Isoprinosine Update: Immunovir - Een veelbelovend, betaalbaar en veilig antiviraal medicijn

Door Alina Garcia MD, fibromyalgie en vermoeidheid Centrum, Las Vegas

Uit recente onderzoek, (gepresenteerd tijdens de 2009 International Association van de chronisch vermoeidheidssyndroom conferentie in Reno, Nevada Conferentie door de Universiteit van Miami), bleek dat Isoprinosine (ISP) een veelbelovend potentieel heeft voor de behandeling van het chronisch vermoeidheidssyndroom Immune Deficiency Syndrome.

Zestig patiënten werden onderzocht, en de behandeling heeft bij alle patiënten geleid tot klinische en immunologische verbetering.

Isoprinosine (ISP), een niet-giftig immuunsysteem stimulerend medicijn, is een nucleoside, dat is een basische verbinding, bestaande uit cellen. Het is uiterst veilig en is in Ierland en Canada al 20 jaar beschikbaar. Tot nu toe is ISP niet uitgebreid gebruikt in de VS. Hoewel de Universiteit van Miami een kleiner onderzoek heeft gedaan, en een groter placebo gecontroleerd onderzoek noodzakelijk is, zijn deze voorlopige resultaten veelbelovend voor patiënten van deze meedogenloze aandoening.

ISP is uitgebreid onderzocht in aids-onderzoek en subacute scleroserende Pan encefalitis (SSPE). Onderzoekers in Brazilië hebben resultaten gepubliceerd waaruit bleek dat ISP zelfs de replicatie van viraal RNA mogelijk kan remmen. Latente virussen worden vaak geassocieerd met chronische vermoeidheid en fibromyalgie.

ISP heeft aangetoond een belofte te zijn voor de behandeling van CFIDS. Specifiek via zijn immuun modulerende functies. Cheney, et al., heeft aangetoond dat de ISP de Natural Killer (NK)-cel functie verbetert, die zoals bekend onderdrukt is bij veel CFIDS-en FM-patiënten.

Ik gebruik al een aantal jaren Isoprinosine bij geselecteerde patiënten met in de meeste gevallen gunstige klinische uitkomsten. ISP is kosteneffectiever dan de andere immuunmodulatoren en kan daarom een meer haalbare optie zijn voor sommige patiënten. De Fibromyalgia and Fatigue Centers Inc.zijn gewijd aan de behandeling van chronische vermoeidheid en fibromyalgie met behulp van een geďntegreerde alomvattende aanpak.

Merk namen:

  • Delimmun
  • Groprinosin
  • Imin
  • Immunosin
  • Immunovir
  • Imunovir
  • Isovir
  • Isprinol
  • Pranosine
  • Qualiprinol
  • Viruxan

Update on the Antiviral Isoprinosine (Immunovir)

Monday, June 29th, 2009:

 by Jacob Teitelbaum MD

New research is suggesting that the prescription antiviral Immunovir (Isoprinosine) may be very helpful in treating viral infections in CFS. Though prescription, it is not approved in the U.S., so it isn't covered by insurance. Physicians in the U.S. (and elsewhere) can order it from Canada or Ireland. It is safe and well tolerated, and compared to other antivirals, relatively reasonably priced at about $100 per month. Though not needed for everyone with CFS, it offers another helpful treatment tool for the 15% who don't adequately improve with the SHINE Protocol, or for those with chronic symptoms suggesting a long term viral infection.

For more information on this helpful medication, how to dose it, and how your physician can order it, I invite you to read our guest article by Alina Garcia MD, an excellent CFS & fibromyalgia specialist who works at the Las Vegas Fibromyalgia and Fatigue Center.

 

Isoprinosine description

Isoprinosine is an immunomodulator and is approved for immunorestoration in chemotherapy in some countries. Patients on chemotherapy are particularly susceptible to different viral infections as a result of chemotherapy-induced immunodepression. Adjuvant therapy with Isoprinosine can restore the cell-mediated immune response to the individual's baseline levels.

It can therefore be prescribed during chemotherapy to restore the immune response and as a prophylaxis against reactivation of latent herpes simplex or herpes varicelliform zoster (shingles) infections, or for treatment or management of other secondary viral infections.

In these instances, the dosage used is the standard 50 mg/kg/day of lean body weight, up to a maximum of 3g daily (6x 500 mg tablets), divided evenly during waking hours. Schedule of treatment depends on the type of chemotherapeutic agent used. Isoprinosine is only administered after the infusion and only when the desired immune suppression against the cancerous cells has taken effect. At that point between infusions when it is desirable for the immune system to normalise, Isoprinosine treatment is initiated in order to enhance the normal immune response recovery. The number of treatment days depends on the length of time between infusions and also the immune profile of the individual patient.

