia fication thus inhibiting endocytosis, degradation, [59, 60]. recycling, and secretion of protein [51]. Giardia possesses peripheral vacuoles instead of a defined RESULTS & DISCUSSION OF THE STUD- endosomal/lysosomal system [52]. The observa- IES OF THE EFFICACY AND SAFETY OF tion that treatment of Giardia trophozoites with CQ IN THE TREATMENT OF GIARDIASIS CQ results in a nonproductive infection of Giardia-specific virus (giardiavirus) being the vi- A cure rate for CQ is not reported but it is for rus confined in the peripheral vacuoles, suggest amodiaquine, another antimalarial drug [61]. that the drug could inhibit peripheral vacuoles Stimulated by these observations, in order to draw functions [53]. Other possible mechanisms of ac- more accurate conclusions regarding the efficacy tion of CQ could be deduced on the related com- of the CQ treatment in giardiasis in children, 2 pound quinacrine. Quinacrine administration re- randomised clinical trials (RCTs) have addressed sults in the decrease of the oxygen consumption in the use of CQ in Cuban children. The first one was Giardia trophozoite, likely by the inhibition of published in 2003. CQ (cure rate 86%) was given NADH oxidase [54]. Quinacrine induces damages in a dose of 10 mg b.i.d. for 5 days and it was as 4 Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 Escobedo et al.

Table 1. Summary of studies of CQ in giardiasis.

Author (Year) [Reference] Participants Parasitological Efficacy and/or Commentary

Basnuevo & Sotolongo, 1946 [41] 2 cases (a 31 year old woman and a 5 year old Follow-up at day 5 and 10. Both cases cured. girl) treated. For the adult: 1rst day: 1g divided into 2 doses in lunch and dinner. 2nd day: 500 mg divided into 2 doses in lunch and dinner. 3rd to 5th day: 250 mg daily. For the girl: 1rst day: 500 mg divided into 2 doses. 2nd day: 250 mg. 3rd to 5th day: 250 mg divided into 2 doses.

Basnuevo & Sotolongo, 1946 [42] 15 cases (2-66 years): adults and children treated. 12 cases cured. For adults: 1rst day: 1g. 2nd to 4th day: 500 mg daily. For children: 2-5 years: 250 mg daily for 4 days. 5-10 years: 500 mg daily for 4 days. 10-15 years: 750 mg initially and after 500 mg for 4 days.

Schneider & Uzan, 1947 [43] 16 cases [(2-41y): (8<17y and 817y)] treated. 13 cured. Adults: 300 mg a day for 5 days. 2 cases cured after a second round of 5 additional Children: 150 mg a day for 5 days. days, 10 days after. Only minor gastrointestinal side effect in one case.

Swartzwelder & Papermaster, 1947 [44] 5 cases treated. Temporary disappearance or reduction in the num- 3 children with 35-40 lbs. 125 mg twice a day for ber of Giardia cysts in 4 of 5 cases, which reap- 3 days. peared or persisted in the stools following a brief interval. No reduction was observed in one case. No 1 child with 26 lb. 62 mg daily for 4 days. significant untoward reactions were observed. 1 child 30 lb. 62 mg daily for 3 days.

Benetazzo & Tonca, 1955 [67] 49 adult cases treated with a 5 days treatment as Reduction of Giardia cysts in faeces after 24h and follow: disappearance after 72h in 81% of cases (93% using 1g/day for the first day, 0.50g/day for the 2nd day the higher dosage). No side effect reported, al- and 0.25g/day for the remaining days though 4 patients had moderate nausea and dizzi- ness. Patients were coprologically examined every or 10 day for a period of 30-60 days after treatment. 1g/day for the first 2 days and 0.5g/day for the The percentage of efficacy was affected by the remaining days. initial treatment with the lower dose and the quality of the drug stock. Disappearance of the parasite from faeces corre- lated in a 30% of cases with symptoms remission, in a 60% of cases with symptoms reduction and in 10% with symptoms persistence.

Chloroquine in Giardiasis Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 5

Table (1) contd….

