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Thread: The Cheap, Safe and Effective Treatment for Multiple Sclerosis That the Drug Companie

  1. #1

    The Cheap, Safe and Effective Treatment for Multiple Sclerosis That the Drug Companie

    The Cheap, Safe and Effective Treatment for Multiple Sclerosis That the Drug Companies are Trying to Keep Secret





    In a recent interview, a victim of Multiple Sclerosis revealed how she has been symptom-free for the past 10 years. The success she has experienced has compelled her to bring her research to the medical community in hopes of helping other MS sufferers. The National MS Society (backed by the pharmaceutical industry which funds it) has actively suppressed her.

    Mount Jackson, VA (PRWEB) May 25, 2007 -- In a recent interview, a victim of Multiple Sclerosis revealed how she has been symptom-free for the past 10 years. The success she has experienced has compelled her to bring her research to the medical community in hopes of helping other MS sufferers. The National MS Society (backed by the pharmaceutical industry which funds it) has actively suppressed her.

    MS has been extensively researched, yet it is still unknown exactly what causes it. The medical community has been focusing on the idea that it is an autoimmune disease since 1935. The common theory is that the immune system is attacking Myelin, the insulation on the nerves; however, there is no proof of this.

    more:

    http://www.emediawire.com/releases/2007/5/emw528759.htm

  2. #2
    MS is a perfect disease for scam artists and medical fraud. Since 85% of people with MS have RRMS (relapsing-remitting) and some may have prolonged periods of remission, it is very easy to pick out a few people who had a spontaneous remission after trying some new "treatment" and claiming that the treatment was successful.

    The claim that that NMSS is supressing a cure is a bogus as the claims that the Spinal Cord Society makes that health care professionals are in a conspiracy to prevent a SCI cure for fear we will be put out of our jobs. The NMSS spends millions every year supporting research of new therapies that have a legitimate research foundation, and are being conducted by researchers who have appropriate training and credentials. They are not going to support a bogus therapy that has no scientific basis.

    (KLD)

  3. #3
    Agree w/KLD. MS can go into remission for a day, a week, a month or years. What is being claimed is bogus and potentially harmful.

    The MS Sociiety is not suppressing a real cure or treatment. One woman's "story" does not a cure make, especially when it comes to MS.

  4. #4
    Super Moderator Sue Pendleton's Avatar
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    It said she did her own clinical trial and then people at NMMS had a problem with the results? And she said they never got a preview copy. Hmmmmm Even if she did a small clinical trial of say 10 patients that would cost at least $1 million over the couple years to treat, unblind and interpret results. Not many nurses I know can cash million dollar checks..
    Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

    Disclaimer: Answers, suggestions, and/or comments do not constitute medical advice expressed or implied and are based solely on my experiences as a SCI patient. Please consult your attending physician for medical advise and treatment. In the event of a medical emergency please call 911.

  5. #5
    There is more to this story than meets the eye. On the surface, the story seems to be straightforward. A person who has or had MS claims that taking histamine and caffeine improves symptoms of fatigue and prevents progression of the disease. She puts the compounds in a dermal patch, called it Prokarin, and starts to market it, using patient testimonials. Because MS is a relapsing-remitting disease in many people, testimonial cases of remissions are not convincing to professionals. All the authorities on the subject seem to be lined up against this therapy. It would seem to be an open and shut case of wishful-thinking and marketing.

    In his article Be Wary of Multiple Sclerosis “Cures“, Stephen Barrett points out that the Therapeutic Claims Committee of the International Federation of Multiple Sclerosis Societies has analyzed more than a hundred alleged treatments and published the results in a book called Therapeutic Claims in Multiple Sclerosis (Source). This committee has decided that there isn't sufficient information on Prokarin to warrant recommending it as therapy. Barrett states that if any compounding pharmacy is selling Prokarin, they should be investigated for what they are claiming.

    According to Laurie Long in an article entitled The Prokarin Controversy, Prokarin was developed by a nurse, Elaine DeLack, who used a transdermal patch to deliver compounds that had been previously approved by the FDA to treat fatigue: caffeine and histamine. In 1988, she apparently searched the literature and found a 1944 paper by Bayard T. Horton of Mayo Clinic who had treated 102 MS patients with intravenous infusions with histamine, reporting that 60% improved. She first injected herself with small amounts of histamine twice a day and then made a cream, adding caffeine and covering it with an adhesive patch. She patented the use of this cream and licensed the rights to make it to independent compounding pharmacists (Source).

