Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.
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PMID:Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity of zidovudine. 762 95

A feared complication of therapy with 6-mercaptopurine (6-MP) is myelosuppression. To evaluate whether rigorous blood count monitoring is necessary, we prospectively followed the hematologic profiles of 57 patients with inflammatory bowel disease who were treated with low-dose 6-MP. Most patients (97%) were treated initially with a single dose of 50 mg/day and 79% never used more than 50 mg/day. Blood counts were obtained at weekly intervals over the first month, every two weeks for the second month, and monthly thereafter in the first year. Sixteen (28%) developed mild leukopenia (white blood count < 4.5 x 10(3)/mm3). No patient had a white blood cell count < 2.8 x 10(3)/mm3 and no patient developed leukopenia prior to three months of treatment. In only five patients did the leukopenia prompt a change in 6-mercaptopurine dose. Very mild thrombocytopenia (platelet count of < 145 x 10(3)/mm3) developed in three (5%) and macrocytosis (mean cell volume > 101 fl) was seen in nine (16%). In conclusion, leukopenia was not uncommon in patients treated with low-dose 6-MP, but was not clinically significant. Leukopenia occurred no earlier than three months and as late as 42 months into therapy. Thrombocytopenia was uncommon, mild, and was not associated with apparent bleeding. Macrocytosis may occur in the absence of vitamin B12 and folate deficiencies. Patients can be spared from weekly blood count monitoring when using low-dose 6-mercaptopurine treatment.
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PMID:Low-dose 6-mercaptopurine in inflammatory bowel disease is associated with minimal hematologic toxicity. 805 Mar 12

Macrocytosis and megaloblastic changes in the bone marrow are frequently seen in renal transplant recipients treated with azathioprine (Az). However, severe anemia is a rare side effect of Az. We recently observed a case of severe megaloblastic anemia with pancytopenia in a renal transplant recipient who had been receiving Az therapy for 22 years. The patient was a 46-year-old woman who had been administered Az and prednisolone at a dose of approximately 1.7 mg/kg and 0.17 mg/kg daily, respectively. A bone marrow aspiration revealed megaloblastic anemia with the depletion of myeloid cells and megakaryocytes. She did not have vitamin B12 or folate deficiency. Therefore, FK506 (tacrolimus), a macrolide produced by Streptomyces tsukubaensis, which acts directly on T cells and is known to have less myelosuppression than Az, was substituted for Az. Although the leukopenia improved, the anemia and thrombocytopenia did not improve in the short term. She developed dyspnea and severe subcutaneous bleeding of the right lower extremity due to knee contusions. Hemodialysis was started to treat her uremic state. Although it was impossible to evaluate the long-term effects of FK506 therapy for the pancytopenia in our case, the conversion from Az to a less myelosuppressive drug, such as FK506, should be considered in renal transplant recipients with severe myelosuppression caused by long-term Az treatment.
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PMID:Azathioprine-induced megaloblastic anemia with pancytopenia 22 years after living-related renal transplantation. 953 11

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.
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PMID:Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors). 1209 34

Pemetrexed (Alimta) is a novel, multitargeted antifolate that inhibits at least three of the enzymes involved in folate metabolism, and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated broad antitumor activity in Phase II trials in a wide variety of solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine (Gemzar). A pivotal Phase III study in mesothelioma has been presented. This study indicates the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. The most significant toxicities of pemetrexed, myelosuppression and mucositis have been significantly ameliorated by folate and vitamin B12 supplementation. More importantly, vitamin supplementation has not demonstrated any adverse efficacy. This review discusses the biochemistry and clinical activity of pemetrexed.
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PMID:Pemetrexed (Alimta): a novel multitargeted antifolate agent. 1272 74

Pemetrexed is a novel multitargeted antifolate that inhibits > or = 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors, and is approved in combination with cisplatin for the therapy of malignant mesothelioma. In a recent phase III trial, pemetrexed demonstrated equivalent efficacy to docetaxel, but with significantly less toxicity, in second-line treatment of non-small-cell lung cancer. The most common and serious toxicities of pemetrexed--myelosuppression and mucositis--have been significantly ameliorated by folic acid and vitamin B12 supplementation. More important, vitamin supplementation has not been shown to adversely affect efficacy in some tumor types. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. In this review, the biochemistry and mechanism of action of pemetrexed are discussed.
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PMID:Pharmacology and mechanism of action of pemetrexed. 1511 25

