My previous article discussed the anti-cancer effects of a Chinese herbal drug for malaria called Artemisinin. Synergistic anticancer effects could be obtained in combination with other non-toxic therapies such as butyrate, resveratrol, allicin, curcumin etc.
Anti-Malaria Drug Mefloquine
My previous article on Non-Toxic cancer stem cell therapies discussed the anti-malarial drug Mefloquine as a good candidate. Not only does Mefloquie target cancer stem cells, it has a long history of use combined with Artemisinin in treatment of malaria. This combination of Artemisinin (or derivative) with Mefloquin is well tolerated and extensively studied with many publications in the medical literature. Left Image Malaria Mosquito courtesy of WIkimedia Commons.
According to Dr Sukhai, Mefloquin and Artemisinin derivatives work in synergy to produce greater cancer cell killing effects.(22) An added benefit of Mefloquin is passage across the Blood Brain Barrier for treatment of Central Nervous System. Therefore, this article will explore the use of this combination. Left Image Mefloquin chemical structure courtesy of Med Chem.
Dr Sukhai’s group in Toronto screened a list of on and off patent drugs for anti-leukemic activity. They found the anti-malaria drug, Mefloquine, second most active after Ivermectin. (see red arrow Figure 1 below)
Left Image from Fig 1 Sukhai screening 100 drugs for anti-leukemic activity. Mefloquine (red Arrow) is the second most active after Ivermectin (Green Arrow). EC(50) is concentration required for 50% cell killing effect.
Dr Sukhai determined that mefloquine disrupts lysosomes, directly permeabilizes the lysosome membrane, and releases cathepsins into the cytosol. Artemisinin and derivatives also disrupt lysosomes via Iron-catalyzed lysosomal ROS (reactive oxygen species) production. (Brady Hammacher et al 2011)
Next Dr Sukhai’s group screen 500 drugs for synergy with Mefloquin. Artemisinin (and derivatives) scored highest on the list.(see Fig 2 red arrow below)
Synergistic combinations of mefloquine and artemisinin derivatives artesenuate and artimol synergistically increased ROS (reactive oxygen species) in the leukemia cells. The effect was blocked by the anti-oxidant (Vitamin E) Alpha tocopheral, however, the glutathione precurser NAC (N acetyl cyteine) had NO effect.
Above image from Fig 2C Sukhai showing synergy effects of Artemisinin derivatives with Mefloquine.(22)
Next, Dr Sukhia’s group used haploinsufficiency profiling (HIP), a genomics platform, to elucidate the mechanism of Mefloquine’s anti-leukemic activity. This testing indicated that Mefloquine specifically targets Lysosomal functions, as was previously demonstrated in 1992 by Glaumann et al who studied the effects of Mefloquin in mice liver lysosomes.(18) In a 1992 report by Dr Glaumann, Mefloquin caused expansion of intra-hepatic lysosomes starting at 24 hours after administration, and lasting for 7 days in mice. The lysosomes later harbored multi-lamellar bodies which disappeared after 7-10 days.(18)
Dr Sukhai’s group then studied the effect of Mefloquine on isolated lysosomes taken from cell samples from Leukemia patients, finding that Mefloquine disrupted lysosomes with release of lysosomal contents (cathepsins B and L) Moreover, there was no similar effects on mitochondria. The lysosomal disrupting effect of Mefloquine was selective for AML leukemia cells which showed abundant cathepsin B in the cytoplasm. However, normal hematopoetic cells were unaffected with intact lysosomes and no release of cathepsin B into the cytoplasm..(22)
Leukemia Cell have Upregulated, Larger Lysosomes
Previous authors have reported upregulation of lysosomes and lysosomal enzymes (cethepsins) in cancer cells. (24-26) Dr Sukhai reported that lysosomes tended to be two to three times larger in leukemia cells compare to normal cells.(22) Dr Sukha’s group also reported that in comparison to normal cell, leukemia cells had up-regulated genes responsible for lysosome biogenesis, and over-expressed cathepsin messenger RNA as well. This was also true for LIC (Leukemia initiating stem cells).
Dr Sukahi’s group then did in vivo xenograft studies in mice with implanted leukemia cells, again showing mefloquine effective at reducing tumor size and weight with little or no toxicity to the mouse.(22)
Mefloquin was found to be superior to Chloroquin in a 2012 report by Dr Sharma who found Mefloquin caused cell death in breast cancer cell cultures.
Mefloquin – Malaria Prophylaxis for Travelers
Mefloquin is currently recommended for malaria prophylaxis in travelers. Dosage is usually on 250 mg tablet per week for a few weeks prior to the trip.
Toxicity: There may be neuro-psychiatric symptoms of toxicity reported by some. Artemisinin has been used in combination with Chloroquin or Mefloquin for decades, however long term use can result in neurotoxicity, so caution is advised.
Mefloquine Retinal Toxicity and Neuro-Toxicity
Caution is advised before using Mefloquine as well as other Quinolones. Although originally marketed as safe for malaria prophylaxis, recent studies show an alarming incidence of neurologic toxicity, which may be “clinically occult , and in some cases, irreversible. (Remington Nevin 2014). A possible mechanism of Mefloquin toxicity was elucidated by Dr Anthony Mawson, in his 2013 article, “Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis,” Dr Dow reported in 2006 in a mouse model showing Mefloxine neurotoxicity, impairment of motor function and damage to brain stem nuclei at doses comparable to treatment dosage in humans.
