Ivermectin Antiparasitic Anticancer Wonder Drug

Ivermectin Antiparasitic Anticancer Wonder DrugIvermectin Antiparasitic Anticancer

Wonder Drug

by Jeffrey Dach MD

The 2015 Nobel Prize in Medicine went for discovery of Ivermectin, an “astonishingly safe” FDA approved anti-helminthic drug.

200 million people take the drug globally for prevention or treatment of parasitic disease.

Dr Sharmeen at the University of Toronto screened a library of 100 drugs for activity against a leukemic cell line, and reported Ivermectin as most promising, inducing leukemic cell death at low micromolar concentrations, while sparing normal cells.  Ivermectin was also effective against leukemia mouse xenografts.  Ivermectin was patented in 2012 for treating hematological malignancy.  Dr Hashimoto reported in 2009, Ivermectin effective against ovarian cancer cell lines (14.)   

Ivermectin Antiparasitic Anticancer Wonder Drug Left Image Ivermectin Chemical Structure courtesy of Stanford.EDU.

Inhibits WNT Pathway

Dr Alice Melotti studied Ivermectin as an inhibitor of the WNT‐TCF pathway in cancer. Her report was published in 2014 EMBO molecular medicine. Dr Melotti used a transcriptional reporter assay for TCF activity driven by Beta-CATENIN to test a collection of 1,040 drugs and small molecules. Only one agent, Ivermectin, perfectly tracked the gene expression profile induced by blocking the TCF gene, and therefore  inhibits the WNT pathway. This has profound significance for anti-cancer stem cell therapy, because blocking the WNT pathway is the key to killing cancer stem cells. (15-16)  Blocking the WNT pathway in a breast cancer model killed cancer stem cells.(18)  Similarly, blocking the WNT pathway in Mantle cell lymphoma preferentially killed the cancer stem cells.(16)

Other useful inhibitors of the WNT pathway which target cancer stem cells include dietary agents curcumin and the small molecule PKF118-310, a fungal product. (17) In addition to curcumin, other natural, dietary WNT- Inhibitors include sulforaphane, ECGC, resveratrol, retinoids and curcumin. (19)  

Ivermectin Effective Against Triple Negative Breast Cancer Cells via modulation of P2X4/P2X7-gated Pannexin-1 channels

Dr Dragonov reported in Nov 2015, Scientific Reports on the mechanism of cancer cell killing by Ivermectin. (9)  He notes that tumors have upregulated P2X7 receptors, which are involved with regulation of high ATP concentrations in the tumor micro-environment.  The high ATP  promotes tumor progression, and if the channels are sensitized by Ivermectin, cause cancer cell death. Dr Dragonov found that:

“Ivermectin kills mouse and human triple-negative breast cancer (TNBC) cells through augmented P2X7-dependent purinergic signaling associated with caspase-1 and caspase-3 activation.” (note caspase activation means apoptotic programmed cell death)(9)

In addition, Dr Dragonov hypothesized that Ivermectin kills cancer cells  by enhancing receptor P2X7 sensitivity to extracellular ATP. In doing so, Ivermectin induces both an apoptotic and a non-apoptotic, inflammatory type of cell death.  The inflammatory cell death stimulates the immune system, a beneficial effect, so that the patients own immune system will kill new cancer cells in the future.

Mouse and Human Triple Negative Breast Cancer Cells

Dr Dragonov reports that Mouse and human TNBC cells are sensitive to Ivermectin with IC50 values as low as 2 μM with 24 hr exposure time.(9)

Synergy with other Chemo Agents

Dr Dragonov reports Ivermectin cancer cell killing effects synergistic with chemotherapeutic agents  such as doxorubicin (Adriamycin)  and paclitaxel (Taxol) which induce ROS (reactive oxygen species).(9)  One might speculate Ivermectin would synergize with Artemisinin compounds which induce ferroptosis, a form of oxidative cell death.  One might also speculate on Ivermectin synergy with alpha lipoic acid (ALA) which increases electron flux through the mitochondrial electron transport chain.

Ivermectin Induces Immunogenic Cell Death

Dr Dragonov reports that beneficial long-term clinical response after chemotherapy involves stimulation of a robust anti-cancer immune response, also called induction of “immunogenic cell death (ICD)”.   Ivermectin is one agent which induces ICD immunogenic cancer cell death, and therefore may induce long term or permanent remission after treatment.(9)

Ivermectin Approved for Pediatric Scabies

scabies Ivermectin NEJM

Left Image From NEJM showing  life cycle of scabies parasite involving skin.  Treatment with Ivermectin.

