There have been many comments in this forum regarding
Rapamycin and its Rapalogs. I thought it important to highlight some important risks in using Rapamycin or Rapalogs to treat CFS. Hopefully the overview below provides an understanding of the clinical potential and hazards of Rapamycin/Rapalogs for CFS treatment. I tag
@XenForo ,
@eljefe19 ,
@made_lman ,
@Steve4Andrea and
@Joe Some as they have been involved in some of the discussions.
What is Rapamycin? Rapamycin was initially discovered as an antifungal metabolite produced by
Streptomyces hygroscopicus from a soil sample of Easter Island. It has since been found that rapamycin has potent pharmacological properties including the ability to suppress the immune system as well as the ability to block cell division. Rapamycin and its derivatives (rapalogs) that include temsirolimus, everolimus, ridaforolimus, 32-deoxo-rapamycin, and zotarolimus inhibit the activity of a protein called “mammalian target of rapamycin”, also known as mTOR or TORC1.
What are the normal functions of mTOR? When mTOR is active in our cells, it stimulates protein synthesis, lipid synthesis and energy production. In addition, the active form of mTOR prevents a process called ‘autophagy’ in which proteins and fats are broken down and recycled to produce energy in the mitochondria. Thus, when diet provides ample fuel and nutrients for generating energy, mTOR is activated and stimulates anabolic pathways for building muscle and fat reserves. However, if diet is inadequate or if we are fasting, inactivation of mTOR occurs leading to increases in catabolic pathways where proteins in many tissues including the muscle are degraded and used as fuel to generate energy (ATP). In this way
mTOR acts like a switch: When dietary nutrients are sufficient, mTOR is
turned on and promotes energy production together with new tissue formation and repair. However, when dietary nutrients are limited, mTOR is
turned off and ‘emergency metabolism’ is activated in which metabolic fuel is obtained by degrading proteins and fats from our tissues.
Rapamycin and Rapalogs as anti-cancer drugs. Cell division is critical for many processes in the body including the production of blood cells, repairing damaged or injured tissues and replacing old or defective cells. In contrast to normal cells, cancer cells grow and divide in an unregulated manner. Because of the ability of rapamycin to block protein synthesis, energy production and cell division, it has been examined in clinical trials for anti-cancer activity. However, Rapamycin/Rapalogs have proved to be disappointing with little or no anti-cancer activity in most human trials. Currently, these drugs are only approved for the treatment of a few cancers including renal cell carcinoma (temsirolimus and everolimus) and for patients with specific types of pancreatic cancer or tuberous sclerosis.
Rapamycin/Rapalogs suppress the immune system: The ability of Rapamycin and Rapalogs to block cell division in T-cell lymphocytes dampens overall immune responses and so they have been used as immunosuppressants following organ transplantation. While the ability of Rapamycin to suppress the immune system is critical for preventing immune rejection in transplant patients, it also comes at the significant risk of an overall suppression of immune defences against many infectious diseases. For example, immune suppression by rapamycin in renal transplant patients resulted in an increased incidence of viral infection (34%) and fungal infections (16%). Clearly, there are significant risks associated of
increased infections in any patient treated with rapamycin.
Rapamycin/Rapalogs and aging: One of the intriguing activities of Rapamycin/Rapalogs is that they are able to extend the life spans of multiple laboratory species including fruit flies, worms and mice. It has been suggested that Rapamycin/Rapalogs increase lifespan in laboratory animals by
turning off mTOR and inducing a state of ‘emergency catabolism’ where the proteins and fats in tissues are broken down and used as the metabolic fuel to generate energy (ATP) in the mitochondria. The ability of Rapamycin/Raplogs to trigger such an ‘emergency metabolic’ state may, at least in part, mimic what occurs in long-term calorie restricted diets which can also turn off mTOR and significantly increase life-span. Based on these laboratory experiments, some ‘Wellness Clinics’ and ‘Anti-Aging Clinics’ have been spruiking Rapamycin and Rapalogs to people as an anti-aging treatment. However, such treatments are potentially very dangerous. The ability of Rapamycin/Rapalogs to increase the life-span of laboratory animals occurs in a pathogen-free environment in which infections from bacteria, viruses and fungi do not occur. Humans on the other hand are surrounded by many pathogens, many of which can be lethal in the absence of a fully functional immune system. As mentioned above, the ability of Rapamycin/Rapalogs to suppress the immune system results in a significant
increase in infection rates. Thus, while Rapamycin/Rapalogs can increase life-span in laboratory animals, the findings may be an artefact of the pathogen-free environment that is unique to particular experimental models. Unfortunately, the use of such drugs as anti-aging treatments by ‘rogue’ practitioners is incredibly dangerous and exploits vulnerable people whose long-term health may suffer as a consequence.
Rapamycin and mitochondrial diseases. There maybe some very specific cases where Rapamycin/Rapalogs treatment may be warranted in the future. For example, Leigh Syndrome is caused by mutations in genes responsible for energy production (ATP) in the mitochondria. Many of the symptoms in Leigh Syndrome are similar to those of CFS patients which include i) defects in mitochondrial energy production, ii) disease onset can occur in situations where there is an extra burden energy production such following infections or surgery and iii) lactic acidosis can occur particularly following exercise. Recent studies in a mouse model of Leigh Syndrome have shown that rapamycin improved their symptoms and survival. The similarly between the symptoms of Leigh Syndrome and CFS can lead to the mistaken diagnosis of CFS in people with Leigh Syndrome. It might be possible that in some very specific mitochondrial diseases that Rapamycin/Rapalog treatment could be effective. However, there is currently no clinical evidence that such treatments may be effective in any mitochondrial disease.
