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Clinical Drug Investigation Jan 2013Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by a sustained elevation in platelet count and megakaryocyte hyperplasia.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by a sustained elevation in platelet count and megakaryocyte hyperplasia. Anagrelide is used in the treatment of ET, where it has been shown to reduce platelet count. Anagrelide is metabolized by cytochrome P450 (CYP) 1A2, and previous studies of the effect of food on the bioavailability and pharmacokinetics of anagrelide were conducted prior to the identification of the active metabolite, 3-hydroxyanagrelide.
OBJECTIVES
The objectives of this study were to determine the effect of food and caffeine on the pharmacokinetics of anagrelide and its active metabolite, 3-hydroxyanagrelide, to monitor electrocardiogram (ECG) parameters following drug administration, and to document the relationship between palpitations, ECG changes and caffeine intake
METHODS
Thirty-five healthy subjects who received 1 mg of anagrelide following either a 10-h fast or within 30 min of a standardized breakfast, including two cups of coffee, were studied.
RESULTS
Time to maximum (peak) plasma concentration (C(max)) of anagrelide was 4.0 h in the fed and 1.5 h in the fasted group (p < 0.05); similar results were observed for 3-hydroxyanagrelide. The mean C(max) of anagrelide was 4.45 ± 2.32 ng/mL and 5.08 ± 2.99 ng/mL in the fed/caffeine and fasted groups, respectively; peak concentrations were higher for 3-hydroxyanagrelide in both the fed/caffeine and fasted groups. The most frequent adverse events (AEs) were headache (60 %) and palpitations (40 %). There were no serious AEs and all ECGs were normal, although significant reductions in PR interval, QRS length and QT interval were observed in both groups. Heart rate increased after anagrelide administration in both fed/caffeine and fasted states (p < 0.01); however, increased heart rate was significantly more frequent in the fed/caffeine state than in the fasted state (p < 0.001 for heart rate increase in the first hour after drug administration). There was a trend towards a greater heart rate increase in subjects reporting palpitations than in those without (mean heart rate ± SD at 1 h: 10.1 ± 6.4 vs. 8.0 ± 8.4 beats/min [p = 0.35]; at 4 h: 12.7 ± 7.5 vs. 9.1 ± 8.8 beats/min [p = 0.10], respectively).
CONCLUSION
We conclude that food/caffeine delayed absorption of anagrelide. Anagrelide was generally well tolerated and had small effects on ECG parameters and heart rate. Caffeine may be implicated in a higher increase in heart rate and increased frequency of palpitations observed following administration of anagrelide with food/caffeine versus fasting.
Topics: Adolescent; Adult; Analysis of Variance; Area Under Curve; Arrhythmias, Cardiac; Biotransformation; Caffeine; Chi-Square Distribution; Cross-Over Studies; Cytochrome P-450 CYP1A2; Drug Interactions; Electrocardiography; Fasting; Female; Food-Drug Interactions; Half-Life; Headache; Heart Rate; Hematologic Agents; Humans; Hydroxylation; Intestinal Absorption; London; Male; Metabolic Clearance Rate; Postprandial Period; Quinazolines; Young Adult
PubMed: 23184666
DOI: 10.1007/s40261-012-0032-2 -
Scientia Pharmaceutica 2012A simple, rapid, and stability-indicating reverse-phase liquid chromatographic assay method was developed for Anagrelide Hydrochloride (ANG) in the presence of its...
A simple, rapid, and stability-indicating reverse-phase liquid chromatographic assay method was developed for Anagrelide Hydrochloride (ANG) in the presence of its degradation products generated from forced decomposition studies. The HPLC separation was achieved on a C18 Inertsil column (250 mm × 4.6 mm i.d. particle size is 5 μm), using solution A, a mixture of 0.03 M potassium di-hydrogen phosphate pH-adjusted to 3.0 using ortho-phosphoric acid (buffer): methanol: acetonitrile (90:5:5, v/v/v), and solution B, which contains a mixture of buffer: acetonitrile (10:90, v/v). The UV detector was operated at 251 nm while column temperature was maintained at 40°C, and the gradient program had the flow rate of 1.0 mL min(-1). The developed method was validated as per ICH guidelines with respect to specificity, linearity, precision, accuracy, robustness, and limit of quantification. The method was found to be simple, specific, precise, accurate, and reproducible. Selectivity was validated by subjecting the stock solution of ANG to acidic, basic, photolysis, oxidative, and thermal degradation. The calibration curve was found to be linear in the concentration range of 0.05-152 μg mL(-1) (R(2) = 0.9991). The peaks of degradation products did not interfere with that of pure ANG. The utility of the developed method was examined by analyzing the tablets containing ANG.
