Wednesday, December 10, 2014 2:07:11 PM
Prurisol Phase 2 Clinical Trial Approved To Begin By The FDA
Expanded and updated post with further detail on Prurisol's mechanism and today's news: FDA Agrees That Prurisol Phase 2 Study May Begin, with eligibility for the expedited approval pathway.
Mechanism of Prurisol: PRINS and IL-20
Dysregulation of Suppressor of Cytokine Signaling 3 in Keratinocytes Causes Skin Inflammation Mediated by Interleukin-20 Receptor-Related Cytokines
"It has been reported that the cytokines IL-19, IL-20 and IL-24 are highly expressed in the inflammatory sites of psoriasis, and may thus mediate the progression of psoriasis"
Interleukin-20 as a target in psoriasis treatment.
http://www.ncbi.nlm.nih.gov/pubmed/17911452
Abstract
Interleukin-20 (IL-20) is a new member of the IL-10 cytokine family discovered by a structural algorithm. IL-20 transgenic mice displayed skin abnormalities reminiscent of psoriasis, a finding that has prompted the investigation of this new interleukin in relation to this disease. This article reviews the role of IL-20 and its implication in psoriasis. It is shown that IL-20 and its receptors are found in human skin and that IL-20 is involved in proliferation, angiogenesis, and chemotaxis, all characteristics of psoriasis. We demonstrated that IL-20 induced the thickening of human epidermis in vivo; however, this thickening does not seem to be related to a direct effect of IL-20 on hyperproliferation since the growth of normal human epidermal keratinocytes (NHEKs) cultured in vitro was not affected by IL-20. On the other hand, in vitro, IL-20 stimulated human peripheral blood mononuclear cells (PBMCs) to produce proinflammatory cytokines and, in vivo, IL-20 in combination with PBMCs induced psoriasis. This may suggest that IL-20 indirectly exerts its proliferative effects on keratinocytes via immune cells present in the skin. Finally, we found that blocking IL-20 signaling in psoriasis improves psoriasis, suggesting that IL-20 is a potential target in psoriasis treatment.
Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis.
http://www.ncbi.nlm.nih.gov/pubmed/14712309
"Our data indicate that IL-20 gene polymorphisms should have a role in determining susceptibility to plaque-type psoriasis."
"The anti-apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non-coding RNA, PRINS"
"We hypothesize that the deregulation of the PRINS ncRNA may contribute to psoriasis and results in decreased sensitivity to spontaneous keratinocyte apoptosis via the regulation of G1P3."
http://www.ncbi.nlm.nih.gov/pubmed/20377629
Prurisol compared with approved Psoriasis drug Methotrexate
Methotrexate
63% reduction in lesion appearance
48% reduction in serum PRINS
46% reduction in serum IL-20
Lesions reoccurred in 61 days
Prurisol:
84% reduction in lesion appearance
96% reduction in serum PRINS
87% reduction in serum IL-20
No reoccurence of lesions within 180 days
- Link
PRINS (psoriasis associated RNA induced by stress) is a long non-coding RNA. Its expression is induced by stress, and it may have a protective role in cells exposed to stress. It is over-expressed in the skin of patients with psoriasis. It regulates G1P3, a gene encoding a protein with anti-apoptotic effects in keratinocytes. Overexpression of PRINS may contribute to psoriasis via the down-regulation of G1P3. -PRINS Wiki
Below: A brief overview of clinical and pre-clinical studies of Abacavir for treatment of psoriasis, and studies showing Zidovudin, is effective in the treatment of Psoriasis in Humans with HIV. Abacavir and Zidovudin arenucleoside reverse transcriptase inhibitors.
All below text excerpts, charts and illustrations with links from a variety of sources, including abstracts of studies.
Some random threads below I compiled while looking for a correlation between Abacavir and psoriasis.
Abacavir/lamivudine/zidovudine (INNs, trade name Trizivir) is a pharmaceutical treatment for HIV infection. It is a fixed dose combination of three reverse transcriptase inhibitors patented by GlaxoSmithKline and now marketed by its joint venture with Pfizer, ViiV Healthcare:
Trizivir Wiki
History
In the summer of 1981 the acquired immunodeficiency syndrome (AIDS) was first reported. Two years later the etiological link to AIDS, the human immunodeficiency virus (HIV) was identified. Since the identification of HIV the development of effective antiretroviral drugs and the scientific achievements in HIV research has been enormous. Antiretroviral drugs for the treatment of HIV infections belong to six categories: Nucleoside and nucleotide reverse-transcriptase inhibitors, Non-nucleoside reverse-transcriptase inhibitors, protease inhibitors, entry inhibitors, co-receptor inhibitors and integrase inhibitors. The reverse transcriptase of HIV-1 has been the main foundation for the development of anti-HIV drugs. The first nucleoside reverse-transcriptase inhibitor with in vitro anti-HIV activity was zidovudine. Since zidovudine was approved in 1987, six nucleosides and one nucleotide reverse-transcriptase inhibitor (NRTI) have been approved by FDA. NRTIs approved by the FDA are zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine and the only nucleotide reverse-transcriptase inhibitor (NtRTI) approved is tenofovir. Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors-wiki
Canadian Guidelines for the Management of Plaque Psoriasis
Antivirals
Primary treatment of HIV with the antiviral drug zidovudine (AZT) can have secondary beneficial effects on skin lesions, including nearly complete or complete clearance of symptoms in up to 90% of patients with HIV-associated psoriasis.54 The same treatment was also beneficial, although less dramatically so, in approximately one-third of HIV-negative psoriasis patients.
