This is a thread intended to centralize information regarding the use of cyclodextrin as a potential treatment for atherosclerosis.
I'd like to quote selected material from a 2016 dissertation entitled Targeting cholesterol crystals in atherosclerosis with cholesterol solubilizing 2-hydroxypropyl-β-cyclodextrin. This should serve as a suitable introduction to the subject.
"...While elevated blood cholesterol levels have long been considered a risk factor for atherosclerosis, the pathogenic role of crystalline cholesterol, which accumulates in the arterial intima during atherogenesis, has only recently been identified. CCs potently induce innate inflammatory responses, and are considered responsible for the underlying vascular inflammation driving atherosclerosis development and progression. However, so far it has not been investigated whether decreasing the amount of CCs in atherosclerotic plaques is a valuable strategy for pharmaceutical intervention in atherosclerosis. Therefore, this study investigated the potential of the cholesterol solubilizing and mobilizing compound 2-hydroxypropyl-β-cyclodextrin (CD) to remove vascular CCs and thereby prevent murine atherosclerosis development and progression...Cyclodextrins are cyclic oligosaccharides of natural origin. They are generated from the enzymatic degradation of starch by cyclodextrin glycosyltransferases. These bacterial enzymes are closely related to α-amylases, but have the unique ability to catalyze the cyclization of six to eight α-(1,4)-linked D-glucopyranose units. This enzymatic reaction produces the three main cyclodextrins: α-, β- and γ-cyclodextrin, which contain six, seven or eight glucose units, respectively.
...The oral bioavailability of pharmaceutically interesting cyclodextrins is generally below 4%, which is mainly due to their high molecular weight and their hydrophilic character, which impedes their ability to cross biological membranes and accordingly their absorption from the gastrointestinal tract. However, once absorbed, any intact cyclodextrin subsequently distributes to various tissues including the kidney, adrenal gland, urinary bladder, liver, but most of it accumulates in the kidney. Cyclodextrins disappear from the tissues quite quickly after administration (within the first few hours) and the intact cyclodextrins are excreted via the urine. Similarly, intravenous administration of cyclodextrins results in rapid renal excretion of the unmetabolized cyclodextrin molecules with nearly 100% recovery in the urine...
...oral administration of most cyclodextrins is well tolerated, the parenteral administration of some cyclodextrins, in particular parent α- and β-cyclodextrins can cause problems like renal toxicity. However, some cyclodextrin derivatives, especially hydroxypropylated β-cyclodextrin, have less toxic side effects and are therefore safer for biomedical use than their parent cyclodextrins...In humans, the oral bioavailability of CD ranges from only 0.5 to 3.3%. Approximately half of the orally administered dose is excreted as intact CD via the feces, while the remaining CD is metabolized in the colon by bacterial enzymes. When CD is intravenously administered to humans, it is rapidly excreted from the body as intact, non-metabolized CD molecules into the urine. CD has a small volume of distribution (i.e. the ratio of administered amount to plasma concentration), indicating that CD is not considerably distributed into the tissues. The biological half-life of CD is less than 2 hours and mainly depends on the glomerular filtration rate. Therefore, in individuals with normal kidney function, about 90% of the intravenously administered dose is excreted via the urine within 6 hours, and about 99% within 12 hours post administration (Fig. 2-6). Consequently, parenteral administration of CD will not result in considerable accumulation of CD in individuals with normal kidney function...
...Several studies have highlighted the contribution of crystalline cholesterol to the development, progression and clinical outcomes of atherosclerosis. CCs play a role in late stages of the disease where they physically disrupt the fibrous cap promoting plaque rupture and thrombus formation, thereby initiating the acute clinical events. Moreover, CCs induce inflammatory responses by activating the NLRP3 inflammasome. This already happens in early atherosclerotic plaques and is likely to contribute to disease progression108. However, so far it has not been investigated whether decreasing the amount of CCs in the plaque represents a valuable strategy for pharmaceutical intervention in atherosclerosis...
...CD is known to mediate the removal of cholesterol from cells and its potential pharmacological use in atherosclerosis as a shuttle for cholesterol mobilization from atherosclerotic plaque tissue to serum lipoproteins such as HDL for increased RCT was already proposed nearly 20 years ago. However, the ability of CD to clear cholesterol from atherosclerotic plaque tissue in the walls of blood vessels has not yet been investigated...