PubMed: 23008806
DOI: 10.3797/scipharm.1112-22 -
International Journal of Clinical... Oct 2012Headache is frequently reported as one of the neurological manifestations of essential thrombocythaemia (ET) and other myeloproliferative neoplasms. It is associated... (Review)
Review
Headache is frequently reported as one of the neurological manifestations of essential thrombocythaemia (ET) and other myeloproliferative neoplasms. It is associated with considerable morbidity; yet, it is a frequently under-recognised symptom. In patients with ET, headaches may be attributable to the disease, to the prescribed ET treatment, or unrelated to ET. The majority of headaches in ET are self-limiting and can be managed with standard headache therapies such as paracetamol, but it is vital that the clinician managing these conditions is able to recognise the headaches with a more sinister pathology. In this article, we will review the incidence and management of headaches in ET, whether they are primarily related to the disease or a result of its treatment. Identification of specific headache types in patients with ET may enable physicians to employ the most effective headache medication. This would enhance the patient-physician relationship, increasing patient compliance and thus reducing the risk of adverse outcomes.
Topics: Alkylating Agents; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Headache Disorders; Humans; Hydroxyurea; Immunologic Factors; Interferon-alpha; Phosphorus Radioisotopes; Platelet Aggregation Inhibitors; Quinazolines; Radiopharmaceuticals; Risk Factors; Thrombocythemia, Essential
PubMed: 22889110
DOI: 10.1111/j.1742-1241.2012.02986.x -
Medical Oncology (Northwood, London,... Dec 2012Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of...
Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy.
Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p=<0.05 and p<0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p=0.02 and p=0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET.
Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Bone Marrow Cells; Female; Humans; Hydroxyurea; Janus Kinase 2; Male; Megakaryocytes; Middle Aged; Mutation; Proto-Oncogene Proteins c-bcl-2; Quinazolines; Thrombocythemia, Essential
PubMed: 22418850
DOI: 10.1007/s12032-012-0202-3 -
The Korean Journal of Hematology Jun 2010Essential thrombocythemia (ET) is a chronic myeloproliferative disorder with a prolonged clinical course. Since this disorder is considered to be at increased risk of...
Essential thrombocythemia (ET) is a chronic myeloproliferative disorder with a prolonged clinical course. Since this disorder is considered to be at increased risk of thromboembolism, therapy is mainly focused on the decreased risk of thrombohemorrhagic events by use of cytotoxic agents. Anagrelide is a phosphodiesterase III inhibitor which is utilized in the treatment of ET for the reduction of platelets. However, patients treated with anagrelide might experience cardiovascular adverse effects including myocardial infarction (MI), although these events are rare. Herein, we report a case of a 30-year-old female with well controlled ET by anagrelide, who eventually developed an acute non-ST elevation myocardial infarction (MI). There has no found any cardiovascular risk factors in this ET patient, strongly suggesting that anagrelide might be the cause of MI. Therefore, cardiovascular function should be monitored in those patients prescribed with anagrelide.
PubMed: 21120194
DOI: 10.5045/kjh.2010.45.2.136 -
Journal of Thrombosis and Haemostasis :... Oct 2010Anagrelide is a selective inhibitor of megakaryocytopoiesis used to treat thrombocytosis in patients with chronic myeloproliferative disorders. The effectiveness of...
BACKGROUND
Anagrelide is a selective inhibitor of megakaryocytopoiesis used to treat thrombocytosis in patients with chronic myeloproliferative disorders. The effectiveness of anagrelide in lowering platelet counts is firmly established, but its primary mechanism of action remains elusive.
OBJECTIVES AND METHODS
Here, we have evaluated whether anagrelide interferes with the major signal transduction cascades stimulated by thrombopoietin in the hematopoietic cell line UT-7/mpl and in cultured CD34(+) -derived human hematopoietic cells. In addition, we have used quantitative mRNA expression analysis to assess whether the drug affects the levels of known transcription factors that control megakaryocytopoiesis.