    In 2002, the Tahoma Clinic carried out a double-blind randomized placebo-controlled clinical trial of Prokarin. The clinical trial treated 21 people with Prokarin for a 12-week study period. Five individuals took a placebo. Published in Multiple Sclerosis, a well-respected peer-reviewed journal (Gilson, et al., 2002), the study concluded that there is a “modest statistically significant effect of Prokarin on fatigue as measured by the MFIS (fatigue impact scale). The average percent improvement was 37%. No side effects or adverse effects were observed.

    The National MS Society, however, thought that the trial design made the results difficult to interpret and that the sample size was small. They also thought that there may be potential confounding effects of caffeine. The response by the authors to the criticism was reasonable. For example, they point out that the small number of patients in the study is based on a formal power analysis they had carried out, based on expectations of a large improvement in the fatigue score. Indeed, interviews of patients had indicated that the most common effect was reduced fatigue and the improvement was sometimes obvious within hours after instituting therapy. The trial design is quite standard although they only had 5 control subjects, smaller than usual.

    There were two other criticisms of the study. First, the secondary endpoints of the study were motor and cognitive function. These were not statistically significantly different in the Prokarin group compared to controls. On the other hand, the study did show that within the Prokarin group, there were statistically significant improvements of motor and cognitive function when comparing pre-treatment and post-treatment results. The authors agreed that such differences were not as convincing as the those between the treatment and control groups. They did not emphasize these differences in their paper. The second criticism was that people taking Prokarin often developed a skin reaction at the patch site and this may have broken the blind, hence providing an inadvertent placebo effect.

    Usually when this kind of situation arises, a second clinical trial is carried out to resolve the questions. For example, a second study with more patients, particularly in the control group, would help dispel some of the misgivings concerning sample size. The unblinding issue can perhaps be handled in several ways. The patients could be interviewed to see if they could tell whether they were in the treatment or control group. If the patients did not know or had not thought that the skin reaction meant that they were in the treated group, this may not be a problem. Alternatively, in future trials, it may be possible to give the drug through another route, such as a drug pump.

    So, you start to wonder what is going on. It turns out the that Tahoma clinic is not at all a regular medical clinic. It is an alternative medicine clinic headed by Jonathan V. Wright MD, a Harvard graduate and Michigan MD who co-founded the American Quack Association (AQA). Wright began to practice “nutritional medicine” in 1973 in the Tahoma Clinic, located in Kent, a few miles southeast of Seattle. According to Stephen Barrett (Source), Wright achieved considerable notoriety in the 1990's battling the FDA. In 1991, FDA enforcement officers seized 103 bottles of L-tryptophan after it was implicated in an outbreak of eosinophilia-myalgia syndrome but Wright continued to prescribe it. He countersued and the FDA counter-investigated by posing as patients, and so on. The story reads like a soap opera but it is real.

    Unfortunately, no further study has been carried out since the clinical trial in 2002. Perhaps this is because the study was affiliated with the Tahoma Clinic and the rocky relatonship between this clinic and the FDA does not help. However, I suspect that the main reason is that there is no commercial interest in developing this treatment. Since Elaine DeLack patented and licensed the treatment to compounding pharmacies, no company would be interested in funding a clinical trial. Elaine DeLack formed EDMS LLC, which calls itself the “Innovators of Prokarin™“ (Source). DeLack has a DVD telling the Prokarin story (Source).

    According to a Virginia Pilot article by Alexandria Berger published on April 10, 2000 (Source), over 600 physicians are prescribing Prokarin in the U.S., Canada, and Australia, and 1,600 MS patients are now taking it. Presumably, there are more today. The cost is about $250/month. For example, one compounding pharmacy charges $196 for a one-month supply plus $40 shipping (Source). Interestingly, the web site for the compounding pharmacy warns that Prokarin lowers calcium levels in the blood and that people should take supplemental calcium of 1.5-2.0 grams of calcium. The web site has many testimonials (Source) from patients that have been using the treatment for many years.