Author (Year) [Reference] Participants Parasitological Efficacy and/or Commentary

Lamadrid-Montemayor, 1954 [61] 50 cases treated. 44 (88%) cured. Children from 2-12y: 200 mg daily for 5 days. For 4 of these patients to undergo a second course Children older than 12 and adults: 300 mg daily of treatment in order to eliminate Giardia organ- for 5 days. isms.

Halstead & Sadun, 1965 [68] An adult patient treated with 1 g of CQ on 2 Although parasites were eradicated, symptoms successive days. persisted.

Escobedo et al., 2003 [62] 50 children from 2-13y were treated. 43 cured. Dosage: 10 mg/kg twice daily for 5 days. RCT. Side effects reported by the 50 treated cases (100%): bitter taste 50 (100%), abdominal pain 17 (34%), nausea 12 (24%) and vomiting 6 (12%).

Cañete et al., 2010 [63] 61 children from 2-15y were treated. 52 (85.2%) cured. Dosage: 10 mg/kg twice daily for 5 days. RCT. Side effects reported by 38 cases (62.2%): headache 17 (27.8%), sickness 11 (18%), abdominal pain 8 (13.1%), nausea 3 (4.9%), yellowish colouration of the urine 2 (3.2%) and bitter taste 1 (1.6%).

