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Calcirol - Liquid Vitamin D3

Discussion in 'IdeaLabs' started by haidut, Dec 10, 2017.

  1. Amazoniac

    Amazoniac Member

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  2. Amazoniac

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    - Vitamin D in Health and Disease (tut)

    "Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly. In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent. For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients."

    Just for the sake of context:

    "Figure 1A illustrates the canonical scheme of vitamin D action that prevailed at the time when the most recent dietary intake recommendations for the vitamin were promulgated (1). In this scheme, vitamin D input to the body (whether cutaneous or oral) resulted in conversion to 25-hydroxyvitamin D [25(OH)D] in the liver, with subsequent conversion of 25(OH)D to calcitriol [1,25(OH)2D] in the kidney. Calcitriol functioned as a hormone, circulating in the blood to stimulate the induction of various components of the calcium transport system in the intestinal mucosa. The net result was that active calcium absorption was increased and the efficiency of calcium absorption, normally low, was augmented so as to enable controlled adaptation to varying calcium intakes."

    upload_2019-7-20_20-3-42.png

    "This scheme remains correct, so far as it goes, but it is now understood that many tissues, particularly components of the immune apparatus and various epithelia, are able to express 1-Diokine-hydroxylase and to synthesize calcitriol locally, as depicted in Figure 1B. The upper right-hand branch represents the endocrine pathway, and the lower branch represents the autocrine pathway. There are three key features of the revised scheme: (1) The bulk of the daily metabolic utilization of vitamin D is by way of the peripheral, autocrine pathway; (2) among other effects, the autocrine action always results in expression of the 24-hydroxylase; as a result, locally synthesized calcitriol is degraded immediately after it acts, and, thus, no calcitriol enters the circulation; and (3) local concentrations of calcitriol required to support various tissue responses are higher than typical serum concentrations of calcitriol."

    "Without vitamin D, the ability of the cell to respond adequately to pathologic and physiologic signals is impaired. For example, the ductal epithelium of the breast requires vitamin D to mount an adequate response to cyclic variation in estrogen and progesterone (2). Also, macrophages use vitamin D to enable the synthesis of the bactericidal peptides needed to deal with bacterial invaders (3). In addition, most of the epithelial structures in the body, which turn over relatively rapidly, use vitamin D to signal the transcription of proteins that regulate cell differentiation, cell proliferation, and apoptosis (4)."


    "There are several consequences of this revised understanding. Perhaps most important is that this scheme permits tissue-specific action of vitamin D (as contrasted with what would otherwise be near-universal activation if all tissues were directly responsive to circulating calcitriol concentrations). A second key insight is that the 1-Constatine-hydroxylase in the tissues concerned functions well below its kM (5); hence, the amount of calcitriol that it can produce locally depends on the availability of the precursor compound [i.e., 25(OH)D]. Thus, serum concentration of 25(OH)D becomes a critical factor in ensuring optimal functioning of the various systems that require vitamin D as a part of their signaling apparatus."

    "Until recently, it had been customary, in the management of ESRD [End-stage Renal Disease], to supplement patients with calcitriol or one of its analogs—a logical move, given that renal synthesis of calcitriol in such patients is effectively knocked out. The resulting serum concentrations of calcitriol, however, are generally too low to enable the autocrine functions of the vitamin. Also, because of the short biologic half-life of calcitriol, serum calcitriol concentrations in such patients tend to be low most of the time. Finally, replacing calcitriol increases metabolic clearance of 25(OH)D (6) and certainly does nothing to support normal serum levels of this key metabolite. Thus, calcitriol is not a replacement for vitamin D and, at best, functions solely as a poor replacement for its endocrine function."

