Friday, December 22, 2017

The Use of Autologous T-Cell therapy in Chronic Fatigue Syndrome

The technology for autologous (self-generated) EBV cell destruction development has been stable for two decades. Contemporaneously, a paper was published in Medical Hypotheses about this viability of this treatment. The main difference is the aggregation in lymph nodes, while I believe it to be more CNS-specific. 

If one views the literature, a few themes emerge:
  • EBV-CTL therapy can be effective against imminently fatal and uncontrolled illnesses, such as Stage 4 Nasopharyngeal Carcinoma
  • It is the only effective treatment for chronic active Epstein Barr Virus, which is fatal. Case reports did try Rituximab in 2000, 8 years before the CFS case report.
  • Has one of the best safety profiles I have ever seen in a drug. This is almost certainly due to the patient population.

Atara Biotherapeutics is now using allogenic (non-autologous) EBV cytotoxic cells in Phase I for MS, a study in France is completing a similar study for Lupus. 
EBV is a purposeless fatigue-causing virus safely ensconced in the CNS, and reducing it should reduce fatigue burden in select populations, notably those EBV positive. Other herpesviruses can be completed using this process, but EBV is the most stable train.

EBV has a tepid history within CFS, but the technology for detection of specific epitopes in post-viral EBV CFS has tightened and so has the criteria for inclusion in studies.

Future posts will talk about the rationale of hematopoetic and adipose mediated stem cell transplantation in CFS, as well as CFS being as a derivation of cytokinetically-inverted Multiple Sclerosis.

The Use of CMV-IVIG in Chronic Fatigue Syndrome

Two failed trials for intravenous immunoglobulins exist within the compendium of CFS history, at separate dosage intervals. Sporadic accounts of improvements with higher dosing regimens and frequency are available, as one of the criticisms was the dosing was too low. In practicality, since no insurance company will cover this without co-morbidity, the treatment then costs tens of thousands in the United States.

Evidence suggests that CFS patients have a 70% infectious onset, assume half of those conservatively are EBV-mediated (influenza, parvovirus, rhinovirus, mycoplasma, HIV, lyme as clinically experienced remainders), with an additional 5% (conservative) CMV-mediated.

An alternative to these ambiguous and un-targeted enhancement of the B-cell milieu would be a pilot trial of CytoGam. This drug is not really used in transplants frequently because from a pharmacoeconomic standpoint, it is more efficient to simply use higher amounts of immunoglobulins. Under the current conceptual framework of CFS, this extra IgG is not helpful and may be deleterious, common wisdom (if it is correct) dictates CFS is an issue of defective T-cell and NK cell subset dysregulation.

Loebel et al. 2014 says that both T- and B-cell subsets are defective in chronic fatigue syndrome, and they did not even isolate post-viral onset categories.

I still think Autologous t-cell transplantation is a better modality, but perhaps this one is more palatable in the current climate. 

Saturday, September 2, 2017

Hiltonol in Chronic Fatigue Syndrome

For new readers seeking CFS treatment, Ampligen is a drug that underwent Phase III trials for CFS patients for a few decades and was eventually not approved by the FDA for widespread use. One center in the United States is currently treating patients on a cost-recovery basis but is not accepting new patients at this time. As of 2017, the European status is unknown.

Bottom line: The subset of patients Ampligen helps, so should interferon or hiltonol. 


This post pre-supposes three ideas that are welcome to correction.

- The first is that Ampligen operates primarily as an interferon inducer. But what about RNAse-L? Well Carter certainly couldnt patent poly(ic) as an inteferon inducer because that already occurred as early as 1971, if not earlier. The original clinical trial of Ampligen included IV Poly(i:c) (I cannot currently find it, but its clear the dose was too high and the participants were in world of hurt).

- That Ampligen is not materially different from Poly(I:C), other than the modification at 12 causes less side effects at a similar dose, because of less interferon production.

- Now the biggest stretch The interferon increase will be helpful in enough CFS patients. The temporarily lapse of symptoms in a subset of CFS patients treated with interferon and the steady administration requirement of Rintatolimod suggests the helpful effect is mediated by interferon production.

Thus, interferon alone could help those individuals that Ampligen helped. Further, that Ampligen is bioavailable in small intranasal doses, as is hiltonol (looks like this clinical trial bit the dust) making the route of administration requirement of intravenous ostensibly moot. 

Enter Poly(I:C)LC, an analogue with a lysine modification will increase half-life (as the half life of Ampligen is about 40 minutes and needs biweekly administration). 

Although this is purely speculative, perhaps Ampligen increases the amount of interferon at a ratio specifically helpful to CFS patients, and one runs the risk of deleterious effects with IFN-a or IFN-b alone (Ampligen increases type 1 interferons) but no one ever ran a trial of IFN-b.

Moreover, it is unknown if interferon neutralizing antibodies exist in Ampligen treatment - although after repeated administration of Poly(I:C) interferon stops being efficiently released (this too is cited from the mysterious first Ampligen paper I cannot find, keywords "Carter" "T'So" "1977" or "1975" "Virus").

Ampligen is said not to be immediately curative due to its short half-life and effects and requires repeated dosing. Perhaps not convincingly in the slightest, Poly(IC:LC), or hiltonol, was not effective in the treatment of multiple sclerosis in the 1980s.

Further confouding matters is that interferon treatment can feel like CFS itself, MS patients report malaise and researchers even proposed modeling CFS after an interferon based model.



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Thank you for reading, and I am glad to hear you have cured your CFS through any means necessary. I urge you to consider how your treatment will apply to such a heterogeneous population and the irregular dosing regimens of human blood required to retain activity levels, but appreciate the anecdote. 

Next up are the trials of the most obscure drugs for CFS and some unorthodox ones that were doomed from the start.