    The authors of the clinical trial from the Tahoma Clinic also wrote two papers addressing the mechanism of transdermal histamine treatment for multiple sclerosis (Gilson, et al., 2002ab). The first paper reports their preliminary experience at the Tahoma Clinic treating 55 patients with transdermal histamine, finding that two-third of the patients show improvements of one or more symptoms: extremity strength, balance, bladder control, fatigue, activities of daily living, and cognitive function. These effects apparently were sustained over periods of 3 months or longer. They considered various mechanisms of histamine, including increased blood flow, increased excitability of demyelinated axons, increased cerebral blood flow, suppression of autoimmune responses, and stimulation of remyelination.

    I am wondering why the MS community has not demanded that Prokarin be tested in a larger clinical trial to determine whether this treatment is effective. The absence of a well-understood mechanism is not usually a reason for not doing a clinical trial on a treatment. For example, the mechanism by which interferon-beta is beneficial in MS is still not well-understood. The FDA does not require mechanism in order to conclude efficacy of a therapy.

    I did a literature search for possible relationships of histamine and multiple sclerosis. The search revealed several possibly relevant studies.

    • Theoharides & Konstantinidou (2007) pointed out that mast cell specific tryptase is elevated in the CSF of MS patients. Mast cells are blood cells that carry and release histamine. They suggest that brain mast cell inhibition and corticotropin-releasing hormone antagonists may offer novel therapeutic possibilities. The finding that MS patients have elevated mast cell tryptase in the CSF is interesting because it suggests that these cells may be involved in MS especially during relapses. These authors believe that the mast cells may be having a deleterious effect but the mast cells and the histamine release may be beneficial.

    • Musio, et al. (2006) points out that histamine regulates cytokine networks and studied EAE in histidine carboxylase deficient mice (HDC-/-). These mice are of interest because they are genetically incapable of making histamine. They found that EAE is significantly more severe in these HDC-/- mice. This would tend to support the theory that histamine is beneficial for MS. The authors suggest that endogenous histamine regulates teh autoimmune response against myelin and expression of EAE.

    • Alonso, et al., (2006) examined the relationship of allergic diseases and MS. Histamine 1 (H1) blockers were found to reduce the severity of experimental autoimmune encephalomyelitis (EAE, an animal model of MS). So, using case control methods, the authors identified 163 cases of MS with at least 3 years of assessment before their first symptoms. They examine the cases for history of allergic conditions in the 3 years before first symptom. They found no relationship of history of allergic conditions to MS risk. However, the use of sedating H1 receptor blockers were associated with decreased MS risk, suggesting a possible beneficial effect of H1 receptor blockers. This would seem to argue against histamine itself being beneficial in MS.

    • Logothetis, et al. (2005) did an open label trial using hydroxyzine, an H1 receptor blocker, to see if it reduced symptoms on people with MS. This drug inhibits mast cells and has anxiolytic properties as well. Twenty patients with relapsing-remitting or relapsing-progressive MS completed the 12-month study. Most of the patients on hydroxyzine remained stable or improved neurologically and all by one showed improved mood. Please note that this is an open-label non-controlled trial that would not provide any reliable conclusions. I cite this study because I find it interesting that somebody would take the trouble to carry out such a trial but not retest Prokarin.

    • Kraus, et al. (2004) showed that interferon-beta (IFN-beta) inhibited permeability changes of the blood brain barrier (BBB). This is of interest because the permeability of the BBB increases, especially where there are MS plaques in the brain. They suggest that this significantly contributes to the beneficial effects of IFN-beta treatment of MS. This study is of interest because histamine may play a role in opening up the BBB. For example, histamine has long been known to increase vascular permeability, in the periphery (Twycross, et al., 2003)

    • Lieb, et al. (1998) reports that histamine induces IL-6 expression in human astrocytoma cells by mechanisms involving protein kinase C and nuclear factor IL-6. This is of particular interest because IL-6 has been recently implicated as one of the critical neural gene responses associated with regeneration. The effect of histamine in inducing IL-6 appear to be controlled by NF-IL-6 and requires the transcription factor NF-kappa-B.