Ivermectin is a highly effective anti-parasitic drug,  FDA approved for pediatric scabies (see left image) .  Ivermectin has extensive veterinary use as an anti-parasitic drug for pets, horses and farm animals (See HeartGard header image)

Niclosamide (Niclide) Anti-Parasitic Blocks WNT pathway

Using a high-throughput screening method, Dr Chen identified niclosamide as a potent inhibitor of the Wnt/β-catenin pathway, also down regulating the Nuclear Factor Kappa Beta ( NF-κB), and potent anti-cancer stem cell agent .(20-21)   Niclosamide was found effective against ovarian cancer cell lines, as monotherapy.  Niclosamide was also effective in combination with  conventional chemotherapy, enhancing the ovarian cancer cell killing effect.(22-23)  Niclosamide was an effective anticancer agent when studied in breast cancer, leukemia and glioblastoma  cell models. (25-31)

Using high-throughput drug screening of more than 1,200 clinically approved drugs, the antihelmintic niclosamide was identified as the most promising candidate, selectively targeting Ovarian cancer stem cells, in vitro and in vivo.(22)

Typical Niclosamide treatment dosage for dwarf tapeworm: Adults—2 grams a day for seven days. Treatment may be repeated in seven to fourteen days if needed.(24)  The 2005 WHO safety report on niclosamide found no toxicities, and it was deemed generally safe for use in pregnant women and children.(32)

Unexpected Clinical Benefits of Anti-Parasitic Drugs

The anti-cancer effects of Ivermectin and Niclosamide were unexpected clinical benefits.   Will Ivermectin and Niclosamide revolutionize cancer  treatment, making chemotherapy and stem cell transplant obsolete relics for the medical museum?

Army MEdical Museum Jeffrey DaCh MDLeft Image Medical Museum courtesy of Army.

Articles with Related Interest:

Cancer as a Parasitic Disease

Cancer Stem Cells Targeted NonToxic Therapies

Best Answer for Cancer San Diego

Artemisinin Our Best Anti-Cancer Weapon

Alpha Lipoic Acid AntiCancer Agent

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663

Links and References:

Ivermectin inhibits WNT-TCF pathway

Ivermectin Antiparasitic Anticancer Wonder Drug1) Melotti, Alice, et al. “The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.

Ivermectin used as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

We find that macrocyclic lactones of the Avermectin family have specific anti-WNT-TCF response activity in human cancer cells and that the clinically approved compound Ivermectin (EMEA- and FDA-approved) is a specific WNT-TCF response blocker at low micromolar concentrations.

cancer stem cells
Pre-treatment with Ivermectin and Selamectin inhibits colon cancer stem cell self-renewal in clonogenic spheroid assays.  These results suggest an action on both the bulk of the tumor and its cancer stem cells.

Moreover, they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population.

Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal ß-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases.In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

Wingless/integrase-1 (WNT) signaling.  The name Wnt was a portmanteau of int and Wg and stands for “Wingless-related integration site.  Other cancers also show an active canonical WNT pathway; these include carcinomas of the lung, stomach, cervix, endometrium, and lung as well as melanomas and gliomas

We have used a transcriptional reporter assay for TCF activity driven by APC-insensitive N’?ß-CATENIN, to test a collection of clinical-trial tested small molecules (Microsource 1040 library).  Of the 4 putative antagonists, only one, 4B5 (Avermectin B1), perfectly tracked the gene expression profile induced by dnTCF4.  anti-helmintic agent Avermectin B1, which belongs to the 16-membered Avermectin macrocyclic lactone family derived fromStreptomyces avermitilis.

The drug is used in humans against insect and worm infections, including river blindness caused by Onchocerca volvulus.  The dominant negative forms of TCF (dn-TCF) that can be used to block Wnt signaling in the nucleus. as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

We find that macrocyclic lactones of the Avermectin family have specific anti-WNT-TCF response activity in human cancer cells and that the clinically approved compound Ivermectin (EMEA- and FDA-approved) is a specific WNT-TCF response blocker at low micromolar concentrations.

Ivermectin Inhibits cancer stem cells

Pre-treatment with Ivermectin and Selamectin inhibits colon cancer stem cell self-renewal in clonogenic spheroid assays

These results suggest an action on both the bulk of the tumor and its cancer stem cells.

Moreover, they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population.

commercial form from the pharmacy, Stromectol™,

Selamectin, which scored as toxic in the primary screen at 10 µM, was ˜ tenfold more potent than ivermectin.

Here we report that Ivermectin (Campbellet al, 1983), an off-patent drug approved for human use, and related macrocyclic lactones, have WNT-TCF pathway response blocking and anti-cancer activities. Whereas the exact molecular target for Ivermectin and Selamectin that affects WNT-TCF responses remains to be identified, the present findings show that these drugs block WNT-TCF pathway responses, likely acting at the level of ß-CATENIN/TCF function, affecting ß-CATENIN phosphorylation status.