    "The inadequacy of calcitriol as a substitute for vitamin D itself is further emphasized by three lines of evidence indicating that even the canonical function of vitamin D (facilitation of calcium absorption) cannot be achieved by calcitriol alone. (1) Without doubt, calcitriol is the principal regulator of calcium absorption in typical adults, but it has been recognized for many years that those with frank vitamin D deficiency (e.g., adults with osteomalacia) exhibit calcium malabsorption, despite frequently normal to high-normal levels of circulating calcitriol. This defect is corrected not by giving more calcitriol but by raising serum levels of 25(OH)D. (2) Furthermore, 25(OH)D, administered as such, has been shown to elevate calcium absorption efficiency in typical adults, and it does so without elevating serum calcitriol levels (7). (3) Despite high parenteral dosages of calcitriol (e.g., 2 μg intravenously three times per week), calcium absorption efficiency remains severely depressed in patients who have ESRD and are on renal dialysis (R. Lund, personal communication). A working conclusion is that the optimal regulation of calcium absorption requires both molecules [25(OH)D and calcitriol]. How 25(OH)D is functioning in this setting is unclear, but it may be through binding to membrane vitamin D receptors (8) that, in turn, open calcium channels in the enterocyte and thereby facilitate the transfer of calcium across the cell."


    "There is a large body of epidemiologic data showing an inverse association between incident cancer risk and antecedently measured serum 25(OH)D (26 –29). This evidence has been accumulated for such cancers as prostate, colon, breast, lung, and marrow/lymphoma, among others. Risk reduction for breast cancer, for example, is reported to be as much as 70% for the top quartile of serum 25(OH)D (75 nmol/L) relative to the bottom quartile (45 nmol/L) (29). Furthermore, there is an even larger body of animal data showing that vitamin D deficiency in experimental systems predisposes to development of cancer on exposure to typical carcinogens (30,31). This has been shown both for animals with knockout of the vitamin D receptor and for animals with induced, nutritional vitamin D deficiency. Capping these lines of evidence is a recent randomized, controlled trial of postmenopausal women showing substantial reduction in all-cancer risk, amounting to from 60 to 75%, over the course of a 4-yr study (32). Figure 4 presents the Kaplan-Meier survival curves free of cancer for individuals from that study."

    upload_2019-7-20_20-5-9.png
     
  3. Amazoniac

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  4. baccheion

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    I don't remember.

    Best way to personalize is to check levels via lab work. That is, take a certain amount of K2 MK-4 (follow the ratio above) with D3, then check once serum 25(OH)D has stabilized. The vitamin K test essentially measures percent carboxylated osteocalcin, something exactly relevant in this case.
     
  5. Mauritio

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    What can I do if I get brain fog and low drive to do stuff ,which might be higher bran serotonin ,but still want to use Calcirol/ Vitamin -D to get my levels up ?
     
  6. Amazoniac

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  7. Amazoniac

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    - Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: implications for vitamin D supplementation

    "[..]patients with an ARD had higher plasma PTH values also when stratified for plasma VITD concentration with respect to controls. This occurs notwithstanding the fact that ARD and NARD patients are similar with regard to age and plasma concentrations of VITD, calcium and phosphate. Moreover, ARD patients more frequently displayed increased plasma PTH values than controls. So what our study demonstrates is that ARD patients are more frequently prone to hyperparathyroidism for any given plasma VITD concentration; in other words, in these patients the mechanisms that regulate PTH synthesis seem to be more refractory to plasma VITD. These results are novel and suggest that patients with autoimmune/inflammatory diseases may actually have a failure of vitamin D metabolism, which is poorly evidenced by isolated plasma VITD measurement."

    "One possible explanation for these findings is that chronic inflammatory processes may reduce parathyroid cells sensitivity to VITD. Alternatively, since the active vitamin D metabolite [1,25(OH)2 vitamin D] has immunosuppressive and immunoregulatory effects on immune cells expressing the VDR [23], when activated in chronic inflammation, immune cells may consume higher quantities of 1,25(OH)2 vitamin D; this event may lead to lower availability of 1,25(OH)2 vitamin D to parathyroid cells with consequent PTH hyperproduction to restore this deficit. The 100 log lower concentration of the active vitamin D metabolite (measured in picomoles per litre instead of nanomoles per litre as happens for VITD) may explain why this deficit could barely affect plasma VITD concentration. 1,25(OH)2 vitamin D measurement in patients with ARD may help to disclose this hypothesis. It must be pointed out, however, that recent reports indicate that the measurement of 25(OH) vitamin D is a better indicator of vitamin D status than 1,25(OH) vitamin D. In fact, 25(OH) vitamin D has a much longer half-life (~3 weeks) than 1,25(OH) vitamin D (4 h); furthermore, 1-hydroxylation is tightly influenced by calcium concentration regulated by the calcium needs of humans, while 25(OH) vitamin D synthesis is substantially dependent on substrate availability [24]."