    • Rozniecki, et al. (1995) reported elevated mast cell tryptase in cerebrospinal fluid of MS patients. Mast cells are located perivascularly in the brain opposite to neurons and have been shown to secrete vasoactive and inflammatory mediators, in addition to histamine. While they found elevated tryptase, they did not find elevation of histamine or its major metabolite methylhistamine. This is puzzling since mast cells contain and release histamine. One possibility is that the mast cells have released and hence are depleted of histamine in MS by the time the cerebrospinal fluid is collected. There may have been an initial release of histamine.

    • Merrill & Mohlstrom (1987) examined the effects of histamine on killer cells obtained from people with MS, using an assay of antibody-dependent cellular cytotoxicity (ADCC) to oligodendrocytes. They found that ADCC was depressed in killer cells from MS patients. However, this can be boosted to normal control levels by histamine binding to H1 receptors of the cells. Interestingly, cimetidine (an H2 receptor blocker) also elevated ADCC of the cells. The authors concluded that endogenous histamine production and H2 receptor binding could be mediating a suppressive effect of MS ADCC to oligodendrocytes.

    In summary, while there are not many studies, some of them are intriguing enough to warrant further investigation. Several investigators have reported that mast cell specific tryptase is elevated in the cerebrospinal fluid of MS patients, suggesting a possible role of these cells which carry and release histamine (Theoharides & Konstantinidou, 2007). These cells are known to be present in the perivascular space of the brain. While the investigators speculated that these cells play a deleterious role, they may be also have a beneficial role. This notion is supported by the work of Musio, et al. (2006) who found that mice that cannot make histamine have significantly worse experimental allergic encephalomyelitis (an experimental model of MS in mice). One study of H1 histamine receptor blockers have yielded equivocal results (Logothetis, 2005) while another retrospective correlation study suggested that taking of H1 receptor blockers by allergy sufferers may be associated with a reduced risk of MS (Alonso, et al., 2006) although allergy suffering itself does not seem to be related. One possibility is that there may be a histamine depletion in patients with MS, perhaps accounting for why their cerebrospinal fluid levels show increase mast-cell specific tryptase but no histamine or methylhistamine (Rozniecki, et al. 1995). Finally, one early study (Merrill & Mohlstrom, 1987) suggest that killer cells from MS patients have suppressed responses to oligodendrocytes and that cimetidine blockade of H2 receptors reverses this suppression, suggesting that endogenous production and H2 receptor binding could be suppressing the killer cell response to myelin-producing cells. Thus, there appears to be some grounds for considering a beneficial effect of histamine in MS.

    Wise.