Isoprinosine can also be administered for immunorestoration after chemotherapy, surgery or radiation.

Prescribing information, recommended dosage:

The prescribing physician will ultimately decide about the details of therapy (dosing, duration, etc.). According to dosing information obtained from published references; patients with cancer can take 2000 mg to 3000 mg of Isoprinosine daily for two months (4-6 tabs of 500 mg Isoprinosine per day). Then they may stop taking Isoprinosine for two months, and then resume taking it at the same dose for another two months.

How Does Isoprinosine work?

Isoprinosine is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses due to the drug.
The action of Isoprinosine can be summarized as follows:

--- Normalizes the cell-mediated immunity by stimulating the differentiation of T-lymphocytes into T-cytotoxic cells and T-helper cells and increasing lymphokine production
--- Increases production of IL-1 (interleukin-1) and IL-2 (interleukin-2) and IFN-? (gamma interferon)
--- Increases NK cell (natural killer cell) function
--- Increases the humoral immune response by stimulating the differentiation of B- lymphocytes into plasma cells and by enhancing antibody production
--- Increases the number of IgG and complement surface markers
--- Potentiates neutrophil, monocyte and macrophage chemotaxis and phagocytosis
--- Inhibits viral growth by suppressing viral RNA synthesis while potentiating depressed lympocytic
--- RNA synthesis and translational ability

Other benefits of Isoprinosine treatment: Studies have documented the ability of Isoprinosine to slow the progression of AIDS in HIV-infected persons by increasing the total number and activity of T-cells, T-helper cells and NK (natural killer) cells. The largest study, which was published in The New England Journal of Medicine on June 21, 1990 found that HIV infected people with CD4 cells count over 500 experienced significant benefits from Isoprinosine therapy. T-lymphocyte defects are common in cancer and AIDS patients according to a study in Medical Oncological Tumor Pharmacotherapy in 1989, which found that Isoprinosine and levamisole (another immune-boosting drug) mimic the actions of the thymic hormones to promote T-cell development. Combinations of Isoprinosine, low-dose Interleukin 1 and 2, and other immune-modulating hormones such as Melatonin are suggested as possibly effective cancer therapies.


Caution! Before starting to take this medicine, it is vital that you should consult your doctor! Do not use it on your own initiative, without medical advice.

Isoprinosine and Chronic Fatigue Syndrome (ME/CFS) Doctors Report: In 1999 Dr. Byron Hyde reported that a small Isoprinosine study was 'milestone' in the treatment of ME/CFS. Dr. Paul Cheney calls Isoprinosine a 'very good immune-modulator' and appears to have used it extensively to boost NK cell functioning and reduce Th2 dominance in the immune system. In 2007 Dr. De Meirleir stated that he felt that Inosine - an amino acid available in health food stores - was as effective as Isoprinosine.

Chronic Fatigue Syndrome (ME/CFS) studies - Few studies have assessed Isoprinosine's effectiveness in ME/CFS. After a small single blind, placebo-controlled trial of 16 patients in 1999 Dr.Hyde's published study (2003) indicated that 6/10 patients improved and that their natural killer cell activity and T-helper cell numbers increased but no changes were seen in IFN-y, IL-1@, IL-10 and IL-12 levels. At the 2009 IACFS/ME conference Dr. Hone reported that Isoprinsine conferred 'significant (clinical)improvement' and increased NK cell functioning and reduced Epstein-Barr Virus levels in patients with reduced natural killer cell activity.

Dosages:

Because of its immunomodulatory properties Dr. Cheney recommends staggering dosages:

According to Cheney, this medicine works best when you use this "pulsing" treatment of two months on, one month off, and the different amounts each week during the months that you are taking it, rather than taking it at the same dose all through the "on" months, or at the same dose continuously for six months. It may be that all immune modulators work like this, working better and for longer periods of time when they are pulsed.