RCT, randomised control trial. efficacious as tinidazole (cure rate 91%) in the unusual and are related to the total dose consumed. treatment of giardiasis in paediatric patients. Ob- The side effects commonly seen at therapeutic served side effects were generally restricted to gas- concentrations are referred to as pruritus, seen in trointestinal disturbances, such as a bitter taste, African population, which peaks 24 h after oral nausea and abdominal pain [62]. Based on this dose [64]. This was not reported in any of the arti- previously RCT, a second one was performed cles reviewed. The adverse effects reported after comparing a similar dose of CQ with MTZ [15 treatment with CQ have been previously and ex- mg/Kg bodyweight divided in three daily does for tensively reported (i.e. for malaria) even though five days] [63]. All children were asked to provide the prolonged use of the drug may induce more three faecal samples on days 3, 5 and 7 after serious side-effects, including alopecia, blood dy- treatment completion. The frequency of cure was scrasias, neuromyopathies, deafness and lesions in slightly higher for CQ than for MTZ, although the the cornea and retina [65]. Noteworthy, in the two difference was not statistically significant. Head- reported RCTs, no patients reporting adverse ef- ache was more common in patients treated with fects needed any additional drug therapy to reverse CQ as was bitter taste. Yellowish colouration of the symptoms; thus, these events were considered the urine was more frequent in the MTZ treated to be ephemeral and of low intensity [62, 63]. group. CQ IN THE TREATMENT OF GIARDIASIS: SIDE EFFECTS AFTER USE OF CQ IN WHERE DOES IT FIT? GIARDIASIS CQ has been for years a silent presence in the In general, CQ is widely available and consid- antigiardial armamentarium. Irrespective of the ered to be a relatively well-tolerated medication, mechanisms of action of CQ against Giardia, it is which warrants its widespread use. Side effects are confirmed that this drug deserves to be considered either low or not reported in the other studies re- as a treatment option. Although the majority of viewed. Serious adverse events with oral CQ are data regarding the use of CQ were limited to a 6 Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 Escobedo et al. case report and case series, as reviewed here, only search and around US $2 billion to bring a single three prospective clinical trials including larger new drug to market. Trying out existing drugs for numbers of patients (principally children) with diseases other than what they were originally in- giardiasis have been published detailing clinical tended for, is therefore, cost-effective and com- and parasitological responses to medical therapy paratively easy, while these drugs have approval [61-63]. How the results of these trials affect the from regulatory agencies and have known phar- use of medical therapy in regard to patient selec- macokinetics and safety profile [66]. In this barren tion, severity of disease, and timing of medical time for new therapies (mainly antiparasitic treatment in relation to other therapy, has yet to be drugs), the present review indicates that the poten- determined. Larger, well-controlled trials are tial of this old drug against G. lamblia is worthy of needed to discern the potential role of CQ in the further consideration and could increase the physi- management of Giardia infections in children and cian's armamentarium against giardiasis. CQ has adults and to determine the minimal effective dose been shown to display several additional attractive and duration of therapy necessary. advantages that deserve our attention: it is gener- The second important question is: what is the ally considered a safe drug in humans, with a future for CQ in the treatment of giardiasis? Al- known side-effect profile; and it is relatively inex- though, it is difficult to answer that question at pre- pensive. Although a better understanding of the sent, drug repurposing of already approved drugs is mechanisms involved in the action of CQ both an attractive opportunity to identify alternative in vitro and in vivo against Giardia is required, the treatment options for several parasitic neglected encouraging results of the scarce studies and the diseases, including giardiasis. Taking into consid- attractive merits of this drug indicate that it will eration the increased percentage of recognized have potential as a therapeutic approach for treat- cases of giardiasis refractory to treatment with stan- ing giardiasis, especially for patients who fail to- dard drugs, particularly 5-nitroimidazoles, the evi- or are intolerant to more standard therapies, or are dence on CQ efficacy emerging from the studies unable to undergo recommended therapy due to reviewed here are very encouraging. It is also im- co-morbid illness. portant to take into account that selection of medi- CONFLICT OF INTEREST cation also depends on drug approval and avail- ability in individual countries and requires cau- The authors confirm no conflicts of interest tious assessment of potential adverse effects, con- with the article content. sideration of patient co-morbidities, and efficacy. ACKNOWLEDGEMENTS There is a need of more RCTs, including also data on co-infection, especially in countries endemic Authors acknowledge the priceless help of Mrs for malaria, in order to evaluate the eventual im- Raffaella Lalle (Central Library “G. Marconi”, pact of CQ use for the treatment of giardiasis on CNR, Rome, Italy) to retrieve hardcopies of some the potential increase of CQ-resistant Plasmodia, of the oldest publications used in this review. in particular P. vivax. Further studies will also help REFERENCES to clarify the efficacy of CQ as single antigiardial agent or in combination with other antigiardial [1] Ross AG, Olds GR, Cripps AW, Farrar JJ, McManus drug. As doses may differ for different indications, DP. Enteropathogens and chronic illness in returning a dose-finding trial may be required. travelers. N Engl J Med 2013; 368: 1817-25. [2] World Health Organization. The World Health Report 1996. Fighting disease fostering development. Ge- CURRENT & FUTURE DEVELOPMENTS neva, Switzerland: World Health Organization 1996. Up to now, studies on the treatment of Giardia [3] Ang LH. Outbreak of giardiasis in daycare nursery. infections with CQ are scarce and mainly limited Commun Dis Public Health 2000; 3: 212-3. [4] Escobedo AA, Almirall P, Alfonso M, Cimerman S, to case series and case reports. Much work is Chacin-Bonilla L. Sexual transmission of giardiasis: needed to identify new therapies; according to a A neglected route of spread? Acta Trop 2014; 132: recent estimate, it takes about 10-15 years of re- 106-11. Chloroquine in Giardiasis Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 7

