Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated activity in clinical trials in a variety of tumor types, including lung, breast, colon, mesothelioma, pancreatic, gastric, bladder, head and neck, and cervix. Pemetrexed is rapidly metabolized into active polyglutamate forms that are potent inhibitors of several tetrahydrofolate cofactor-requiring enzymes critical to the synthesis of purines and thymidine. Functionally, pemetrexed acts as a prodrug for its polyglutamate forms. Two different transporters are known to take extracellular folates, and some antifolates, into the cell. These are the reduced folate carrier and the folate receptor. One of the many attributes that make pemetrexed unique is that methodology has been developed to eliminate and control the many of its associated clinical toxicities. Multivariate analyses demonstrated that pretreatment total plasma homocysteine levels significantly predicted severe thrombocytopenia and neutropenia, with or without associated grade 3/4 diarrhea, mucositis, or infection. Routine vitamin B12 and folic acid supplementation have resulted in decreased frequency/severity of toxicities associated with pemetrexed without affecting efficacy, making this novel antifolate a safe and efficacious anticancer agent.
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PMID:Biochemical pharmacology of pemetrexed. 1565 31

Pemetrexed (Alimta) shows single-agent activity in advanced colorectal cancer. In two phase II studies in which patients received pemetrexed at 600 mg/m2 or 500 mg/m2 as first-line treatment for metastatic disease, objective response rates were 15.4% and 17.2%. These trials were conducted prior to supplementation with folic acid and vitamin B12, which markedly decreased the frequency of hematologic toxicities of pemetrexed; routine supplementation is now included in all clinical trials of the agent. The marked improvement in toxicity and tolerance with vitamin supplementation suggests the need to reexamine optimal dosing in pemetrexed combination schedules. In a National Surgical Adjuvant Breast and Bowel Project phase II trial in 54 patients with previously untreated advanced colorectal cancer, pemetrexed at 500 mg/m2 plus oxaliplatin (Eloxatin) at 120 mg/m2 every 21 days with folic acid/vitamin B12 supplementation resulted in an objective response of 23%. Three additionalpatients (5.6%) had unconfirmed partial response (partial response at one visit), and 27 patients (50%) had stable disease. Median progression-free survival was 5.3 months and median duration of response was 5.7 months; median overall survival was approximately 11.05 months. Grade 3/4 neutropenia was observed in only 17% of patients and treatment was well tolerated. A phase I/II study is under way to identify and assess the optimal combination of pemetrexed/irinotecan in second-line treatment of advanced colorectal cancer. Planned studies include a phase I study examining the combination of pemetrexed and oxaliplatin given every 2 weeks as first-line treatment, and a phase I/II trial to identify the optimal pemetrexed/ oxaliplatin dose in a 21-day schedule and to compare pemetrexed/ oxaliplatin with FOLFOX4 in first-line treatment of metastatic disease. All of these trials include vitamin supplementation. A phase III trial comparing the every-3-week pemetrexed/oxaliplatin regimen with FOLFOX4 as first-line treatment will be initiated if the outcome of the phase II trial is encouraging.
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PMID:Pemetrexed in advanced colorectal cancer. 1565 39

Pemetrexed (Alimta) is active in a variety of solid tumors, including breast and gynecologic cancers. Phase II trials of pemetrexed at a dose of 600 mg/m2 without vitamin B12 and folic acid supplementation in largely pretreated metastatic breast cancer patients demonstrated objective response rates of 21% and 28%, with generally manageable neutropenia constituting the primary toxicity. In phase II trials using 500 mg/m2 with or without vitamin supplementation in anthracycline- and taxane-pretreated patients, response rates were lower (approximately 9%) and treatment was generally well tolerated irrespective of vitamin supplementation status. A phase II trial is currently comparing pemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementation in patients with previously untreated advanced breast cancer. In a phase II trial in patients with advanced cervical cancer, pemetrexed at 600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementation produced similar response rates, with the frequency of neutropenia being somewhat lower among patients receiving the lower dose and vitamin supplementation. Preliminary results in an ongoing phase II trial indicate activity of the regimen of gemcitabine (Gemzar) at 1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementation in patients with ovarian cancer. Ongoing and future studies will establish optimal dosing regimens of pemetrexed and potential benefits of vitamin supplementation in the settings of metastatic breast cancer and gynecologic malignancies.
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PMID:Phase II studies of pemetrexed in metastatic breast and gynecologic cancers. 1565 40

