If I’m going to spontaneously combust so be it - but it’s really helpful to read all the various and varying effects that people feel.
Does anyone (other that Agetron 
)have any long term oral effects that dentists/periodontists have noticed?
What about dry eyes - I have bad dry eye issues for years, I wonder if oral Rapamycin will help. Have been reading about drops, but by the time those are available otc or even through eye doctors mine may have turned to dust.
Are you talking about rapamycin eye drops? No research on this at all yet - but I have seen people here talk about trying this DIY. I recommend doing some research (on Pubmed) to see if you can find any past papers that might touch on this, as I’ve not run across it before.
I saw this a while ago. I’m not really able to understand it of course, I’m a fiction writer not at all a scientist.
Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-γ , IL-12 , CIITA and Ctss ); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1 ) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.
Good find! This would seem to suggest its worth a try, if you have this issue.
Dry eye syndrome is a common eye disease.[3] It affects 5–34% of people to some degree depending on the population looked at.[5] Among older people it affects up to 70%.[10] In China it affects about 17% of people.[11] The phrase “keratoconjunctivitis sicca” means “dryness of the cornea and conjunctiva” in Latin[12]
Actually dry eyes lead me to Rapamycin. (3 things: periodontal issues, dry eyes, dodgy knees. And all three came up with Rapamycin and here I am, experimentally drugging. Rapamycin is literally the only thing I take aside from D because deficient, and creatine which I’ve stopped because youall seem to think the combination is iffy.)
How actually to get legit Rapamycin eye drops ?
You would have to get a doctor to review the research (so pull as much of it together that you can, you can use Sci-Hub - Wikipedia to find the actual papers, if they are behind a paywall). https://www.sci-hub.st
Then, I would guess that if the doctor agreed with your research, they could identify a compounding pharmacy and have it made for you.
Your best luck would probably be starting with a doctor that is already familiar with rapamycin, from our list: Rapamycin Prescription, Doctors that Prescribe It
Contact one that is licensed in your state, and explain the situation…
Or do a variation of the DIY rapamycin skin cream DIY Rapamycin skin cream
If you find this, do let me know! I have dry eyes, too. They aren’t bothersome, but they stop me from wearing contacts…. But hey, perhaps rapamycin is going to fix my vision
I’m not a pharmacist but I noticed at work that one of the patients had liquid sirolimus (had a g-tube due to inability to swallow) so it would seem like that form might be handy for topicals. I’m not sure about the inactive ingredients in it or if it would be something that could safely go into the eyes though. I’d love to do it myself though.
I found this:
Ingredients in the rapamune solution from page 23:
Wow thanks. I will read and then try to get the eye doctor lady I go to to read these. She seems receptive but who knows. As I write my right eye is inflamed and swollen on the surface. I have the usual drops they prescribe but it’s getting more frequent … I was hoping oral Rapamycin would reach my eyes,and maybe it still will im not on it long enough. But drops would be fantastic - for those who have dry eye disease - it would be a life changer.
Sorry for the off-topic response. I had dry scratchy eyes for almost a year (one was usually worse than the other), then took a tablespoon of flax oil once a day for two weeks, and my eyes have been OK ever since with very rare and short-duration exceptions. That happened to me in in my late 40s. Am 70 now.
For sure I’m going to try this - easy enough and why not! Thank you.
I wouldn’t experiment with the eyes. There are some rare cases of HSV keratits that could lead to blindness with topical immunosuppressants. PCPs are quick to refer to ophthalmologists with any of eye issues for a reason.
What is wrong with topical cyclosporine for dry eyes ? It’s well established, relatively safe and efficacious. Ophthalmologists prescribe them all the time.
Flax oil has many benefits and very little down side. You can get it with or without the polyphenols and I think there are phytoestrogens in there too. So don’t OD, but otherwise this is harmless.
BTW, we have 12 year old King Charles Cavalier and this breed tends to suffer from keratoconjunctivitis. At 12 she’s pretty old and it did affect her right eye. I had her on oral rapamycin at 3 mg per week (she’s about ten kilo - big for cavalier) based on Kaeberlein’s 0.1 mg per kg given 3x weekly with food for about 3 months.