Other side-effects and toxicities of Rapamycin/Raplogs: The use of Rapamycin in renal transplant recipients was found to lead to edema in 60% of patients, aphthous ulcers in 55% of patients, as well as Mucositis in other patient populations. Rapamycin treatment resulted in 90% of patients experiencing alopecia, as well as loss of testicular function and reduced male fertility. In addition, rapamycin treatment leads to metabolic changes, including hyperlipidemia, decreased insulin sensitivity, glucose intolerance, and an increased incidence of new-onset diabetes. Chronic rapamycin treatment has also been associated with gastrointestinal events including diarrhea. Cancer and transplant patients may be willing to tolerate these significant side-effects because benefits of treatment (ie. curing a terminal disease) outweigh the risks.
Rapamycin/Rapalogs and CFS. As outlined above, the use of Rapamycin/Rapalogs have significant risks and toxicities associated with immune-suppression, infection, glucose intolerance, new-onset diabetes, impaired wound healing and muscle wastage. CFS patients wishing to use Rapamycin/Rapalogs need to understand all of these dangers and their potential for seriously impacting on their long-term health. In fact, CFS patients suffer from a range of issues that Rapamycin/Rapalogs could actually make worse. The 2 main concerns in using Rapamycin/Rapalogs to treat CFS are:
1) Many studies have shown that CFS patients have defects in their ability to generate energy (ATP) resulting in reduced exercise capacity and longer recovery times. Thus, CFS patients are metabolically deficient. The ability of Rapamycin/Rapalogs to block catabolic pathways necessary for energy production in CFS patients
that are already unable to generate sufficient energy (ATP) for daily life may actually make their symptoms worse and possibly even delay their recovery.
2) Many studies have also shown that CFS patients also have an altered immune systems. In some aspects, immune functions seem to be impaired (e.g. reduced functions of NK-Cells) while in other aspects the immune system seems to be chronically activated (eg. increased circulation of some pro-inflammatory cytokines). Most importantly, there is good evidence that some CFS patients have an impaired immune system that appears unable to completely eradicate fungal, bacterial and/or mycoplasma infections. Treating a CFS patient,
who already has a low-level chronic infection due to a weakened immune system, with a drug that further suppresses immune defence could leave the patient with a severe immune-deficiency and allow either existing or new infections to over-run the immune system resulting in serious medical consequences. Even if the CFS patient’s immune system is perfectly functional and they don’t have an underlying chronic infection,
treating a CFS patient with Rapamycin/Rapalogs and suppressing their immune system could further burden an already sick patient leading to a worsening of health and reduce their likelihood of recovery.
Thus, doctors need to clearly explain these risks to CFS patients in terms of
i) providing detailed information of the medical risks that can arise due to immune suppression, increased infection, metabolic impairment including glucose intolerance and diabetes,
ii) providing ‘informed consent’ so that patients are fully aware of all the risks and are acknowledging that they are willing to try a non-approved and experimental medicine for CFS
iii) providing patients with frequent and comprehensive monitoring (such as comprehensive biochemical, cellular and metabolic blood/urine testing) so any potential health issues caused by treatment with Rapamycin/Rapalogs can be quickly identified.
Clinical trials that test new medicines are generally very good at following points i-iii above. If you are taking Rapamycin/Rapalogs as part of a CFS clinical trial, you would almost certainly have been made aware of the issues above and would receive regular testing to monitor health.
However, in other cases, ‘rogue doctors’ can recruit patients with unproven and potentially dangerous treatments. In such cases, patients are often not given the opportunity to full understand the risks involved so they can make ‘informed consent’. In such cases, patients are sometimes victims of unscrupulous practitioners and are at risk of adverse outcomes. I would encourage any CFS patient that has been given Rapamycin/Rapalog treatment without being told of the risks outlined above to seek further independent medical advice.
To Rapamycin or not to Rapamycin, that is the question: I couldn’t find any publications for the use of Rapamycin or Raplogs in the treatment of CFS in scientific or medical journals (using PubMed). Reports of cures for any disease in the press and online without any detailed publication in a scientific/medical journal is usually the first alarm bell that warns of potential quackery, medical exploitation or unscrupulous practitioners spruiking costly and sometimes ineffective or dangerous ‘treatments’. The best way to minimize risk in any treatment is to be well informed. In the absence of any cure, this forum provides a wonderful resource and fantastic information for all of us struggling with CFS. In frustration with a disease that stubbornly refuses to respond to most treatments, many of us (including myself) have sometimes tried unproven therapies. It is fantastic that this forum allows us to discuss our outcomes in trying to manage CFS. However, with any unproven treatment, the balance between risk and benefit needs careful consideration.
Rodger
References:
Cell Metab. 2014 March 4; 19(3): 373–379.
J Clin Invest. 2013;123(3):980–989
Cancer Cell 2007
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