3-aminopyridine-2-carboxaldehyde-thiosemicarbazone has been researched along with Methemoglobinemia* in 7 studies
1 review(s) available for 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Methemoglobinemia
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Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia.
The anticancer agent 3-aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase's small subunits, M2 and M2b (p53R2). Unfortunately, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe(2+)) in hemoglobin. This creates Fe(3+) methemoglobin that does not deliver oxygen. Fe(2+) in hemoglobin normally auto-oxidizes to inactive Fe(3+) methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen, ascorbate and, most importantly, intravenously administered methylene blue as a therapeutic antidote. Topics: Antidotes; Antineoplastic Agents; Enzyme Inhibitors; Hemoglobins; Humans; Methemoglobin; Methemoglobinemia; Methylene Blue; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones | 2012 |
3 trial(s) available for 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Methemoglobinemia
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A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells.
We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study.. Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine.. Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine.. 3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves. Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease Progression; Drug Interactions; Female; Gemcitabine; Humans; Hypoxia; Leukocytes, Mononuclear; Lung Neoplasms; Male; Methemoglobinemia; Middle Aged; Pyridines; Thiosemicarbazones; Treatment Outcome | 2008 |
Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia.
This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine.. Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m2/day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h.. In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m2). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/ m2 dose level. Objective evidence of clinical activity was observed in four patients.. The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m2/day of 3-AP on days 2-5 given prior to cytarabine administered at a dose of 1,000 mg/m2/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring. Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Monitoring; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Methemoglobinemia; Middle Aged; Pyridines; Recurrence; Thiosemicarbazones | 2008 |
A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer.
3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer.. 3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m(2). Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m(2) in cohorts of three to six patients. Following the gemcitabine 1000 mg/m(2) dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m(2).. 3-AP at 105 mg/m(2) administered over 2 h followed in 1-4 h by gemcitabine at 1000 mg/m(2) produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m(2) administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis.. 3-AP at 105 mg/m(2) infused over 2-4 h followed by gemcitabine at 1000 mg/m(2) on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials. Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Male; Methemoglobinemia; Middle Aged; Neoplasms; Pyridines; Ribonucleotide Reductases; Thiosemicarbazones | 2004 |
3 other study(ies) available for 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Methemoglobinemia
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Rediscovery of the susceptibility of G6PD deficient persons to methemoglobinemia from oxidant drugs, and to hemolysis from methylene blue.
Topics: Enzyme Inhibitors; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Methemoglobinemia; Methylene Blue; Middle Aged; Pyridines; Thiosemicarbazones | 2007 |
Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine.
We report occurrence of severe methemoglobinemia in a patient on novel experimental anti-cancer drug, Triapine. Treatment with methylene blue led to massive hemolysis due to concomitant G6PD deficiency. We recommend that G6PD screening be done in high-risk populations prior to commencement of Triapine therapy. Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Methemoglobinemia; Middle Aged; Pyridines; Thiosemicarbazones | 2006 |
Drug-induced haemolysis and methaemoglobinaemia in glucose 6-phosphate dehydrogenase deficiency.
Topics: Antineoplastic Agents; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Male; Methemoglobinemia; Middle Aged; Pyridines; Thiosemicarbazones | 2005 |