Hydroxychloroquin – Eight Clinical Trials
Because of concern for adverse effects of mefloquin and chloroquin, namely retinal toxicity and neurotoxicity, further clinical studies of autophagy inhibitors with the anti-malarial quinolones has been carried out with hydroxychloroquine (Plaquenel), nicely summarized by Dr Solitro in a 2015 report in which Table One lists eight completed clinical trials published in the medical literature. synergy with conventional chemotherapeutic agents was demonstrated in Lymphoma, myeloma, glioblastoma and pancretic ductal adenocarcinoma. The lymhoma study in dogs showed a 93% response rate for the combination of doxorubicin and hydroxychloroquin. Dosage and safety of the drug regimens were determined.
Ivermectin (Stromectal) a Safer and More Effective Choice
As demonstrated by Dr Sharmeen in 2010 Blood, Ivermectin is the most effective anti-leukemic agent with astonishing safety and lack of toxicity, so the lack of clinical trials using Ivermectin as an anti-leukemic agent is puzzling. Ivermectin does not cross the blood brain barrier, accounting for lack of CNS toxicity. although not effective for CNS neoplasm such as glioblastoma, the drug is other wise very effective at low dosage outside the CNS. Ivermectin has been used and studied in combination with artemisinin derivatives in anti-malarial programs. For more on Ivermectin, see my previous article Targeting Cancer Stem Cells With Nontoxic Therapies.
Left Upper Image: Figure 1 from Sharmeen S, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603.
The Artemisinin – Mefloquine combination has been found synergistic for AML (acute myelogenous leukemia) and cancer stem cells , with mechanism involving lysosomal disruption leading to cancer cell death. It is highly probably that this combination will also be effective for many other cancers having upregulated lysosomal compartments. NIH funding of future studies of the autophagy inhibitors such as Artemisinin and the anti-malarial quinolones such as chloroquin, mefloquine, hydrozyquinolone etc. are advised. Because of adverse effects of retinal toxicity and neurotoxicity, Mefloquin been for the most part, replaced by hydroxychloroquin (Plaquenel) which is considered a safer drug with a less toxic profile. Considering the disturbing revelations about adverse neurological effects of mefloquine, perhaps the highly effective anti parasitic drug Ivermectin, with astonishingly safe profile, should be considered before the quinolones. As always, work closely with a knowledgeable physician when contemplating any changes in treatment options.
Links and References
Artemisinin combined with Mefloquin
1) Universal Drug Store Order Mefloquin
Lariam 250mg Mefloquine Tablet….Manufactured by Roche Products Ltd, Product of European Union Shipped from United Kingdom,
8 tablets $45.00 US
Coartem (Riamet) Riamet (Artemether/Lumefantrine)
20/120mg Tablet Manufactured by Novartis Pharmaceuticals UK
Product of United Kingdom Shipped from United Kingdom
24 tablets $70 US telephone 866-456-2456
2) Table 5. Dosing Schedule for Artesunate plus Mefloquine*
>13 years 200 (4) 200 200 1000 (4) 500 (2)
alternatively the total dose of mefloquine may be split into three, with one third of the dose being taken on days 1, 2 and 3.
3) P.U. Agomo,et al. 2007. Efficacy and safety of Artesunate +Mefloquine (Artequin®) in the Treatment of Uncomplicated Falciparum malaria in Ijede Community, Ikorodu LGA, Lagos State, Nigeria. Journal of Medical Sciences, 7: 816-824.
4) full pdf free
Krudsood, S., et al. “Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand.” The American journal of tropical medicine and hygiene 67.5 (2002): 465-472.
The investigational therapy in
Group A consisted of artesunate, 4–5 mg/kg/day,
and mefloquine, total dose 25 mg/kg, (∼8.5 mg/kg/day),
given in equal doses simultaneously once a day over a three day
The reference therapy in
Group B was artesunate, 4–5 mg/kg/day, and mefloquine, total dose 25 mg/kg given sequentially (i.e., no mefloquine dose on the first day, 15
mg/kg on the second day, and 10 mg/kg on the third day) over
a three-day period. Artesunate (Plasmotrim-200 and -50
Lactab), mefloquine (Mephaquin-250 Lactab), and placebotomeflo
quine were supplied by Mepha, Ltd. (Aesch,
In conclusion, artesunate and mefloquine can be coadministered
from the first day of therapy. The treatment regimen once a day for three days offers optimal efficacy while maintaining good safety and tolerability, independent from age.
5) Reuter, Stephanie E., et al. “Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria.” Journal of Antimicrobial Chemotherapy (2014): dku430.
Mefloquine is an orally administered blood schizontocide, active against the erythrocytic stages of P. falciparum infection.4 The total recommended dose of mefloquine, administered in combination with artesunate for the treatment of malaria infection, is
25 mg/kg typically given as a split dose over 2 days (15 + 10 mg/kg)
or 24 mg/kg administered over 3 days (8 + 8 + 8 mg/kg).4–7
The coformulated product was administered as tablets containing 200 mg of mefloquine and 100 mg of artesunate (FarManguinhos, Rio de Janeiro, Brazil; Batches #070008 and #069002).
The separate products comprised mefloquine administered as 250 mg tablets (Roche, Basel, Switzerland; Batch #B1100) and 50 mg artesunate tablets (Guilin Pharmaceutical, Guangxi, China; Batch #031201).
6) Krudsood, S., et al. “New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine.” Antimicrobial agents and chemotherapy 54.9 (2010): 3730-3737.
The patients (n = 25/arm) were treated with
(i) two fixed-dose tablets
(AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or
(ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight.