HIV infection is associated with numerous abnormalities affecting both the myeloid and lymphoid lineages. We studied the features associated with peripheral cytopenias as the first sign of HIV infection in children. Peripheral blood (PB) counts, PB and bone marrow (BM) lymphocyte subsets, as well as viral load and serum levels of ferritin, vitamin B12, and folic acid were determined. Five children were naive of treatment (Group 1) and three were under HAART (Group 2). In Group 1 all patients had anemia of chronic disease. One had a bone marrow culture positive for Mycobacterium avium intracellulare and pancytopenia. Besides this, neutropenia and thrombocytopenia were seen in one patient each. In Group 2 anemia was found in all, neutropenia in one, and thrombocytopenia in two patients. Peripheral blood cytopenias were due to HAART toxicity in one patient. In the other two they were due to iron or folate deficiency. Bone marrow cytology showed cell abnormalities mainly in granulocytic precursors and megakaryocytes. All except two (taking HAART) patients had a high viral load. There was a straight correlation between viral load in PB and bone marrow. Viral load was correlated with peripheral CD4 but not with CD8 lymphocytes. A decrease in bone marrow B lymphocytes was seen in all patients. The introduction of HAART improved peripheral cytopenias. Bone marrow examination was useful for determining the etiology of the cytopenias and for detection of opportunistic infection. Hemopoietic cell abnormalities were similar to those seen in adults and indicative of HIV infection.
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PMID:Bone marrow features in children with HIV infection and peripheral blood cytopenias. 1584 Jul 62

An eight-month-old Border collie was presented with anorexia, cachexia, failure to thrive and stupor. Laboratory tests demonstrated a mild anaemia, neutropenia, proteinuria and hyperammonaemia. Serum bile acid concentrations were normal, but an ammonia tolerance test (ATT) was abnormal. The dog responded to symptomatic therapy for hepatoencephalopathy. When a low serum cobalamin (vitamin B12) concentration and methylmalonic aciduria were noted, the dog was given a supplement of parenteral cobalamin. Two weeks later, a repeat ATT was normal. Cobalamin supplementation was continued every two weeks, and all clinical signs, except for proteinuria, resolved despite withdrawing all therapy for hepatoencephalopathy. A presumptive diagnosis of hereditary selective cobalamin malabsorption was made, based on the young age, Border collie breed, low serum cobalamin concentration and methylmalonic aciduria. Although hereditary selective cobalamin malabsorption in Border collies, giant schnauzers, Australian shepherd dogs and beagles has previously been reported in North America, to the authors' knowledge this is the first report of the condition in the UK and the first to document an abnormal ATT in a cobalamin-deficient dog.
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PMID:Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie. 1603 51

(1) Chemotherapy does not appear to prolong the survival of patients with inoperable pleural mesothelioma, and the tumour response rate barely exceeds 20%. A combination of cisplatin + doxorubicin seems to provide the best response rates. (2) In a trial of second-line docetaxel therapy in patients with non small cell lung cancer, survival was extended by about 3 months compared with palliative care (7.5 versus 4.6 months). (3) Pemetrexed, an antifolate closely related to methotrexate and raltitrexed, has been authorized for use for both conditions. (4) In a randomised single-blind trial involving 456 patients with previously untreated pleural mesothelioma, survival was prolonged by about 3 months by a cisplatin + pemetrexed combination in comparison with cisplatin + placebo (12.1 versus 9.3 months). The respective tumour response rates were 41.3% and 16.7%. This is the only available comparative trial of pemetrexed in patients with mesothelioma. A more appropriate comparator would have been a cisplatin-based regimen such as cisplatin + doxorubicin. (5) A "non inferiority" trial of second-line treatment in 571 patients with locally advanced or metastatic non small cell lung cancer showed no significant difference in median survival time with pemetrexed versus docetaxel (about 8 months with both treatments). However, this trial does not rule out the possibility that pemetrexed is less effective than docetaxel. (6) Supplementation with folic acid and vitamin B12 reduces haematological and gastrointestinal complications associated with the antifolate activity of pemetrexed. (7) Despite this supplementation, more than 15% of patients in the mesothelioma trial developed severe neutropenia, leukopenia or fatigue during cisplatin + pemetrexed therapy. Pemetrexed aggravates the nausea and vomiting provoked by cisplatin, a drug that is highly emetic. (8) The adverse effects of pemetrexed were similar to those of docetaxel in the trial comparing the two drugs. However, neutropenia (5% versus 40%) and febrile neutropenia (2% versus 13%) occurred less frequently with pemetrexed. (9) Patients receiving pemetrexed must be monitored closely for some rare but potentially severe adverse effects; they include angina, myocardial infarction and stroke, liver damage, and bullous skin rash. (10) According to the summary of product characteristics (SPC), pemetrexed therapy must be administered in combination with folic acid and vitamin B12 supplementation in order to reduce haematological toxicity, and also with corticosteroid therapy to reduce the risk of serious skin reactions. (11) In practice, given the absence of a better alternative, and pending the results of a second trial, the cisplatin + pemetrexed combination can be used as a first-line regimen for patients with pleural mesothelioma. However, pemetrexed cannot replace docetaxel in second-line treatment of non small cell lung cancer.
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PMID:Pemetrexed: new drug. Pleural mesothelioma: a first encouraging trial. 1640 Jul 41