Cell toxicity appears at doses greater (> 10 µM for 12 h or longer or > 5 µM for 48 h or longer for Ivermectin) than those required to block TCF responses and induce apoptosis.

This drug does not cross the blood–brain barrier.

Indications may include treatment for incurable ß-CATENIN/TCF-dependent advanced and metastatic human tumors of the lung, colon, endometrium, and other organs.

Moreover, they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population.

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2) NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011

3) Chhaiya, Sunita B., et al. “IJBCP International Journal of Basic & Clinical Pharmacology.”  International Journal 2.6 (2013): 799. Chhaiya, Sunita. Ivermectin pharmacology and therapeutic applications Sunita Chhaiya 2012

4) The Pharmacokinetics and Interactions of Ivermectin in Humans.  Canga, Aránzazu González, et al.”The pharmacokinetics and interactions of ivermectin in humans—a mini-review.” The AAPS journal 10.1 (2008): 42-46.

Ivermectin is exceptionally potent, with effective dosages
levels that are unusually low. In the treatment of onchocerciasis,
the optimal dose of ivermectin is 150 µg/kg, but the
frequency of administration is still controversial, ranging from
150 µg/kg once to three times yearly. The optimal duration of
treatment has not been established (6).

It is effective in most patients with scabies after a single oral dose of 200 µg/kg, but often the regimen involves two or three repeated doses, separated by interval of 1 or 2 weeks (7).

prolonged prothrombin ratios were observed in 148  subjects given ivermectin orally. Although no patients suffered bleeding complications, factor II and VII levels were reduced in most of them, suggesting interference with vitamin K
metabolism.

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Take Ivermectin with FOod every 4 days.

5) J Clin Pharmacol. 2002 Oct;42(10):1122-33.
Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.  Guzzo CA1, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC.

Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.

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6) Editorial Commentary: Ivermectin as a Complementary Strategy to Kill Mosquitoes and Stop Malaria Transmission? Richard W. Steketee1 and Feiko O. ter Kuile2

Repeated doses of up to 800 µg/kg have been used in the treatment of onchocerciasis [8–10]. Furthermore, earlier dose-escalation studies with ivermectin have shown that doses up to 2000 µg/kg (ie, 5 times the highest US Food and Drug Administration–approved dose) are well tolerated with no indication of central nervous system or general toxicity [11]. Additional dosing during the third day of the ACT treatment (as done in this trial) or at day 7 (and perhaps at day 14)

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Ivermectin safely given incombination with Artemisinin Derivative Artemether

7)  Efficacy and Safety of the Mosquitocidal Drug Ivermectin to Prevent Malaria Transmission After Treatment: A Double-Blind, Randomized, Clinical Trial
André Lin Ouédraogo1,a, Guido J. H. Bastiaens2,a, Alfred B. Tiono1, Wamdaogo M. Guelbéogo1, Kevin C. Kobylinski3,4, Alphonse Ouédraogo1, Aïssata Barry1, Edith C. Bougouma1, Issa Nebie1, Maurice San Ouattara1, Kjerstin H. W. Lanke2, Lawrence Fleckenstein5, Robert W. Sauerwein2, Hannah C. Slater6, Thomas S. Churcher6, Sodiomon B. Sirima1, Chris Drakeley7, and Teun Bousema2,7
Background. Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans.
Methods. In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates.
Results. The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07–1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment.
Conclusions. We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes.

8) Chaccour, Carlos J., et al. “Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination.” Malar J 12.153 (2013): 10-1186.

Recent publications have highlighted the likely benefit of combining ivermectin with drugs such as artemisinin combination therapy (ACT). ACT is
highly effective in most malaria-endemic settings but does not prevent malaria-transmission in the first weeks after treatment [53,54].
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87)  Ivermectin Use in Scabies ROBERT S. FAWCETT, M.D., M.S., York Hospital Family Practice Residency, York, Pennsylvania.  Am Fam Physician. 2003 Sep 15;68(6):1089-1092.

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ivermectin cancer cell death

2015

9)  Draganov, Dobrin, et al. “Modulation of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).

We found that Ivermectin kills mouse and human triple-negative breast cancer (TNBC) cells through augmented P2X7-dependent purinergic signaling associated with caspase-1 and caspase-3 activation.
FIg 7 Model of P2X4/P2X7/Pannexin-1-induced cancer cell death.