Antipsoriatic effects of zidovudine in human immunodeficiency virus-associated psoriasis.
Zidovudine improves psoriasis in human immunodeficiency virus-positive males.
Duvic M1, Crane MM, Conant M, Mahoney SE, Reveille JD, Lehrman SN.
Abstract
BACKGROUND AND DESIGN:
Patients with human immunodeficiency virus (HIV) infection can develop severe psoriasis, which is difficult to treat using conventional therapy. Anecdotal case reports have suggested that administration of zidovudine can improve psoriasis in the HIV-infected patient. An open-label study was conducted to determine the safety and effectiveness of zidovudine therapy in 24 patients with HIV-associated psoriasis and to correlate response with laboratory and clinical variables.
RESULTS:
Of 19 evaluable patients, 90% had either partial (58%) or complete (32%) improvement of their HIV-associated psoriasis during zidovudine therapy. Greater than 75% reduction in the body surface area involved was positively associated with antigenemia and an age younger than 30 years.
CONCLUSIONS:
Zidovudine therapy, at a dosage of 1200 mg/d, appears to be beneficial in the treatment of HIV-associated psoriasis, although long-term relapses occurred and the associated arthritis did not improve.
Zidovudine for the treatment of HIV-negative patients with psoriasis: a pilot study.
Townsend BL1, Cohen PR, Duvic M.
Abstract
BACKGROUND:
Zidovudine, an inhibitor of HIV replication, has been reported to improve psoriasis in HIV-positive patients.
OBJECTIVE:
Our purpose was to evaluate the safety, tolerance, and effectiveness of oral zidovudine for treating psoriasis in HIV-negative patients in a small, open-label study.
METHODS:
Each subject received 200 mg of zidovudine every 4 hours during waking hours, for a total of 1000 mg/day. Treatment was continued for 8 weeks, at which time the patient's response to therapy was evaluated. If a response was evident, treatment was continued for an additional 8 weeks. Clinical response was correlated with histologic changes in skin lesions at 0 and 4 weeks.
RESULTS:
Thirty-three percent of HIV-negative patients with psoriasis showed improvement by up to 80% after 16 weeks of therapy; decreased elevation and scaling of the psoriasis plaques were the most notable changes. No complete remissions occurred.
CONCLUSION:
This is the first report of the use of zidovudine to treat HIV-negative patients with psoriasis. Although zidovudine was well tolerated, it may be more effective in HIV-positive patients with psoriasis.
Psoriasis and HIV Infection
L. Leal,a M. Ribera,a and E. Daudénb Servicio de Dermatología, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain Servicio de Dermatología, Hospital Universitario La Princesa, Madrid, Spain
Antiretroviral Treatment
Exacerbation of psoriasis lesions with increasing degrees of immunosuppression suggested antiretroviral treatment as a therapeutic strategy. With the introduction of the first drugs that acted specifically against HIV (with zidovudine [AZT] as the only such drug available), several cases were reported of partial improvement of psoriasis lesions that had previously been refractory to other treatments.(33) The drug was shown to be useful and safe, though its mechanism of action against psoriasis was unknown. It probably acts by reducing keratinocyte proliferation due to its mechanism of interference with DNA synthesis. The introduction of combined therapies has made it very difficult to evaluate the effect of these drugs separately and there is thus nothing in the literature in this regard. As with earlier single-drug therapy, current combined therapies achieve clinical improvement of psoriasis lesions, even in recalcitrant cases resistant to other treatments. (35, 36)
33. Porras B, Costner M, Friedman-Kien AE, Cockerell CJ. Update on cutaneous manifestations of HIV infection. Med Clin North Am. 1998;82:1033-80.
35. Fischer T, Schwörer H, Vente C, Reich K, Ramadori G. Clinical improvement of HIV-associated psoriasis parallels a reduction of HIV viral load induced by effective retroviral therapy. AIDS. 1999;13:628-9.
36. De Socio VL, Simonetti S, Stagni G. Clinical improvement of psoriasis in an AIDS patient effectively treated with combination antiretroviral therapy. Scand J Infect Dis.
Psoriasis in the Patient With Human Immunodeficiency Virus, Part 2: Review of Treatment
Antiretroviral Therapy
The demonstration of HIV transcripts using in situ hybridization in dermal dendritic cells in psoriatic lesions but not on nonlesional skin suggests that HIV infection might play a direct role in the initiation of psoriatic inflammation. The hypothesis is supported by the observations of an improvement of psoriasis in HIV-infected individuals after antiretroviral t herapy with zidovudine (also known as azidothymidine [AZT]). The apparent clearing of psoriasis with AZT was first reported in 2 HIV positive patients by Duvic et al in 1987 and has been followed by numerous anecdotal confirmations. In an open-label study of 19 assessable HIV-positive patients with psoriasis, 90% had either a partial or complete improvement during therapy with AZT at dosages of 1200 mg daily.
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