Mefloquine is associated with nausea, vomiting, and dizziness. When used at a stat dose of 25 mg/kg (MQ25), high rates of early (≤1 h) vomiting occurred, especially in children <7 and adults >50 years old (29, 34). Vomiting was reduced by 43% by giving MQ at 15 and 10 mg/kg (MQ15-10) 24 h later and by 2- and 3-fold in those who received an artemisinin derivative on the first day of treatment, followed by MQ25 on the second day of treatment or later (19, 34). The 15- to 10-mg/kg split dose alone also increased the mean area under the concentration-time curve from zero hour to infinity (AUC0-∞) by ∼50% to 51,020 ng·day/ml compared to MQ25 alone (34,106 ng·day/ml), and a 20% increase was seen when MQ was combined with artesunate: 24,343 (MQ15-10) versus 20,292 (MQ25) ng·day/ml (28). Similar AUC results were found in artesunate-treated children who received MQ25 on day 0 (21,196 ng·day/ml) or delayed to day 1 (28,196 ng·day/ml) (24). An increased AUC translates into more time that MQ concentrations are above the MPC and MIC, which are important pharmacokinetic (PK) parameters for parasite killing.
Serious dose-related acute psychiatric side effects occurred in 1/2,089 (15 mg/kg) and 1/1,217 (25 mg/kg) patients
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A population PK model of nonfixed MQ, delivered at 8 mg/kg daily for 3 days in 50 patients, resulted in a mean whole-blood maximum concentration of drug (Cmax) of 2,202 ng/ml and an AUC0-∞ of 31,395 ng·day/ml, a 40% increase compared to a previous population PK model of 24,343 ng·day/ml of AS plus MQ15-10
7) Am J Trop Med Hyg. 2003 May;68(5):608-12.
Efficacy of mefloquine and a mefloquine-artesunate combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon Basin of Peru. Marquiño W1, Huilca M, Calampa C, Falconí E, Cabezas C, Naupay R, Ruebush TK 2nd.
Patients with uncomplicated P. falciparum infections between the ages of 5 and 50 years were randomly assigned to be treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS (4 mg/kg/day for three days).
8) Chin Med J (Engl). 2001 Jun;114(6):612-3.
Efficacy of dihydroartemisinin-mefloquine on acute uncomplicated falciparum malaria. Wang W1, Yang W, Micha ST.
To evaluate the clinical efficacy of dihydroartemisinin-mefloquine on acute uncomplicated falciparum malaria.METHODS:Fifty-four patients with symptomatic falciparum malaria were allocated to receive oral dihydroartemisinin at a single dose of 120 mg on day 1, followed by mefloquine, 750 mg and 500 mg on days 2 and 3, respectively.
Follow-up was performed on days 1, 2, 3, 4, 7, 14, 21, and 28.
RESULTS:All patients had a rapid initial response to treatment. The parasite clearance time (PCT) after treatment was 30.7 +/- 3.6 hours. The fever subsidence time (FST) after treatment was 21.2 +/- 2.8 hours. Two patients had a recrudescence 21 and 25 days respectively after the disappearance of parasitemia, hence the recrudescence rate was 3.7% and the cure rate was 96.3%. No serious adverse effects were observed, only mild and transient nausea, vomiting and loss of appetite.
CONCLUSION:A combination of dihydroartemisinin and mefloquine is effective in the treatment of acute uncomplicated falciparum malaria.
9) full free pdf
nice chart showing plama level of mefloquin after dosage over time
Southeast Asian J Trop Med Public Health. 2007 Mar;38(2):205-12.
Pharmacokinetics of mefloquine with dihydroartemisinin as 2-day regimens in patients with uncomplicated falciparum malaria.
Thuy le TD1, Hung le N, Hung NC, Na-Bangchang K.
The objective of this study was to investigate the pharmacokinetics of mefloquine (MQ) when given as 750 mg at two different times in combination regimens with dihydroartemisinin (DHA) in patients with acute uncomplicated falciparum malaria. A total of 12 Vietnamese patients (6 in each group) were randomized to receive two MQ-DHA regimens as follows:
regimen-A: an initial oral dose of 300 mg DHA, followed by 750 mg MQ and 300 DHA 6 and 24 hours later;
regimen-B: an initial dose of 300 mg DHA, followed by 300 mg DHA and 750 mg MQ at 24 hours. Both combination regimens were well tolerated. All patients responded well to treatment with no recrudescence during a 42 day follow-up period. The pharmacokinetics of MQ following both regimens were similar but pooled data from both groups suggest that the kinetics of MQ was different from that observed in Vietnamese healthy subjects reported in a previous study.
The median (95% CI) time period for maintenance of whole blood MQ concentrations above 500 ng/ml was 16 (0-24) days. It was concluded that since no pharmacokinetic drug interaction was observed, MQ dose given 24 hours after an initial dose of DHA is a preferable combination treatment regimen with regard to patient compliance.
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2009 full free pdf
10) Gutman, Julie, et al. “Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria.” Malar J 8 (2009): 58.
Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria
Julie Gutman,corresponding author1,2 Michael Green,1 Salomon Durand,4 Ofelia Villalva Rojas,4 Babita Ganguly,1 Wilmer Marquiño Quezada,4 Gregory C Utz,3 Laurence Slutsker,1 Trenton K Ruebush, II,1 and David J Bacon3
All drugs were administered as whole tablets with water at a dose of 25 mg/kg (15 mg/kg on the first day and 10 mg/kg on the second day) along with artesunate at a dose of 4 mg/kg/day for three days under supervision by clinical staff.
All three MQ formulations had a terminal half-life (t1/2) of 14.5–15 days and time to maximum plasma concentration (tmax) of 45–52 hours.
The maximal concentration (Cmax) and interquartile range was
2,820 ng/ml (2,614–3,108) for Lariam, 2,500 ng/ml (2,363–2,713) for Mephaquin, and 2,750 ng/ml (2,550–3,000) for Mefloquina AC Farma.
