#1

It seems the dosing was too low… the dog aging project is using 0.15mg/kg of rapamycin

Methods:

Seventeen client-owned dogs aged 6–10 years, weighing 18–36 kg, and without significant systemic disease were included in a prospective, randomized, placebo-controlled, masked clinical trial. Low-dose rapamycin (0.025 mg/kg) or placebo was administered three times per week for 6 months. Baseline, 6-month, and 12-month evaluation included physical examination, cardiology examination, and clinicopathology. Three-month evaluation included physical examination and clinicopathology. Owners completed online questionnaires every 2 weeks.

Results:

There were no statistically significant differences in echocardiographic parameters between rapamycin and placebo groups at 6 or 12 months. No clinically significant adverse events occurred. In 26.8% of the bi-weekly surveys owners whose dogs received rapamycin reported perceived positive changes in behavior or health, compared to 8.1% in the placebo group (p = 0.04).

Discussion:

While no clinically significant change in cardiac function was observed in dogs treated with low-dose rapamycin, the drug was well-tolerated with no significant adverse events.

相关阅读：

A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience. (2017) 39:117–27. doi: 10.1007/s11357-017-9972-z, PMID: [PMC free article] [考研] [CrossRef] [Google Scholar]

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#2

Dogs in the previous trial [Kaeberlein’s second study] received 0.05 mg/kg three times weekly in one rapamycin treatment group and 0.1 mg/kg three times weekly in another rapamycin treatment group (both compared to a placebo group in that trial), whereas dogs in this trial’s rapamycin treatment group received 0.025 mg/kg three times weekly. … Because the treatment duration was substantially extended from 10 weeks in the prior trial to 6 months in the current trial, we chose the lower dose of 0.025 mg/kg three times weekly out of caution for potential adverse events. Clinically significant adverse events were not seen in the dogs of this report, even over the longer duration of the study. Additionally, dogs in the previous trial had a mean age of 9.7 years, while the mean age in the present trial was 7.8 years for the treatment group and 8.5 years for the placebo group.

The failure to demonstrate differences in echocardiographic parameters between treatment groups in the study reported here could indicate that the dose in the present study was too low or could relate to the prior trial enrolling an older cohort of dogs with more potential for pre-existing age-related cardiac dysfunction. Additionally, the small number of dogs enrolled decreased the statistical power of the study. The diversity of the breeds enrolled may have been a contributing factor as well. …

A total of five dogs in the rapamycin group (and four in the placebo group) were reported to have mild and transient thrombocytopenia at least once during the study. A total of five dogs in the rapamycin group (and four in the placebo group) were reported to have visible lipemia at least once during the study. Increased serum cholesterol concentrations were not associated with lipemia in these dogs and serum triglycerides were not measured as part of the routine chemistry profile in this study. As thrombocytopenia (65) and hyperlipidemia (40, 66) are known adverse events in humans treated with rapamycin and other mTOR inhibitors, continued monitoring of these parameters in future studies of rapamycin in dogs is indicated. …

Additionally, the mean change in HOMA-IR over 6 months was not significantly different between rapamycin and control groups (+0.26 ± 2.4 and − 0.15 ± 1.5; p = 0.67). [For context, optimal HOMA-IR < 1.0; > 1.9 indicates early insulin resistance, and > 2.9 indicates substantial IR. So if those numbers are real, they’re not necessarily trivial].

In response to the question, “Has your dog experienced any positive changes in behavior or other things that you would associate with good health within the past week? (please explain)” owners of dogs in the rapamycin group replied with a “yes” response in 26.8% of all surveys [n = 59 out of 220 submissions, representing six of the nine dogs (66%) in this group] while owners of dogs in the placebo group replied with a “yes” response in 8.1% of all surveys [n = 14 out of 172 submissions, representing five of the eight dogs (62.5%) in this group]. This frequency of positive owner-reported outcomes in the rapamycin treatment group was significantly greater than in the placebo group (p = 0.04).

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#3

This is disappointing but there could be several reasons.

  1. Could possibly be a dosing issue.
  2. In the original study there was an improvement in the fractional shortening of the heart. FS can be a poor representation at times of left ventricular systolic function and actually the cardiac ejection fraction didn’t improve, even in the initial study. So maybe the expectations were too high.
    3 Rapamycin May be more of a preventative than a curative drug, so perhaps it prevents heart failure but doesn’t do much to a normally functioning heart.
  3. Obviously, the sample size is very small.
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#4

Summary: Could have been better. Could have been worse.

#5

That pretty much sums it up.