First Month:

•Week One: 6 tablets a day (M-F)
•Week Two: 2 tables a day (M-F)
•Week Three: 6 tablets a day (M-F)
•Week Three: 2 tables a day (M-F)

Second Month: Repeat first month

Third Month: Stop Isoprinosine

Four Month: Repeat Month 1
Fifth Month: Repeat Month 1

Six Month: Stop Isopoprinosin

Dosering:

Eerste maand:

Week 1: 6 tabletten per dag  op maandag t/m vrijdag  (3x 2 tabletten met 6 uur tussentijd)
Week 2: 2 tabletten per dag  op maandag t/m vrijdag  (2x 1 tablet met 12 uur tussentijd)
Week 3: 6 tabletten per dag  op maandag t/m vrijdag  (3x 2 tabletten met 6 uur tussentijd)
Week 4: 2 tabletten per dag  op maandag t/m vrijdag  (2x 1 tablet met 12 uur tussentijd)

Tweede maand:  Herhaal eerste maand

Derde maand: Stop met Isoprinosine

Daarna: Herhaal eerste, tweede en derde maand.

Inname met water voor of tijdens een maaltijd of voedsel.

Isoprinosine vs  inosine

Unfortunately, a lot of Dr cheneys patients have found that inosine taken sublingually causes severe headaches. This came as a surprise, because isoprinosine taken orally had no such side effects. That is a definite indication that inosine is not identical to isoprinosine.

 

Warnings

  • This medication should not be used by children, care should be taken to keep Isoprinosine out of reach of children. This medication should be kept away from heat and moisture as they have been known to break down the medicine causing it to not work the way it should. This medication should not be taken by individuals with gout or those with a predisposition of developing gout.

    Read more: Isoprinosine Side Effects | eHow.com http://www.ehow.com/about_5568787_isoprinosine-side-effects.html#ixzz1F3BZMP5T



    •  

    Herpes Virus Expert Sheds Light on Chronic Fatigue Syndrome Mysteries

    by John W. Addington
    May 2, 2003

    Dharam V. Ablashi, DVM, MS, Dip.Bact., co-discoverer of unusual "juicy" white blood cells and current American Association of Chronic Fatigue Syndrome President, has done much to advance the understanding of the cause of Chronic Fatigue Syndrome (CFS).

    Dr. Ablashi has many more credits to his name. He is internationally renowned for his work with herpes viruses and has served on national and international scientific committees including NIH and W.H.O. He is Director of the Herpesvirus Programs at Advanced Biotechnologies Inc, and Adjunct Professor of Microbiology at the Georgetown University School of Medicine in Washington, D.C. Furthermore, Dr. Ablashi has shared in the publishing of over 285 scientific papers, 11 books, and he has lectured worldwide.

    However, it is Ablashi's research regarding human herpes virus 6 (HHV-6) particularly that has involved him with Chronic Fatigue Syndrome.

    Ablashi was working with the National Cancer Institute in the mid-80's when he and his associates discovered odd balloon-shaped white blood cells which they described as “juicy.” These researchers published their findings about this new virus in 1986. Later they confirmed this was a herpes virus, and as it was the sixth such virus to be discovered it was called human herpes virus 6.

    Other Herpes Viruses

    Other herpes viruses are involved in cytomegalovirus, chickenpox, infectious mononucleosis, herpes simplex, and shingles. The herpes virus that causes mononucleosis, Epstein-Barr virus, also know as HHV-4, was initially suspected as a cause of CFS. Ablashi has done research on this virus also and he published in 1995 that "the involvement of Epstein-Barr virus in CFS patients is diminishing." Nevertheless, he stated that there could "be a subset of CFS patients in whom Epstein-Barr virus may be a major contributing factor to disease manifestation."

    HHV-6

    As a childhood infection, HHV-6 can cause the rash-like condition roseola. Dr. Ablashi explains that, "HHV-6 infection usually occurs in childhood during the first year of life and then the virus becomes latent." HHV-6 has two forms designated as HHV-6A and HHV-6B. It is HHV-6B that is associated with roseola and over 90% of adults retain this virus dormant in their system throughout their lives. Ablashi states that "variant A is more common in AIDS patients and patients with CFS."

    As the research developed with HHV-6, many researchers, including Ablashi, performed studies to determine whether that virus might be the cause of CFS. These studies, while not always consistent, have often found a majority of CFS patients show signs of recurrent HHV-6 infections. This is not so with healthy persons.

    In a study published in the Journal of Clinical Virology, Dr. Ablashi and associates looked for unique signs of HHV-6 infection in 35 CFS patients. While dormant, HHV-6 can be detected in most adults. These researchers studied immune system markers that would detect reactivation or possibly active HHV-6 infection.

