Dataset Information

Pharmacokinetics and distribution of 2-hydroxypropyl-?-cyclodextrin following a single intrathecal dose to cats.

ABSTRACT: 2-Hydroxypropyl-?-cyclodextrin (HP-?-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1-/- mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [14 C]-HP-?-CD (approximately 200??Ci/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24?hours postdose for subsequent processing and quantitative whole-body autoradiographic analysis. HP-?-CD-derived radioactivity absorbed from the CBMC was widely distributed to cat tissues; most tissues were observed to have reached their highest concentration at 1?hour postdose. HP-?-CD-derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403??g?Eq/g or 0.28?mM) and remained high (49.7 ?g?Eq/g or 0.03?mM) at 24?hours. The relatively long half-life (11-30?hours) in cerebral ventricles and the subarachnoid space surrounding the brain and spinal cord might contribute to the efficacy of HP-?-CD in NPC1 cats. Other tissues with high concentrations of radioactivity were nasal turbinates, pituitary gland, and urinary bladder, while relatively low concentrations were observed in blood and bile.

SUBMITTER: Kao ML

PROVIDER: S-EPMC7317750 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacokinetics and distribution of 2-hydroxypropyl-β-cyclodextrin following a single intrathecal dose to cats.

Kao Mark L ML Stellar Susan S Solon Eric E Lordi Alfred A Kasica Nicole N Swain Gary G Bagel Jessica H JH Gurda Brittney L BL Vite Charles H CH

Journal of inherited metabolic disease 20191215 3

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1-/- mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [<sup>14</sup> C]-HP-β-CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each ...[more]

PMID: 31707730

Similar Datasets

Project description:Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/ ) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.

Dataset Information

Pharmacokinetics and distribution of 2-hydroxypropyl-?-cyclodextrin following a single intrathecal dose to cats.

Publications

Pharmacokinetics and distribution of 2-hydroxypropyl-β-cyclodextrin following a single intrathecal dose to cats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets