Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrazofurin was administered to 21 patients with solid tumors at a dose of 200 mg/m2 iv weekly, because this dose had been shown to be well-tolerated and pharmacologic effects of a single dose at this level persisted for up to 7 days. An anemia consistent with a disturbance in rbc production was seen in most patients. Other toxic effects included stomatitis, rash, and myelosuppression. No complete or partial responses were noted, but two patients with alveolar cell carcinoma of the lung each had stable disease for 12 months. Most of the patients in this study tolerated the weekly dosage schedule well with only minimal myelosuppression, suggesting that this agent and schedule might be acceptable for use in combination chemotherapy. Several theoretic reasons favor the use of pyrazofurin in this manner. Pyrazofurin should also be evaluated more fully in patients with polycythemia vera, mycosis fungoides, and psoriasis, since other orotidylate decarboxylase inhibitors have been shown to be effective in these diseases.
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PMID:Clinical trial of weekly pyrazofurin. 15 7

Fourteen cases of pyoderma gangrenosum were seen over a period of 24 years at the Hull Royal Infirmary Dermatology Department. Several associated conditions were found. Seven cases were associated with rheumatoid arthritis of which five were sero-positive, including one with Felty's syndrome. One case was associated with both ulcerative colitis and psoriasis; one with polycythemia rubra vera; two patients had diverticular disease including one who also had rheumatoid arthritis; one had positive syphilis serology. In three cases there was no significant associated disease identified. Ten out of the fourteen cases were women, indicating a female preponderance by a ratio of about 2F:1M; a figure similar to that stated by Seitzinger. The age of presentation ranged from 30 to 80 years.
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PMID:Pyoderma gangrenosum: associations revisited. 142 51

The presence of mast cells, often in an activated state or increased numbers, has been noted in various cutaneous disorders. Recent studies suggest that mast cells are of primary importance in these conditions and their presence does not merely represent a secondary event. This review focuses on atopic dermatitis, contact hypersensitivity reactions, bullous pemphigoid, fibrosing conditions, neurofibromatosis, wound healing, polycythemia vera, and psoriasis, in which there is significant evidence to indicate a pathophysiologic role for mast cells.
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PMID:The mast cell in health and disease. 169 80

Hydroxyurea is commonly used in the treatment of various hematologic disorders, e.g., chronic myelogenous leukemia (CML), polycythemia vera, and occasionally, at lower doses, for severe psoriasis vulgaris. Cutaneous side effects such as alopecia, diffuse hyperpigmentation, poikiloderma, atrophy of the skin, or nail changes occur, especially with long-term treatment. Painful leg ulcers in association with hydroxyurea have only rarely been reported. We describe 2 patients who developed spontaneous painful leg ulcers during long-term hydroxyurea therapy for a myeloproliferative disorder; these ulcers healed only after hydroxyurea was withdrawn.
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PMID:Leg ulcers associated with long-term hydroxyurea therapy. 970 57

Ruxolitinib (INCB-018424) is a potent, orally available, selective inhibitor of both JAK1 and JAK2 of the JAK-STAT signaling pathway, being developed by Incyte Corp and Novartis AG. Ruxolitinib was initially developed to target the constitutive activation of the JAK-STAT pathway in patients with myeloproliferative neoplasms (MPNs). Meaningful reductions in spleen size and constitutional symptoms have been noted in patients with myelofibrosis (both primary and post-essential thrombocythemia/polycythemia vera). Data from a phase I/II clinical trial led to ongoing registration trials in the US and Europe. Toxicity (primarily decreased erythropoiesis and thrombocytopoiesis) has been managed by close control of dosing. The inhibition of inflammatory cytokine signaling through JAK1 inhibition has led to intriguing results in patients with rheumatoid arthritis and psoriasis (using a topical cream formulation). Ruxolitinib is a well tolerated, first-in-class JAK2 inhibitor with various potential clinical indications.
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PMID:Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. 2050 62