    Among the CFS patients, 54% showed evidence of HHV-6 reactivation whereas this was only true in 8% of the healthy individuals. Further testing over a two and a half year period revealed two subsets of CFS patients had persistent HHV-6 infection. Ablashi and his co-authors wrote that these results "show a significantly high frequency of HHV-6 reactivation in CFS patients…and a decrease in cellular immune responses."

    Hormone Imbalance and HHV-6

    Neuroendocrine function has often shown to be imbalanced in CFS patients. Neuroendocrine refers to the brain's control of proper hormone balance for good health. Thus the question arises as to how this relates to Ablashi's research on HHV-6.

    Dr. Ablashi offered this explanation. "First, the data generated by us clearly show that HHV-6 variant A is present in the cerebral spinal fluid of most, but not all, CFS patients. The virus seems, therefore, to be carried to the central nervous system (CNS) via [white blood cells], where it has been found to be latent. When the [white blood cells] come in contact with [brain] cells/tissues, somehow the virus becomes activated, spreads to the CNS and induces CNS manifestations. …This may be a method in which HHV-6A participates in neuroendocrine dysfunction."

    HHV-6 Treatment

    When asked about the potential treatment of HHV-6 infection for those with CFS, Dr. Ablashi offered some insightful comments. He states, "Dr. Daniel Peterson, with whom I collaborated on a CFS project, tried ganciclovir, foscarnet and Ampligen in his CFS patients, who were identified by us and two other labs, to contain active HHV-6 infection."

    Ganciclovir

    "Four patients treated with ganciclovir showed the presence of HHV-6A, even after anti-viral treatment. Only one patient improved slightly for a short while."

    Ampligen

    "Two patients treated with Ampligen improved initially and did make remarkable recoveries. When treatment was discontinued after 1 1/2 years, however, HHV-6A was found to be activated from latency and these patients started to show signs of the illness."

    Foscarnet

    "The patient treated with foscarnet improved greatly since he returned to work on a full time basis. We found no HHV-6A infection after foscarnet treatment. Another CFS patient treated elsewhere with foscarnet also improved greatly and returned to college. In her case, the viral DNA copies in the plasma and CNS after treatment were greatly reduced. Foscarnet, therefore, is quite effective in suppressing HHV-6A infection, but it is also associated with toxicity. Most physicians, because of this, are not willing to experiment with it."

    Whey Protein Combined with Foscarnet

    Patients considering foscarnet may be interested in research by Dr. Ablashi which tested the drug's effectiveness in combination with whey protein. Ablashi found that when used in combination with foscarnet, the effect is greater than each has individually.

    Conclusion

    Both through his ongoing research and his work with the American Association of Chronic Fatigue Syndrome, Dr. Ablashi has extended himself on behalf of those with CFS. And for that, the CFS community applauds him.

    For assistance with issues related to CFS and HHV-6, Dr. Ablashi can be contacted through: The American Association of Chronic Fatigue Syndrome, online at www.aacfs.org
    E-mail: Admin@aacfs.org; Voice mail: 206-781-3544.



    Dr Alblashi HHV-6 Foundation
     
    The HHV-6 Foundation is also engaged in finding and/or developing effective antiviral agents. Progress in this area has been slow; they have checked out over 60 compounds, only two of which (red marine algae, amantadine) have worked in more advanced testing. Dr. Ablashi noted, however, a variety of antivirals (ampligen, Isoprinosine, alpha 2a interferon (?), acyclovir, valcyclovir, valganclyclovir) that have been successful in small trials. Three of these will be covered in the Clinical trials session of the conference.

    Susan Levine. Incidence of HHV-6 and EBV infection in Chronic Fatigue Syndrome patients.

    The herpesviruses have long been of interest in CFS. Several researchers believe that EBV and HHV-6 reactivation plays an important role in a subset of CFS patients. Questions regarding proper diagnostic procedures have, however, muddied this issue considerably. Dr. Levine’s study was designed to bring some clarity to this issue.

    Dr. Levine employed a variety of different tests (EBV, HHV-6 – IgG, IgM, PCR; EBV – viral capsid antigen (VCA), early antigen (EA), EBV nuclear antigen (EBNA); HHV-6 – antigenemia), to determine if HHV-6 and EBV reactivation was present in CFS patients, and if it was, to determine the best means of testing for it.

    She found that CFS patients tested normally to two common antibody tests (VCA, EBNA) but that about a third of CFS patients – compared to zero controls – tested positive for high levels of antibodies to EBV’s early antigen (AG). About a third of the CFS patients also exhibited elevated levels of antibodies to HHV-6 and about 20% were positive in the HHV-6 antigenemia tests vs. zero controls.

