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Bexarotene Alzheimers drug scam

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Bexarotene Alzheimers drug scam

With only the poorest of studies showing a modest reduction in the progression of Alzheimer’s disease, the use of drugs as a treatment is a major scam not in the patients’ interest.  Three articles on tobacco science for bexarotene.

The rate of the disease has increase 71% in the 55 to 74 age group from 1999 to 2010, placing the U.S. as having the second highest rate behind Finland.  Recent report for the UK, carried in the BMJ, placing them as a contender for first place--see.  Five medications are currently used to treat the cognitive problems of AD: four areacetylcholinesterase inhibitors (tacrinerivastigminegalantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist.[164] The benefit from their use is small.[165][166] No medication has been clearly shown to delay or halt the progression of the disease”  Wiki, and this positive finding is based on very biased studies.

 

Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent approved by the U.S. Food and Drug Administration (FDA) (in late 1999) and the European Medicines Agency (EMA) (early 2001) for use as a treatment for cutaneous T cell lymphoma (CTCL).[1]  It is a third-generation retinoid. In 2012 and 2013, bexarotene researchers reported that bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's-like symptoms and the findings were promoted in the media.[16][17] In 2013, several research groups reported on their attempts to reproduce these findings. The results were mixed: none of the studies found a reduction in amyloid plaques, but several of the studies found that soluble forms of β-amyloid were reduced.[18][19][20][21][22]  https://en.wikipedia.org/wiki/Bexarotene   As is the norm

Bexarotene Alzheimer’s drug scam

This highlights the ability of PhARMA to market a drug for other conditions on tobacco science.  Mouse study not duplicated by researchers from competing companies--jk. 

Last year, scientists reported what seemed like a breakthrough approach to treating Alzheimer's disease. In the journal Science, researchers suggested that the drug bexarotene--marketed as Targretin--could rapidly break apart beta amyloid plaque deposits characteristically found in the brains of Alzheimer's patients.  The authors of the study published Feb. 9, 2012, claimed that, in mice, the drug eradicated most of the plaques and rapidly reversed symptoms of Alzheimer's, including pathological, cognitive and memory deficits related to the onset of the disease. But new research suggests those findings may have been too good to be true.

 

In separate studies that attempted to replicate the original one, researchers from the University of Chicago, Northwestern University, Massachusetts General Hospital, Washington University in St. Louis and the University of Tübingen in Germany found that bexarotene did not reduce the number of plaques in the brains of three different strains of mice during or after treatment. The findings were published in the May 24 issue of the journal Science.

 

Bexarotene has yet to be tested as a treatment for Alzheimer's disease in humans, but the new study results raise concerns about patient safety.  "Anecdotally, we have all heard that physicians are treating their Alzheimer's patients with bexarotene, a cancer drug with severe side effects," said co-author Robert Vassar, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine, in a statement. "This practice should be ended immediately, given the failure of three independent research groups to replicate the plaque-lowering effects of bexarotene."

 

The FDA approved bexarotene in 1999 to treat refractory cutaneous T-cell lymphoma, a type of skin cancer, but once approved, drugs are often prescribed for off-label use. The drug can cause serious side effects, including pancreatitis, thyroid problems, headaches, fatigue, weight gain, depression, nausea and vomiting and rash.

 

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http://www.fiercebiotechresearch.com/press-releases/multiple-research-teams-unable-confirm-high-profile-alzheimers-study?utm_medium=nl&utm_source=internal  May 28, 2013

Multiple Research Teams Unable to Confirm High-Profile Alzheimer's Study


Teams of highly respected Alzheimer's researchers failed to replicate what appeared to be breakthrough results for the treatment of this brain disease when they were published last year in the journal Science.

Those results, presented online Feb. 9, 2012, suggested that the drug bexarotene (marketed as Targretin®) could rapidly reverse the buildup of beta amyloid plaques (Aβ) — a pathological hallmark of Alzheimer's disease — in the brains of mice. According to the authors of the 2012 report, drug treatment quickly removed most of the plaques and brought rapid reversal of the pathological, cognitive and memory deficits related to the onset of Alzheimer's.

However, the new reports from extensive and carefully controlled studies did not show any reduction in the number of plaques or total area occupied by the plaques during or after treatment. These results are described in three "technical comments" — one of which comes from researchers at the University of Chicago, Northwestern University, Massachusetts General Hospital, Washington University in St Louis and University of Tubingen in Germany — to be published in the May 24, 2013, issue of Science.

