An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens

Nagai, Noriaki; Mano, Yu; Ito, Yoshimasa

doi:10.1248/bpb.b16-00592

Cited by 8 publications

(8 citation statements)

References 22 publications

(43 reference statements)

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“…Low compliance by demented patients can be partially circumvented as disulfiram can be administered by subcutaneous implantation 53 . Development of novel encapsulated or nanoparticle-assisted forms of the drug 54 , 55 might additionally help in the establishment of a potential therapy. However, safety in AD patients and impact on cognition have to be investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

Reinhardt

Stoye

Luderer

et al. 2018

Sci Rep

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ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an alpha-secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPP-alpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer’s disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy. Here we screened a FDA-approved drug library and identified disulfiram as a novel ADAM10 gene expression enhancer. Disulfiram increased ADAM10 production as well as sAPP-alpha in SH-SY5Y human neuronal cells and additionally prevented A-beta aggregation in an in vitro assay in a dose-dependent fashion. In addition, acute disulfiram treatment of Alzheimer model mice induced ADAM10 expression in peripheral blood cells, reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits. Alcohol-dependent patients are subjected to disulfiram-treatment to discourage alcohol-consumption. In such patients, enhancement of ADAM10 by disulfiram-treatment was demonstrated in peripheral blood cells. Our data suggest that disulfiram could be repurposed as an ADAM10 enhancer and AD therapeutic. However, efficacy and safety has to be analyzed in Alzheimer patients in the future.

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Section: Discussionmentioning

confidence: 99%

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

Reinhardt

Stoye

Luderer

et al. 2018

Sci Rep

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“…We previously showed that the instillation of suspensions containing DIS nanoparticles can supply more DDC to the aqueous humor and lens than a conventional formulation (DIS-sol) [ 28 , 29 ]. However, the delivery of a sufficient amount of the drug to the retina by eye drops is difficult; so, we need to improve ophthalmic DDSs for retinal drug delivery.…”

Section: Resultsmentioning

confidence: 99%

“…After oral administration and instillation, DIS is converted to DDC by the aldehyde dehydrogenase (ALDH) in the intestine and cornea [ 17 ]. The DDC converted from DIS inhibits NFκB, resulting in attenuation of iNOS expression and excessive NO production in the ophthalmic field [ 28 , 29 , 32 ]. In addition, our previous study showed that the inhibition of NO by DIS instillation attenuated the onset of lens opacity and an increase in intraocular pressure [ 28 , 29 , 32 ] and that the oral administration of DIS recovered retinal ATP dysfunction [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

Deguchi

Ogata

Yamaguchi

et al. 2020

Cells

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We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.

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“…We previously reported that drug nanoparticles, such as tranilast [ 19 , 20 ], indomethacin [ 21 , 22 , 23 ], cilostazol [ 24 ], dexamethasone [ 25 ], ketoprofen [ 26 ], ibuprofen [ 27 ], and disulfiram [ 28 , 29 ], can be prepared by bead mill treatment. Therefore, we attempted to design the NIL nano based on our previous findings.…”

Section: Discussionmentioning

confidence: 99%

Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin

Deguchi

Otake

Nakazawa

et al. 2017

IJMS

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Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina); therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NILnano), and demonstrated whether the instillation of NILnano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NILnano (mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-β-cyclodextrin, benzalkonium chloride, d-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg × 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NILnano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NILnano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NILnano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy.

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An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens

Cited by 8 publications

References 22 publications

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks

In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin

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