    "ARD patients exhibit disorder in PTH, but not in calcium and phosphate levels, which are normal. Hence, the PTH elevation is compensatory and sufficient to maintain normal calcium values without influencing phosphate levels too much. This is the calcium-phosphate profile typical of secondary hyperparathyroidism due to hypovitaminosis D, where calcium is normal or slightly reduced but never increased [23]. This fact supports again our hypothesis that ARD patients have an impairment of vitamin D metabolism better disclosed by assaying simultaneously VITD and PTH rather than by measuring VITD in isolation."

    "The relationship between the presence of an ARD, inflammation and PTH increase is confirmed by stratifying patients for immunosuppressive or steroid treatments; in fact, treatment did not alter either PTH or VITD concentration. Moreover, both categories of ARD patients maintained a higher refractoriness to PTH suppression in comparison with NARD, suggesting a possible disease-associated impairment of PTH/vitamin D metabolism."​

    :think:
     
  8. Amazoniac

    Amazoniac Member

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    Time is valuable, I thought it would be a nice gesture on my part to support your Rolex purchase.

    - The vitamin D positive feedback hypothesis of inflammatory bowel diseases

    "We propose that subchronic, reduced exposure to ultraviolet (UV) light, and consequent 1-25 dihydroxyvitamin D3 deficiency, can initiate a feedback cycle that may manifest as inflammatory bowel disease (IBD) and which can persist even after sun or UV exposure is normalized (Figure 1). This results from a cascade of physiological dysregulations and feedback loops. Reduced sunlight exposure, in the absence of supplemental vitamin D, causes temporary hypocalcemia (12, 13). Calcium and 1-25 dihydroxyvitamin D3 deficiencies reduce IL-10 suppression (14), which leads to an increase in tumor necrosis factor alpha (TNF-α), IL-6, and possibly IFN-gamma (15), which in turn increases the likelihood of inflammatory bowel disease (16). Once inflamed, the bowel mucosa absorbs less calcium, even if sun exposure and active 1-25 dihydroxyvitamin D3 levels are restored (17, 18). The cycle can be self-maintaining and can even escalate over time as the microbiome changes in response to general malabsorption and the consequent availability to the gut flora of unabsorbed micronutrients (19). The resultant immune shift due to reduction of anti-inflammatory factors may manifest as persistent inflammation, as is seen in the autoimmune etiologies of IBDs. Low UVB exposure (across spatial and temporal gradients) may be a valuable predictor of IBD epidemiologically, may explain global patterns of IBD, and may explain the etiology in many cases currently classified as idiopathic."

    upload_2019-9-14_19-34-30.png

    "Altitude [] impacts sun exposure for a number of reasons. Ozone, water vapor, oxygen, and carbon dioxide filter nearly all UVC radiation and approximately 90% of UVB radiation, therefore higher elevations have greater exposure to UV radiation as a result of the diminishing atmosphere (30)."

    "Why does autoimmune dysfunction occur in some vitamin D deficiencies and not others? Although there are two vitamin D receptor polymorphisms which may increase and decrease the risk of CD in Caucasians (36), the tipping point in the imbalance of immune pathways that leads to chronic, persistent inflammation seen in autoimmune diseases is often inscrutable. Our hypothesis suggests an etiology of inflammation that may be under evolutionarily novel conditions that involve TNF-α upregulation, low sunlight exposure, vitamin D deficiency and hypocalcemia. As noted in Figure 1 TNF-α upregulation is one of the downstream effects of Vitamin D deficiency and hypocalcemia. Nielsen also points out that “in addition to T-cell regulation, the production of anti-inflammatory cytokines including IL-4, IL-10, and TGF-Beta, is increased by vitamin D.” (21)"

    "Under other conditions, this TNF-α pro-inflammatory pathway serves an adaptive function. “Several viruses and other pathogens encode proteins that inactivate caspase-8, thus preventing the infected cells from undergoing apoptotic death that would otherwise prevent the virus from replicating… (and) necroptosis provide(s) an alternative pathway for cell death… at the cost of inflammation.” (37) Thus functional necroptosis enhances inflammation because cell contents are released when dying cells rupture and release their contents into extracellular space."