"The drug has no impact on plaque burden in three strains that exhibit Aβ amyloidosis," according to that group's comment. "We have failed to support earlier findings by Cramer et al that Targretin is efficacious in reducing plaque burden in transgenic mouse models of cerebral Aβ deposition."

Comment co-author Sangram Sisodia, PhD, professor of neurosciences at the University of Chicago, said he and his colleagues were curious about the initial report in 2012.

"We were surprised and excited, even stunned, when we first saw these results presented at a small conference," said Sisodia. "The mechanism of action made some sense, but the assertion that they could reduce the areas of plaque by 50 percent within three days, and by 75 percent in two weeks, seemed too good to be true."

"We all went back to our labs and tried to confirm these promising findings," Sisodia added. "We repeated the initial experiments — a standard process in science. Combined results are really important in this field. None of us found anything like what they described in the 2012 paper."

The researchers found no effects on plaque burden in three different strains of mice that were treated with bexarotene.

The discrepancy, besides being disappointing, also raises concerns about patient safety. The Food and Drug Administration approved bexarotene in December 1999 for a very specific use: treatment of refractory cutaneous T-cell lymphoma, a type of skin cancer. Once approved, the drug became legally available by prescription for "off-label" uses as well.

"Anecdotally, we have all heard that physicians are treating their Alzheimer's patients with bexarotene, a cancer drug with severe side effects," said co-author Robert Vassar, PhD, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine. "This practice should be ended immediately, given the failure of three independent research groups to replicate the plaque-lowering effects of bexarotene."

Bexarotene has never been tested as a treatment for Alzheimer's disease in humans, not even to determine the optimal dose or duration of treatment. This drug has significant side effects, including major blood-lipid abnormalities, pancreatitis, liver function test abnormalities, thyroid axis alterations, leucopenia, headaches, fatigue, weight gain, depression, nausea, vomiting, constipation and rash.

The two other technical comments came from research teams led by Kevin Felsenstein, Todd Golde, David Borchelt and colleagues at the University of Florida and by Bart DeStrooper and colleagues at the University of Leuven, Belgium.

There is no cure or effective treatment for Alzheimer's disease, which is a progressive type of dementia that occurs when nerve cells in the brain die. When Alzheimer's was first identified in 1906, it was considered a rare disorder. Today, Alzheimer's is the most common cause of dementia.  An estimated 5.3 million Americans have the disease.  . 

This work was supported by the Cure Alzheimer's Fund. Additional authors include Karthikeyan Veeraraghavalu of the University of Chicago; Rudolph Tanzi, Can Zhang and Sean Miller of Massachusetts General Hospital; Jasmin K. Hefendehl and Mathias Jucker of the University of Tübingen; Tharinda W. Rajapaksha and Robert Vassar of Northwestern University Feinberg School of Medicine; and Jason Ulrich and David M. Holtzman from the Washington University School of Medicine.

University of Chicago: John Easton
773-795-5225, 
john.easton@uchospitals.edu

Northwestern University: Marla Paul, 
312-503-8928, 
marla-paul@northwestern.edu

http://www.sciencemag.org/content/340/6135/924.6.full

Science 24 May 2013:  Vol. 340 no. 6135 p. 924  DOI: 10.1126/science.1235505

TECHNICAL COMMENTS

 

Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models”

  • ABSTRACT

    Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) reported that bexarotene rapidly reduces β-amyloid (Aβ) levels and plaque burden in two mouse models of Aβ deposition in Alzheimer’s disease (AD). We now report that, although bexarotene reduces soluble Aβ40 levels in one of the mouse models, the drug has no impact on plaque burden in three strains that exhibit Aβ amyloidosis.

