Looking at WF10's progress...
Wolf, many seem to thinking nothing has been happening since the P3 started, and while we wait for results.
Wrong.
The truth is, research has continued. One of the references in the expanded patent was to transplantation. Let's look at the record...
2000 - WF10 in xenotransplantation - a potential new approach.
Kemp E, Dieperink H, Horn T, Johansen A, Jensen J, Kemp G, Larsen S, Lillevang S, Svendsen M, Freilow E, Kuhlmann I, Kemp K.
Transplant Proc 2000 Aug;32(5):1018-9
2001 - High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity.
Hansen A, Kemp K, Kemp E, Bouchelouche K, Bouchelouche P, Dieperink H, Horn T, Larsen S.
Pharmacol Toxicol. 2001 Aug;89(2):92-5. Related Articles, Links
2002 - Immunosuppression in Xenotransplantation with WF10
Kemp K.; Dieperink H.; Hansen A.; Horn T.; Johansen A.; Jensen J.; Kemp G.; Larsen S.; Lillevang S.; Svendsen M.; Freilow E.; Kuhlmann I-L.; Kemp E.
Pharmacology & Toxicology, 1 June 2002, vol. 90, no. 6, pp. 346-348(3)
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It's interesting to go to PubMed, and when you find an article, follow the research that's been happening...
Let's start here...
Development of WF10, a novel macrophage-regulating agent.
ncbi.nlm.nih.gov
Then, click the link that says "Related Articles, Links", and start following what others are finding out.
Let's take Alzheimer's disease, just for curiosity's sake...
We already know that WF10 showed promise in treating AIDS-related dementia.
"Blood Macrophage TNF- Expression, Elevated in AIDS Dementia is Downregulated by In-Vitro by WF10 Exposure
A pathogenesis-based Phase 2 clinical study was recently completed testing the immunomodulator, WF10, in 18 patients AIDS-associated dementia is a late complication of HIV disease. Many studies have implicated brain-associated macrophages as producing factors harmful for brain, leading to pathologic changes thought to be associated with dementia. In an earlier study, we found that dementia patients had markedly elevated levels of CD14/CD69 cells as compared to patients with late-stage HIV disease (Lancet 349:692, 1997). In the current study, we added analysis of intracellular TNF- expression to studies on patients with dementia, late-stage HIV disease, and mid- to early-stage HIV disease. Intracellular macrophage TNF- expression was markedly elevated in dementia, and only slightly less elevated in advanced HIV disease as compared to patients with early-to mid- HIV disease. WF10 treatment of blood from patients with dementia showed a marked downregulation of macrophage TNF- expression. The current study suggests that macrophage expressed TNF-, a known neurotoxin, may be inappropriately expressed in dementia and be downregulated by the immunomodulator WF10. In conjunction with other clinical reports (Herndier, this meeting) showing downregulation of immunologic activation markers in patients with early-stage HIV disease treated with WF10, these data suggest that WF10 may be useful in treatment HIV disease and AIDS-related dementia."
dimethaid.ca
So, we go to page 2 of 5...
26: Wesselingh SL, Thompson KA.
Immunopathogenesis of HIV-associated dementia.
Curr Opin Neurol. 2001 Jun;14(3):375-9. Review.
PMID: 11371763 [PubMed - indexed for MEDLINE]
"Related Articles, Links", again...
16: Epstein LG.
HIV neuropathogenesis and therapeutic strategies.
Acta Paediatr Jpn. 1998 Apr;40(2):107-11.
PMID: 9581298 [PubMed - indexed for MEDLINE]
"The HIV infected and activated macrophages/microglia produce excessive amounts of pro-inflammatory cytokines, including tumor necrosis factor alpha, and platelet activating factor. These products are directly toxic to human neurons in vitro."
Hmmm....an older paper, though. Anything newer?
10: Williams KC, Hickey WF.
Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS.
Annu Rev Neurosci. 2002;25:537-62. Epub 2002 Mar 27. Review.
