UMLS:C0026986 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cooperative group included 18 provincial and district hospitals. A retrospective study was carried out on 140 cases of therapy related leukemia (TRL) caused by bimolane (BML) for psoriasis from 1984 to 1992. This series of BML-TRL consists of 90 male and 50 female patients. 87.1% of them were from 20 to 50 years old. Annual incidence varied from 4 to 24 cases, and was maintained at this level through the period from 1986 to 1991 without any declining tendency. The average time interval between BML administration and diagnosis of leukemia was 46 months. 138 cases were diagnosed as ANLL and 2 cases were suspected of having ALL. Subtype frequency was shown as follows: M3 > M2 > M5 > M4 > M1 > M6. 67.1% of the patients had a low peripheral white blood cell counts (< 5 x 10(9)/L). 116 patients received chemotherapy. A 26.7% remission rate was obtained with 18.1% complete remission and 8.6% partial remission. A 115 day median survival was calculated through a follow up survey of 95 patients. Finally, we concluded that: (1) This has been the largest group of non-cancer-therapy-related-leukemia patients ever reported. This type of leukemia is characterized by a shorter latent period, higher remission rate less incidence of myelodysplastic syndrome and more frequent occurrence of leukopenia, as compared with other types of TRL. BML is supposed to be a strong leukemia-causing cytotoxic agent. Use of this drug in psoriasis and other benign diseases is not recommended.
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PMID:[140 cases of acute leukemia caused by bimolane]. 815 36

Compounds that induce cancer cells to differentiate are clinically effective for several types of malignancies. The 1,25-dihydroxyvitamin D3[1,25(OH)2D3(C)] induces leukemic cells, including HL-60, to differentiate and/or no longer proliferate, but it causes hypercalcemia. Development of vitamin D analogs that are more potent in their abilities to affect leukemic cells without causing greater hypercalcemia, may be useful therapeutically. A novel analog [1,25(OH)2-16ene-D3(HM)] has a double bond between C-16 and C-17; it appears to be an extremely effective antileukemic agent with the same or fewer effects on serum calciums. We define the potency of this compound and compare it with seven, previously reported, potent analogs of 1,25(OH)2D3. HM inhibited clonal growth of HL-60 cells by 50% at 1.5 x 10(-11) M. This was about equipotent to 1,25(OH)2-16ene-23yne-D3(V), about 100-fold more potent than many of the other analogs, and 1000-fold more potent than 1,25(OH)2D3. The rank order of leukemic inhibitory activity was: 1,25(OH)2-16ene-D3(HM) > or = 1,25(OH)2- 16ene-23yne-D3(V) > 1,25(OH)2-23ene-D3(EX) = 1,24(OH)2-22ene-24-cyclopropyl-D3(BT) = 22-oxa- 1,25(OH)2D3(EU) = 1,25(OH)2-24-homo-D3(ER) > 1,25(OH)2D3(C) > 1,25(OH)2-24- dihomo-D3(ES). The rank order of their effects on induction of differentiation of HL-60 cells, as measured by superoxide production and nonspecific esterase activity, was similar to their antiproliferative activities. In contrast, each analog slightly stimulated proliferation of normal human myeloid clonal growth. Serum calcium levels were the same or slightly less when either 1,25(OH)2-16ene-D3(HM) or 1,25(OH)2D3 (0.0625, 0.125, or 0.25 microgram) was given intraperitoneally to mice for 5 weeks. HM bound to 1,25(OH)2D3 receptors about 1.5-fold more avidly than 1,25(OH)2D3. In fact, this vitamin D3 appears to be the most avid binder to 1,25(OH)2D3 receptors that has been identified to date. In contrast, HM had a greater than 50-fold lower affinity for the D-binding proteins as compared with 1,25(OH)2D3, thus increasing the availability of the compound for target tissues. Further differentiation experiments showed that HM was more potent than 1,25(OH)2D3 in the presence of serum, but was equipotent in serum-free conditions. Taken together, our experiments suggest that 1,25(OH)2-16ene-D3(HM) may be more potent than 1,25(OH)2D3(C) because of its higher affinity to the 1,25(OH)2D3 receptors and its low affinity to the D-binding protein present in serum. HM is an ideal compound for clinical studies including patients with preleukemia and other neoplasia, as well as several skin disorders, such as psoriasis.
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PMID:1,25(OH)2-16ene-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia. 820 63

A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.
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PMID:Clinical toxicity of cytokines used as haemopoietic growth factors. 865 81

Acrodermatitis continua of Hallopeau (ACH) is a rare manifestation of pustular psoriasis which may considerably disable affected patients. In this case report we confirm the efficacy of acitretin in the treatment of ACH and, in addition, describe the course of the myelodysplastic syndrome (MDS) from which the patient was suffering. During acitretin treatment, there was a transformation into acute myeloid leukaemia. We discuss the effect of retinoids on the bone marrow of normal subjects, patients with MDS, and patients with acute myeloid leukaemia. Our experience in the present case, and the information from the available literature, lead us to advise against the use of the aromatic retinoids, acitretin and etretinate, in patients with MDS. If such treatment is indicated, intensive haematological supervision is mandatory.
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PMID:Acrodermatitis continua of Hallopeau in a patient with myelodysplastic syndrome. 873 86

The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.
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PMID:Vitamin D analogs: mechanism of action and therapeutic applications. 1156 85

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

Isotechnika is developing the immunosuppressive drug ISA 247, a calcineurin inhibitor that is undergoing clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II). Preclinical development for uveitis is also underway. Other autoimmune disease indications that could be explored include arthritis, type I diabetes and Crohn's disease. ISA 247 was being co-developed as R 1524 by Isotechnika and Roche. However, Roche is no longer involved in the development of this compound. Based on analysis of previously collected data, the trans-ISA 247 isomer was found to be more bioavailable and it is expected that this isomer can be administered at a lower dose compared with the previous formulation that consisted of an equivalent mixture of the two geometric isomers (cis and trans). Preclinical observations indicate that ISA 247 has the potential to be more potent and less toxic than other marketed immunosuppressants in its class used for the prevention of transplant rejection. Experiments to date suggest that ISA 247 is about three times as potent as ciclosporin, while genotoxicity studies in animals have shown that the compound has a significantly reduced tendency to cause renal toxicity. The combination of reduced toxicity and improved potency would give ISA 247 a therapeutic benefit over existing calcineurin-based treatments. Isotechnika and Roche entered into a co-development and commercialisation agreement in April 2002, with Roche gaining the exclusive worldwide marketing rights for ISA 247; Isotechnika received milestone payments of $US4 million and $CAN21.9 million in September 2002 and May 2003, respectively. The agreement was restructured in April 2004, under which Isotechnika will now solely manage and fund the clinical development of trans-ISA 247. Upon successful completion of these trials, Isotechnika will conduct at its own expense a phase IIb study in renal transplantation and phase III studies in psoriasis. Roche will have the right to opt-in to the development and commercialisation of trans-ISA 247 for transplant indications up to the end of the phase IIb renal transplantation trial. Isotechnika retains all rights to develop and commercialise the product outside of transplant indications. Under an agreement signed with Cellgate Inc. on 25 April 2006, Isotechnika has the option to obtain an exclusive licence to develop and commercialise conjugates consisting of Cellgate's patented transporter technology, for the topical delivery of ISA 247 in patients with mild-to-moderate psoriasis. Cellgate will perform studies to evaluate the feasibility of using their technology to topically deliver ISA 247. In return, Isotechnika will pay Cellgate Inc. a total of $US500 000, with $US100 000 paid upfront, and the remainder at predetermined time points. Upon successful completion of the studies, Isotechnika has the option to further develop and commercialise conjugates for topical delivery of ISA 247. Isotechnika and Atrium Medical Corporation announced an exclusive worldwide licensing agreement for ISA 247 alone and in combination with TAFA 93 with respect to drug-eluting devices, in September 2005. Atrium's implantable products include those for the local, non-systemic treatment of vascular and cardiovascular disorders, soft tissue repair and other disorders. In May 2006, Isotechnika licensed ISA 247 to Lux Biosciences for ophthalmic indications. Under terms of the agreement, Lux Biosciences obtains the exclusive worldwide marketing rights to ISA 247 for treatment and prophylaxis of all ophthalmic indications. The company will be responsible for development, registration and marketing of the drug for ophthalmic indications and will make upfront and milestone payments to Isotechnika in addition to royalties on any sales. Isotechnika formalised a manufacturing agreement with Swiss-based Lonza