    PCR tests of the blood lymphocytes indicated that the CFS patients all harbored the HHV-6A virus while the controls harbored the HHV-6B virus. Several researchers believe that not only are these different viral types but they are completely different viruses and should be denoted as such. (See HHV-6 and CFS).

    Dr. Levine’s study, then, presented evidence that a substantial subset of CFS patients have an active chronic low level herpesvirus infection. Antibody tests suggest that HHV-6A is active and replicating in about 30% of CFS compared to zero controls. EBV replication, on the other hand, does not appear to be occurring. Instead this study appears to back up Dr. Glaser’s theory that EBV is active enough in CFS to produce immune system altering proteins but is shut down before it can replicate.

     Amantadine

    Chronic Fatigue Syndrome (ME/CFS) Studies   - Amantadine was poorly tolerated by ME/CFS patients and showed little benefit in a cross-over study with carnitine.

    Chronic Fatigue Syndrome (ME/CFS) Doctors Report  - Over a small sampling of patients Dr. Bell found that 40% could not tolerate the drug (mostly due to jitteriness and anxiousness) and 40% reported from moderately improved to excellent results. Amantadine seemed to be most effective in treating moderately ill patients. Dr. De Meirleir reports Amantadine relieves fatigue in some ME/CFS patients.



    Recent research by others has shown that amantadine successfully inhibits Borna disease virus (BDV) in both cultured cells and in an infected human. Among the CFS patients we studied, some had antibodies against BDV in their plasma and BDV RNA in their blood. One group of these patients, from a single family, began using amantadine and found improvement in their CFS symptoms.

    To further investigate this dymanic, we administered amantadine to 22 patients with CFS. Three patients withdrew from the study because of side-effects from the treatment. The other 19 took 200 mg per day of amantadine for eight weeks. When we evaluated the effects of the substance on patients with and without antibodies against BDV in their plasma, 6 of 11 patients with BDV antibodies showed a good response, whereas only 2 of 6 patients without the antibodies showed improvement.

    There have been many conflicting reports about the effectiveness of amantadine on BDV. So the mechanism of the effect of this substance is unclear, but we consider it one of a range of therapies for some CFS patients


    Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome.
     

    Carnitine is essential for mitochondrial energy production. Disturbance in mitochondrial function may contribute to or cause the fatigue seen in Chronic Fatigue Syndrome (CFS) patients. Previous investigations have reported decreased carnitine levels in CFS. Orally administered L-carnitine is an effective medicine in treating the fatigue seen in a number of chronic neurologic diseases. Amantadine is one of the most effective medicines for treating the fatigue seen in multiple sclerosis patients. Isolated reports suggest that it may also be effective in treating CFS patients. Formal investigations of the use of L-carnitine and amantadine for treating CFS have not been previously reported. We treated 30 CFS patients in a crossover design comparing L-carnitine and amantadine. Each medicine was given for 2 months, with a 2-week washout period between medicines. L-Carnitine or amantadine was alternately assigned as fist medicine. Amantadine was poorly tolerated by the CFS patients. Only 15 were able to complete 8 weeks of treatment, the others had to stop taking the medicine due to side effects. In those individuals who completed 8 weeks of treatment, there was no statistically significant difference in any of the clinical parameters that were followed. However, with L-carnitine we found statistically significant clinical improvement in 12 of the 18 studied parameters after 8 weeks of treatment. None of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment. Only 1 patient was unable to complete 8 weeks of treatment due to diarrhea. L-Carnitine is a safe and very well tolerated medicine which improves the clinical status of CFS patients. In this study we also analyzed clinical and laboratory correlates of CFS symptomatology and improvement parameters.
     
    Dr Myhill: Acumen laboratories now routinely check A-L-carnitine levesl for me and they are almost always low in CFSs.



    Foscarnet
    This phosphonic acid derivative (marketed by Clinigen as foscarnet sodium under the trade name Foscavir) is an antiviral medication used to treat herpes viruses, including drug resistant cytomegalovirus (CMV) and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2). It is particularly used to treat CMV retinitis. Foscarnet can be used to treat highly treatment experienced patients with HIV as part of salvage therapy.[1][2][3]

    Mechanism of action

    Foscarnet is a structural mimic of the anion pyrophosphate[4] that selectively inhibits the pyrophosphate binding site[citation needed] on viral DNA polymerases at concentrations that do not affect human DNA polymerases. Because foscarnet is not activated by viral kinases it maintains activity against viruses like HSV and VZV that have respectively developed mutant thymidine kinase and UL97 encoded protein kinase, to gain resistance to other DNA polymerase inhibtors, like acyclovir and ganciclovir. Therefore, foscarnet is often used in acyclovir- or ganciclovir-resistant disease.