Ivermectin induces P2X4/P2X7-dependent activation of Pannexin-1 channels and release of ATP. The release of ATP might be transiently protective, but only in cell types that are highly sensitive to Ivermectin-induces cell swelling when ATP and Ca2+ signaling are essential for control of cell volume. In cancer cells where no cell size changes can be observed (for example human TNBC MDA-MB-231 cells), high concentrations of ATP (1–3?mM) immediately enhance Ivermectin cytotoxicity. Potentiated P2X7 receptor signaling drives a fast progressing necrotic/pyroptotic mechanism driven by NADPH oxidases-generated ROS, cytosolic Ca2+/CaMKII activation, and MPTP, and characterized by caspase-1 cleavage, due to possible NLRP3 inflammasome activation. Necrotic killing is followed by a slower progressing apoptotic cell death program mediated by caspase-3 activation. The failure of the default apoptotic pathway might be attributed to faster activation of caspase-1, inadequate autophagic control of mitochondrial MPTP, collapse of cellular energy metabolism, resulting in rapid progression of necrotic cell death. Damage to mitochondria and ER stress as well as potential depletion of cellular ATP reserves simultaneously promote autophagy that might render even the slower apoptotic pathway immunogenic.
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2004

10) Drinyaev, Victor A., et al. “Antitumor effect of avermectins.” European journal of pharmacology 501.1 (2004): 19-23.

11) Searching for Ivermectin Deficiency Syndrome by Dr Simon Yu author of Accidental Cure.

12) 2012 Patent for Ivermectin as treatment for hematologic malignancy (including mantle cell lymphoma.)  Use of synergistic combinations of an avermectin and an antineoplastic compounds for the treatment of hematological malignancies EP 2498785 A1 (text from WO2011054103A1)

13) Sharmeen, Sumaiya, et al. “The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.” Blood 116.18 (2010): 3593-3603.

To identify known drugs with previously unrecognized anticancer activity, we compiled and screened a library of such compounds to identify agents cytotoxic to leukemia cells. From these screens, we identified ivermectin, a derivative of avermectin B1 that is licensed for the treatment of the parasitic infections, strongyloidiasis and onchocerciasis, but is also effective against other worm infestations. As a potential antileukemic agent, ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. Ivermectin also delayed tumor growth in 3 independent mouse models of leukemia at concentrations that appear pharmacologically achievable. As an antiparasitic, ivermectin binds and activates chloride ion channels in nematodes, so we tested the effects of ivermectin on chloride flux in leukemia cells. Ivermectin increased intracellular chloride ion concentrations and cell size in leukemia cells. Chloride influx was accompanied by plasma membrane hyperpolarization, but did not change mitochondrial membrane potential. Ivermectin also increased reactive oxygen species generation that was functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with cytarabine and daunorubicin that also increase reactive oxygen species production. Thus, given its known toxicology and pharmacology, ivermectin could be rapidly advanced into clinical trial for leukemia.

14) Hashimoto, Hisashi, et al. “Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines.” Drug discoveries & therapeutics 3.6 (2009).  Ivermectin inactivates blocks kinase PAK1 Ovarian Cancer Hashimoto 2009.

WNT PATHWAY Upregulared

15)  Kimura, Yoshizo, et al. “The Wnt signaling pathway and mitotic regulators in the initiation and evolution of mantle cell lymphoma: Gene expression analysis.” International journal of oncology 43.2 (2013): 457-468.

For an accurate understanding of mantle cell lymphoma (MCL), molecular behavior could be staged into two major events: lymphomagenesis with the t(11;14) translocation (initiation), and evolution into a more aggressive form (transformation). Unfortunately, it is still unknown which genes contribute to each event. In this study, we performed cDNA microarray experiments designed based on the concept that morphologically heterogeneous MCL samples would provide insights into the role of aberrant gene expression for both events. A total of 15 MCLs were collected from the files, which include a total of 237 MCL patients confirmed by histology as CCND1-positive. We posited four stepwise morphological grades for MCL: MCL in situ, MCL with classical form (cMCL), MCL with aggressive form (aMCL), and MCL with intermediate morphology between classical and aggressive forms at the same site (iMCL). To identify genes involved in initiation, we compared the tumor cells of MCL in situ (n=4) with normal mantle zone B lymphocytes (n=4), which were selected by laser microdissection (LMD). To identify genes contributing to transformation, we selected the overlapping genes differentially expressed between both cMCL (n=4) vs. aMCL (n=5) and classical vs. aggressive areas in iMCL (n=2) obtained by LMD. A significant number of genes (n=23, p=0.016) belonging to the Wnt signaling pathway were differentially expressed in initiation. This specific activation was confirmed by immuno­histochemistry, as MCL in situ had nuclear localization of phosphorylated-β-catenin with high levels of cytoplasmic Wnt3 staining.  For transformation, identified 60 overlapping genes included a number of members of the p53 interaction network (CDC2, BIRC5 and FOXM1), which is known to mediate cell cycle progression during the G2/M transition. Thus, we observe that the Wnt signaling pathway may play an important role in initial lymphomagenesis in addition to t(11;14) translocations, and that specific mitotic regulators facilitate transformation into more aggressive forms.