Alzheimer’s disease (AD), the major cause of adult-onset dementia, is characterized by progressive memory loss and severe cognitive decline that are associated with cerebral deposition of β-amyloid (Aβ) peptides. Familial, autosomal dominant AD (FAD) is caused by expression of mutant variants of Aβ precursor proteins (APP) and presenilins (PS), and expression of these mutant genes in mice leads to cerebral deposition of Aβ peptides (1). Cramer et al. (2) reported that bexarotene (Targretin), a retinoid X receptor (RXR) agonist approved by the U.S. Food and Drug Administration (FDA), rapidly reduces Aβ levels in the interstitial fluid, reduces amyloid plaque burden, and rescues behavioral deficits in transgenic mouse models of Aβ amyloidosis. For example, 6-month-old mice expressing FAD-linked APPswe and PS1∆E9 polypeptides [APP/PS1 mice (3)] that received daily oral doses of Targretin exhibited a reduction of Aβ plaques by ~75% within 7 days and significantly reduced levels of soluble and insoluble Aβ peptides that accompanied increases in brain levels of apoE, ABCA1, ABCG1, encoded by RXR-target genes, and elevated levels of highly lipidated HDL. Similarly, Cramer et al. (2) reported that 8-month-old mice expressing APPswe and PS1L166P polypeptides [APPPS1-21 mice (4)], treated with Targretin for 20 days showed lowered Aβ levels and amyloid plaques. Finally, Cramer et al. (2) reported the presence of Aβ-laden microglia in mice treated with Targretin for 3 days, although a similar analysis was not reported for vehicle (H2O)–treated animals.

In view of the important implications of these findings for the development of novel AD therapeutics, we have attempted to replicate these findings. We noted that Cramer et al. (2) used a limited number of mice (N = 5 for APP/PS1 mice), and of mixed gender, the latter a confound in the author’s interpretation of results, because female APP/PS1 mice exhibit accelerated amyloid deposition, elevated Aβ deposition, and elevated amyloid burden, particularly at 6 months of age, compared with their male counterparts (5).

We performed studies on three mouse models of Aβ amyloidogenesis. In the first, cohorts of 6-month-old male APP/PS1 mice (3) [the same strain used by Cramer et al. (2)], were treated orally with 100 mg per kg of weight (mg/kg) of Targretin or vehicle (6.6% dimethyl sulfoxide; 4% ethanol; 89.6% sunflower oil) for seven consecutive days. Fixed hemibrains were sectioned and stained with 3D6, an Aβ N-terminal–specific antibody (6), and bound primary antibodies were visualized using fluorescently labeled secondary antibodies; representative images from individual animals treated with vehicle or Targretin are shown in Fig. 1, A and D, respectively. Colabeling studies with 3D6 and microglia-specific Iba1 antibodies revealed that Aβ was abundantly present within microglia that surrounded plaques in both vehicle- (Fig. 1, B and C) and Targretin-treated mice (Fig. 1, E and F). Amyloid plaque area (Fig. 1G) and plaque numbers (Fig. 1H), in the cortex and hippocampus of seven animals per group were quantified and revealed no significant differences between groups in these measures. Pieces of tissue from corresponding hemibrains were homogenized, then subjected to sandwich enzyme-linked immunosorbent assay (ELISA) analysis to assess levels of tris-buffered saline –soluble (s) and formic acid–extractable insoluble (ins) Aβ peptides. We observed a medium effect size [Cohen’s d (7)] for soluble and insoluble Aβ40 and soluble Aβ42, and a small effect size for insoluble Aβ42 between vehicle and Targretin treatment groups (Fig. 1I). Finally, Western blot analysis using antibodies to ABCA1 revealed an ~2.32-fold increase in ABCA1 levels in the brains of Targretin-treated animals compared with the vehicle cohort (Fig. 1, J and K) (*P < 0.001), thus establishing engagement of an RXR target in the brain.

 

