First human studies with a high-molecular-weight iron chelator

Dragsten, Paul R.; Hallaway, Philip E.; Hanson, Gregory J.; Berger, Arthur E.; Bernard, Bruce K.; Hedlund, Bo E.

doi:10.1016/s0022-2143(00)70021-7

Cited by 57 publications

(43 citation statements)

References 40 publications

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“…These include the generation of a high molecular weight form of the chelator coupled to hydroxyethyl starch. In a clinical trial, high plasma concentrations of hydroxyethyl starch-DFO were obtained (3 mM) after a 4-h intravenous infusion (Dragsten et al, 2000), and this treatment was well tolerated and led to substantial urinary iron excretion (Dragsten et al, 2000). However, the major problem with DFO was not overcome, that is, the need for long infusions.…”

Section: A Siderophoresmentioning

confidence: 99%

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Kalinowski

Richardson

2005

Pharmacological Reviews

653

782

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Section: A Siderophoresmentioning

confidence: 99%

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Kalinowski

Richardson

2005

Pharmacological Reviews

653

782

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“…In general, DFO is not injected intravenously for two reasons. First, it is a small molecule and is eliminated rapidly through the kidney, with a plasma half-life that is less than 10 min in humans (Mahoney et al, 1989;Dragsten et al, 2000). Second, the injec- 3.…”

Section: Downloaded Frommentioning

confidence: 99%

“…A single clinical trial of DFO for treatment of Alzheimer's disease showed that twice daily intramuscular injections slowed cognitive decline by 50% over 2 years (Crapper McLachlan et al, 1991). The use of DFO for stroke treatment has not been clinically tested, probably because of problems administering DFO systemically including: 1) injection as an intravenous bolus causes acute hypotension, and 2) DFO is rapidly filtered by the kidney and eliminated in the urine (Dragsten et al, 2000).…”

mentioning

confidence: 99%

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Hanson

Roeytenberg²,

Martínez³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

197

119

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Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the bloodbrain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9 -18.5 M) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 M, p Ͻ 0.05).Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p Ͻ 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p Ͻ 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.

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“…Firstly, it is a small molecule and is eliminated rapidly through the kidney. Secondly, the injection of an intravenous bolus can cause acute hypotension that is rapid and can be lethal (Dragsten et al, 2000). Subcutaneous and intramuscular injections of DFO are often associated with local injection site reactions.…”

Section: Deferoxaminementioning

confidence: 99%

Insights into direct nose to brain delivery: current status and future perspective

et al. 2013

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Now a day's intranasal (i.n) drug delivery is emerging as a reliable method to bypass the bloodbrain barrier (BBB) and deliver a wide range of therapeutic agents including both small and large molecules, growth factors, viral vectors and even stem cells to the brain and has shown therapeutic effects in both animals and humans. This route involves the olfactory or trigeminal nerve systems which initiate in the brain and terminate in the nasal cavity at the olfactory neuroepithelium or respiratory epithelium. They are the only externally exposed portions of the central nervous system (CNS) and therefore represent the most direct method of noninvasive entry into the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. The potential for treatment possibilities with olfactory transfer of drugs will increase as more effective formulations and delivery devices are developed. Recently, the apomorphine hydrochloride dry powders have been developed for i.n. delivery (Apomorphine nasal, Lyonase technology, Britannia Pharmaceuticals, Surrey, UK). The results of clinical trial Phase III suggested that the prepared formulation had clinical effect equivalent to subcutaneously administered apomorphine. In coming years, intranasal delivery of drugs will demand more complex and automated delivery devices to ensure accurate and repeatable dosing. Thus, new efforts are needed to make this noninvasive route of delivery more efficient and popular, and it is also predicted that in future a range of intranasal products will be used in diagnosis as well as treatment of CNS diseases. This review will embark the existing evidence of nose-to-brain transport. It also provides insights into the most relevant pre-clinical studies of direct nose-brain delivery and delivery devices which will provide relative success of intranasal delivery system. We have, herein, outlined the relevant aspects of CNS drugs given intranasally to direct the brain in treating CNS disorders like Alzheimer's disease, depression, migraine, schizophrenia, etc.

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First human studies with a high-molecular-weight iron chelator

Cited by 57 publications

References 40 publications

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Insights into direct nose to brain delivery: current status and future perspective

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