16) Mathur, Rohit, et al. “Targeting Wnt pathway in mantle cell lymphoma-initiating cells.” Journal of hematology & oncology 8.1 (2015): 63.

Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin’s lymphoma. Despite initial intense chemotherapy, up to 50 % of cases of MCL relapse often in a chemoresistant form. We hypothesized that the recently identified MCL-initiating cells (MCL-ICs) are the main reason for relapse and chemoresistance of MCL. Cancer stem cell-related pathways such as Wnt could be responsible for their maintenance and survival.
Methods  We isolated MCL-ICs from primary MCL cells on the basis of a defined marker expression pattern (CD34-CD3-CD45+CD19-) and investigated Wnt pathway expression. We also tested the potential of Wnt pathway inhibitors in elimination of MCL-ICs.
Results  We showed that MCL-ICs are resistant to genotoxic agents vincristine, doxorubicin, and the newly approved Burton tyrosine kinase (BTK) inhibitor ibrutinib. We confirmed the differential up-regulation of Wnt pathway in MCL-ICs. Indeed, MCL-ICs were particularly sensitive to Wnt pathway inhibitors. Targeting β-catenin-TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs.
Conclusions:  Our results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors.

Curcumin inhibits WNT

17) Invest New Drugs. 2010 Dec;28(6):766-82. doi: 10.1007/s10637-009-9311-z.
Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells.
Leow PC1, Tian Q, Ong ZY, Yang Z, Ee PL.
Aberrant activation of the Wnt/β-catenin signaling pathway promotes osteosarcoma tumorigenesis and metastasis. In this study, we tested the hypothesis that osteosarcoma progression may be delayed by disrupting the Wnt/β-catenin pathway using small molecule inhibitors such as curcumin and PKF118-310. Effective inhibitions of the Wnt/β-catenin pathway by curcumin and PKF118-310 in osteosarcoma cells were shown by the suppression of both intrinsic and activated β-catenin/Tcf transcriptional activities using luciferase reporter assays. Western blot analysis revealed that there was no change in the amount of cytosolic β-catenin, although nuclear β-catenin was markedly reduced by treatment with either compounds. We next performed wound healing and Matrigel invasion assays and observed a dose-dependent decrease in osteosarcoma cell migration and invasion with curcumin and PKF118-310 treatment. Overexpression of the wild-type β-catenin plasmid in osteosarcoma cells resulted in enhanced cell invasiveness but this effect was significantly overcome by curcumin. Gelatin zymography and Western blotting showed that reduced cell invasion with curcumin and PKF118-310 treatment correlated with the activity and protein level of matrix metalloproteinase-9 under conditions of intrinsic or extrinsic Wnt/β-catenin activation. Using cell apoptosis assay and cell cycle analysis, we further showed that the anti-proliferative effect of PKF118-310 is attributed to PKF118-310-induced apoptosis and G2/M phase arrest. Lastly, we observed that these anti-cancer effects correlated with the decreased expression of cyclin D1, c-Myc and survivin. Our findings strongly suggest that curcumin and PKF118-310 have great therapeutic potential for the treatment of osteosarcoma.

18) Hallett, Robin M., et al. “Small molecule antagonists of the Wnt/beta-catenin signaling pathway target breast tumor-initiating cells in a Her2/Neu mouse model of breast cancer.” PloS one 7.3 (2012): e33976.
Recent evidence suggests that human breast cancer is sustained by a minor subpopulation of breast tumor-initiating cells (BTIC), which confer resistance to anticancer therapies and consequently must be eradicated to achieve durable breast cancer cure.
Methods/Findings: To identify signaling pathways that might be targeted to eliminate BTIC, while sparing their normal stem and progenitor cell counterparts, we performed global gene expression profiling of BTIC- and mammary epithelial stem/progenitor cell- enriched cultures derived from mouse mammary tumors and mammary glands, respectively. Such analyses suggested a role for the Wnt/Beta-catenin signaling pathway in maintaining the viability and or sustaining the self-renewal of BTICs in vitro. To determine whether the Wnt/Beta-catenin pathway played a role in BTIC processes we employed a chemical genomics approach. We found that pharmacological inhibitors of Wnt/β-catenin signaling inhibited sphere- and colony-formation by primary breast tumor cells and primary mammary epithelial cells, as well as by tumorsphere- and mammosphere-derived cells. Serial assays of self-renewal in vitro revealed that the Wnt/Beta-catenin signaling inhibitor PKF118–310 irreversibly affected BTIC, whereas it functioned reversibly to suspend the self-renewal of mammary epithelial stem/progenitor cells. Incubation of primary tumor cells in vitro with PKF118–310 eliminated their capacity to subsequently seed tumor growth after transplant into syngeneic mice. Administration of PKF118–310 to tumor-bearing mice halted tumor growth in vivo. Moreover, viable tumor cells harvested from PKF118–310 treated mice were unable to seed the growth of secondary tumors after transplant.