11) ALIN, M. HASSAN, et al. “Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria.” British Journal of Clinical Pharmacology 41.6 (1996): 587.
Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either
artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days)
or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route.
13) Croft, Ashley M. “Malaria: prevention in travellers.” BMJ clinical evidence 2010 (2010).
14) Juckett, Gregory. “Malaria prevention in travelers.” American family physician 59.9 (1999): 2523-30.
Mefloquin Gastric Cancer 2016
15) Biochem Biophys Res Commun. 2016 Feb 5;470(2):350-5.
Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway. Liu Y1, Chen S2, Xue R3, Zhao J4, Di M5.
Deregulation of PI3K/Akt/mTOR pathway has been recently identified to play a crucial role in the progress of human gastric cancer. In this study, we show that mefloquine, a FDA-approved anti-malarial drug, effectively targets human gastric cancer cells. Mefloquine potently inhibits proliferation and induces apoptosis of a panel of human gastric cancer cell lines, with EC50 ~0.5-0.7 µM. In two independent gastric cancer xenograft mouse models, mefloquine significantly inhibits growth of both tumors. The combination of mefloquine with paclitaxel enhances the activity of either drug alone in in vitro and in vivo. In addition, mefloquine potently decreased phosphorylation of PI3K, Akt, mTOR and rS6. Overexpression of constitutively active Akt significantly restored mefloquine-mediated inhibition of mTOR phosphorylation and growth, and induction of apoptosis, suggesting that mefloquine acts on gastric cancer cells via suppressing PI3K/Akt/mTOR pathway. We further show that mefloquine-mediated inhibition of Akt/mTOR singaling is phosphatase-dependent as pretreatment with calyculin A does-dependently reversed mefloquine-mediated inhibition of Akt/mTOR phosphorylation. Since mefloquine is already available for clinic use, these results suggest that it is a useful addition to the treatment armamentarium for gastric cancer.
Breast Cancer cell line – mefloquin
16) Sharma, Natasha, et al. “Inhibition of autophagy and induction of breast cancer cell death by mefloquine, an antimalarial agent.” Cancer Letters 326.2 (2012): 143-154.
Autophagy has been recognized as a potential target for cancer therapy. The antimalarial drug chloroquine (CQ) is able to inhibit autophagy and therefore is being considered for cancer therapeutics. However, the relatively low potency of CQ prompted us to investigate whether other lysosomotropic agents might be more effective, and thus potentially more useful. We therefore compared the cytotoxic efficacy of CQ, the quinoline analog mefloquine (MQ), and the fluoroquinolones ciprofloxacin and levofloxacin in several human breast cancer cell lines. We found that MQ was the most potent compound tested; it inhibited autophagy, triggered endoplasmic reticulum stress, and caused cell death in T47D and MDA-MB-231. Altogether, our study demonstrates superior potency of MQ over CQ and the ability of MQ to produce anticancer effects in both hormone receptor positive and negative breast cancer cell lines, suggesting its usefulness in treating various types of cancer.
Prostate Cancer – mefloquin
17) full free
Yan, Kun-Huang, et al. “Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo.” Oncology letters 5.5 (2013): 1567-1571.
Krudsood et al(7) reported that MQ caused a blood plasma concentration of 5,796 ng/ml (15.35 µM) in a clinical study on Plasmodium falciparum-infected adults.
Dow et al(8) noted that higher blood levels of MQ were reached under therapeutic regimens (2.1–23 µM) rather than in prophylaxis (3.8 mM) (9,10).
1992 Mefloquin in Lysosomes
Abstract: Mefloquine was administered in a single dose (1–30 mg/100 g) to rats in order to study its subcellular distribution and effects on rat liver lysosomal structure and function. Subcellular fractionation showed a significant enrichment of mefloquine in lysosomes. Even repeated administration of mefloquine did not affect the levels of cytochrome-P-450 or its reductase, indicating, although not proving, that it is not metabolized by this mono-oxygenase system. Mefloquine caused an expansion of the lysosomal apparatus, earliest seen by 24 h and lasting for some 7 days. Initially, cytoplasmic constituents were seen inside the lysosomes. Later, the lysosomes harboured myelin-like figures (multilamellar bodies) disappearing after 7–10 days. The proteolytic and lipolytic capacity was assessed in isolated lysosomes. Mefloquine caused increased protein degradation but decreased breakdown of lipids. Concomitantly, all five major phospholipids (phosphatidyl-choline, -ethanolamine, -inositol, -serine and sphingomyelin) increased in the lysosomes. It is concluded that:
(1) mefloquine is a lysosomotropic drug that accumulates in lysosomes;
(2) mefloquine impairs lipid degradation with ensuing accumulation of lipids in lysosomes; and
(3) lysosomal trapping explains the high volume distribution of mefloquine.
2014 AML STEM CELLS – Mefloquine Fenretinide Vit A Parthenolide full free
19) Zhang, Hui, Hai Fang, and Kankan Wang. “Reactive oxygen species in eradicating acute myeloid leukemic stem cells.” Stem Cell Investigation 1.6 (2014).
Most recently, Sukhai et al. an antimalarial agent called ‘mefloquine’ for its capacity in targeting newly AML-stem cells (32). This study reveals a previously unappreciated mechanism for AML-stem cells killing. Mefloquine is able to disrupt lysosome integrity releasing hydrolases, lipases, proteases and cathepsins. This disruption subsequently increases the levels of ROS and triggers death of AML cells and stem cells in a caspase-independent manner. Mefloquine is widely used for malaria therapy and chemoprevention, its clinical safety has been already characterized in large cohorts of clinical trials. Its AML targeting efficacy will be next for evaluation.
