How does it affect LDL and LDL particle sizes?
their recommended dosage is 1 pill per day (100mg), but this seems way too small\
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While dose–response effects were present with C15:0 in the BioMAP panel, there were decreased activities at the highest dose (50 µM). While this could suggest that there were inconsistencies with the assay, this U-shaped activity profile of C15:0 is consistent with a true optimal active concentration of C15:0 at 17 to 20 µM. For example, when mitochondrial repair activities of C15:0 were assessed at 10, 20, 50, 100, and 200 µM, the optimal concentration for lowering mitochondrial reactive oxygen species production was 20 µM [2]. Similarly, while Trieu et al. showed a linear association between higher circulating C15:0 concentrations and lower risk of incident cardiovascular disease, there was a U-shaped association between circulating C15:0 concentration and risk of all-cause mortality; in this study, the lowest risk of mortality was among people with circulating C15:0 concentrations of 0.2 to 0.3% total fatty acids [11]. When including our current findings, these studies support the idea that C15:0 concentrations of 20 µM may be ideal for supporting human longevity.
A human population pharmacokinetic model, based on a series of studies involving oral administration of pure C15:0 to healthy adults and children, estimated that the average baseline circulating C15:0 concentration in people is 24.9 µM74. These levels are consistent with our studies, which demonstrated cell-based PPARα/δ agonist, anti-inflammatory, antifibrotic, and mitochondrial protective C15:0 activities between 10 and 50 µM, with most of our studies demonstrating optimal activities at 20 µM. Human pharmacokinetic studies support that a single dose of 200 mg of C15:0 results in 20 µM circulating C15:0 concentrations (approximately 5 µg/ml)75. Further, the average reported dietary intake of C15:0, based on a population of women from the 1990s, was 220 ± 100 mg per day, which is consistent with the amount needed to achieve approximately 20 µM circulating C15:0 concentrations76. Combined, these studies support potential targeted circulating C15:0 concentrations from 20 to 30 µM.
and the only 15:0 in iollo is Cholesteryl ester 15:0 7.53011539803889…
Oral C15:0 achieved active concentrations in vivo
Given that C15:0 demonstrated cell-based anti-inflammatory and antifibrotic activities between 6.7 and 20 µM (equal to 2.5 to 5 µg/ml), we first sought to understand oral doses of C15:0 needed to achieve these plasma concentrations in appropriate models. Here, 8- to 10-week old Sprague Dawley rats (n = 6 males) dosed orally once with C15:0 at 35 mg/kg body weight had increased C15:0 plasma levels within 30 minutes (Fig. 4). A maximum C15:0 plasma concentration of 4.98 µg/ml (20 µM) was achieved at 1 hour. C15:0 plasma levels were elevated above baseline levels throughout the 24-hour period, with a minimum concentration of 0.7 µg/ml. Thus, a single oral dose of C15:0 at 35 mg/kg succeeded in achieving our targeted active plasma concentrations in this rodent model, between 2.5 to 5 µg/ml (equivalent to 6.7 to 20 µM), from 1 to 8 hours post-dose. Plasma total C17:0 levels also increased, albeit less so than C15:0, following a single oral dose of C15:0; similar, sustained increases were not apparent with C13:0 (Fig. 4). These findings support de novo elongation of C15:0 to C17:0.
Figure 4
Plasma deuterated C15:0 (a), C17:0 (b), and C13:0 (c) concentrations achieved over 24 h in male Sprague Dawley rats (n = 6 total, 3 per time point between 15 min and 12 h) dosed orally once with deuterated C15:0 (35 mg/kg body weight). Upper edge of box, maximum; line inside box, median; diamond, mean; lower edge of box, minimum.
Full size image
Daily oral C15:0 maintained safety in vivo at high doses over 14 days
To further evaluate the safety of C15:0 at increasing doses, Sprague Dawley rats (n = 10 per group, 5 females and 5 males, 7 to 8 weeks old) were dosed orally once daily for 14 days with C15:0 at 35, 175 and 350 mg/kg body weight. A non-dosed vehicle control group was included. Safety assessments included clinical observations, body weight, food intake, clinical chemistries, and histology (liver, kidney, heart, and adrenal glands). Additionally, total plasma C15:0 and C17:0 concentrations were measured at Day 14. There were no mortalities or observed abnormal behaviors in animals throughout the 14-day study across all study groups, and there were no significant differences when comparing body weights and organ weight-to-body weight ratios or the prevalence of abnormal clinical chemistry values or histologic observations between C15:0-supplemented and non-supplemented control animals (Suppl Table 3). Following 14 days of daily oral supplementation with C15:0 at three increasing doses, increasing plasma total C15:0 and total C17:0 concentrations were evident (p < 0.0001) (Suppl Fig. 3). Males dosed 35, 175, or 350 mg/kg oral C15:0 had significantly higher total C15:0 and C17:0 plasma concentrations at Day 14 compared to baseline controls (Suppl Table 3). Females dosed 175 or 350 mg/kg oral C15:0 had significantly higher total C15:0 plasma concentrations at Day 14 compared to baseline controls, while only females dosed 350 mg/kg oral C15:0 had significantly higher C17:0 plasma concentrations compared to baseline controls (Suppl Table 3).
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To convert a drug dose from mouse to human, we need to use a method called allometric scaling. This accounts for the differences in metabolism between species. Let’s go through this step-by-step:
Starting dose: 35 mg/kg for mouse
The conversion factor from mouse to human is typically 0.081. This is derived from the body surface area (BSA) normalization method.
Calculate the human equivalent dose (HED): HED = Animal dose × (Animal Km / Human Km)
Where Km is a factor based on body surface area. Mouse to Human conversion:
HED = 35 mg/kg × (3/37) = 35 × 0.081 = 2.835 mg/kg
Now, we need to consider the C:15 notation. This likely refers to a concentration of 1 part drug to 15 parts vehicle or diluent. To account for this, we divide our result by 15: 2.835 mg/kg ÷ 15 = 0.189 mg/kg
Therefore, the human equivalent dose would be approximately 0.189 mg/kg.
(for 350mg mouse=> 1.89mg/kg human, which is 84mg for 44kg human, so maybe 100mg/day is a decent dose).
It’s important to note that this is an estimated starting point for human dosing. Actual safe and effective doses in humans would need to be determined through clinical trials. Also, factors such as the specific drug, its mechanism of action, and the targeted therapeutic effect can influence the final human dose.