    • Gillson G, Richard TL, Smith RB and Wright JV (2002). A double-blind pilot study of the effect of Prokarin on fatigue in multiple sclerosis. Mult Scler 8: 30-5. In this 12-week study with 29 subjects, the effect of Prokarin (n=22), a proprietary blend of histamine and caffeine, was compared to placebo group (n=7) for the following outcomes: 1) fatigue as measured by the Modified Fatigue Impact Scale (MFIS); 2) lower limb function as measured by timed walk test; 3) upper limb function as measured by the pegboard test; 4) cognitive function as measured by the Paced Auditory Serial Additions Test (PASAT); 5) serum caffeine level; 6) change in brain chemistry as measured by quantitative magnetic resonance spectroscopy assay of N-acetyl aspartate (NAA); and 7) safety as measured by routine blood chemistry, TSH and urinalysis. Data were acquired at baseline, 4, 8 and 12 weeks. The Prokarin group MFIS mean was significantly different rom the mean of the placebo group at 12 weeks (df=24, t=2.08, P=<0.02), with respective means of 37.40, SD=15.18, for the Prokarin group and 53.2, SD=11.39 for the controls. For the secondary endpoints (PASAT, 25 foot timed walk, peg test, and magnetic resonance spectroscopy [MRS]), there were no significant differences between the Prokarin-treated group and the placebo group. However, there were significant improvements within the Prokarin group for each of these measures for the pre- versus posttreatment comparison at 12 weeks. Serum caffeine data indicated that caffeine exerted no independent effect on performance. No laboratory abnormalities were seen, and the treatment was well tolerated. CONCLUSION: There was a modest-size statistical effect of Prokarin on fatigue in multiple sderosis (MS) compared with the placebo group. A larger trial is warranted, based on this pilot study. Life Diagnostics, Calgary, Alberta, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=11936486
    • Gillson G, Wright JV, DeLack E and Ballasiotes G (1999). Transdermal histamine in multiple sclerosis: part one -- clinical experience. Altern Med Rev 4: 424-8. Histamine has a long history of therapeutic use in many diseases, including multiple sclerosis (MS). Recently, transdermal histamine has been successfully employed for the amelioration of symptoms of both relapsing-remitting and progressive multiple sclerosis. This paper summarizes preliminary experiences with transdermal histamine for MS at the Tahoma Clinic: 67 percent of 55 patients using histamine transdermal cream had improvements in one or more areas, including extremity strength, balance, bladder control, fatigue, activities of daily living, and cognitive functioning, sustained for periods of up to three months. One-third of patients had improvements in three or more areas of functioning. Five possible mechanisms of action are postulated: augmentation of subnormal cerebral tissue levels of histamine; improved electrical function of demyelinated fibers; increased cerebral blood flow; suppression of autoimmune responses; and stimulation of remyelination. These will be discussed in detail in Part 2 of this article. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10608915
    • Gillson G, Wright JV, DeLack E and Ballasiotes G (2000). Transdermal histamine in multiple sclerosis, part two: a proposed theoretical basis for its use. Altern Med Rev 5: 224-48. This paper is the companion to an earlier publication, which discussed preliminary results of transdermal histamine use for ameliorating symptoms of both relapsing-remitting and progressive multiple sclerosis (MS). Here we include preliminary findings on the impairments of digestion and assimilation in MS patients seen in a private clinic. Although only a small number of patients was surveyed, an association was found between impaired gastric acid production, impaired protein hydrolysis, and subnormal plasma histidine levels in patients with MS. Impaired digestion might, therefore, impair the ability of MS patients to synthesize histamine. This paper discusses how impairment of histamine synthesis might lead to symptoms of MS, and conversely how exogenously administered histamine might alleviate symptoms. Various mechanisms of action are suggested, including: enhanced gastric acid and pancreatic enzyme secretion, augmentation of subnormal cerebral tissue levels of histamine, improved electrical function of demyelinated fibers, increased cerebral blood flow, suppression of aberrant autoimmune responses, and stimulation of remyelination. We also discuss the observed failure of digestive function in MS and point out that pathological changes which parallel CNS findings have been found in the enteric nervous system (ENS) of patients with Parkinson's disease. Similar parallels might exist between the CNS and ENS in multiple sclerosis. Tahoma Clinic, 515 West Harrison, Kent, WA 98032. gillson@uswest.net http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10869103
    • Theoharides TC and Konstantinidou AD (2007). Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci 12: 1615-28. Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA. theoharis.theoharides@tufts.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=17127408