[5] Escobedo AA, Almirall P, Robertson LJ, Mørch K, [20] Requena-Méndez A, Goñi P, Lóbez S, Oliveira I, Franco RM, Hanevik K, et al. Giardiasis: The ever Aldasoro E, Valls ME, et al. A family cluster of present threat of a neglected disease. Infect Disord giardiasis with variable treatment responses: Refrac- Drug Targets 2010; 10: 329-48. tory giardiasis in a family after a trip to India. Clin [6] Berkman DS, Lescano AG, Gilman RH, Lopez SL, Microbiol Infect 2014; 20: 135-8. Black MM. Effects of stunting, diarrhoeal disease, [21] Meltzer E, Lachish T, Schwartz E. Treatment of and parasitic infection during infancy on cognition in giardiasis after nonresponse to nitroimidazole. Emerg the late childhood: A follow-up study. Lancet 2002; Infect Dis 2014; 20: 1742-4. 359: 564-71. [22] Nabarro LEB, Lever RA, Armstrong M, Chiodini PL. [7] Halliez MCM, Buret AG. Extra-intestinal and long Increased incidence of nitroimidazole-refractory term consequences of Giardia duodenalis infections. giardiasis at the Hospital for Tropical Diseases, Lon- World J Gastroenterol 2013; 19: 8974-85. don: 2008-2013. Clin Microbiol Infect. 2015; 21(8): [8] Bartelt LA, Sartor RB. Advances in understanding 791-6. [Epub ahead of print] Giardia: Determinants and mechanisms of chronic [23] Escobedo AA, Cimerman S. Giardiasis: A pharma- sequelae. F1000Prime Rep 2015; 7: 62. cotherapy review. Expert Opin Pharmacother 2007; 8: [9] McIntyre P, Boreham PF, Phillips RE, Shepherd RW. 1885-902. Chemotherapy in giardiasis: Clinical responses and in [24] Lalle M. Giardiasis in the post genomic era: Treat- vitro drug sensitivity of human isolates in axenic cul- ment, drug resistance and novel therapeutic perspec- ture. J Pediatr 1986; 108: 1005-10. tives. Infect Disord Drug Targets 2010; 10: 283-94. [10] Lo Line MC, Sankale M, Pene P. Les giardiasis re- [25] Krafts K, Hempelmann E, Skórska-Stania A. From belles. Méd Afrique Noire 1987; 34: 1063-8. methylene blue to chloroquine: A brief review of the [11] Taylor GD, Wenman WM, Tyrrell DL. Combined development of an antimalarial therapy. Parasitol Res metronidazole and quinacrine hydrochloride therapy 2012; 111: 1-6. for chronic giardiasis. CMAJ 1987; 136: 1179-80. [26] Jensen M, Mehlhorn H. Seventy-five years of Reso- [12] Al Karawi M, Salam I, Mohamed AE. Combined oral chin® in the fight against malaria. Parasitol Res 2009; and endoscopic mepacrine therapy in a case of persis- 105: 609-27. tent chronic symptomatic giardiasis. Trans R Soc [27] Coatney GR. Pitfalls in a discovery: The chronicle of Trop Med Hyg 1988; 82: 581. chloroquine. Am J Trop Med Hyg 1963; 12: 121-8. [13] Rowedder A, Meier R, Wegmann W, Gyr K. Com- [28] WHO. Guidelines for the treatment of malaria. Second bined oral and endoscopic mepacrine therapy in ther- edition. Geneva: World Health Organization 2010. apy-resistant symptomatic giardiasis. Schweiz Med [29] Reed SL. Amebiasis: An update. Clin Infect Dis Wochenschr 1991; 121: 1383-6. 