Fenretinide Vit A
Fenretinide is a well-tolerated vitamin A derivative that lacks a carboxyl functional group likely necessary for retinoid receptor activity. Our most recent study has shown that it is capable of eradicating LSCs but not normal hematopoietic progenitor/stem cells, at physiologically achievable concentrations (5 µM). Fenretinide-induced AML-stem cells death is associated with the rapid generation of ROS, induction of genes responsible for stress responses and apoptosis, and repression of genes involved in NF-?B and Wnt signaling (34). Though there is no clinical trial ongoing for AML treatment, fenretinide has been verified its safety and low toxicity in phase II-III clinical trials for solid tumors such as small cell lung cancer, breast cancer and prostate cancer (82-85). Moreover, via bioinformatics analysis we have observed that fenretinide down-regulated genes are significantly correlated with genes related to a poor prognosis/relpase of AML. We anticipate that fenretinide is a potent AML-stem cells targeting candidate in the treatment of AML.
Parthenolide (PTL) and dimethylaminoparthenolide (DMAPT)
PTL is a naturally occurring small molecule that has been evaluated for in vitro and in vivo efficacy on AML progenitor and stem cell populations. However, low soluble feature makes its pharmacologic potential less attractive. Instead, DMAPT, a dimethylamino analog of PTL, demonstrates 1,000-fold greater solubility in water than PTL. Both of DMAPT and PTL show similar efficacy on AML-stem cells through the similar molecular mechanisms, including the elevated ROS, p53 activation and NF-KB inactivation. Canine xenograft experiments, an equivalent to phase I clinical trials, show that the pharmacologic properties of DMAPT are superior to PTL (26,27). These data call for further studies on clinical safety and translational efficacy of DMAPT/PTL in AML treatment.
Cancer Stem cells – Mefloquin and thioridazine (Mellaril) AML cell line
20) Sachlos, Eleftherios, et al. “Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.” Cell 149.6 (2012): 1284-1297.
compounds that induce differentiation can be identified based on the reduction of GFP intensity in neoplastic hPSC reporter lines and could be exploited for chemical screening.
This hPSC-screening platform was validated by using an assembled library of 51 defined compounds with established stem cell and anticancer activity
Compounds that can induce differentiation of neoplastic hPSCs are potential anticancer candidates.
the ideal compound should only differentiate neoplastic hPSCs while not affecting normal hPSCs.
we extended our tests to chemical libraries composed of 590 well-established annotated compounds from the NIH Clinical Collection and Canadian Compound Collection
11 compounds were identified to induce differentiation as indicated by a reduction in both GFP percentage residual activity (%RA) and Hoechst %RA (Figures 2B and 2C). Four of these compounds (indatraline, thioridazine, azathioprine, and mefloquine) were identified as candidate compounds based on clustering and levels of Hoechst %RA in excess of 30%.
Only thioridazine and mefloquine were found to possess EC50 values lower than the 10 µM target threshold
At both 1 µM and 10 µM salinomycin reduced AML-blast CFU potential (Figure 3J) but also reduced HSPC CFU potential over all doses tested (Figure 3I), indicative of nonspecific toxicity in the hematopoietic system. In contrast, mefloquine and thioridazine reduced AML-blast CFU formation (Figure 3J) while having little effect on HSPC CFU potential (Figure 3I) and multilineage composition (Figure S3D), indicating that mefloquine and thioridazine do not alter normal hematopoiesis.
Mefloquin Patent 2002 – University of California
21) Treatment of cancer with mefloquine, its purified enantiomers, and mefloquine analogs
US 20030216426 A1
Regents Of The University Of California
Cancers, particularly solid tumors (e.g., breast, colon and ovarian cancers) and cancers of the hematologic system, e.g., hemopoietic cancers such as leukemias, lymphomas or myelomas, are treated by administration of a therapeutically effective amount of a compound having the formula (I):
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Mefloquine – anti-malarial drug effective for AML Progenitors (stem Cells)
22) Sukhai, Mahadeo A., et al. “Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” The Journal of clinical investigation 123.1 (2013): 315-328.
To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice.
23) Mefloquine psychosis violence retinoid toxicity Mawson Anthony 2013
Mawson, Anthony. “Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis.” Medical Science Monitor Basic Research 19 (2013): 579-583.
The use of mefloquine in the prevention and treatment of malaria has been increasingly linked to a broad range of neuropsychiatric effects, including depression, psychosis, and violence.
The symptoms of mefloquine toxicity may result from the spillage of stored retinoids from the damaged liver into the circulation and their transport to the gut and brain, causing the adverse neuropsychiatric and gastrointestinal symptoms as a function of an endogenous form of hypervitaminosis A.
Lysosomes in Cancer
24) Appelqvist, Hanna, et al. “The lysosome: from waste bag to potential therapeutic target.” Journal of molecular cell biology 5.4 (2013): 214-226.
Rapidly dividing cells, such as cancer cells, are highly dependent on effective lysosomal function, and dramatic changes in lysosomal volume, composition, and subcellular localization occur during transformation and cancer progression (Kirkegaard and Jäättelä, 2009; Kallunki et al., 2013). In a wide variety of cancers, cathepsins are highly upregulated and mislocalization during neoplastic progression results in secretion of both active and inactive forms of cathepsins.
Cancer cells often display p53 mutations that are believed to contribute to treatment resistance. Interestingly, a small molecule screen revealed that a majority of compounds capable of inducing cell death independent of p53 did so by triggering LMP and cathepsin-mediated killing of tumor cells (Erdal et al., 2005).