Ltd in June 2004. Under the terms of the agreement, Lonza will manufacture sufficient quantities of trans-ISA 247 in a GMP environment for use in the company's upcoming clinical trials. Isotechnika completed the phase III SPIRIT trial of ISA 247 for psoriasis in Canada. The randomised, double-blind trial compared the efficacy of three doses of ISA 247 (0.2 mg/kg [low dose], 0.3 mg/kg [mid dose] and 0.4 mg/kg [high dose] twice daily) with placebo, with equal numbers of patients assigned to each of the four groups. Subsequent to the first 12 weeks, those patients who received placebo moved into the mid-dose group for the remaining 12 weeks of the study. Patients already receiving ISA 247 remained in their respective dosing groups for the final 12 weeks of the trial. Patients completing the 24-week SPIRIT trial were given the opportunity to continue therapy for an addditonal 36 weeks or to discontinue therapy. Those patients who chose to enrol in the extension trial were moved from the 0.2 mg/kg bid (low-dose) or 0.4 mg/kg bid (high-dose) groups into the the 0.3 bid mg/kg bid (mid dose) group. Patients who commenced the SPIRIT trial in the mid-dose group remained on the same dosage regimen for the duration of the extension trial. The goal of the extension trial is to demonstrate continued therapeutic benefit to psoriasis patients while gathering long-term safety data. So far, data has been received on 193 patients receiving treatment for a total of 48 weeks. A phase IIa trial investigating the safety and efficacy of ISA 247 in renal transplantation was completed in the US and Canada in January 2003. The trial compared ISA 247 with ciclosporin (Neoral in approximately 130 stable renal transplant patients who underwent transplantation at least 6 months prior to enrolment; patient recruitment was completed in October 2002. Half of the patients were treated with ciclosporin and the other half received ISA 247 over a 90-day period. An extension trial was then initiated in which another 200 patients were treated with ISA 247 for up to 6 months from the time of transplantation. Results from the trial were reported. All endpoints were achieved in a multiple ascending dose study of trans-ISA 247 in November 2004. The study, initiated in June 2004, was conducted by SFBC Anapharm in Montreal, Canada and involved 43 healthy volunteers. Final dosing recommendations are to be determined in phase III trials in patients with psoriasis. Interim results reported in September 2004, of a double-blind, parallel-group, placebo and moxifloxacin controlled, randomised single-dose QTc trial in healthy volunteers, showed no evidence of QTc prolongation when trans-ISA 247 was administered at therapeutic doses. A single ascending dose (SAD) trial for trans-ISA 247 was completed in July 2004. The SAD trial was conducted among healthy volunteers to assess the appropriate dosage of trans-ISA 247 for further clinical evaluations. The trial commenced in March 2004 with approximately 46 subjects enrolled under the supervision of MDS Pharma Services in Phoenix, Arizona, USA. Isotechnika received US FDA approval for the SAD trial in February 2004. A European patent (No. EP 0 991 660) entitled 'Deuterated and Undeuterated Cyclosporine Analgoues and Their Use as Immunomodulating Agents' was issued to Isotechnika for ISA 247, in October 2006. A US patent entitled 'Novel Cyclosporin Analogue Formulations' was issued to Isotechnika (No. 7 060 672) for ISA 247 in June 2006. The patent claims have been filed in 36 countries, and in the US it is the first patent to be issued in this patent family. Isotechnika was issued a US patent (No. 6 998 385, entitled 'Cyclosporine Analogue Mixtures and their use as Immunomodulating Agents') in February 2006 covering mixtures of cis- and trans- isomers of ISA 257. This patent is the first US patent to be issued in this family of patents. These patent claims have been filed in 36 countries. Three patents relating to this claim were previously issued in the following countries; Morocco (No. 26337 issued 1 October 2004); Pakistan (No. 138338 issued 30 September 2004) and South Africa (No. 2004/2270 issued 25 May 2005). A US patent (No 6 686 454) was issued in February 2004 entitled 'Antibodies to Specific Regions of Cyclosporine Related Compounds'. This patent covers a novel, simple and cost-effective assay used in the use and management of ISA 247. It also received another US patent entitled 'Deuterated Cyclosporine Analogs and their Use as Immunomodulating Agents'. Isotechnika has received patents for chemical composition of ISA 247 in New Zealand (November 2001; New Zealand Patent No. 502362), Canada (December 2001; Canadian Patent No. 2 298 572), South Korea (June 2006; South Korean Patent No. 585348) and Australia (November 2002; Australian Patent No. 750245). In addition, Isotechnika announced in August 2003 that it had been granted US patent No. 6 605 593, entitled 'Deuterated Ciclosporine Analogs and their use as Immunomodulating Agents'. An additional US patent covering ISA 247 was granted in September 2003.
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PMID:ISA 247: trans-ISA 247, trans-R 1524, ISA(TX)247, ISAtx 247, ISATx247, LX 211, LX211, R 1524, R-1524. 1732 8