RESULTS
In UT-7/mpl cells, anagrelide (1μm) did not interfere with MPL-mediated signaling as monitored by its lack of effect on JAK2 phosphorylation. Similarly, the drug did not affect the phosphorylation of STAT3, ERK1/2 or AKT in either UT-7/mpl cells or primary hematopoietic cells. In contrast, during thrombopoietin-induced megakaryocytic differentiation of normal hematopoietic cultures, anagrelide (0.3μm) reduced the rise in the mRNA levels of the transcription factors GATA-1 and FOG-1 as well as those of the downstream genes encoding FLI-1, NF-E2, glycoprotein IIb and MPL. However, the drug showed no effect on GATA-2 or RUNX-1 mRNA expression. Furthermore, anagrelide did not diminish the rise in GATA-1 and FOG-1 expression during erythropoietin-stimulated erythroid differentiation. Cilostamide, an exclusive and equipotent phosphodiesterase III (PDEIII) inhibitor, did not alter the expression of these genes.
CONCLUSIONS
Anagrelide suppresses megakaryocytopoiesis by reducing the expression levels of GATA-1 and FOG-1 via a PDEIII-independent mechanism that is differentiation context-specific and does not involve inhibition of MPL-mediated early signal transduction events.
Topics: Antigens, CD34; Blood Platelets; Cell Line; GATA1 Transcription Factor; Gene Expression Regulation; Humans; Megakaryocytes; Nuclear Proteins; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinazolines; Receptors, Thrombopoietin; Signal Transduction; Transcription Factors; Transcription, Genetic
PubMed: 20586925
DOI: 10.1111/j.1538-7836.2010.03970.x -
Journal of Clinical Oncology : Official... Jun 2009Essential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Essential thrombocythemia (ET) manifests substantial interpatient heterogeneity in rates of thrombosis, hemorrhage, and disease transformation. Bone marrow histology reflects underlying disease activity in ET but many morphological features show poor reproducibility.
PATIENTS AND METHODS
We evaluated the clinical significance of bone marrow reticulin, a measure previously shown to have relatively high interobserver reliability, in a large, prospectively-studied cohort of ET patients.
RESULTS
Reticulin grade positively correlated with white blood cell (P = .05) and platelet counts (P = .0001) at diagnosis. Elevated reticulin levels at presentation predicted higher rates of arterial thrombosis (hazard ratio [HR], 1.8; 95% CI, 1.1 to 2.9; P = .01), major hemorrhage (HR, 2.0; 95% CI, 1.0 to 3.9; P = .05), and myelofibrotic transformation (HR, 5.5; 95% CI, 1.7 to 18.4; P = .0007) independently of known risk factors. Higher reticulin levels at diagnosis were associated with greater subsequent falls in hemoglobin levels in patients treated with anagrelide (P < .0001), but not in those receiving hydroxyurea (P = .9). Moreover, serial trephine specimens in patients randomly assigned to anagrelide showed significantly greater increases in reticulin grade compared with those allocated to hydroxyurea (P = .0003), and four patients who developed increased bone marrow reticulin on anagrelide showed regression of fibrosis when switched to hydroxyurea. These data suggest that patients receiving anagrelide therapy should undergo surveillance bone marrow biopsy every 2 to 3 years and that those who show substantially increasing reticulin levels are at risk of myelofibrotic transformation and may benefit from changing therapy before adverse clinical features develop.
CONCLUSION
Our results demonstrate that bone marrow reticulin grade at diagnosis represents an independent prognostic marker in ET, reflecting activity and/or duration of disease, with implications for the monitoring of patients receiving anagrelide.