This finding suggests that cancer cells insensitive to traditional therapies may be killed by agents that trigger the lysosomal cell death pathway. Indeed, oncogene-driven transformation is associated with increased cathepsin expression and higher sensitivity toward lysosome-mediated cell death
full free pdf full free html
25) Kirkegaard, Thomas, and Marja Jäättelä. “Lysosomal involvement in cell death and cancer.” Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1793.4 (2009): 746-754.
26) Cancer Res. 2005 Apr 15;65(8):2993-5. Lysosomes as targets for cancer therapy. Fehrenbacher N1, Jäättelä M.
Autophagy – Chloroquine
full free pdf
Guan, Jun-Lin, et al. “Autophagy in stem cells.” Autophagy 9.6 (2013): 1-20.
Treatment with chloroquine is sufficient to completely
suppress the generation of DCIS spheroids/3D structures
and ex vivo invasion of autologous breast stroma, induce apoptosis
and eliminate cytogenetically abnormal spheroid-forming
cells in the organ culture, and abrogate xenograft tumor formation
via reduced expression of autophagy-associated proteins,144
confirming that autophagy is necessary for the survival of CSClike
precursor cells pre-existing in pre-malignant lesions.
autophagy is necessarily required for the
maintenance and expansion of breast CSC populations.
Loss of autophagy, therefore, leads to
deficient glycolysis and appears to intrinsically contribute to the
decreased proliferation of mammary tumor cells
sulforaphane combined with chloroquin
Vyas, Avani R., et al. “Augmentation of D, L-sulforaphane-mediated prostate cancer chemoprevention by pharmacologic inhibition of autophagy using chloroquine in a transgenic mouse model.” Cancer Research 73.8 Supplement (2013): 3695-3695.
Chaanine, Antoine H., et al. “High‐dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy.” Physiological reports 3.7 (2015): e12413.
Rosenthal, A. R., et al. “Chloroquine retinopathy in the rhesus monkey.” Investigative ophthalmology & visual science 17.12 (1978): 1158-1175.
MACDONALD, RONALD D., and Andrew G. Engel. “Experimental chloroquine myopathy.” Journal of Neuropathology & Experimental Neurology 29.3 (1970): 479-499.
Roos, J. M., M. C. Aubry, and W. D. Edwards. “Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease.” Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 11.5 (2002): 277.
The antimalarial drug chloroquine and its derivative
hydroxychloroquine have been used to treat autoimmune
diseases such as rheumatoid arthritis and systemic lupus
erythematosus for several decades . Their toxic
effects include retinopathy, myopathy and neuropathy
Hydroxychloroquine was used for to treat rheumatoid
arthritis in two patients and chloroquine was given to the
one with systemic lupus erythematosus. The total dosage
was 2 g daily for 2 years in one patient and was unknown in
the other two patients.
pancreatic CA chloroquin inhibits autophagy
Frieboes, Hermann B., et al. “Chloroquine-Mediated Cell Death in Metastatic Pancreatic Adenocarcinoma Through Inhibition of Autophagy.” JOP. Journal of the Pancreas 15.2 (2014): 189-197.
The anti-malarial drug chloroquine disrupts
autophagy by inhibiting the acidification of the
lysosomes that fuse with the autophagosomes, thus
preventing the degradation of metabolic stress
products and thereby inducing cellular apoptosis
[21, 22, 23].
Cancer stem cells – chloroquin
Choi, Dong Soon, et al. “Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.” Stem cells 32.9 (2014): 2309-2323.
Interestingly, CQ has been identified as a cancer stem cell targeting agent for other aggressive cancers including breast cancer11, 12, glioblastoma multiforme13, and chronic myeloid leukemia14. However, the mechanism by which CQ affects the CD44+/CD24-/low CSCs remains unclear.
Eur J Pharmacol. 2016 Jan 15;771:139-44. doi: 10.1016/j.ejphar.2015.12.017. Epub 2015 Dec 11.
Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies.
Chloroquine, a drug used for over 80 years to treat and prevent malaria and, more recently, to treat autoimmune diseases, is very safe but has a plethora of dose-dependent effects. By increasing pH in acidic compartments it inhibits for example lysosomal enzymes. In the context of cancer, Chloroquine was found to have direct effects on different types of malignancies that could potentiate chemotherapies. For example, the anti-malaria drug may inhibit both the multidrug-resistance pump and autophagy (mechanisms that tumor cells may use to resist chemotherapies), intercalate in DNA and enhance the penetration of chemotherapeutic drugs in cells or solid cancer tissues. However, these activities were mostly demonstrated at high doses of Chloroquine (higher than 10mg/kg or 10mg/l i.e. ca. 31µM). Nevertheless, it was reported that daily uptake of clinically acceptable doses (less than 10mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the survival of glioblastoma patients (Sotelo et al., 2006; Briceno et al., 2007). However, the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined. The present article reviews the several known direct and indirect effects of different doses of Chloroquine on cancer and how those effects may indicate that a fine tuning of the dose/schedule of Chloroquine administration versus chemotherapy may be critical to obtain an adjuvant effect of Chloroquine in anti-cancer treatments. We anticipate that the appropriate (time and dose) addition of Chloroquine to the standard of care may greatly and safely potentiate current anti-cancer treatments.
Melanoma-chloroquin – inhibits autophagy
Egger, Michael E., et al. “Inhibition of autophagy with chloroquine is effective in melanoma.” journal of surgical research 184.1 (2013): 274-281.