We report here a 57-year-old man treated with etanercept for 6 months for psoriasis who developed myelodysplasia with acute myeloid leukemia. Leukemia cells had distinct karyotype associated with poor prognosis. The patient did not respond to cytosine arabinoside 100 mg/m(2) continuous infusion over 7 days with daunorubicin 45 mg/m(2) daily for 3 days. He also did not respond to salvage induction therapy with gemtuzumab (6 mg/m(2) on day 1 and 4 mg/m(2) on day 8) and intravenous continuous infusion cytosine arabinoside 200 mg/m(2). We review other cases of lymphoma and leukemia associated with tumor necrosis factor inhibitors and suggest mechanisms by which inhibition of the TNF-alpha family may predispose to cancer. We also suggest that all patients being considered for TNF-alpha treatment be screened for hematologic malignancies or premalignancies with blood counts and bone marrow aspirates/biopsies if indicated.
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PMID:TNF-alpha inhibitor etanercept and hematologic malignancies: report of a case and review of the literature. 1831 33

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.
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PMID:Curcumin: from ancient medicine to current clinical trials. 1832 53

For many years, methotrexate has been used in the treatment of certain chronic medical disorders e.g. rheumatoid arthritis and psoriasis as well as a number of malignant disorders e.g. acute lymphoblastic leukemia, certain types of lymphoma and breast carcinoma. Its use has been associated with various systemic toxicities and complications. The association between methotrexate therapy and the development of lymphoma and pseudolymphoma is well established. In patients treated with methotrexate, the development of leukemia has been attributed to either the primary disorder e.g. rheumatoid arthritis or to other drugs used concomitantly e.g. cyclophosphamide. Reported here are two patients with rheumatoid arthritis and one patient with psoriasis treated with low dose methotrexate for variable periods of time. Two of these patients developed acute myeloid leukemia on myelodysplastic syndrome background, while the third patient developed pre-B acute lymphoblastic leukemia that expressed few myeloid markers and had a positive philadelphia chromosome. To our knowledge, these are the first reported cases of methotrexate-induced acute leukemia.
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PMID:Methotrexate-induced acute leukemia: report of three cases and review of the literature. 2417 73

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