Evaluation of off-label rapamycin use on oral health.

Rapamycin (sirolimus) is an FDA approved drug with immune modulating properties that is being prescribed off-label in adults as a preventative therapy to maintain healthspan. We recently published one of the first reports on 333 adults with a history of off-label rapamycin use. Along with presenting evidence that rapamycin can be used safely in adults of normal health status, we discovered that about 26% of rapamycin users also reported oral health changes. Given the recent evidence highlighting the potential benefits of rapamycin and its derivatives in enhancing oral health, we conducted a secondary data analysis to profile the oral health of off-label rapamycin users, the true incidence of mouth sores, and present specific case studies of periodontal bone loss quantification using an FDA-approved artificial intelligence platform. Contrary to expected findings and previous literature, dimensions of rapamycin usage (such as length of use, dosage, and interval) were not found to be related to the incidence of mouth ulcers in rapamycin users. Notably, among rapamycin users, the most deleterious forms of ulcers were found to be infrequent and not statistically linked to rapamycin usage, with most rapamycin users having a common transient form of mouth ulcers. Additionally, we describe the general oral health outcomes of off-label rapamycin users and provide recommendations for individuals engaging in off-label rapamycin to be regularly checked by a dentist or an oral health care provider. This report was limited by being a secondary data analysis taken from survey data that focused on a more holistic health model. Future studies will use a focused survey that collects data on more dimensions of oral health outcomes while including questions on oral health for non-rapamycin-using participants.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults.

Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.

Autophagy in diabetic nephropathy: a review.

Diabetes mellitus (DM) is the leading cause of end stage renal disease. 40% of the patients worldwide will require replacement therapy after 20 years of DM worldwide. Early-stage diabetic nephropathy is characterized by hyperfiltration related to hypeglycemia-induced afferent artery vasodilatation with micro-and macroalbuminuria. Later on, proteinuria with arterial hypertension may appear, culminating in glomerular filtration rate (GFR) decline and end stage renal disease. Forty percent of diabetic patients develop microvascular and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2-2 phenotype. The most frequent complications in the daily clinical practice are diabetic kidney disease, diabetic retinopathy and vascular disease, such as coronary artery disease and stroke. Various pathways are involved in the pathogenesis of diabetic kidney disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines (Interleukins), have been recognized as main players in the development and progression of diabetic kidney disease. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Overexpression of the renin-angiotensin-aldosterone system (RAAS) in the kidney, the vitamin D-Vitamin D receptor-klotho axis, and autophagy. Differences in the ATG5 protein levels or ATG5 gene expression involved in the autophagy process have been associated with diabetic complications such as diabetic kidney disease. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagic mechanism, as in hyperglycemic condition, can contribute to the development and progression of diabetic kidney disease.

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

Rapamune does not attenuate high cholesterol-induced atherosclerosis in rabbits.

Solid-organ transplant recipients are prone to develop atherosclerosis. The objectives of this study were to investigate the effects of Rapamune (Wyeth Canada, Saint-Larent, QC, Canada) on the rabbit model of atherosclerosis. The rabbits were assigned to four groups: group I, regular diet (control); group II, 1% cholesterol diet; group III, control with Rapamune (1 mg/kg/d orally); and group IV, high cholesterol diet with Rapamune. Blood samples for serum lipids (triglycerides [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C]), as well as malondialdehyde, and protein carbonyls, the indices of oxidative stress were collected at the end of 2 months on the respective diet regimen. Aortic tissue for atherosclerotic changes were also collected for oxidative stress indices were also collected. Rapamune reduced serum levels of TG, TC, LDL-C, and HDL-C. Rapamune elevated the oxidative stress in rabbits on high cholesterol diet. Rapamune did not attenuate extent of atherosclerosis (group II vs. group IV, 45.00 ± 12.00 vs. 57.28 ± 2.99%); intimal thickness (group II vs. group IV, 32.38 ± 7.14 × 10(3) vs. 21.90 ± 11.98 × 10(3) µm(2)); intimal/medial ratio (group II vs. group IV, 0.50 ± 0.06 vs. 0.35 ± 0.06); and macrophage accumulation (group II vs. group IV, 69.72 ± 5.02 vs. 61.52 ± 8.94%) in the intima of rabbits on high cholesterol diet. The data suggest that (1) Rapamune increased the oxidative stress in rabbits on high cholesterol diet and (2) Rapamune did not attenuate the hypercholesterolemic atherosclerosis in the rabbit model.

Comparative Sirolimus Pharmacokinetics After Single-Dose Administration of Two Prototype 0.5-mg Tablets in Healthy Volunteers.

Availability of a lower dose tablet would add to the dosing flexibility of currently available 1- and 2-mg sirolimus tablets for optimal concentrations and patient compliance. A randomized, 3-period crossover study was conducted in 30 fasting healthy volunteers (29 men, aged 31 ± 8 years, weight 79 ± 12 kg). Subjects were given 5 mg of sirolimus, either as doses of the 0.5-mg nonshellac-core prototype, 0.5-mg shellac-core prototype, or approved 1-mg tablet. Whole blood samples were collected at selected time points for 144 hours after dosing and analyzed using LC/MS/MS assay. Noncompartmental pharmacokinetic analysis was performed, followed by bioequivalence assessment. Twenty-four subjects completed all dosing periods, and no formulation-associated adverse events were reported. Ratios of maximum plasma concentration (Cmax ), area under the concentration-time curve to the last measured concentration (AUCT ), and area under the concentration-time curve from time 0 to infinity (AUC) for the nonshellac-core prototype compared with the 1-mg tablet were within the 80% to 125% range dictated by bioequivalence conventions. Similar results were observed when comparing the ratios of AUCT and AUC for the shellac-core prototype, while 90% confidence interval of the ratio of Cmax values was 105% to 129%. Within the context of clinical equivalence standards established by a phase 3 study comparing liquid to tablet formulations, it was concluded that both prototypes were clinically bioequivalent to the reference formulation.