Cancer cells adapt to the stress resulting from accelerated cell growth and a lack of nutrients by activation of the autophagy pathway. Two proteins that allow cell growth in the face of metabolic stress and hypoxia are hypoxia-inducible factor-1a (HIF-1a) and heat shock protein 90 (Hsp 90). We hypothesize that chloroquine (CQ), an antimalarial drug that inhibits autophagosome function, in combination with either echinomycin, a HIF-1a inhibitor, or 17-dimethylaminoethylamino-17-dimethoxygeldanamycin (17-DMAG), an Hsp 90 inhibitor, will result in cytotoxicity in melanoma.
MATERIALS AND METHODS:
Multiple human melanoma cell lines (BRAF wild-type and mutant) were tested in vitro with CQ in combination with echinomycin or 17-DMAG. These treatments were performed in hypoxic (5% O2) and normoxic (18% O2) conditions. Mechanism of action was determined through Western blot of autophagy-associated proteins HIF-1a and Hsp 90.
Chloroquine, echinomycin, and 17-DMAG each induced cytotoxicity in multiple human melanoma cell lines, in both normoxia and hypoxia. Chloroquine combined with echinomycin achieved synergistic cytotoxicity under hypoxic conditions in multiple melanoma cell lines (BRAF wild-type and mutant). Western blot analysis indicated that echinomycin reduced HIF-1a levels, both alone and in combination with CQ. Changes in LC3 flux indicated inhibition of autophagy at the level of the autophagosome by CQ therapy.
Targeting autophagy with the antimalarial drug CQ may be an effective cancer therapy in melanoma. Sensitivity to chloroquine is independent of BRAF mutational status. Combining CQ with the HIF-1a inhibitor echinomycin improves cytotoxicity in hypoxic conditions.
Eur J Pharmacol. 2009 Dec 25;625(1-3):220-33. doi: 10.1016/j.ejphar.2009.06.063. Epub 2009 Oct 15.
Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.
Solomon VR1, Lee H.
Chloroquine (CQ), N’-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as “Resochin” by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans. CQ was “re-discovered” during World War II in the United States in the course of anti-malarial drug development. The US government-sponsored clinical trials during this period showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. Consequently, CQ was introduced into clinical practice in 1947 for the prophylaxis treatment of malaria (Plasmodium vivax, ovale and malariae). CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus and amoebic hepatitis. More recently, CQ has been studied for its potential as an enhancing agent in cancer therapies. Accumulating lines of evidence now suggest that CQ can effectively sensitize cell-killing effects by ionizing radiation and chemotherapeutic agents in a cancer-specific manner. The lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed, CQ may be one of the most effective and safe sensitizers for cancer therapies. Taken together, it appears that the efficacy of conventional cancer therapies can be dramatically enhanced if used in combination with CQ and its analogs.
full free pdf
Ann Intern Med. 2006 Mar 7;144(5):337-43.
Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Sotelo J1, Briceño E, López-González MA.
Malignant cell clones resistant to chemotherapy and radiotherapy frequently lead to treatment failure in patients with glioblastoma multiforme. Preliminary studies suggest that adding chloroquine to conventional therapy may improve treatment outcomes.
To examine the effect of adding chloroquine to conventional therapy for glioblastoma multiforme.
DESIGN: Randomized, double-blind, placebo-controlled trial.
SETTING: National Institute of Neurology and Neurosurgery of Mexico.
PATIENTS: 30 patients with surgically confirmed glioblastoma confined to 1 cerebral hemisphere, with a Karnofsky performance score greater than 70, no comorbid disease, and age younger than 60 years.
INTERVENTIONS: Oral chloroquine at 150 mg/d for 12 months beginning on postoperative day 5 or placebo. All pat ients received conventional chemotherapy and radiotherapy.
MEASUREMENTS: Primary outcome was survival after surgery; surviving patients were followed up to October 2005. Periodic evaluation using the Karnofsky scale and imaging studies, as well as hematologic tests and ophthalmologic examinations, was done in all patients.
RESULTS: Median survival after surgery was 24 months for chloroquine-treated patients and 11 months for controls. At the end of the observation period, 6 patients treated with chloroquine had survived 59, 45, 30, 27, 27, and 20 months, respectively; 3 patients from the control group had survived 32, 25, and 22 months, respectively. Although not statistically significantly different, the rate of death with time was approximately half as large in patients receiving chloroquine as in patients receiving placebo (hazard ratio, 0.52 [95% CI, 0.21 to 1.26]; P = 0.139).
LIMITATIONS: The observed advantage of chloroquine may be due to chance; differences in pretreatment characteristics and conventional treatment regimens could not be adjusted for because of the small sample size.
Chloroquine may improve mid-term survival when given in addition to conventional therapy for glioblastoma multiforme. These results suggest that larger, more definitive studies of chloroquine as adjuvant therapy for glioblastoma are warranted.
Kimura, Tomonori, et al. “Chloroquine in cancer therapy: a double-edged sword of autophagy.” Cancer research 73.1 (2013): 3-7.
The dosage of chloroquine usually ranges between 100 and 500 mg/day. Side effects are minimal at low doses, while many more toxic effects occur at higher doses, such as visual disturbances, gastrointestinal upset, electrocardiographic changes, headache, and pruritus.
Salinomycin – antibiotic
Naujokat, Cord, and Roman Steinhart. “Salinomycin as a drug for targeting human cancer stem cells.” BioMed Research International 2012 (2012).
Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC) drug transporters, activation of the Wnt/ß-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/ß-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.