WNT- Inhibitors- in Food – sulforaphane ECGC resverarol retinoids curcumin

19)  Tarapore, Rohinton S., Imtiaz A. Siddiqui, and Hasan Mukhtar. “Modulation of Wnt/β-catenin signaling pathway by bioactive food components.” Carcinogenesis 33.3 (2012): 483-491.
Sulforaphane (SFN), a natural agent found in cruciferous vegetables such as broccoli, has been reported to inhibit the growth of breast CSCs in vitro and in vivo through inhibition of Wnt-regulated self-renewal (112).
Preclinical and epidemiological data suggest the role of vitamin D in exerting antiproliferative and prodifferentiating effects on a variety of stem and progenitor cells (113,114). Genistein has been reported to act synergistically with a vitamin D derivative to inhibit the growth of prostate cells and regulate genes that are involved in stem cells renewal (115–117). A recent study by Kakarla et al. (118) showed that curcumin inhibits Wnt/β-catenin signaling in mammary stem cells by inhibiting their self-renewal capability. Another study by Yu et al. (119) showed that curcumin in combination with the therapeutic cocktail of leucovorin, 5-fluorouracil and oxaliplatin (FOLFOX) eliminated colon CSC population suggesting that curcumin by itself or together with the conventional chemotherapeutic could be an effective treatment strategy for preventing the emergence of chemoresistant colon cancer cells by reducing/eliminating CSCs.
Flavanoids (genistein), curcumin, epigallocatechin-3-gallate (EGCG), resveratrol, lupeol, retinoids, lycopene, deguelin and SFN are been described here.
Niclosamide WNT inhibitor

20)   Lu, Wenyan, et al. “Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway.” PloS one 6.12 (2011): e29290.
The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.

21)  Chin J Cancer. 2012 Apr;31(4):178-84. Niclosamide, an old antihelminthic agent, demonstrates antitumor activity by blocking multiple signaling pathways of cancer stem cells.  Pan JX1, Ding K, Wang CY.
Niclosamide, an oral antihelminthic drug, has been used to treat tapeworm infection for about 50 years. Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs. Recently, several groups have independently discovered that niclosamide is also active against cancer cells, but its precise mechanism of antitumor action is not fully understood. Evidence supports that niclosamide targets multiple signaling pathways (NF-κB, Wnt/β-catenin, Notch, ROS, mTORC1, and Stat3), most of which are closely involved with cancer stem cells. The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed. A method for synthesizing a phosphate pro-drug of niclosamide is provided. Given its potential antitumor activity, clinical trials for niclosamide and its derivatives are warranted for cancer treatment.
Taken together, our data support that niclosamide has two independent effects: inhibita NF-kB activation and increases ROS (Figure 1).
In a recent study using a high-throughput screening approach, Chen et al.[13] validated that niclosamide is a potent inhibitor of the Wnt/β-catenin pathway
Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem cells. These exciting findings warrant clinical trials of niclosamide in cancer patients.

Ovarian Cancer

22)  Yo, Yi-Te, et al. “Growth Inhibition of Ovarian Tumor–Initiating Cells by Niclosamide.” Molecular Cancer Therapeutics 11.8 (2012): 1703-1712.Growth Inhibition of Ovarian Tumor–Initiating Cells by Niclosamide Yo Yi-Te Molecular Cancer Therapeutics 2012

A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.

23) Arend, R. C., et al. “Inhibition of Wnt/β-catenin pathway by niclosamide: a therapeutic target for ovarian cancer.” Gynecologic oncology 134.1 (2014): 112.

The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients’ ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer.

24) Niclosamide (Oral Route) Mayo CLinic
Niclosamide may be taken on an empty stomach (either 1 hour before or 2 hours after a meal). However, to prevent stomach upset, it is best taken after a light meal (for example, breakfast).
Niclosamide tablets should be thoroughly chewed or crushed and then swallowed with a small amount of water. If this medicine is being given to a young child, the tablets should be crushed to a fine powder and mixed with a small amount of water to form a paste.
For dwarf tapeworm: Adults—2 grams a day for seven days. Treatment may be repeated in seven to fourteen days if needed.