    "A variety of treatments for IBD may be more successful if combined with Vitamin D and Calcium supplementation in order to break the feedback cycle. Only two clinical trials with small sample sizes have directly tested Vitamin D supplementation for therapeutic use in existing IBD, finding potential but inconclusive support, as noted by Nielson in a recent review(21). This dearth of evidence was surprising in light of the fact that “suboptimal circulating levels of 25-hydroxyvitamin D are common in IBD and appear to be associated with an increased risk of flares, IBD-related hospitalizations and surgeries, an inadequate response to tumor necrosis factor [TNF] inhibitors.” (21)"
     
  9. Amazoniac

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  10. Arnold Grape

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    Can anyone comment on how much vitamin k one might need to balance out approx 3-4 drops of Calcirol daily? I tend to eat a lot of grass fed butter, so I’m not sure how that factors in, but I also use a few drops of estroban about 2 times weekly. I have noticed what I perceive to be adrenaline symptoms lately and lack of ability to sleep 7 hours the last week.
     
  11. johnsmith

    johnsmith Member

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    I had my 25 Hyrdroxy D tested in the middle of summer after taking 4 drops of Calcirol applied topically on my chest daily for 6 months. I was also getting a decent amount of sun exposure. My levels came back quite high...

    118 (Ref 51-75)

    Does anyone know what this might mean? Is it's bad? Since then I've reduced my dose to two drops daily. It's good to know the supplement was definitely working well. I was also using rubbing alcohol to clean my skin prior to application.

    My Ionized Calcium Serum levels were 1.31 (ref. 1.16-1.35) and a few months prior my calcium levels were slightly high.
     
  12. baccheion

    baccheion Member

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    1-1.5 mg K2 MK-4 orally for each 30-35 ng/mL of 25(OH)D. Unsure how that translates into topical amounts. Also need to ensure sufficient vitamin A (RDA), magnesium, and calcium (at least 1:1 ratio with phosphorus; 0.75:1 if 25(OH)D is near/at 100 ng/mL).
     
  13. Amazoniac

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    Jorge, you know what goes well with the Rolex? No, another one would be weird, especially on the same arm. A Montblanc.

    - Mechanisms of Neuroprotective Action of Vitamin D3

    "Although affinity of [] receptors to calcidiol is ~700 times less than to calcitriol, calcidiol concentrations in blood are much (700-1000 fold) higher than those of calcitriol [1]."

    "Traditionally, vitamin D3 was considered as a hormone-regulator of Ca2+ and phosphate homeostasis [1, 3, 18]. However, results of recent studies provide convincing evidence on the role of vitamin D3 in other biochemical processes in various tissues including the nervous system [2, 3]. Physiological concentrations of calcitriol in brain are around 10 pM; this vitamin can cross the blood–brain barrier and bind to nuclear vitamin D3 receptors in the brain [19, 20]. Nuclear vitamin D3 receptors have been found in brain neurons, glial cells, spinal cord, and the peripheral nervous system [20-24]. Membrane vitamin D3 receptors have also been identified in the brain [25], which also contains enzymes of biosynthesis and metabolism of active forms of vitamin D3 (figure) [6, 26]. So, vitamin D3 can be considered as para- and autocrine hormone neurosteroid playing an important role in the nervous system [3, 4, 23, 27, 28]."

    "The neuroprotective effect of vitamin D3 is associated with reduction of Ca2+ level in the brain [3, 27, 29]. High level of this ion increases manifestations of neurotoxicity [8], which is attenuated by administration of calcitriol [27, 29]. Vitamin D3-induced decrease in brain Ca2+ may involve two distinct mechanisms. Calcitriol stimulates expression of Ca2+ binding proteins—parvalbumin and calbindins D9k and D28k [11, 14, 22, 30, 31]; it also inhibits expression of L-type Ca2+ channels in hippocampus [11, 14]. Both effects protect neurons against toxic damage by reducing cell calcium [11, 22, 30]."