Solitro, A. R., and J. P. MacKeigan. “Leaving the lysosome behind: novel developments in autophagy inhibition.” Future medicinal chemistry 8.1 (2016): 73.
cancer cells upregulate and demonstrate an increased dependence upon this intracellular recycling process (autophagy). Particularly in malignancies that currently lack targeted therapeutic options, autophagy inhibitors are the next hopeful prospects for the treatment of this disease. In this review, we discuss the rapid evolution of autophagy inhibitors from early lysosomotropic agents to next-generation lysosome-targeted drugs and beyond.
chloroquine, now considered the founder of lysosome-targeted autophagy inhibitors
The primary discovery at this point was chloroquine’s mechanism of action: the compound readily crossed the lysosomal membrane and became protonated, causing its accumulation within the lysosome. Chloroquine’s continued sequestration caused a significant increase in the lysosome’s pH, inactivating acid hydrolase enzymes and rendering the lysosome nonfunctional
In 1959, a hydroxylated version of chloroquine was synthesized to reduce the retinopathy, indigestion and tinnitus effects of treatment, while maintaining the benefits of oral bioavailability and fast gastrointestinal absorption
Like chloroquine, hydroxychloroquine was primarily investigated in malaria and inflammatory disease research until the 2000s. At the turn of the century, the autophagy field was primed to investigate the next lysosomotropic agent as a potential autophagy inhibitor. In vitro studies were intriguing, showing apoptosis after hydroxychloroquine treatment across numerous cancer cell lines as well as the stalling of growth and proliferation in breast cancer cells [27–29]. These initial studies paved the way for further investigation of hydroxychloroquine in the context of cancer.
Lymphoma mouse models have also been informative, as chloroquine derivatives have been shown to synergize with chemotherapy through autophagy inhibition to improve disease outcomes [46,47].
Dow, G., et al. “Mefloquine induces dose-related neurological effects in a rat model.” Antimicrobial agents and chemotherapy 50.3 (2006): 1045-1053.
Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats’ normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.
Malaria, caused by parasitic protozoa of the genus Plasmodium, is endemic in tropical regions inhabited by approximately 50% of the global population (46). There are estimated to be 350 to 500 million clinical cases and at least a million deaths annually (46). Malaria is also a problem for travelers. In the United States alone, there were 1,337 cases of imported malaria and eight deaths in 2002 (37). In the United States, there are five approved drugs available for malaria chemoprophylaxis. These are mefloquine, doxycycline, atovaquone-proguanil (Malarone), chloroquine, and hydroxychloroquine sulfate (4). Of these, only mefloquine, chloroquine, and hydroxychloroquine sulfate have sufficiently long half-lives to permit weekly dosing (4). Weekly dosing enhances compliance with prophylactic dosing regimens. However, resistance of malaria parasites to chloroquine and hydroxychloroquine sulfate has become extremely widespread (46). Consequently, mefloquine, doxycycline, and atovaquone-proguanil are most commonly used for malaria prophylaxis, although atovaquone-proguanil is most often prescribed for shorter excursions. When given for malaria prophylaxis, mefloquine is given as a 250-mg tablet once weekly (4).
Outside the United States, mefloquine is most commonly administered in combination with artesunate for treatment of malaria (45). Unfortunately, mefloquine has also been associated with neurological sequelae, including anxiety, panic attacks, suicidal ideation, nightmares, sleep disturbances, dizziness, tremor, headache, mood changes, and fatigue (1, 31). These effects generally occur more frequently at the treatment dose, even in the absence of malaria, than at the prophylaxis dose (31, 33).
Mefloquine induced delays in beam traverse time that appeared to be correlated with dose and plasma concentration. Impaired motor performance of this nature can occur as a result of anatomical changes, including damage to the vestibular apparatus and/or loss of vestibular or proprioceptive function due to degeneration of the relevant brain stem nuclei (7). For example, ataxia has been associated with the pathological effect of oil-soluble artemisinin antimalarials on vestibular brain stem nuclei (14, 15). The brain stem structure that we observed to be primarily targeted by mefloquine was the n. gracilis. The n. gracilis is a component of the dorsal column system which transfers proprioceptive signals
Mefloquine remains a valuable drug for those patients who do not experience adverse effects. However, the continued use of mefloquine will remain controversial given its association with neurological effects in some individuals. Here we have demonstrated that mefloquine induces dose- and concentration-related neurological effects in rats that may have clinical relevance and could result in permanent damage to the central nervous system.
Sharmeen S, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603.
Xiang, Wei, et al. “Mefloquine Effectively Targets Blast Phase Chronic Myeloid Leukemia through Inducing Oxidative Stress and Lysosomal Disruption.” (2016): 5426-5426.
Li, Hui, et al. “Therapeutic effects of antibiotic drug mefloquine against cervical cancer through impairing mitochondrial function and inhibiting mTOR pathway.” Canadian journal of physiology and pharmacology 999 (2016): 1-8.
Carson, Dennis, Lorenzo Leoni, and Howard Cottam. “Treatment of cancer with mefloquine, its purified enantiomers, and mefloquine analogs.” U.S. Patent Application No. 10/509,693.Roche under the trademark Lariam®.
Sirima, Sodiomon B., et al. “Comparison of artesunate–mefloquine and artemether–lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial.” The Lancet Infectious Diseases 16.10 (2016): 1123-1133.
Lee, Sue J., et al. “Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: A pooled analysis of 19, 850 individual patients.” PloS one 12.2 (2017): e0168780.
Adverse CNS Effects Artequin-Mefloquin
Ekanem, Theresa, et al. “Combination therapy antimalarial drugs mefloquine and artequin induce reactive astrocyte formation on the hippocampus of rats.” BMC Proceedings. Vol. 2. No. S1. BioMed Central, 2008.
Link to this article: Artemisinin Mefloquine Combination for Leukemia
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