25) Yo, Yi-Te, et al. “Growth inhibition of ovarian tumor–initiating cells by niclosamide.” Molecular cancer therapeutics 11.8 (2012): 1703-1712.
A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.

26) Osada, Takuya, et al. “Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.” Cancer research 71.12 (2011): 4172-4182.
Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC. Cancer Res; 71(12); 4172–82.

27) Wieland, Anja, et al. “Anticancer effects of niclosamide in human glioblastoma.” Clinical Cancer Research 19.15 (2013): 4124-4136. Anticancer effects of niclosamide in human glioblastoma Clinical Cancer Research Wieland Anja 2013

Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo.

Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs’ malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-κB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy.

Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. Clin Cancer Res; 19(15); 4124–36. ©2013 AACR.

28) Jin, Yanli, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-κB pathway and generation of reactive oxygen species. Cancer research 70.6 (2010): 2516-2527. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells Jin Yanli Cancer research 2010
NF-κB may be a potential therapeutic target for acute myelogenous leukemia (AML) because NF-κB activation is found in primitive human AML blast cells. In this report, we initially discovered that the potent antineoplastic effect of niclosamide, a Food and Drug Administration–approved antihelminthic agent, was through inhibition of the NF-κB pathway in AML cells. Niclosamide inhibited the transcription and DNA binding of NF-κB. It blocked tumor necrosis factor–induced IκBα phosphorylation, translocation of p65, and expression of NF-κB–regulated genes. Niclosamide inhibited the steps TAK1→IκB kinase (IKK) and IKK→IκBα. Niclosamide also increased the levels of reactive oxygen species (ROS) in AML cells. Quenching ROS by the glutathione precursor N-acetylcysteine attenuated niclosamide-induced apoptosis. Our results together suggest that niclosamide inhibited the NF-κB pathway and increased ROS levels to induce apoptosis in AML cells. On translational study of the efficacy of niclosamide against AML, niclosamide killed progenitor/stem cells from AML patients but spared those from normal bone marrow. Niclosamide was synergistic with the frontline chemotherapeutic agents cytarabine, etoposide, and daunorubicin. It potently inhibited the growth of AML cells in vitro and in nude mice. Our results support further investigation of niclosamide in clinical trials of AML patients. Cancer Res; 70(6); 2516–27

29) Wang, Yu-Chi, et al. “Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells.” PloS one 8.9 (2013): e74538.
The primary cause of death from breast cancer is the progressive growth of tumors and resistance to conventional therapies. It is currently believed that recurrent cancer is repopulated according to a recently proposed cancer stem cell hypothesis. New therapeutic strategies that specifically target cancer stem-like cells may represent a new avenue of cancer therapy. We aimed to discover novel compounds that target breast cancer stem-like cells. We used a dye-exclusion method to isolate side population (SP) cancer cells and, subsequently, subjected these SP cells to a sphere formation assay to generate SP spheres (SPS) from breast cancer cell lines. Surface markers, stemness genes, and tumorigenicity were used to test stem properties. We performed a high-throughput drug screening using these SPS. The effects of candidate compounds were assessed in vitro and in vivo. We successfully generated breast cancer SPS with stem-like properties. These SPS were enriched for CD44high (2.8-fold) and CD24low (4-fold) cells. OCT4 and ABCG2 were overexpressed in SPS. Moreover, SPS grew tumors at a density of 103, whereas an equivalent number of parental cells did not initiate tumor formation. A clinically approved drug, niclosamide, was identified from the LOPAC chemical library of 1,258 compounds. Niclosamide downregulated stem pathways, inhibited the formation of spheroids, and induced apoptosis in breast cancer SPS. Animal studies also confirmed this therapeutic effect. The results of this proof-of-principle study may facilitate the development of new breast cancer therapies in the near future. The extension of niclosamide clinical trials is warranted.

30) 2016 full free
Lin, Chi Kang, et al. “Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in ovarian cancer.” Oncotarget 7.8 (2016): 8993-9006.
Ovarian cancer treatment remains a challenge and targeting cancer stem cells presents a promising strategy. Niclosamide is an “old” antihelminthic drug that uncouples mitochondria of intestinal parasites. Although recent studies demonstrated that niclosamide could be a potential anticancer agent, its poor water solubility needs to be overcome before further preclinical and clinical investigations can be conducted. Therefore, we evaluated a novel nanosuspension of niclosamide (nano-NI) for its effect against ovarian cancer. Nano-NI effectively inhibited the growth of ovarian cancer cells in which it induced a metabolic shift to glycolysis at a concentration of less than 3 μM in vitro and suppressed tumor growth without obvious toxicity at an oral dose of 100 mg/kg in vivo. In a pharmacokinetic study after oral administration, nano-NI showed rapid absorption (reaching the maximum plasma concentration within 5 min) and improved the bioavailability (the estimated bioavailability for oral nano-NI was 25%). In conclusion, nano-NI has the potential to be a new treatment modality for ovarian cancer and, therefore, further clinical trials are warranted.

