Treatment Of Psoriasis With Oral Mycophenolic Acid

Jones, E. Linn; Epinette, Warren W.; Hackney, Victor C.; Menéndez, Luis; Frost, Phillip

doi:10.1111/1523-1747.ep12610346

Cited by 105 publications

(37 citation statements)

References 17 publications

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“…The toxicity of mycophenolic acid for humans has been variously reported. Several studies showed only mild gastrointestinal distress and none-tomild hematological disturbances (6,8,11,13,17), but one study showed significant hematological toxicity (15). The further implication of these experiments is that inhibitors of guanosine nucleotide synthesis may be attractive candidates for antileishmanial agents.…”

Section: Resultsmentioning

confidence: 99%

“…Marr and colleagues have shown that allopurinol or its derivatives may be effective antileishmanial agents due to parasite-specific incorporation of such compounds into adenosine metabolites (3,18). Mycophenolic acid prevents the conversion of IMP to GMP in Landschutz ascites cells, calf thymus, and LS cells (7) and has been used experimentally for the oral treatment for psoriasis (8,11,15,17). Here we demonstrate that mycophenolic acid and allopurinol are both partially effective antileishmanial agents in the human macrophage model of leishmaniasis.…”

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confidence: 99%

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In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages

Berman¹,

Webster²

1982

Antimicrob Agents Chemother

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The possibility that purine inhibitors or analogs might be effective antileishmanial agents led to the determination of the antileishmanial activity of mycophenolic acid and allopurinol in vitro. The drugs were tested against Leishmania tropica amastigotes (mammalian forms) within human macrophages, a model in which achievable serum concentrations of antileishmanial agents currently in use eliminate approximately 90% of the parasites. Mycophenolic acid, an inhibitor of guanosine nucleotide synthesis from inosinic acid, was shown here to inhibit guanosine nucleotide synthesis in L. tropica promastigotes (insect forms). When tested against L. tropica amastigotes within macrophages, mycophenolic acid eliminated 50% of the parasites at achievable peak human serum levels (20 ,ug/ml) and 40%o of the parasites at trough serum levels (1 to 10 pLg/ml). This demonstrates that an inhibitor of guanosine nucleotide synthesis is partially effective against L. tropica in vitro. The purine analog allopurinol was also tested and was found to eliminate 50% ofL. tropica amastigotes in this model. Because mycophenolic acid and allopurinol are partially, but not completely, effective antileishmanial agents in this in vitro model, their in vivo utility remains to be determined by clinical trials.Leishmaniasis affects perhaps 100 million persons at any one time throughout the tropical and neotropical world (1). The [GIBCO]) in the absence (control cultures) or in the presence (experimental cultures) of anti-Leishmania agents (4). Cultures were processed in duplicate. Culture medium, containing antileishmanial agents where appropriate, was changed at 3 days. At the end of 6 days of incubation, control and experimental cultures were fixed, and the mean number of amastigotes per 100 macrophages was determined by counting 100 to 200 macrophages in each culture.Viability of amasttes after exposure to drugs. The viability of anastigotes was assessed by determining the number that were capable of transforming into promastigotes. Drug-exposed and control macrophages were scraped into Schneider medium revised (GIBCO) containing 30%o heat-inactivated fetal bovine serum (10)

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages

Berman¹,

Webster²

1982

Antimicrob Agents Chemother

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“…Safety (hematology and biochemistry, including serum protein electrophoresis, immunophenotyping, and urine studies), immunogenicity, pharmacokinetic, and biologic activity assessments (antibody titers; Physician's Global Assessment) were performed at each of these scheduled visits. The Physician's Global Assessment, an evaluation of the extent/worsening of the patient's condition relative to pretreatment, was performed in the traditional manner employing a 7-point scale, with the degree of improvement compared with baseline evaluation denoted in the following manner: 0 = 100%, completely clear; 1 = 90%; 2 = 75%; 3 = 50%; 4 = 25%; 5 = 0%; 6 = deterioration (24).…”

Section: Figurementioning

confidence: 99%

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

et al. 1999

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Psoriasis is a multifactorial disease of uncertain etiology that affects approximately 2% of the population (1). Psoriatic lesions are characterized by a clinical triad consisting of skin induration, scaling, and erythema. The histologic correlates of these clinical findings include inflammation, abnormal keratinocyte proliferation/terminal differentiation, and dermal angiogenesis. The inflammatory infiltrate, particularly pronounced at the dermal-epidermal junction, consists largely of activated T cells and antigen-presenting cells (APCs) and precedes the development of epidermal hyperproliferation (2). Increased levels of inflammatory cytokines have been detected in lesional psoriatic epidermis, which may result in the potentiation of T-cell activation (3) as well as hyperproliferation and accelerated differentiation of keratinocytes (4, 5). These and other data derived from T cell-based therapeutics (6-8) suggest that activated T cells play an important role in triggering and perpetuating the disease. Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage φX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

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“…These findings have been supported by several studies including open-label, longterm studies and a multicenter, double-blind, placebocontrolled trial. [3][4][5][6][7][8] The questionable increased incidence of carcinogenicity and latent viral infections associated with the use of mycophenolic acid discouraged the continuation of studies of this drug for psoriasis. Careful review of these data demonstrated that all patients with psoriasis who developed herpes zoster infection and other viral and bacterial infections during therapy with mycophenolic acid had uncomplicated infectious disease and had been receiving dosages of mycophenolic acid higher than 3 g/d.…”

Section: Commentmentioning

confidence: 99%