1992; 14: 385-93. [14] Elliott AM, Klaus BD, North DS, Martin HP. Fura- [30] Savarino A, Lucia MB, Rastrelli E, Rutella S, Golotta zolidone-induced mood disorder during the treatment C, Morra E, et al. Anti-HIV effects of chloroquine: of refractory giardiasis in a patient with AIDS. Clin Inhibition of viral particle glycosylation and syner- Infect Dis 1998; 26: 1015. gism with protease inhibitors. J Acquir Immune Defic [15] Abboud P, Lemeé V, Gargala G, Brasseur P, Ballet Syndr 2004; 35: 223-32. JJ, Borsa-Lebas F, et al. Successful treatment of met- [31] Brouwers J, Vermeire K, Schols D, Augustijns P. ronidazole- and albendazole-resistant giardiasis with Development and in vitro evaluation of chloroquine nitazoxanide in a patient with acquired immunodefi- gels as microbicides against HIV-1 infection. Virol- ciency syndrome. Clin Infect Dis 2001; 32: 1792-4. ogy 2008; 378: 306-10. [16] Nash TE, Ohl CA, Thomas E, Subramanian G, Keiser [32] Zic JA, Horowitz DH, Arzubiaga C, King Jr LE. P, Moore TA. Treatment of patients with refractory Treatment of cutaneous sarcoidosis with chloroquine. giardiasis. Clin Infect Dis 2001; 33: 22-8. Review of the literature. Arch Dermatol 1991; 127: [17] Mørch K, Hanevik K, Robertson LJ, Strand EA, Lan- 1034-40. geland N. Treatment-ladder and genetic characterisa- [33] Fazzi P. Pharmacotherapeutic management of pulmo- tion of parasites in refractory giardiasis after an out- nary sarcoidosis. Am J Respir Med 2003; 2: 311-20. break in Norway. J Infect 2008; 56: 268-73. [34] Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh [18] Kampitak T. Selective immunoglobulin M deficiency AF, Kremer JM, et al. 2012 update of the 2008 in a patient with refractory giardiasis. J Investig Al- American College of Rheumatology recommenda- lergol Clin Immunol 2010; 20: 358-60. tions for the use of disease-modifying antirheumatic [19] Tejman-Yarden N, Miyamoto Y, Leitsch D, Debnath drugs and biologic agents in the treatment of rheuma- A, Gut J, McKerrow, JH, et al. A reprofiled drug, au- toid arthritis. Arthritis Care Res (Hoboken) 2012; 64: ranofin, is effective against metronidazole-resistant 625-39. Giardia lamblia. Antimicrob Agents Chemother [35] Lee SJ, Silverman E, Bargman JM. The role of anti- 2013; 57: 2029-35. malarial agents in the treatment of SLE and lupus ne- phritis. Nat Rev Nephrol 2011; 7: 718-29. 8 Recent Patents on Anti-Infective Drug Discovery, 2015, Vol. 10, No. 2 Escobedo et al.