    However, acyclovir- or ganciclovir-resistant mutants with alterations in viral DNA polymerase may be resistant to foscarnet.[5][6]

    Administration     Intravenous only

    Side effects

    Nephrotoxicity - Increase in serum creatinine levels occurs on average in 45% of patients receiving foscarnet. Other nephrotoxic drugs should be avoided. Nephrotoxicity is usually reversible and can be reduced by dosage adjustment and adequate hydration.
    Electrolyte disturbances - Changes in calcium, magnesium (Harisson 16th ed page2244) potassium and phosphate levels occurs commonly and regular monitoring of electrolytes is necessary to avoid clinical toxicity.
    Genital ulceration - Occurs more commonly in men and usually occurs during induction use of foscarnet. It is most likely a contact dermatitis due to high concentrations of foscarnet in urine. It usually resolves rapidly following discontinuation of the drug.
    CNS - Paraesthesias,irritability and hallucinations


     

    In Development

    Artesunate - Artesunate is a well tolerated drug approved for malaria (in Europe) that possess antiviral activity as well. In vitro (lab) studies found it was highly effective against one of HHV-6’s cousins; the cytomegalovirus.

    An HHV-6 Foundation funded study indicates artesunate also effectively inhibits HHV-6A in the lab. This drug is particularly promising because, in contrast to ganciclovir and foscarnet, it hits HHV-6 early in its life cycle. If HHV-6 produces a kind of smoldering infection that alters cell functioning in ME/CFS and other diseases then hitting it early will be critical. What a boost it would be to find an already approved drug that was effective against HHV-6.

    Cycloprovir – analogue of ganciclovir but potentially much more effective against HHV-6. (Valcyte converts to ganciclovir in the body. Ganciclovir interferes with viral replication.

    CMX001 – a variant of Cidofovir – is highly effective again many DNA viruses and is 3x’s better than Cidofovir against all herpes viruses in the lab. Its antiviral activity in animal models is very good as well. In the first clinical study it was well tolerated.

    CMV423 – a new compound very effective against HHV-6 and cytomegalovirus

    HPMP-5-azal  – Six times more effective against HHV-6 than Cidofocir. Much more efficient and much less of the drug is needed. This is important because toxicity is a big problem with cfidovir. Possibly a big hit.
     

    Marabavir (MBV) – inhibits cytomegalovirus replication. Currently in Phase III trials. Good against EBV. Contrary to previous reports, possibly good against HHV-6. About 50-100 times more efficient than cidofovir in some tests.
     

    Arysulfone derivatives – good antiviral activity, among most potent of anti-virals.

     



     



    hhv-6foundation.webs.com


    Kutapressin is a drug which consists of processed extract from porcine livers that contain peptides. Nexco Pharmaceuticals has introduced a generic form of kutapressin, called Nexavir, which is based on the original formula. Kutapressin has demonstrated efficacy against HHV-6 in a 1994 in-vitro study  (Ablashi, Berneman et al. 1994) as it inhibited replication by over 90% and has also been used in the treatment of patients with herpes zoster. Results of uncontrolled studies have indicated that treatment with kutapressin results in the abatement of symptoms among many patients with CFS. Kutapressin has also improved the NK cell function in CFS patients.

    Ampligen,is a mismatched double-stranded RNA with broad antiviral and immunomodulatory properties produced by Hemispherx Biopharma, Inc.  Hemispherx recently completed Phase III trials for Ampligen as a treatment for CFS and is currently pursuing FDA approval of the product. In a 1994 study, Ampligen was found to inhibit replication of HHV-6A in in-vitro testing at concentrations of 100 and 200 pg/ml (Ablashi, Berneman et al 1994). When the Ampligen was removed from the virus-infected cell culture, HHV-6 infection reappeared slowly but never reached the same level as before. No toxicity of the cells was noted. In a 1995 randomized, double-blinded placebo controlled study (Strayer et al) of CFS patients, patients on Ampligen had improved Karnofsky performance scores, increased capacity for daily living (ADL), reduced cognitive impairment and improved work on the treadmill. Patients on Ampligen also required less medication to control their symptoms. 