    "The second mechanism of the neuroprotective action of vitamin D3 is related to inhibition of brain γ-glutamyl transpeptidase, the key enzyme of glutathione metabolism [3, 19]. Increasing antioxidant defense by increasing brain glutathione, 1-100 pM calcitriol decreased hydrogen peroxide and exerted a neuroprotective effect during brain damage caused by iron and zinc ions [32, 33]. Neuroprotective effect of calcitriol was also demonstrated using experimental brain ischemia, administration of glutamate, 6-hydroxydopamine, and other neurotoxic agents [8, 27, 29, 34]."

    "The interaction of vitamin D3 with reactive oxygen and nitrogen species is also important for neuroprotection. Nanomolar concentrations of calcitriol (0.1-100 nM) protected neurons against direct effects of superoxide and hydrogen peroxide [29, 33, 35]. However, reactive oxygen and nitrogen species modulate effects of vitamin D3: they inhibit association of nuclear vitamin D3 receptors with DNA; singlet oxygen, superoxide, and peroxynitrite cause irreversible inhibition, whereas the effect of peroxide is partially reversible [36]. In contrast to these reactive species, nitric oxide causes reversible inhibition of receptor association with DNA. This suggests that nitric oxide (NO) might act as a natural modulator of genome effects of vitamin D3 in the brain [36]. Calcitriol can reduce NO level by inhibiting expression of inducible nitric oxide synthase in the spinal cord and brain [3, 19]. Thus, one of the important mechanisms of neuroprotective action of vitamin D3 involves inhibition of production of an oxidant (NO) molecule in the brain [3]."

    "The neuroprotective role of vitamin D3 is also associated with neutrophin induction [32]. In brain neurons and glial and Schwann cells, calcitriol stimulates expression of nerve growth factor, NT3 neurotrophin, glial neurotrophic factor, and also neurotrophin receptor p75NTR [4, 21, 22, 28, 34, 37, 38]. Calcitriol stimulates neuritogenesis and its deficit results in decreased expression of p75NTR and the neurotrophins [18, 27]. Neurotrophin induction underlies the neuroprotective effect of vitamin D3 in brain ischemia [13] and the general anti-neurodegenerative properties of this vitamin [3]. For example, D3 prevents death of dopaminergic neurons in experimental models of Parkinson’s disease in animals [7, 29, 34]. The development of Alzheimer’s disease is characterized by significant reduction in nuclear vitamin D3 receptors [31]. Administration of vitamin D3 (accompanied by induction of nerve growth factor) decreases the progression of Alzheimer’s disease [12, 29]. Chronic administration of vitamin D3 to rats decreases degenerative processes in hippocampus during aging [20]. This suggests the importance of antineurodegenerative activity of vitamin D3 for manifestation of its neuroprotective effect."

    "Results of recent studies provide convincing evidence for involvement of vitamin D3 in immunological processes protecting the nervous system [16, 39, 40]. In the central nervous system, calcitriol plays the role of an immunosuppressor. It acts as inducer of anti-inflammatory cytokine interleukin-4 and transforming growth factor; calcitriol also decreases expression of proinflammatory cytokines interleukin-6, tumor necrosis factor, and macrophage colony stimulating factor [19, 41-43]. Calcitriol decreases expression of proteins of major histocompatibility complex class II and cofactor CD4, which play important roles in autoimmune processes in the nervous system [3, 39]. In a model of experimental allergic encephalomyelitis (in mice or rats), calcitriol inhibited autoimmune damage of nervous system, whereas deficit of this vitamin increased the autoimmune damage [19, 39]."​
     
  14. bdawg

    bdawg Member

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    @Amazoniac what do you expect activated d3 aka calcitriol supplementation to do in healthy subjects
     
  15. Amazoniac

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    What it already does when you supplement the parent substance, but less controlled for skipping regulatory steps, although it can still be degraded. Killcidiol is also active (as implied in the first sentence quoted above) and stays in the body for longer, a sharp elevation in killcitriol will be cleared fast and signal decomposition of killcidiol. It would be amalgam to poisonoic acids supplementation.
    - Calcirol - Liquid Vitamin D3

    You can find decent amounts of killcidiol in foods, making it possible to appear to nature if you want. In spite of eventually being converted, killciol seems better for being mostly inert and because it supports Rolex, Montblanc and a bulgarian's finesse. There are discussions on this topic:
    - Is calcifediol better than cholecalciferol for vitamin D supplementation?
     