PMID: 12052920 [PubMed - indexed for MEDLINE
"This review focuses on the role of the extended macrophage/monocyte family in the central nervous system during HIV or SIV infection. The accumulated data, buttressed by recent experimental results, suggest that these cells play a central, pathogenic role in retroviral-associated CNS disease. While the immune system is able to combat the underlying retroviral infection, the accumulation and widespread activation of macrophages, microglia, and perivascular cells in the CNS are held in check. However, with the collapse of the immune system and the disappearance of the CD4(+) T cell population, productive infection reemerges, especially in CNS macrophages. These cells, as well as noninfected macrophages, are stimulated to high levels of activation. When members of this cell group become highly activated, they elaborate a wide spectrum of deleterious substances into the neural parenchyma. In the final phases of HIV or SIV infection, this chronic, widespread, and dramatic level of macrophage/monocyte/microglial activation constitutes a self-sustaining state of macrophage dysregulation, which results in pathological alterations and the emergence of various neurological problems."
20: Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C.
The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis.
J Neurol Sci. 2002 Oct 15;202(1-2):13-23. Review.
PMID: 12220687 [PubMed - indexed for MEDLINE]
"Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood-brain barrier, behave as one of the immune effector cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M phi, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS)."
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A lot of evidence that strongly suggests a role for WF10 in these conditions. Nothing conclusive, yet. But as outside research progresses, we're starting to find that an increasing number of "diseases" are starting to fall under the umbrella of "chronic immune system activation" - they're not "diseases" at all.
The potential role of WF10 is clear.
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Lets relate all this info back to WF10 P3...
hivdent.org
"Changes in Monocyte/Macrophage Neurotoxicity in the Era of HAART: Implications for HIV-Associated Dementia"
AIDS (01.04.02) Vol 16; P 31-38
Leonard Kusdra; Dawn McGuire; Lynn Pulliam
"HIV-1 associated dementia (HAD) is a neurodegenerative disease associated with memory loss and dementia. It is believed that brain damage is a result of activated immune cells, especially Monocyte/Macrophages (M/MF) and their toxic secretions. The authors have previously reported an elevation in a certain set of macrophages (CD14 and CD69) in the blood of subjects with HAD compared to cognitively normal, HIV-positive subjects. They showed that this subset of cells secreted substances that were toxic when added to human brain cell cultures. In the current study, the authors sought to monitor any changes in M/MF subset in patients who were on the newer antiretroviral drugs (highly active antiretroviral therapy: HAART). The authors analyzed blood samples in three cohorts: Patients diagnosed with HAD (n=13), HIV seropositive patients with no dementia (HIV-ND; n=12) and seronegative controls (n=8). M/MF were isolated and cultured, and supernatants tested in brain cell cultures for effects on brain cell survival or function. The activities of several proteins critical to normal brain cell function were tested. Results of the study indicated that in patients with HIV- related dementia who were treated with HAART, the previously described macrophage subset was still much higher than was found in HIV seropositive patients without dementia or in the HIV- negative controls. However, it was also noted that subset levels in HAART-treated patients with dementia had nonetheless dropped by more than 50 percent, compared to levels described in a previous study before the HAART era. In addition, the macrophage subset from HAART-treated subjects was less toxic to brain cells in culture. Instead of killing the cells outright, there was abnormal production and activity of critical cellular proteins, suggesting an impairment of cell function. The authors speculate that the observation of brain cell dysfunction rather than cell death may be relevant to the recent clinical observations of patients with AIDS dementia: The decline in mental function appears to be more chronic and more subtle than in the era before HAART. However, cognitive dysfunction and brain injury have not been eliminated in the era of HAART; they remain an ongoing and serious problem among many individuals with HIV. In other studies, these researchers have found similar increases in the monocyte/macrophage (CD14/CD69) subset in individuals _____without HIV infection who have Alzheimer's disease. They suggest that there may be important similarities in the pathophysiology of these otherwise different dementing illnesses."
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This is all old research...just thought I'd post a little bit of it. It's difficult to understand, unless one takes the time to sit down and actually follow the research trail...but the evidence is overwhelming.
Research absolutely convinces me that the P3 will be an enormous success. So will WF10.
Do you think DMX will have trouble licensing WF10 to a pharma that wants to known for eliminating Alzheimer's Disease?
Rhetorical question...>g<
Jim |