    • Alonso A, Jick SS and Hernan MA (2006). Allergy, histamine 1 receptor blockers, and the risk of multiple sclerosis. Neurology 66: 572-5. BACKGROUND: It is unclear whether allergic diseases are associated with multiple sclerosis (MS), but histamine 1 receptor blockers, used in the treatment of allergic conditions, decreased the severity of experimental autoimmune encephalomyelitis (an animal model of MS). OBJECTIVE: To assess the association of allergy history and use of histamine 1 receptor blockers with the risk of MS. METHODS: Using a case-control study nested in the United Kingdom-based General Practice Research Database cohort, the authors identified 163 incident cases of MS with at least 3 years of follow-up before their first symptoms (index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Previous history of allergic disease and use of histamine 1 receptor blockers in the 3 years before the index date were assessed through computerized medical records. RESULTS: History of any allergic condition in the 3 years before the index date was not associated with MS risk (adjusted odds ratio [OR] 1.2, 95% CI 0.8 to 1.8). However, use of sedating histamine 1 receptor blockers was associated with decreased MS risk (adjusted OR 0.2, 95% CI 0.1 to 0.8). CONCLUSION: These results do not support a strong link between allergic conditions and multiple sclerosis (MS) risk but suggest a possible beneficial effect of antihistamines on the onset of MS. Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. aalogut@alumni.unav.es http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16505314
    • Logothetis L, Mylonas IA, Baloyannis S, Pashalidou M, Orologas A, Zafeiropoulos A, Kosta V and Theoharides TC (2005). A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis. Int J Immunopathol Pharmacol 18: 771-8. Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted. Department of Neurology, Aristotle University, AHEPA Hospital, Thessaloniki, Greece. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16388727
    • Musio S, Gallo B, Scabeni S, Lapilla M, Poliani PL, Matarese G, Ohtsu H, Galli SJ, Mantegazza R, Steinman L and Pedotti R (2006). A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice. J Immunol 176: 17-26. Histamine can modulate the cytokine network and influence Th1 and Th2 balance and Ab-isotype switching. Thus, pharmacological blockade or genetic deletion of specific histamine receptors has been shown to reduce the severity of experimental autoimmune encephalomyelitis (EAE), a prototypic Th1-mediated disease with similarities to human multiple sclerosis. To study the comprehensive contribution of endogenous histamine to the expression of EAE, we attempted to induce EAE in histidine decarboxylase-deficient mice, which are genetically unable to make histamine. In this study, we show that EAE is significantly more severe in HDC-/-, histamine-deficient mice, with diffuse inflammatory infiltrates, including a prevalent granulocytic component, in the brain and cerebellum. Unlike splenocytes from wild-type mice, splenocytes from HDC-/- mice do not produce histamine in response to the myelin Ag, whereas production of IFN-gamma, TNF, and leptin are increased in HDC-/- splenocytes in comparison to those from wild-type mice. Endogenous histamine thus appears to regulate importantly the autoimmune response against myelin and the expression of EAE, in this model, and to limit immune damage to the CNS. Understanding which receptor(s) for histamine is/are involved in regulating autoimmunity against the CNS might help in the development of new strategies of treatment for EAE and multiple sclerosis. Immunology and Muscular Pathology Unit, National Neurological Institute “C. Besta,“ Milan, Italy. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16365391
    • Gillson G, Richard TL, Smith RB and Wright JV (2002). A double-blind pilot study of the effect of Prokarin on fatigue in multiple sclerosis. Mult Scler 8: 30-5. In this 12-week study with 29 subjects, the effect of Prokarin (n=22), a proprietary blend of histamine and caffeine, was compared to placebo group (n=7) for the following outcomes: 1) fatigue as measured by the Modified Fatigue Impact Scale (MFIS); 2) lower limb function as measured by timed walk test; 3) upper limb function as measured by the pegboard test; 4) cognitive function as measured by the Paced Auditory Serial Additions Test (PASAT); 5) serum caffeine level; 6) change in brain chemistry as measured by quantitative magnetic resonance spectroscopy assay of N-acetyl aspartate (NAA); and 7) safety as measured by routine blood chemistry, TSH and urinalysis. Data were acquired at baseline, 4, 8 and 12 weeks. The Prokarin group MFIS mean was significantly different rom the mean of the placebo group at 12 weeks (df=24, t=2.08, P=<0.02), with respective means of 37.40, SD=15.18, for the Prokarin group and 53.2, SD=11.39 for the controls. For the secondary endpoints (PASAT, 25 foot timed walk, peg test, and magnetic resonance spectroscopy [MRS]), there were no significant differences between the Prokarin-treated group and the placebo group. However, there were significant improvements within the Prokarin group for each of these measures for the pre- versus posttreatment comparison at 12 weeks. Serum caffeine data indicated that caffeine exerted no independent effect on performance. No laboratory abnormalities were seen, and the treatment was well tolerated. CONCLUSION: There was a modest-size statistical effect of Prokarin on fatigue in multiple sderosis (MS) compared with the placebo group. A larger trial is warranted, based on this pilot study. Life Diagnostics, Calgary, Alberta, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=11936486
