Long-Term Parenteral Administration of 2-Hydroxypropyl-β-Cyclodextrin Causes Bone Loss

Abstract

Cyclodextrins are oligosaccharides which are used in the pharmaceutical industry and research as vehicles for application of apolar substances such as steroids. The aim of this study was to examine the long-term effects of parenteral administration of 2-hydroxypropyl-b-cyclodextrin (HP-b-CD) on bone. Sham-operated (SHAM) or ovariectomized (OVX) adult rats were subcutaneously injected with physiological saline, 50, or 200 mg/kg HP-b-CD daily. After 4 months, body weight in OVX rats and uterine weight in SHAM rats were significantly lower after administration of 200 mg/ kg HP-b-CD, relative to vehicle controls. At 200 mg/kg, HP-b-CD was hepatotoxic as measured by increased serum transaminases, and reduced serum albumin. Moreover, 200 mg/kg HP-b-CD led to decreased vertebral and tibial bone mineral density (BMD), and to cortical thinning at the tibial shaft. Bone loss in HP-b-CD-treated rats was associated with increased bone resorption as measured by increased renal deoxypyridinoline excretion. Although 50 mg/kg HP-b-CD was devoid of overt signs of organ toxicity and did not impair BMD, bone resorption was already increased. In summary, subcutaneous long-term administration of HP-b-CD at a daily dose of 200 mg/kg led to increased bone resorption and subsequent bone loss. Minor alterations in bone metabolism were also seen at 50 mg/kg.

Topological Aspects of the Design of Nanocarriers for Therapeutic Peptides and Proteins

“…CDs are highly biocompatible when administered in common ways [25]. Chemical modifications of the CD exterior further increase biocompatibility [26,27] by suppressing their side activities. For example, non-modified β-CD exhibits kidney toxicity upon systemic administration in vivo because of the accumulation of its complex with cholesterol as insoluble crystals [28].…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…13,14) However, as described above CyDs occasionally show toxicity in the lung, 114) bone, 115) ears, 116) and kidney. 117) In contrast to the abundant safety data of CyDs, very few data are available on the safety of CyD-based supermolecules.…”

“…CyDs are also useful in inhibiting neuromuscular blockade by rocuronium (trade name: Bridion ® ) 111) and in increasing the immune responses of vaccines (adjuvant). 112,113) However, CyDs occasionally show toxicity in the lung, 114) bone, 115) ears, 116) and kidney. 117) Moreover, blood retention of CyDs is generally short, 13,117) resulting in low bioactivities.…”

Effects of Isx-9 and stress on adult hippocampal neurogenesis: Experimental considerations and future perspectives

“…However, some studies have raised concerns regarding its safety when chronically administered at high doses. 36,37 Thus, while it is likely that procedural stress has an impact, we cannot rule out the possibility that vehicle-induced toxicity might underlie, at least in part, the impairment in cell proliferation and/or neuronal commitment that we observed in vehicletreated (non-stressed) animals. 19 Again, the potential confounding effects associated with vehicle administration further highlight the importance of including a na€ ıve group (not treated with vehicle) when studying adult hippocampal neurogenesis.…”