By my rough estimation there is about 30-40 % improvement in the swelling, redness and eye discharge in the period of those 3 months, but it took good several weeks for some improvement to appear. She also seems to be more active and mobile (balance on her hind legs to get food).
This is just my case study, although the dog is also on her zesty paws supplements, taurine and Sulforaphane (she has a vet. clinical diagnosis of an abdominal tumor by XR and palpation - seems to be stable).
This is good to hear. I came to rapamycin because of dry eye disease, periodontal issues, and osteoarthritis. (To read these things you’d think “falling apart” - it sounds much worse than it feels or looks, but I’m not waiting for it to get too bad). I’ve only just had my first 5 mg dose this week, I’ll update as time passes. I’d take this from rapamycin if I had to choose just one thing : dry eye sucks. I’ll go get zesty paws also 
just in case
Dry eye is a disease of the tears and ocular surface. Numerous factors contribute to the onset of the disease, but once dry eye has developed, inflammation of various ocular surface tissues propagates the disease as both cause and consequence of ocular surface damage. Individuals with dry eye suffer from ocular discomfort (dry, gritty feeling; itching; stinging/burning; pain/soreness) and blurred vision. Improvement in these symptoms can be affected by administration of artificial tears, but the relief is transitory as the underlying inflammation persists. Therefore, an agent capable of reducing inflammation and inducing tear secretion should be an effective therapy for dry eye.
The phosphodiesterase 4 (PDE4) enzymes regulate a host of biological processes by degrading the intracellular second messenger cAMP. PDE4 inhibitors have been intensively investigated as anti-inflammatory therapies because increases in cAMP levels are known to attenuate inflammatory responses in multiple cell types. Other agents that increase cAMP have been shown to induce tear secretion. Therefore, PDE4 inhibitors should serve the dual role of reducing inflammation and inducing tear secretion providing an effective treatment for dry eye.
In this letter, we describe our efforts to create a novel, potent series of PDE4 inhibitors with aqueous solubility compatible with topical ocular delivery. Furthermore, we disclose efficacy in an in vivo model for dry eye and an in vivo test for tear secretion.
Having identified a novel series of water soluble PDE4 inhibitors, we sought to demonstrate in vivo efficacy. To explore the anti-inflammatory nature of our compounds, we utilized the rabbit model of lacrimal gland inflammation-induced dry eye, in which corneal staining was used to measure ocular surface health. Of the many new PDE4 inhibitors screened in this model (data not shown), compound 18 looked to be the most promising, so a full dose response study was run. Compound 18 was extremely effective at protecting the eye, equivalent to the corticosteroid dexamethasone from 10 ng/mL to 10 μg/mL. To explore the ability of our compounds to induce tear secretion, we utilized the phenol red thread test in rats. At doses of 10 μg/mL and 100 μg/mL, compound 18 was effective at inducing tear secretion. Thus, compound 18 demonstrates the potential effectiveness of PDE4 inhibitors for the treatment of dry eye.
Following the evaporation of the tear film, activated TRPM8 receptors allow Ca2+ ions to enter the cell [20,21]. The increased intracellular calcium concentration activates calcium-dependent protein kinases (protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII)). PKC and CaMKII phosphorylate downstream target proteins, resulting in the activation of transcriptional factors (nuclear factors of activated T cells (NFAT) and cAMP response element-binding proteins (CREB)), which enhances the expression of genes that regulate the production and secretion of neuropeptides (substance P and calcitonin gene-related peptide (CGRP)) [20,21]. These neuropeptides stimulate tear production in lacrimal glands. Upon binding to neurokinin-1 and CGRP receptors, substance P and CGRP initiate the activation of cyclic adenosine monophosphate (cAMP) and PLC-driven intracellular signaling cascades within the lacrimal gland cells.