The incidental discovery of neutropenia during routine blood counting represents a common problem for clinicians. However, there are no reported data of systematic evaluations of adults with incidental neutropenia. As such, this was the aim of the present study. Ninety-seven adults with incidental neutropenia were submitted to a clinical and laboratory approach including medical evaluation, complete blood count (CBC), serial CBC, direct and indirect antiglobulin test, bone marrow smear and biopsy, assessment of folate, vitamin B12 and iron status, serum liver enzymes, serum proteins, serological exams for hepatitis B and C virus, cytomegalovirus, mononucleosis, human immunodeficiency virus and toxoplasmosis, detection of lupus erythematosus cells, antinuclear and anti-DNA antibodies and rheumatoid factor, dosage of free thyroxin and thyrotropin, chest roentgenogram and abdominal echography. Chronic idiopathic neutropenia of adults was identified in 34.0% of the individuals, neutropenia due to exposure to chemical agents was seen in 16.5%, infectious diseases in 9.3%, autoimmune diseases in 9.3%, haematological diseases in 9.3%, thyroid disorders in 8.2%, ethnic neutropenia in 7.2%, drug-related neutropenia in 2.1%, cyclic neutropenia in 2.1% and iron deficiency in 2.1%. Recovery or improvement of the neutrophil count was seen upon treatment or recuperation from infectious, autoimmune, haematological and thyroid diseases and iron supplementation. We conclude that the evaluation of individuals with incidental neutropenia using a structured approach may make the identification of clinically silent diseases possible, and provide an opportunity for early treatment, avoiding complications of the diseases and consequences of neutropenia.
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PMID:Causes of incidental neutropenia in adulthood. 1680 47

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0-2, and adequate organ function. Pemetrexed from 300 to 1,200 mg m(-2) was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB(12). Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m(-2), and infection and skin rash at 1,200 mg m(-2). The MTD/RD were determined to be 1,200/1,000 mg m(-2), respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1,200/1,000 mg m(-2), respectively, that is, a higher RD than without FA/VB(12) (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.
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PMID:A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours. 1694 Sep 81

We report the case of an 11-year-old girl with a recurrent progressive locally advanced abdominal mesothelioma. First, there was an incomplete surgical resection without any complementary chemotherapy, followed by a slow progression of the disease. Three years later, after two macroscopically complete surgical resections of peritoneal and ovarian tumors, she failed to respond to treatment with gemcitabin-carboplatin and gemcitabin-cisplatin, and developed splenic tumors and large multicystic hepatic tumors. She was then treated with pemetrexed. The schedule of chemotherapy was pemetrexed 400 mg intravenously plus cisplatin 60 mg once every 3 weeks associated with folic acid and vitamin B12. The tumor reduction was evaluated with positron emission tomography scan and tomodensitometry every three courses. Chemotherapy tolerance was good apart from a grade III neutropenia at the second course, a fever of unknown origin at the fifth course and a grade III thrombocytopenia at the sixth course. As tolerance and clinical responses were good, pemetrexed posology was increased up to 10%. After six courses, hepatic and splenic lesion tumors were initially diminished and then stablilized. Thus, a surgical resection was attempted: a first surgery followed by a second one 3 days later allowed completion of a difficult left hepatectomy, and resection of the hilum and splenic tumors. Fourteen months after the surgery, the girl remained in partial remission with stable disease. So far, pemetrexed associated with cisplatin revealed a good tolerance and promising results regarding its antitumoral efficacy in a progressive metastatic abdominal mesothelioma in childhood.
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PMID:Efficacy of a combination of pemetrexed and multiple redo-surgery in an 11-year-old girl with a recurrent multifocal abdominal mesothelioma. 1707 25

A 48-year-old man was referred to our hospital in December, 2005 because of general fatigue, gait disturbance and bradycardia. He had a history of polysurgery due to recurrent ileus and had been treated with home total parenteral nutrition for the short-bowel syndrome since 2003. Clinical findings on admission included marked emaciation and severe weakness of the extremities. Pancytopenia was noted in the peripheral blood. The serum levels of copper and ceruloplasmin were 3 microg/dl and 3 mg/dl, respectively, while Vit. B12 and folate were within the normal range. The bone marrow demonstrated cytoplasmic vacuolation in the myeloid and megakaryocytic series, and sideroblastic changes. No evidence of hematologic malignancies was presented. The diagnosis was copper deficiency and the patient was treated with copper supplementation. Four weeks after copper therapy, the serum level of copper rose to 50 microg/dl and ceruloplasmin to 14 mg/dl. Significant improvements in the hematologic profile, ECG findings and weakness of extremities were noted. Although bicytopenia (anemia and neutropenia) is considered to be a feature of hematologic disorders caused by copper deficiency, the present case showed pancytopenia. The exact mechanism of the unusual association of thrombocytopenia and other abnormalities with copper deficiency remains to be elucidated.
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PMID:[Copper deficiency with pancytopenia, bradycardia and neurologic symptoms]. 1744 78


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