The four Janus kinases (JAKs) comprise a family of intracellular, nonreceptor tyrosine kinases that first gained attention as signaling mediators of the type I and type II cytokine receptors. Subsequently, the JAKs were found to be involved in signaling downstream of the insulin receptor, a number of receptor tyrosine kinases, and certain G-protein coupled receptors. Although a number of cytoplasmic targets for the JAKs have been identified, their predominant action was found to be the phosphorylation and activation of the signal transducers and activators of transcription (STAT) factors. Through the STATs, the JAKs activate gene expression linked to cellular stress, proliferation, and differentiation. The JAKs are especially important in hematopoiesis, inflammation, and immunity, and aberrant JAK activity has been implicated in a number of disorders including rheumatoid arthritis, psoriasis, polycythemia vera, and myeloproliferative diseases. Although once thought to reside strictly in the cytoplasm, recent evidence shows that JAK1 and JAK2 are present in the nucleus of certain cells often under conditions associated with high rates of cell growth. Nuclear JAKs have now been shown to affect gene expression by activating other transcription factors besides the STATs and exerting epigenetic actions, for example, by phosphorylating histone H3. The latter action derepresses global gene expression and has been implicated in leukemogenesis. Nuclear JAKs may have a role as well in stem cell biology. Here we describe recent developments in understanding the noncanonical nuclear actions of JAK1 and JAK2.
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PMID:JAKs go nuclear: emerging role of nuclear JAK1 and JAK2 in gene expression and cell growth. 2189 41

The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases, including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases.
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PMID:JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms. 2331 59

A potent Jak2 inhibitor could solve numerous diseases including hypertension and cardiovascular diseases, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, psoriasis and rheumatoid arthritis. So, identifying potent Jak2 inhibitors is of great interest to researchers and pharmaceutical companies. Virtual screening and molecular docking are important tools for structure based drug discovery but selecting an appropriate method to calculate the electrostatic potential is critical. In this study, four semi empirical (AM1, RM1, PM3, and MNDO) and two empirical (DFT, HF) charges were investigated for their performance on the prediction of docking pose using Glide XP. The result shows that AM1 has the best charge model for our study. Further, we performed a 3D-quantitative structure-activity relationship (3D-QSAR) study of 76 decaene derivatives. Since 3D-QSAR methods are known to be highly sensitive to ligand conformation and alignment method, we did a comparative 3D-QSAR study of AM1 charge docked pose alignment based QSAR (structure based) and pharmacophore based QSAR. We found a better QSAR model in the structure based method. Hence, the results clearly demonstrate that selecting an appropriate method to calculate the electrostatic potential for docking studies and a good alignment of the ligand for 3D-QSAR is critical. Finally, extensive pharmacophore and e-pharmacophore based virtual screening followed by subsequent docking studies identified 27 lead molecules which could be potent Jak2 inhibitors.
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PMID:Jak2 inhibitor--a jackpot for pharmaceutical industries: a comprehensive computational method in the discovery of new potent Jak2 inhibitors. 2487 39

The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.
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PMID:Janus Kinase Inhibitors: A Review of Their Emerging Applications in Dermatology 2977 37

The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is a ubiquitous intracellular signaling network. Selective JAK-inhibitors have anti-inflammatory properties and have been approved in many countries for the treatment of rheumatoid arthritis (tofacitinib, baricitinib) and myelofibrosis or polycythemia vera (ruxolitinib). The aim of the publication was to summarize and critically analyze the efficacy and safety of JAK-inhibitors in skin diseases, such as psoriasis, alopecia areata, atopic dermatitis and vitiligo. Databases PubMed, Scopus and EBSCO were searched. After exclusions, 17 articles were analyzed (11 randomized clinical trials, 4 case reports, 1 retrospective study of a case series and 1 nonrandomized pilot study). The strongest evidence of JAK-inhibitor efficacy was established for treatment of psoriasis. Additionally, data are available on the potential efficacy of JAK-inhibitors in alopecia areata, atopic dermatitis and vitiligo. Mostly, JAK-inhibitors are used orally. However, there are studies showing efficacy of topical administration of this group of drugs in psoriasis and vitiligo. Further research is needed, especially the head-to-head comparison studies with JAK-inhibitors and current therapeutic methods to verify the superiority of this new group of drugs in dermatological diseases.
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PMID:JAK-inhibitors in dermatology: current evidence and future applications. 3043 38


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