     In 1994, Sudaholnik evaluated the 2-5A and RNAase L levels in 15 CFS patients before and after Ampligen treatment compared to healthy controls. Patients had lower levels of 2-5A and increased levels of RNAase L activity. Therapy with Ampligen resulted in significant downregulation of the 2-5A/RNAase L pathway. Also the levels of HHV-6 replication in PBMCs significantly decreased after treatment. For additional information regarding Ampligen, please refer to:http://www.hemispherx.net/content/rnd/drug_candidates.htm

    Whey protein ImmunoPro(which enhances glutathione production) was found to inhibit HHV-6 in testing done at Advanced Biotechnologies (Ablashi et al. unpublished data). Further, it was found to reduce the toxicity of foscarnet and potentiate the foscarnet (thus reducing the amount of dose administered) when the two were tested together. Of course, clinical trials are necessary to determine if there is any clinical benefit.

    Isoprinosine

    Isoprinosine is a synthetic purine derivative licensed in 1971 that exhibits both immune modulating and antiviral properties. Isoprinosine modulates T cell and NK function (Diaz-Mitoma et al., 2003). Isoprinosine did not exhibit side effects in safety studies or post-marketing experience (Diaz-Mitoma et al, 2003).

    Isoprinosine has been used by physicians in Europe for CFS patients with evidence of active HHV-6 infection, although no in vitro efficacy studies have been done specifically for HHV-6 infections.

    Isoprinosine is not currently available in the United States.

    Immunoglobulin

    Study results using intravenous immunoglobulin (IVIG) for treatment of CFS have been mixed. Several clinical studies have been done in patients with CFS utilizing IVIG compared to placebo. One double-blind, placebo controlled study of 30 CFS patients (Peterson et al. 1990) did not demonstrate symptom amelioration or improvement in functional status. A similar study of 99 CFS patients from Australia (Vollmet-Conna, 1997) also showed lack of statistically significant benefit of IVIG compared to albumen.  However, another randomized, double-blinded study (Lloyd et al., 1990) comparing monthly high-dose IVIG (2 g/kg) versus placebo showed improvement as defined by decrease in symptoms, increased functional status and improved immunologic measures. A study of relapsing/remitting MS patients (Fazekas et al., 1997) compared IVIG at smaller doses (0.15-0.2 mg/kg) to placebo. In this 150 patient study benefits were noted in the IVIG  group as measured by the Kurtzke expanded disability status score. Over 90% of immunoglobulin batches tested by Dr. Sudhir Gupta of at University of California, Irvine contained IgG antibody to both HHV-6 and EBV at levels sufficient to inhibit the cell free virus.

    While the reasons for the discrepancies among these studies remains unclear, it is thought that if humoral immunity is more important than cell mediated immunity to control an HHV-6 infection then IVIG would be a valuable treatment. IVIG is also expensive and is associated with a variety of adverse effects.

    Interferon:

    HHV-6 infection induces production of certain cytokines from infected macrophages which play a role in controlling and containing the viral infection (Inoue et al, 1993). One of these cytokines, Interferon, has broad antiviral properties and has been shown to have in vitro activity against HHV-6 infections. 

    However there is little information regarding treatment of HHV-6 with any of the three types of interferon. Treatment with alpha interferon has contributed to improved quality of life scores in CFS patients (See & Tilles, 1996). Interferon beta has been used to treat MS patients for over 20 years as it has shown effectiveness in decreasing the progression of the disease and reducing disability (Fillipini, 2003), particularly with relapsing/remitting MS.

    One group demonstrated in vitro that interferon beta at concentrations of 0.5 ug/ml reduced the replication of HHV-6 in a line of T cells. Additionally, they examined the sera of MS patients treated with interferon beta compared to control MS patients and found that the treatment group had reduced levels of HHV-6 DNA and lower levels of IgM antibody reactivity. The group also noted that the sera obtained after treatment showed decreased levels of HHV-6 DNA as compared to the pretreatment sera. Another study (Alvarez-Lafuente, 2004) evaluated 105 patients with relapsing/remitting who were treated with interferon beta, and compared them to similar patients who were not treated and found that the viral load was twice as high by quantitative PCR in the untreated patients versus the treated cases. These effects were only seen during relapse; no differences were seen when patients were in remission. Additionally, all cases of HHV-6 were variant A. Thus, interferon beta may exert some of the same antiviral properties exhibited in HHV-6 treatment as for MS.