[36] Sarkany RP. The management of porphyria cutanea [52] Touz MC, Rivero MR, Miras SL, Bonifacino JS. tarda. Clin Exp Dermatol 2001; 26: 225-32. Lysosomal protein trafficking in Giardia lamblia: [37] Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding Common and distinct features. Front Biosci (Elite Ed) chloroquine to conventional treatment for glioblas- 2012; 4: 1898-909. toma multiforme: A randomized, double blind, pla- [53] Tai JH, Ong SJ, Chang SC, Su HM. Giardiavirus en- cebo-controlled trial. Ann Intern Med 2006; 144: 337- ters Giardia lamblia WB trophozoite via endocytosis. 43. Exp Parasitol 1993; 76: 165-74. [38] Amaravadi RK, Lippincott-Schwartz J, Yin XM, [54] Paget TA, Jarroll EL, Manning P, Lindmark DG, Weiss WA, Takebe N, Timmer W, et al. Principles Lloyd D. Respiration in the cyst and trophozoite and current strategies for targeting autophagy for can- forms of Giardia muris. J Gen Microbiol 1989; 135: cer treatment. Clin Cancer Res 2011; 17: 654-66. 145-54. [39] Galli-Valerio B. La lambliase et son traitment per [55] Upcroft JA, Campbell RW, Upcroft P. Quinacrine- l’atébrine. Schweiz Med Wschr 1937; p. 1181. resistant Giardia duodenalis. Parasitology 1996; 112: [40] Hartman HR, Kyser FA. Giardiasis and its treatment. 309-13. JAMA 1941;116: 2835-9. [56] Gillin FD, Diamond LS. Inhibition of clonal growth [41] Basnuevo JG, Sotolongo F. Giardiasis y Aralen of Giardia lamblia and Entamoeba histolyica by met- (cloroquina) (SN-7618)-(W-7618)-(7-cloro-4-(4 dieti- ronidazole, quinacrine and other antimicrobial agents. laino-1-metilbutilamino) quinolina difosfato. Rev J Antimicrob Chemother 1981; 8: 305-16. KUBA Med Trop 1946; 12: 71-2. [57] Namgung R, Ryu JS, Kee KT, Soh CT. The effect of [42] Basnuevo JG, Sotolongo F. Tratamiento de la giardia- metronidazole and quinacrine on the morphology and sis con aralen (cloroquina) (SN-7618)-(W-7618)- 7- excystation of Giardia lamblia. Yonsei Rep Trop cloro-4-(4 dietilaino-1-metilbutilamino) quinolina di- Med 1985; 16: 28-44. fosfato. Rev KUBA Med Trop 1946; 12: 131-6. [58] Basnuevo JG, Soler DF, Cowley CO. La mezcla [43] Schneider J, Uzan M. Sur l´utilisation d´un nouveau cloroquina-quinacrina (3:1) en el tratamiento de la medicament synthetique dans le traitement de la lam- giardiasis. Rev KUBA Med Trop 1954; 10: 54-6. bliase. Bull Soc Pathol Exot Filiales 1947; 40: 155-6. [59] Walzer PD, Wolfe MS, Schultz MG. Giardiasis in [44] Swartzwelder JC, Papermaster TC. The effect of travelers. J Infect Dis 1971; 124: 235-7. Aralen on Giardia lamblia infections in children. J [60] Genç S. The treatment of giardiasis and trichomonia- Parasitol 1947; 33: 22. sis with resochin and metronidazole. Mikrobiyol Bul [45] Schneider J. Traitement de la giardiase (lambliase) 1976; 10: 303-6. par le metronidazole. Bull Soc Pathol Exot Filiales [61] Lamadrid-Montemayor F. Comparative study of 1961; 54: 84-95. chloroquine and amodiaquin in the treatment of [46] Mandoul R, Dargelos R, Millan J. Destruction des giardiasis. Am J Trop Med Hyg 1954; 3: 709-11. protozoaires intestinaux de la souris par un dérivé ni- [62] Escobedo AA, Núñez FA, Moreira I, Vega E, Pareja tré de l’imidazole. Bull Soc Pathol Exot Filiales 1961; A, Almirall P. Chloroquine and albendazole in the 54: 12-6. treatment of paediatric patients with giardiasis. Ann [47] Darbon A, Portal A, Girier L, Pantin J, Leclaire C. Trop Med Parasitol 2003; 97: 367-71. Traitement de la giardiase (lambliase) par le metroni- [63] Cañete R, Ribas D, Escobedo AA, González ME, dazole. Presse Med 1962; 70: 15-6. Almirall P, Brito K. A randomized, controlled, open- [48] Gordts B, Hemelhof W, Asselman C, Butzler J-P. In label trial evaluating the efficacy and safety of vitro susceptibilities of 25 Giardia lamblia isolates of chloroquine in the treatment of giardiasis in children. human origin to six commonly used antiprotozoal West Indian Med J 2010; 59: 607-11. agents. Antimicrob Agents Chemother 1985; 28: 378- [64] Sowunmi A, Walker O, Salako LA. Pruritus and an- 80. timalarial drugs in Africans. Lancet 1989; 334: 213. [49] Nava-Zuazo C, Estrada-Soto S, Guerrero-Alvarez J, [65] Jong EC, Nothdurft HD. Currents drugs for antima- León-Rivera I, Molina-Salinas GM, Said-Fernández larial chemoprophylaxis: A review of efficacy and S, et al. Design, synthesis, and in vitro antiprotozoal, safety. J Travel Med 2001; 8 (Suppl 3): 48-56. antimycobacterial activities of N-{2-[(7-chloroquinolin- [66] Chong CR, Sullivan DJ Jr. New uses for old drugs. 4-yl)amino]ethyl}ureas. Bioorg Med Chem 2010; 18: Nature 2007; 448: 645-6. 6398-403. [67] Benetazzo B, Tronca M. Results of treatment with [50] Baveja UK, Bathia VN, Warhurst DC. Giardia lam- certain antimalaria drugs. Arch It Sci Med Trop 1955; blia: In-vitro sensitivity to some chemotherapeutic 36:155. agents. J Communicable Dis 1998; 30: 79-84. [68] Halstead SB, Sadun EH. Alimentary hypersensitivity [51] Steinman RM, Mellman IS, Muller WA, Cohn ZA. induced by Giardia lamblia; report of a case of acute Endocytosis and the recycling of plasma membrane. meat intolerance. Ann Intern Med 1965; 62: 564-9. J Cell Biol 1983; 96: 1-27.