The cAMP pathway stimulates the opening of chloride (Cl-) channels, allowing the secretion of Cl- ions into the lacrimal gland ducts. This is followed by the efflux of sodium (Na+) ions and water, creating an osmotic gradient that drives the secretion of tears. Activated PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) [19,20]. IP3 diffuses into the ER of lacrimal gland cells and binds to IP3 receptors, causing the release of Ca2+ ions from intracellular stores. The increase in intracellular calcium concentration activates calcium-activated chloride channels (CaCCs) present on the apical membrane of lacrimal gland cells [20,21]. These channels allow the efflux of chloride ions (Cl-) from the cytoplasm into the lumen of the lacrimal gland ducts. The efflux of chloride ions creates an osmotic gradient, which drives the movement of sodium ions (Na+) and water from the interstitium into the lumen of the ducts through paracellular and transcellular pathways. Along with fluid secretion, the activation of the PLC pathway also stimulates the secretion of electrolytes into the lacrimal gland ducts. The combined effect of fluid and electrolyte secretion in the lacrimal gland results in tear production. Since TRPM8/neuropeptide-dependent activation of cAMP and PLC in lacrimal gland cells is essential for optimal tear production and proper hydration of the ocular surface, any dysfunction of the TRPM8 receptors leads to reduced tear production and causes dryness of the ocular surface.
Approximately half of corneal TRPM8+ neurons express the TRPV1 channel that allows the passage of calcium, sodium, and potassium ions [31]. TRPV1 is highly expressed in corneal and conjunctival TRPM8+ sensory neurons, and in anterior eye samples and trigeminal ganglia of mice and rats with DED [22]. An increased osmolarity of the tear film triggers a conformational change in these TRPV1 channels, leading to their opening. Massive influxes of cations cause disruption to cellular homeostasis [23]. Accordingly, THO-dependent prolonged activation of TRPV1 channels causes tear film instability and compromises the integrity of the epithelial barrier in the eyes, exacerbating DED [23,24]. Also, activation of TRPV1 in human CECs importantly contributes to the development of ocular inflammation in DED patients [32]. TRPV1-dependent increases in the intracellular concentration of calcium, which leads to the activation of mitogen-activated protein kinase (MAPK) and transcriptional factor NF-κB, resulting in an enhanced production of inflammatory cytokines (IL-6 and IL-8) [32]. Additionally, the nociception experienced with DED is a result of TRPV1 activation on the ophthalmic branch of the corneal trigeminal nerve endings [33]. Bearing in mind that a continuous activation of TRPV1 aggravates DED [22,23,24], Benitez-Del-Castillo and colleagues conducted phase I and II pilot clinical trials to test the safety and efficacy of SYL1001 (TRPV1-specific short interfering RNA) in DED patients [34]. Topical administration of SYL1001 significantly extended tear break-up time, prevented THO, improved the disease index score of ocular surfaces, and attenuated conjunctival hyperemia in the eyes of DED patients, without causing any severe side effects [34].
Purpose: Phosphodiesterase type 4 (PDE4) inhibitors prevent catalysis of intracellular cAMP in multiple cell types. With respect to dry eye therapy, relevant consequences of elevated cAMP include anti-inflammatory and pro-secretory effects. Cilomilast is a potent and selective PDE4 inhibitor which inhibits inflammatory cell activation and cytokine secretion. Cilomilast was evaluated for topical ocular efficacy in several models of dry eye disease.
Results: In both the rat and rabbit models of dry eye, cilomilast (BID) provided steroid-equivalent inhibition of corneal staining at concentrations of 0.001 to 0.1% w/v. Topical administration of 0.05% cilomilast normalized tear protein concentrations and tear clearance in sex steroid-deficient rats. Cilomilast significantly increased tear secretion above vehicle from 10 min to 4 hrs after topical administration in normal rats. Topical 0.05% cilomilast (BID) also normalized tear secretion in dry eye rats. Cilomilast inhibited hyperosmolarity-induced TNF secretion in CEPI cells (EC50 = 450 nM).