    Interferon therapy is associated with several adverse effects including fever, fatigue, myalgia, nausea, and headache, among others (Fillipini, 2003)

    Transfer factor:

    Transfer factor (TF) is a molecule that can transfer cell-mediated immunity from an immune donor to a non-immune recipient. TF seems to have the properties of a cytokine that can induce an immune response in the recipient. While TF is antigen specific, it is not species specific and can thus be transferred from one species to another without an allergic reaction in the recipient. There are several potential sources of TF; one of the most common is and accessible is bovine colostrums (Jones, 2003).

     

    Few studies have been published regarding the efficacy of TF. One study described 28 patients given TF from bovine colostrum with specific activity for HHV-6 compared to 10 patients who were given TF devoid of activity for HHV-6. The group given the HHV-6-specific TF showed significant improvement in symptom s as well as improved NK immune function compared to the placebo group (Fudenberg and Pizza, 1989; Brewer and Wilson, 2003).

    Another report (Ablashi et al, 1996) was published on the treatment of two CFS patients with active HHV-6 infections treated with HHV-6 specific TF. One patient improved rapidly and resumed normal activities and the other patient did not improve. These studies, among others, have reported no adverse effects from the use of TF. However, if the patient is lactose intolerant he or she should not use the TF from colostrums but find another source of HHV-6 specific TF, such as human cell line. While the data for TF in the treatment of HHV-6 infection is limited, it may be an attractive option that warrants further investigation as it has proven to be an effective therapy in some cases and has a clean safety record. 



    Inosine

    Inosine is a precursor to adenosine, an important energy molecule, and plays many supportive roles in the body.  Inosine is a small molecule that helps restore nerve function and is one of the few supplements shown to help regrow nerve connections in laboratory animals.  It is being used in research and by some physicians for patients with MS, stroke injury , brain injury and autism.  It is most effective when administered at the time of injury.  It is used in France and Russia to improve energy production in the heart.

    In 2002, researchers at Harvard's Children's Hospital, lead by Dr. Larry Benowitz, began using Inosine to switch damaged nerve cells in the cerebral cortex into a growth state. In 2002, they reported that inosine helped stroke-impaired rats to regrow nerve connections between brain and spinal cord and partially recover motor function.  Benowitz's team reported that inosine could cause nerve cells in rats to sprout new axons -- the tendrils that nerve cells reach out to one another with.

    The protein, called inosine, acts as a kind of master switch to turn on a number of genes involved in the growth of nerve cells, the team at Boston's Children's Hospital and Harvard University reports.  "Inosine switches on a whole constellation of genes," Dr. Larry Benowitz said.

    Benowitz indicated his team found that inosine can cause severed nerves to regenerate axons in rats. "It juices them up nicely," he said, but adding that the experiment will have to be repeated before he can be sure it really works the way he thinks it does.

    Benowitz said his team found in the latest experiment, published in the Journal of Neuroscience, that inosine passes through the nerve cell's membrane and activates an enzyme that in turn controls the cell's molecular program for axon growth.

    "We think it is directly targeting and activating a protein kinase, an enzyme, inside the cell, that is the linchpin of the signaling pathway that activates growth," Benowitz said. Inosine promotes the production of a substance known as 2,3-DPG that is necessary for the transport of oxygen molecules from the red blood cells to body tissues for energy.

    In 2004, Dr. Craig Hooper and colleagues at Thomas Jefferson University, Philadelphia, administered inosine to 11 people with MS in a study.  Among 11 people taking inosine for 10 or 15 months,  neurological exams showed some clinical improvement in three patients, and stability in 8 patients. Some areas of myelin damage seen on MRI in two patients could not be detected after treatment (Multiple Sclerosis, October 2001). Based on these findings, a larger study is underway at the University of Pennsylvania, comparing inosine to placebo in 30 people with relapsing-remitting MS.

    Precaution:  Although it has few or no side effects, inosine is broken down to the purine end-product, uric acid.  Because of this, inosine supplements should not be used in people with a history of gouty arthritis, hyperuricemia or purine autism unless being monitored by a physician. Pregnant women and nursing mothers should also avoid its use.

    Recommended Dose: 1 capsule

    Amount per capsule: Inosine (hypoxanthine ribose) - 500 mg

    Other ingredients:  magnesium stearate, silicon dioxide

     

    Het gebruik van Isoprinosine, een immuunstimulerend middel, is o.a. getest in de Scandinavian Isoprinosine-trial bij HIV-patiënten. 2 patiënten in de ISP groep en 17 in de placebo-groep ontwikkelden AIDS. En bij CVS, met zeer goede resultaten. Studie NEJM