Pemetrexed (Alimta, Eli Lilly) is a multitargeted antifolate that inhibits at least three enzymes in the nucleic acid synthetic pathways. The US Food and Drug Administration recently approved pemetrexed, in combination with cisplatin, for the first-line treatment of advanced malignant pleural mesothelioma. Moreover, pemetrexed was recently shown to be as efficacious as docetaxel (Taxotere, Aventis) in the second-line treatment of non-small cell lung cancer, and its toxicity profile was preferable. The main toxicity seen with pemetrexed is myelosuppression, which is considerably reduced by coadministration of folic acid and vitamin B12. Multiple Phase II clinical trials have demonstrated that pemetrexed has promising single-agent activity in many other solid tumors, including head and neck, breast and colorectal cancers. Combination regimens consisting of pemetrexed and other chemotherapeutics or novel molecular-targeted agents are currently under investigation. Future studies will better define and likely expand the role of pemetrexed for the treatment of cancer.
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PMID:Pemetrexed: a novel antifolate agent enters clinical practice. 1527 Jun 56

Anemia, a common complication associated with inflammatory bowel disease (IBD), is frequently overlooked in the management of IBD patients. Unfortunately, it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population. Anemia in IBD is pathogenically complex, with several factors contributing to its development. While iron deficiency is the most common cause, vitamin B12 and folic acid deficiencies, along with the effects of pro-inflammatory cytokines, hemolysis, drug therapies, and myelosuppression, have also been identified as the underlying etiology in a number of patients. Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD. Because the diagnosis of anemia in IBD often presents a challenge, combinations of several hematimetric and biochemical parameters should be used. Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia, anemia due to chronic disease, or mixed anemia in IBD patients. With regard to treatment, the newly introduced intravenous iron formulations have several advantages over orally-administered iron compounds in treating iron deficiency in IBD. In special situations, erythropoietin supplementation and biological therapies should be considered. In conclusion, the management of anemia is a complex aspect of treating IBD patients, one that significantly influences the prognosis of the disease. As a consequence, its correction should be considered a specific, first-line therapeutic goal in the management of these patients.
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PMID:Anemia in inflammatory bowel disease: a neglected issue with relevant effects. 2470 37

Anemia is one of the commonest extraintestinal manifestations of inflammatory bowel disease (IBD). The pathogenesis of anemia in IBD is complex but iron deficiency combined with inflammation is the most common factor related to the development of anemia. However, other causes such as vitamin B12 and folate deficiency, hemolysis, myelosuppression and drug also should not be overlooked. In addition to ferritin, inflammatory markers and new biochemical parameters such as hepcidin and ferritin index are being tested as diagnostic a tool. First step for treatment is disease activity control and iron supplementation. Although oral iron is widely used, intravenous iron therapy should be considered in patients who are intolerant to oral iron therapy, have severe and refractory anemia or are in active disease state. Recently, new intravenous iron formulations have been introduced and due to their safety and easy usage, they have become the standard treatment modality for managing anemia in IBD. Erythropoietin and transfusion can be considered in specific situations. Vitamin B12 and folate supplementation is also important in patients who are deficient of these micronutrients. Since anemia in IBD patients could significantly influence the disease outcome, further studies and standard guideline for IBD are needed.
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PMID:[Management of anemia in patients with inflammatory bowel disease]. 2579 77

Objectives: We aim to determine the feasibility, safety, maximally tolerated dose (MTD), recommended dose and potential anti-tumor activity of intrathecal pemetrexed (IP). Materials and Methods: Lung adenocarcinoma patients with recurrent or progressive leptomeningeal metastases (LM) after intrathecal chemotherapy were recruited. IP dose was escalated from 10 mg. A minimum of three patients and a maximum of six were enrolled in each cohort. Schedule protocol was IP twice per week for 2 weeks in induction therapy, followed by once per week for 4 weeks in consolidation therapy. Serial samples of plasma and cerebrospinal fluid (CSF) were obtained for pharmacokinetic studies. Results: Thirteen patients were enrolled between March 2017 and July 2018. EGFR driver oncogene was identified in most of the patients. Severe adverse events (AEs) were encountered in 31% (4/13) of the cases, including myelosuppression, radiculitis, and elevation of hepatic aminotransferases (EHA). Study protocol was revised due to lethal myelosuppression. Following protocol revision, vitamin B12 and folic acid supplementation was given at the beginning of treatment, and myelosuppression was well-controlled. Dose-limiting toxicities (DLT) were myelosuppression, radiculitis, and EHA. Two patients (2/2) developed dose-limiting myelosuppression at 15 mg level. One patient (1/6) experienced dose-limiting radiculitis and EHA at 10 mg level. MTD was 10 mg. Response rate was 31% (4/13) and disease control rate was 54% (7/13). The drug concentration showed a decreasing trend in serial CSF samples following each IP. After IP, the peak plasma concentration was reached at 4 h in two cases, 6 h in two cases, 9 h in one case, and 12 h in one case, respectively. Conclusion: Pemetrexed was appropriate for intrathecal administration. IP at 10 mg dose in combination with vitamin supplementation on the schedule of 1-2 times per week showed controllable toxicity and good efficacy. This regimen paves the way for subsequent clinical trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03101579.
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PMID:A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. 3154 65


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