31) safety of Niclosamide WHO report 2005  Safety Review WHO on Niclosamide 2005

32)  Cancers 2016, 8(7), 66; doi:10.3390/cancers8070066
Review: A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers..Kamal Ahmed 1,†, Holly V. Shaw 1,†, Alexey Koval 1 and Vladimir L. Katanaev 1,2,*

First introduced in 1981 as an anti-parasitic for veterinary applications [150], ivermectin was approved in 1987 for the treatment of onchocerciasis and more recently for lymphatic filariasis in humans [151,152]. It has also been reported to activate chloride channels of nematodes, causing parasite paralysis and death [153].
Ivermectin inhibits proliferation of human colon cancer and lung cancer cells both in vitro and in vivo [154]. The anti-proliferative action, affecting both the bulk tumor cells and CSCs, was linked in this study to inhibition of WNT signaling. The mechanism of this inhibition is rather unusual: ivermectin inhibits C-terminal phosphorylation of β-catenin, overactivating by an unknown mechanism protein phosphatases PP2A and PP1. As a result, the activity of β-catenin as a co-factor in transcription of the WNT target genes is reduced [154].
Ivermectin also has a cytotoxic action due to activation of mammalian chloride channels, similarly to its effects in nematodes [155]. Importantly, the anti-WNT IC50 of ivermectin is 5–10 times (~1–2 µM vs. 10 µM) lower than that of its toxic effect against chloride channels. Unfortunately, oral bioavailability of the drug, as for other antiparasitic drugs discussed in this section, is very low. Upon normal oral dosing its plasma levels do not exceed 60 nM. Intraperitoneal delivery at 10 mg/kg in the form of a cyclodextrin conjugate, likely achieving high plasma concentrations, was well tolerated and suppressed growth of colorectal cancer in mouse xenograft studies [154]. Toxicity studies in vivo have also demonstrated a wide therapeutic index for ivermectin [151,156]. The scarcity of data regarding the pharmacokinetics and the safety profile of ivermectin delivered to humans by means other than oral delivery make it compulsory for ivermectin to be tested in safety studies before any further clinical interventions.

33)   Eur J Clin Pharmacol. 1996;50(5):407-10.
Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus.

Baraka OZ1, Mahmoud BM, Marschke CK, Geary TG, Homeida MM, Williams JF.
To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 micrograms kg-1. SETTING:
Medical Department at Soba University Hospital, Khartoum.
PATIENTS:Twenty five patients and fourteen healthy volunteers.
METHODS: Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay.
RESULTS:  The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml-1; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 ng.h.ml-1. In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations.
CONCLUSIONS:
Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.

34) pdf
Guzzo, Cynthia A., et al. “Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects.” Journal of Clinical Pharmacology 42 (2002): 1122-1133.

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Ivermectin Antiparasitic Anticancer Wonder Drug
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Ivermectin Antiparasitic Anticancer Wonder Drug
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Ivermectin Antiparasitic Anticancer Wonder Drug
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Jeffrey Dach MD
  • Mariapj

    Finally someone talking about Ivermectin as the super potential medicine it is. I have been preaching about Ivermectin/Ivomec since 2008 when I started treating myself for Lyme Disease. Your articles and studies validate my research (I am a Journalist too). My Husband was treated for Lymphoma last year and I presented research to the Oncologist/Hematologist thinking maybe it was Borrelia or parasites because he also had malaria several times in his life, and well you probably know I was looked like a crazy person stating facts they didn’t want to listen. Thank you deeply for your articles and may the world learn about this. Count on me for sharing and would love to interview you for my Video Blog Lymevlog where i present treatments for Lyme and cancer – what a coincidence ah? http://lymetherollercoaster.blogspot.com/ and this one https://lymevlog.wordpress.com/

  • Mariapj

    The Ivomec is veterinary, it is the first version created of the Ivermectin, for cattle and swine. For the animals is injectable but people in Countries of South America swallow it at 1 ml per 50 kilos to treat malaria. The small bottle is the “human liquid version”, not sold in the US and treatment is made one drop per kilogram of weight, so everyone has the dose according to weight. I have treated Lyme Disease and Babesiosis with these, both in a very low dose once a week. My Colombian Dr recommended to not take regular doses due to my infection was spread all over my body, so the low dose was a must, and still i got very very swollen!

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