  16. bdawg

    bdawg Member

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    what do you think of calcification risks? also are you saying theres negative feedback?

    this is synthetic calcitriol im talking about, bypassing the mostly biologically inert to detrimental d3 oral supp conversion pathway
     
  17. Amazoniac

    Amazoniac Member

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    I guess that the system of control is not adapted to these odd inputs, it can make the situation worse. It will be cleared fast and call for more to maintain a desired concentration, but the previous excess signalled the degradation of the original metabolite; you can end up low on both toxins. But depleting toxins can't be a bad thing, it's a dream therapy.

    The risk of unwanted calcification should increase, but the same protective factors apply to it as well. Example:
    - Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease
     
  18. bdawg

    bdawg Member

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    thanks for that - and good tip on mag

    I guess i just want to give the VDR receptors a good hit and oral cholecalciferol aint gonna do that.

    calcifediol might be a better option being up the chain like you suggested
     
  19. Amazoniac

    Amazoniac Member

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    It's one of the justifications to develop analogs of killcitriol that can exert some of its functions while being less impacting on killcium, another toxin whenever supplemented since leads to instant killcification of soft tissues followed by premature death; extremely toxic!!1

    - The future of vitamin D analogs

    "Non-classical properties of 1,25(OH)2D3 include prodifferentiating and antiproliferative effects on normal and cancer cells (Colston et al.,1981; Jensen et al., 2001) as well as immunomodulatory effects. However, in order to obtain these non-classical effects, 1,25(OH)2D3 doses of the nanomolar range are necessary, while physiological 1,25(OH)2D3 serum concentrations are in the picomolar range. Since supraphysiological doses of 1,25(OH)2D3 result in hypercalcemia, 1,25(OH)2D3 analogs were developed to minimize the calcemic side effects while preserving or augmenting the beneficial effects of 1,25(OH)2D3. Both industry and academic institutions have synthesized a vast amount of vitamin D analogs. Some of these analogs have tissue-specific effects with low calcemic side effects and can be given at higher doses compared to the mother compound."​
     
  20. Amazoniac

    Amazoniac Member

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    Jorge, I don't know why simpler nomenclature proposed a long time ago wasn't adopted:

    - Nomenclature of Vitamin D - IUPAC

    "[..]revival of interest in vitamin D analogues and their chemistry as a result of the developments in vitamin D metabolism and function has rendered cumbersome some of the older systems for naming these compounds, resulting in the use of undesirable abbreviations like 1a,25—(OH)2D3 in the literature. Therefore, the Commission on Biochemical Nomenclature asked H. F. DeLuca to develop, in consultation with other experts, a simplified and extended system of trivial names for vitamin D metabolites."

    "From the biochemical point of view, the most important ones are calciol, calcidiol and calcitriol for cholecalciferol, 25-hydroxycholecalciferol and 1a,25-dihydroxycholecalciferol, respectively. Calciol is not necessarily preferred to cholecalciferol for vitamin D3 itself, but the new names are recommended for hydroxylated derivatives."

    "Many investigators have used modifications of purely trivial names to show relationships between compounds." "These recommendations are intended to give convenient short trivial names to the common, biologically important derivatives of vitamin D."

    "The term vitamin D3 may be used as a synonym for calciol, but it should not be abbreviated to D3 and then modified to forms like 1,25-(OH)2D3. This type of representation of vitamin D3 metabolites is strongly discouraged."

    upload_2019-10-29_19-55-38.png

    I suggest an improvement: killciol > killcidiol > killcitriol.


    Regarding those numbers..

    - About Vitamin D | University of California (representation is clearer here)

    upload_2019-10-29_19-56-36.png

    - Vitamin D - Wikipedia
    - Calcitriol - Wikipedia
     
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