...The atherosclerosis mouse models showed that CD has beneficial effects on atherosclerosis development and is even efficient in mediating the regression of atherosclerotic plaques. However, the underlying molecular mechanisms of CD-mediated atheroprotection remained unclear. The finding that decreased murine atherosclerosis was accompanied with a reduction in crystalline cholesterol in the plaques supported the hypothesis that CD’s cholesterol solubilizing capacities might contribute to its anti-atherogenic properties...
...CD treatment of CC-loaded macrophages promotes the intracellular esterification and storage of crystalderived cholesterol. macrophages alone are able to dissolve CCs to a low extent and to export the crystal-derived cholesterol out of the cells. This basal efflux of crystal-derived cholesterol was significantly increased at 24 hours when macrophages were treated with CD. However, longer CD treatment did not further increase D6-cholesterol efflux from the macrophages suggesting that the maximum CD-mediated cholesterol efflux capacity is reached at 24 hours...
... Export of free cholesterol from macrophages is primarily mediated by the cholesterol efflux transporters ABCA1 and ABCG1, which transfer the cholesterol to ApoA-1 or HDL particles, respectively...CD mediates the dissolution of intracellular CCs and subsequently promotes esterification for intracellular storage as well as efflux of crystal-derived cholesterol. Free cholesterol can be further metabolized to other bioactive derivatives...
...CD-mediated efflux of crystal-derived cholesterol could also be further enhanced by addition of rHDL indicating active export of crystal-derived cholesterol via the cholesterol efflux transporters ABCA1 and ABCG1...
It was observed that CD treatment results in LXR-dependent upregulation of macrophage cholesterol efflux transporters and facilitates the export of crystal-derived cholesterol from macrophages in vitro. To determine whether this could also occur in vivo, RCT and excretion of crystal-derived cholesterol was monitored in mice...
...Almost no D6-cholesterol was detected in the feces of vehicle-treated mice [note: control group]. In contrast, large amounts of crystal-derived D6-cholesterol were excreted via the feces six hours after the first CD treatment of mice injected with D6‑CC-loaded WT BMDMs...Urinary excretion of crystal-derived D6-cholesterol from CD-treated mice injected with D6‑CC-loaded WT BMDMs peaked at approximately nine hours after the first CD injection and again at approximately 18 hours after the first CD injection (two hours after the second CD injection)...
...The findings presented in the previous chapters led to the hypothesis that CD might exert its beneficial effects on murine atherosclerosis by dissolving plaque CCs and promoting the production of the endogenous LXR agonist 27-HC. Subsequent activation of LXR transcription factors would induce the expression of cholesterol efflux transporters and thus facilitate removal of cholesterol from the tissue and ultimately the whole body.
Simply switching from atherogenic to chow diet significantly reduced the amount of CCs in the plaques as compared to the pretreatment control. This diet-induced CC reduction could be directly correlated to a reduction of serum cholesterol levels upon diet change and indicates the reversibility of CC deposition in diet-induced murine atherosclerotic plaques. However, the diet change did not reverse atherosclerotic plaque size. In contrast, CD treatment in both regression models (with or without diet change) reduced the amount of existing CCs in the plaques while also mediating a reduction in plaque size, even under continuous feeding of the atherogenic diet...
...Altogether these studies indicate that CCs represent a viable treatment target in atherosclerosis and that reducing the amount of CCs in atherosclerotic plaques by genetic or pharmacological means can indeed impede atherogenesis. CD in particular was able to both prevent vascular CC deposition and remove pre-existing CCs from atherosclerotic plaque tissues, and was therefore effective in mediating atherosclerosis regression..."
[bolding is mine]
Open issues:
1) Is it sufficiently safe for humans to self-administered CD?
2) Oral versus subcutaneous adminstration
3) Ototoxicity and nephrotoxicity
4) Dosing levels
5) Particular molecular form of cyclodextrin
6) Availability and purity
My reading of this paper is that a short-course of intravenous CD might be effective, while avoiding toxicities.
Edited by Richard McGee, 28 July 2017 - 12:01 AM.
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