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 patiŽnten werden onderzocht, en de behandeling heeft bij alle patiŽnten 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 patiŽnten van deze meedogenloze aandoening.

ISP is uitgebreid onderzocht in aids-onderzoek en subacute scleroserende Pan encefalitis (SSPE). Onderzoekers in BraziliŽ 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-patiŽnten.

Ik gebruik al een aantal jaren Isoprinosine bij geselecteerde patiŽnten 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 patiŽnten. De Fibromyalgia and Fatigue Centers Inc.zijn gewijd aan de behandeling van chronische vermoeidheid en fibromyalgie met behulp van een geÔntegreerde 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:

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


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    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-patiŽnten. 2 patiŽnten in de ISP groep en 17 in de placebo-groep ontwikkelden AIDS. En bij CVS, met zeer goede resultaten. Studie NEJM