Conclusions: Topical administration of the anti-inflammatory and pro-secretory selective PDE4 inhibitor cilomilast suppressed corneal staining and normalized tear secretion, clearance, and protein concentration in animal models of dry eye. Pro-secretory effects of cilomilast did not exhibit tachyphylaxis. Anti-inflammatory efficacy was equivalent to dexamethasone. These data support the utility of selective PDE4 inhibitors such as cilomilast in the topical treatment of dry eye.
https://iovs.arvojournals.org/article.aspx?articleid=2374879
We investigated the effect of cilomilast on several well-described measures of ocular surface inflammation: proinflammatory cytokine expression and APC infiltration. Dexamethasone was chosen as the comparative treatment because its therapeutic efficacy has been demonstrated in numerous DED experiments.9 The proinflammatory cytokines IL-1α, IL-1β, and TNF-α are elevated in the tears and ocular surface of DED patients.20,28 Topical cilomilast significantly reduced the corneal expression of TNF-α and the conjunctival expression of IL-1α, IL-1β, and TNF-α. These cytokines are produced in large quantities by leukocytes, including APCs such as dendritic cells.29 These cytokines are also produced by corneal and conjunctival epithelium.30,31 Infiltration of the cornea by APCs has been described in both experimental and clinical DED.20,32 APC enumeration was performed, revealing that cilomilast significantly decreased the presence of CD11b+ APCs in the peripheral and central cornea. These findings are consistent with previous reports indicating that PDE4 inhibition reduces the ability of APCs to produce proinflammatory cytokines (e.g., TNF-α) and promote immune activity.29
We also investigated the effect of cilomilast treatment on IL-17–associated immune responses in DED. For this experiment, the DED induction phase was extended to 6 days to ensure that a robust adaptive immune response was generated. Infiltration of the conjunctiva by pathogenic T cells is a universal feature of DED.33 Th17 cells are a recently discovered population of T cells that have been implicated in the immunopathogenesis of DED.3,6–8 IL-6 and IL-23 promote the differentiation and expansion of Th17 cells.34,35 IL-17, the signature cytokine of Th17 cells, promotes DED by disrupting the corneal epithelial barrier following desiccating stress.
Cyclosporine was chosen as the comparative treatment because cyclosporine’s method of action specifically targets T cells, including Th17 cells.36 Treatment with topical cilomilast significantly reduced the conjunctival expression of IL-6, IL-23, and IL-17, and the draining lymph node expression of IL-23 and IL-17. These findings indicate that treatment with topical cilomilast reduces the IL-17–associated immunity.
There was a reduction of 10% to 20% in CFS score in the vehicle-treated compared with the DED-untreated eyes. The vehicle effect was also seen on the infiltration of CD11b+ cells in the cornea and CD45+IL17+ cells in the conjunctiva. This is perhaps due to the lubricating effect of the vehicle on the ocular surface. Lower expression of IL-23 in the draining lymph nodes might be due to the reduced migration of CD11b+ cells to the draining lymph nodes.
Importantly, treatment with topical cilomilast consistently reduced corneal epitheliopathy scores by approximately 40% from baseline. Moreover, topical cilomilast was significantly more effective than its associated vehicle at reversing ocular surface damage, suggesting that the beneficial effects of cilomilast treatment are not solely attributable to lubrication of the ocular surface. Topical application of the anti-inflammatory medications dexamethasone and cyclosporine produced CFS reductions that were comparable to those produced by the topical application of cilomilast. In summary, our findings indicate that topical cilomilast ameliorates DED as determined by clinical and inflammatory measures. The therapeutic efficacy of cilomilast was comparable or superior to that of dexamethasone and cyclosporine. These findings suggest that topical cilomilast may be an effective therapeutic modality for clinical DED. Additional investigations will be required to determine the optimal dosage and duration of cilomilast treatment.
Wow. This is all way beyond my capabilities of understanding but thank you for putting it here - I always hope something will come up that will help those of us who suffer with this.
The opthalmologist prescribed a 600$ a month eye drop - turns out it’s available in the EU for 16€ a bottle - evo drops - same main ingredient.
What eye drop is that?