    • Kraus J, Ling AK, Hamm S, Voigt K, Oschmann P and Engelhardt B (2004). Interferon-beta stabilizes barrier characteristics of brain endothelial cells in vitro. Ann Neurol 56: 192-205. Multiple sclerosis (MS) is accompanied by a breakdown of the blood-brain barrier (BBB) leading to edema formation and aggravation of the disease. Interferon-beta (IFN-beta) has been approved for the treatment of MS and besides its immunomodulatory effects has been demonstrated to lead to a stabilization of BBB integrity in vivo. To investigate whether human recombinant IFN-beta exerts direct effects on the BBB, we used an in vitro BBB model in which brain endothelial cells in coculture with astrocytes form a tight permeability barrier for 3H-inulin and 14C-sucrose. Removal of the astrocytes from the coculture or alternatively addition of histamine resulted in an increased paracellular permeability for small tracers across the brain endothelial cell monolayer. Strikingly, in the presence of IFN-beta, permeability increase under both conditions was inhibited. Permeability changes were accompanied by minor changes in the staining for tight junction-associated proteins in brain endothelial cell monolayers. Taken together, our data demonstrate a direct stabilizing effect of IFN-beta on BBB cerebral endothelial cells in vitro that might significantly contribute to the beneficial effects of IFN-beta treatment in MS in vivo. Max-Planck Institute for Physiological and Clinical Research, Department of Vascular Cell Biology, Bad Nauheim, Germany. joerg.kraus@ukmuenster.de http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15293271
    • Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC and Zylicz Z (2003). Itch: scratching more than the surface. Qjm 96: 7-26. In origin, itch can be cutaneous (“pruritoceptive“, e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia. Sir Michael Sobell House, Churchill Hospital, Oxford, OX3 7LJ, UK. robtwy@yahoo.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12509645
    • Lieb K, Schaller H, Bauer J, Berger M, Schulze-Osthoff K and Fiebich BL (1998). Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6. J Neurochem 70: 1577-83. Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1beta, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1beta-induced IL-6 expression required the transcription factor nuclear factor-kappaB (NF-kappaB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-kappaB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved. Abteilung Psychiatrie, Universitat Freiburg, Germany. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9523575
    • Rozniecki JJ, Hauser SL, Stein M, Lincoln R and Theoharides TC (1995). Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 37: 63-6. Multiple sclerosis (MS) lesions are associated with infiltration of T lymphocytes and macrophages that appear to mediate myelin destruction and gliosis (scarring). Mast cells are located perivascularly in the brain, are juxtaposed to neurons, and have been shown to secrete vasoactive and inflammatory mediators in response to neuropeptides and direct nerve stimulation. Mast cells have been previously identified in MS lesions, are activated by myelin basic protein, and can participate in the regulation of blood-brain barrier permeability, as well as in myelin destruction. Here, cerebrospinal fluid from MS patients and controls with other neurologic diseases was assayed for histamine, its major metabolite methylhistamine, and the specific mast cell marker tryptase. Histamine and methylhistamine were not elevated in MS. However, the mast cell specific proteolytic enzyme tryptase was significantly elevated in MS, suggesting that mast cell activation may be involved in the pathophysiology of this disease. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=7818259
    • Merrill JE and Mohlstrom C (1987). Regulation of antibody-dependent cellular cytotoxicity in multiple sclerosis by central nervous system hormones. Int Arch Allergy Appl Immunol 82: 195-201. Using oligodendrocytes from primary brain cultures as targets in an antibody-dependent cellular cytotoxicity (ADCC) assay, we have examined the effects of insulin and histamine on killer cells in multiple sclerosis (MS) and other neurological disease (OND) controls compared to normal healthy controls. The effects were shown to be specific for effectors by preincubation experiments. MS patients' ADCC to primary oligodendrocytes was depressed, but could be boosted to normal control levels by histamine binding to the H1 receptor. Significant elevation of MS ADCC by cimetidine alone suggested that endogenous histamine production and H2 receptor binding could be mediating a suppressive effect on MS ADCC to oligodendrocytes. In addition, MS ADCC could be boosted significantly by insulin. MS killer cells were more sensitive in vitro to the boosting effects of both histamine and insulin than either OND or normal controls, both in dose response and magnitude of the increased ADCC. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=2879798
    • Smith JK and Schaller WF (1953). Histamine treatment of multiple sclerosis. Calif Med 79: 370-5. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=13106714
    Last edited by Wise Young; 05-26-2007 at 08:09 AM.

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