Effects of Targretin on amyloid plaque burden and Aβ levels in APP/PS1 mice. Representative images of hemibrain sections from 6-month-old APP/PS1 mice treated with vehicle (A) or 100 mg/kg Targretin (D) that were immunostained with 3D6 antibody. Scale bar, 500 μm. (B) and (E) Representative confocal z-stack projection images of Iba1+ microglia (green) surrounding 3D6+ amyloid plaque deposits (red) in sections from vehicle-treated (B) or Targretin-treated (E) animals. (C and F) Overlay and orthogonal views (XY/XZ sectional) of images shown in (B) and (E), respectively. Arrows point to the intracellular 3D6 immunoreactivity in microglia of both sample groups. These results suggest that microglial phagocytosis of Aβ is not enhanced in Targretin-treated animals. Scale bar, 25 μm. Sections were counterstained with 4′,6-diamidino-2-phenylindole (DAPI) (blue). (G and H) Histograms show the amyloid plaque area fraction and the total number of plaques in cortex (CX) or hippocampus (HP), respectively. No significance was observed in the plaque area fraction (P = 0.122 in cortex; P = 0.234 in hippocampus) or total plaque numbers (P = 0.174 in cortex; P = 0.183 in hippocampus) between the treatment groups. Total areas examined in vehicle- versus Targretin-treated groups are comparable (194338.4 ± 5592.096 μm2 for vehicle group versus 192936 ± 5131.078 μm2 for Targretin group, in cortex with P = 0.437; 87837.57 ± 3391.043 μm2 for vehicle group versus 89502.69 ± 5258.606 μm2 for Targretin group, in hippocampus with P = 0.412). Six sections representing every sixth or twelfth coronal serial section spanning the proximal to distal end of hippocampus, including the cortical regions, were examined to quantify amyloid area fraction and plaque numbers using Image J Foci dMacro and Analyze particles plug-in by applying uniform image threshold. (I) Histograms show fold changes in soluble (s) Aβ40 (*P = 0.279; Cohen’s d: 0.605), formic acid-extractable insoluble (ins) Aβ40 (#P = 0.359; Cohen’s d: 0.509), soluble Aβ42 ($P = 0.247; Cohen’s d: 0.64), and insoluble Aβ42 (%P = 0.676; Cohen’s d: 0.22) after normalization against total protein content. (J) Representative Western blots of detergent-soluble total protein lysates (60 μg loaded in each lane) from hemibrains of vehicle- or Targretin-treated animals probed with antibodies to ABCA1 or β-III tubulin. (K) Quantification of ABCA1 band intensity normalized against β-III tubulin levels (*P < 0.001). Data in (G), (H), (I), and (K) represent mean ± SEM; N = 7 mice per group).

We then treated cohorts of 3- to 4-month-old male 5XFAD mice [line 6799 (8)] that exhibit robust amyloid deposition by 2 to 2.5 months of age with Targretin or vehicle, as above. The brains of 11 male mice per treatment group were analyzed; fig. 2, A and B, shows representative 3D6-labeled sections from individual animals treated with vehicle or Targretin, respectively. Amyloid plaque area (Fig. 2C) and plaque numbers (Fig. 2D) in the cortex and hippocampus were quantified and revealed no significant differences between vehicle or Targretin groups in these measures. Sandwich ELISA assays revealed that in contrast to a small effect size for insoluble Aβ40 and insoluble Aβ42, we observed a very large effect size for soluble Aβ40 and a medium effect size for soluble Aβ42 (Fig. 2E). The significant reduction in levels of soluble Aβ40 (*P = 0.008; Cohen’s d: 1.25) in brains of Targretin-treated mice might be a reflection of the reported rapid reduction of interstitial fluid (ISF) Aβ by this compound (2). Finally, we established target engagement by demonstrating a ~2.46-fold elevation in ABCA1 levels in the brains of Targretin-treated animals compared with the vehicle cohort (Fig. 2, F and G) (*P = 0.004).

 

