Intramuscular desferrioxamine in patients with Alzheimer's disease

McLachlan, Donald R.; Kruck, Theo P.A.; Kalow, W.; Andrews, D. F.; Dalton, Arthur J.; Bell, Mary; Smith, W. Lyndon

doi:10.1016/0140-6736(91)92978-b

Cited by 683 publications

(298 citation statements)

References 15 publications

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“…Protection against oxidative damage has already been demonstrated to slow the clinical progression of AD [28], and chelation therapy with the iron chelator desferrioxamine was able to reduce the disease progression in patients with sporadic AD [9]. The identification of this novel AD-related genetic determinant provides new insights into the pathogenesis of the disease, and may also contribute towards the diagnosis and treatment of individuals from families at risk of AD carrying HFE mutations.…”

Section: Discussionmentioning

confidence: 99%

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

Sampietro

Caputo

Casatta

et al. 2001

Neurobiology of Aging

104

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NEUROBIOL AGING. In the present study we analysed the genotype of HFE, the gene involved in hemochromatosis, in 107 patients with sporadic late-onset AD and in 99 age-matched non-demented controls. We observed that patients carrying the mutant HFE-H63D allele had a mean age at onset of 71.7 Ϯ 6.0 years versus 76.6 Ϯ 5.8 years of those who were homozygous for the wild-type allele (p ϭ 0.001). The frequency of the HFE-H63D mutation was highest (0.22) in the patients aged Ͻ70 years at the time of disease onset, whereas it was 0.12 in those with disease onset at an age of 70 -80 years, and 0.04 in those aged more than 80 years. The APOE genotype did not significantly modify the effect of HFE on age at onset. We conclude that mild disturbances of iron homeostasis associated with a common genetic determinant may interact with other pathogenic mechanisms involved in AD. HFE mutations may anticipate AD clinical presentation in susceptible individuals.

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Section: Discussionmentioning

confidence: 99%

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

Sampietro

Caputo

Casatta

et al. 2001

Neurobiology of Aging

104

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“…Indeed, when the trial was performed it was hypothesized that deferoxamine would target aluminium toxicity in AD. In a single-blind trial of 48 AD patients, deferoxamine reduced the rate of cognitive decline over a 24-month period [221]. This encouraging trial data has not led to further AD clinical development of compounds that target iron.…”

Section: Iron Chelatorsmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…However, DFO and other structurally diverse chelators were used for treatment of acute and chronic neurologic diseases in animals and humans since the mid1980s for reasons completely independent of their hypoxia modulating properties. Indeed, almost two decades ago, a promising study describing the beneficial effects of intramuscular DFO in a 2-year study of Alzheimer's disease progression in humans was published (Crapper McLachlan et al, 1991). Hurn et al (1995) demonstrated that DFO could ameliorate metabolic failure in dogs following stroke.…”

Section: Factor Inhibiting Hypoxia-inducible Factormentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Karuppagounder

Ratan

2012

J Cereb Blood Flow Metab

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A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.

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Intramuscular desferrioxamine in patients with Alzheimer's disease

Cited by 683 publications

References 15 publications

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

The hemochromatosis gene affects the age of onset of sporadic Alzheimer’s disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

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