Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog

Rosseels, Marie-Luce; Delaunois, Annie; Hanon, Étienne; Guillaume, Philippe; Martin, Frédéric; Dobbelsteen, Diels J. van den

doi:10.1016/j.yrtph.2013.08.013

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…In a recent paper on 19 vehicles (Healing et al , ) unwanted effects such as clinical signs, changes in clinical chemistry, urinalysis, and even pathology (hydroxypropyl‐β‐cyclodextrin only, causing kidney findings in rodents) were recorded. The latter finding is well known in the literature along with effects on renal function and systemic haemodynamics (Davis and Brewster, ; Rosseels et al , ). Interestingly, none of the vehicles tested by this group appeared to have an effect on the gastrointestinal tract system.…”

Section: Discussionsupporting

confidence: 55%

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

et al. 2016

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The selection of a vehicle for oral formulations of compounds to be used in non-clinical safety studies is a challenge for poorly soluble compounds. Typically a compromise between solubility and tolerability has to be reached. Vehicle tolerability data are not readily available for a number of vehicles, and a series of oral tolerability studies were, therefore, conducted with Gelucire and Gelucire:PEG400 formulations in rats, dogs and minipigs in order to determine tolerable daily dose volumes in these species. Gelucire and Gelucire:PEG400 formulations were assessed in studies for up to 5 days in minipigs, 7 days in rats and up to 39 weeks in dogs. Gastrointestinal side effects in terms of soft and/or liquid faeces were noted in all species, but the sensitivity to these effects differed between species with the dog being the most sensitive. It was concluded that Gelucire:PEG400 (90:10) was tolerated in Beagle dogs when administered at 1 ml kg(-1) once daily for 39 weeks, and 100% Gelucire was tolerated in the rat and the minipig when administered once daily at 5 ml kg(-1) for 5 days. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 55%

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

et al. 2016

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“…Finally, some agents of lipid raft therapy may have side-effects seemingly unrelated to their activity toward lipid rafts. For example, high doses of hydroxypropyl-β-cyclodextrin had unexpected impact on renal and systemic hemodynamics ( 44 ). These potential toxicities should be carefully considered when designing therapeutic regimens.…”

Section: Discussionmentioning

confidence: 99%

Targeting Lipid Rafts—A Potential Therapy for COVID-19

et al. 2020

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COVID-19 is a global pandemic currently in an acute phase of rapid expansion. While public health measures remain the most effective protection strategy at this stage, when the peak passes, it will leave in its wake important health problems. Historically, very few viruses have ever been eradicated. Instead, the virus may persist in communities causing recurrent local outbreaks of the acute infection as well as several chronic diseases that may arise from the presence of a “suppressed” virus or as a consequence of the initial exposure. An ideal solution would be an anti-viral medication that (i) targets multiple stages of the viral lifecycle, (ii) is insensitive to frequent changes of viral phenotype due to mutagenesis, (iii) has broad spectrum, (iv) is safe and (v) also targets co-morbidities of the infection. In this Perspective we discuss a therapeutic approach that owns these attributes, namely “lipid raft therapy.” Lipid raft therapy is an approach aimed at reducing the abundance and structural modifications of host lipid rafts or at targeted delivery of therapeutics to the rafts. Lipid rafts are the sites of the initial binding, activation, internalization and cell-to-cell transmission of SARS-CoV-2. They also are key regulators of immune and inflammatory responses, dysregulation of which is characteristic to COVID-19 infection. Lipid raft therapy was successful in targeting many viral infections and inflammatory disorders, and can potentially be highly effective for treatment of COVID-19.

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“…Thus far, HPBCD is the only attractive drug candidate to treat NPC disease and offers a small ray of hope for an effective cure for these patients. However, some reports strike a note of warning for the use of HPBCD in NPC patients [7], [8], [9]. Chien et al [7] showed the possibility of HPBCD-induced pneumonia in young pigs and advocated that the pulmonary toxicity of HPBCD should not be neglected.…”

Section: Discussionmentioning

confidence: 99%

“…However, Chien et al [7] reported that chronic HPBCD infusion induced the pneumonia in healthy pigs and suggested the risk of lung toxicity by HPBCD treatment for NPC disease. In addition, some reports have demonstrated that HPBCD caused organ injury, such as renal and liver dysfunction, in animals [8], [9]. Therefore, the safety of HPBCD treatment for NPC patients remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models

Tanaka

Ishitsuka

Yamada

et al. 2014

Molecular Genetics and Metabolism Reports

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Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) or Npc1+/− mice died by 72 h after the injection. In contrast, all of the Npc1−/− mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1+/+ or Npc1+/− mice. However, these pathophysiological changes were significantly alleviated in Npc1−/− mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1−/− mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1+/+ or Npc1+/− mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

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Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog

Cited by 13 publications

References 29 publications

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

Targeting Lipid Rafts—A Potential Therapy for COVID-19

Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models

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