Effects of Targretin on amyloid plaque burden and Aβ levels in 5X FAD and APPPS1-21 mice. (A to G) Representative images of hemibrain sections from 3- to 4-month old 5XFAD mice treated with vehicle (A) or 100 mg/kg Targretin (B) for 7 days that were immunostained with 3D6 antibody. Scale bar, 500 μm. (C and D) Histograms show the amyloid plaque area fraction and the total number of plaques in cortex (CX) or hippocampus (HP), respectively. Total area examined in vehicle- versus Targretin-treated groups are comparable (117841.3 ± 3303.082 μm2 for vehicle group versus 107086.3 ± 6802.094 μm2 for Targretin group, in cortex with P = 0.17; 67039.59 ± 4030.787 μm2 for vehicle group versus 70535.3 ± 2843.477 μm2 for Targretin group, in hippocampus with P = 0.486). (E) Histogram shows fold changes in soluble (s) Aβ40 (*P = 0.008; Cohen’s d: 1.25), insoluble (ins) Aβ40 (#P = 0.292; Cohen’s d: 0.46), soluble Aβ42 ($P = 0.102; Cohen’s d: 0.73), and insoluble Aβ42 (%P = 0.363; Cohen’s d: 0.396) levels after normalization against total protein content. (F) Representative Western blots of detergent-soluble total protein lysates (60 μg per lane) from hemibrains of vehicle- or Targretin-treated 5XFAD animals using antibodies to ABCA1 or β-III tubulin. (G) Quantification of ABCA1 band intensity normalized against β-III tubulin levels (*P = 0.004). Data in (C), (D), (E) and (G) represent mean ± SEM; N = 11 mice per group. (H to M) Amyloid plaque burden is not reduced in 9-month-old APPPS1-21 mice after 26 days of 100 mg/kg per day Targretin treatment. Representative images of hemibrain sections from 9-month-old APPPS1-21 mice treated with vehicle (H2O) (H) or 100 mg/kg Targretin (I) for 26 days that were immunostained with Aβ-specific CN3 antibody. Scale bar, 500 μm. (J) Histogram shows the percentage of amyloid plaque load assessed in neocortex on random sets of every 12th systematically sampled 40-μm-thick sections, analyzed by area fraction technique estimated with the aid of Stereologer software (mean ± SEM; N = 4 mice per group). (K) Histogram shows fold changes in soluble (s) Aβ40 (*P = 0.269; Cohen’s d: 0.32), insoluble (ins) Aβ40 (#P = 0.49; Cohen’s d: 0.013), soluble Aβ42 ($P = 0.182; Cohen’s d: 0.325), and insoluble Aβ42 (%P = 0.495; Cohen’s d: 0.008) levels in vehicle- versus Targretin-treated APPPS1-21 mice, respectively. (L) Representative Western blots of detergent-soluble total protein lysates (60 μg per lane) from hemibrains of vehicle- or Targretin-treated APPPS1-21 mice using antibodies to ABCA1 or β-III tubulin. (M) Quantification of ABCA1 band intensity normalized against β-III tubulin levels (*P = 0.04). Data in (K) and (M) represent mean ± SEM; N = 3 mice per group).

Concerned by the fact that the vehicle used for the aforementioned studies differed from that used by Cramer et al. (2), we orally treated cohorts of 9-month-old male APPPS1-21 mice (4) with 100 mg/kg Targretin suspended in H2O or with H2O as the vehicle. This strain was also used by Cramer and colleagues (2) and exhibits robust Aβ deposition by 8 months of age. Sections were stained with a polyclonal antibody to Aβ [CN3 (9)] and Fig. 2, H and I, are representative Aβ-labeled sections from individual animals treated with H2O or Targretin, respectively. Analysis of amyloid plaque load in four male mice per group failed to reveal a significant difference between H2O or Targretin-treated animals (Fig. 2J), and Meso Scale Discovery (MSD) analysis using the human 6E10 Aβ triplex assay revealed a medium effect size for soluble Aβ species and a small effect size for insoluble Aβ species (Fig. 2K). Finally, we demonstrated an ~1.5-fold elevation in ABCA1 levels in the brains of Targretin-treated animals compared with the vehicle cohort (Fig. 2, L and M (*P = 0.04), thus establishing engagement of an RXR target in the brain.

In summary, although our studies have not examined the rapid effects of bexarotene on ISF Aβ levels or behavior, we have failed to support earlier findings by Cramer et al. (2) that Targretin is efficacious in reducing plaque burden in transgenic mouse models of cerebral Aβ deposition.

  • Received for publication 22 January 2013.

  • Accepted for publication 26 April 2013.

References and Notes

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2.       Acknowledgments: This work was supported by the Cure Alzheimer’s Fund (S.S.S., R.V., D.M.H., and R.E.T.). The authors thank V. Bindokas for expert assistance with confocal microscopy at the Digital Integrated Microscopy Facility of the University of Chicago, N. H. Varvel (University of Tubingen) for assistance in the analysis of the APPPS1-21 mice, X. Zhang for technical assistance, and Elan Pharmaceuticals, Inc., for providing Aβ-specific 3D6 antibody. D.M.H. was the head of the Neuroscience Therapeutic area scientific advisory group for Pfizer from September 2011 to September 2012. S.S.S is a paid consultant of Eisai Research Labs Inc. but is not a shareholder in any company that is a maker or owner of a FDA-regulated drug or device.

 

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  • Response to Comments on "ApoE-Directed Therapeutics Rapidly Clear {beta}-Amyloid and Reverse Deficits in AD Mouse Models"Science 24 May 2013: 924.

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