Topics: Biomarkers; Bone Marrow; Hemoglobins; Hemorrhage; Humans; Hydroxyurea; Leukocyte Count; Platelet Aggregation Inhibitors; Platelet Count; Primary Myelofibrosis; Prognosis; Prospective Studies; Quinazolines; Reticulin; Thrombocythemia, Essential; Thrombosis
PubMed: 19364963
DOI: 10.1200/JCO.2008.20.3174 -
Annals of Hematology Jan 2009Essential thrombocythaemia (ET) is an acquired myeloproliferative disorder with a prolonged clinical course and a near-normal life expectancy. Therapy is stratified... (Review)
Review
Essential thrombocythaemia (ET) is an acquired myeloproliferative disorder with a prolonged clinical course and a near-normal life expectancy. Therapy is stratified according to risk of thrombohaemorrhagic events. In high-risk patients, platelet reduction is generally recommended. In intermediate-risk patients, therapy should be considered depending on the severity of associated risk factors, especially cardiovascular. In low-risk patients, a watch-and-wait approach is appropriate. Hydroxycarbamide is generally first-line therapy. Concerns for possible leukemogenicity make anagrelide or interferon-alpha possible choices in younger patients and those who are resistant or intolerant to hydroxycarbamide. Each pharmacotherapy is associated with specific long-term risks and benefits. The potential risk of major bleeding is the main drawback of aspirin. Hydroxycarbamide is an established, effective drug for ET, but it may increase the risk of transformation to acute myeloid leukaemia and may give mucocutaneous ulcers. Anagrelide is a licensed treatment that also reduces platelet counts and is generally well tolerated, with evidence that some common side effects diminish over time. Anagrelide can have cardiac effects due to inhibition of phosphodiesterase III and therefore requires cautious use in patients with cardiac insufficiency. There is no evidence of leukaemogenicity with anagrelide or interferon-alpha therapy. Interferon-alpha is the only treatment suitable for use during pregnancy, although it is not licensed in ET. While it is effective for platelet reduction, the use of interferon-alpha is restricted by psychiatric side effects. Our knowledge of the optimum pharmacotherapy for each patient with ET continues to evolve through research and clinical trials, particularly into the molecular basis of the disease.
Topics: Algorithms; Antineoplastic Agents; Aspirin; Female; Fibrinolytic Agents; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Pregnancy; PubMed; Quinazolines; Randomized Controlled Trials as Topic; Thrombocythemia, Essential; Thrombocytosis
PubMed: 18629498
DOI: 10.1007/s00277-008-0531-7 -
International Journal of Medical... Apr 2008Anagrelide is often used in the treatment of thrombocythemia in myeloproliferative disease (MPD), but information concerning effects of treatment on cytokines involved... (Clinical Trial)
Clinical Trial
Anagrelide is often used in the treatment of thrombocythemia in myeloproliferative disease (MPD), but information concerning effects of treatment on cytokines involved in regulation of blood platelet levels is limited. Here, we investigated serum levels of thrombopoietin (TPO) and soluble IL-6 receptor (sIL-6R) in relation to response to treatment with and plasma concentrations of anagrelide. Samples from 45 patients with thrombocythemia due to MPD (ET=31, PV=14), being treated with anagrelide for 6 months, were analyzed for TPO, sIL-6R and anagrelide levels. The mean baseline platelet count was 983x10(9)/L. A reduction of platelets to <600 in asymptomatic or <400 x 10(9)/L in symptomatic patients was defined as a complete remission (CR), a reduction with >50% of baseline as partial remission, and <50% reduction as failure. At 6 months, 35 patients were in CR, 1 had a partial remission and 9 were treatment failures. For all patients, there was an increase in TPO of 44% from baseline; this change was more pronounced for patients with partial remission and failure. sIL-6R levels did not change significantly. There was no correlation between levels of anagrelide and cytokine levels at 6 months, and changes of cytokine levels did not relate to changes of platelet counts. Thus, a pronounced increase of TPO levels after 6 months of anagrelide treatment indicated that this treatment affected a major regulatory mechanism for megakaryocyte and platelet formation in MPD.
Topics: Adult; Aged; Humans; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Receptors, Interleukin-6; Thrombocytosis; Thrombopoietin; Treatment Outcome
PubMed: 18414650
DOI: 10.7150/ijms.5.87 -
Blood Jan 2008The role of histopathology in the diagnosis of essential thrombocythemia (ET) is controversial, and there has been little attempt to quantitate interobserver... (Randomized Controlled Trial)
Randomized Controlled Trial
The role of histopathology in the diagnosis of essential thrombocythemia (ET) is controversial, and there has been little attempt to quantitate interobserver variability. Diagnostic bone marrow trephine biopsy specimens from 370 patients with ET by Polycythemia Vera Study Group (PVSG) criteria were assessed by 3 experienced hematopathologists for 16 different morphologic features and overall diagnosis according to the World Health Organization (WHO) classification. Our results show substantial interobserver variability, particularly for overall diagnosis and individual cellular characteristics such as megakaryocyte morphology. Reticulin grade was the dominant independent predictor of WHO diagnostic category for all 3 hematopathologists. Factor analysis identified 3 independent factors likely to reflect underlying biologic processes. One factor related to overall and lineage-specific cellularity and was significantly associated with JAK2 V617F status (P < .001), a second factor related to megakaryocyte clustering, and a third was associated with the fibrotic process. No differences could be discerned between patients labeled as having "prefibrotic myelofibrosis" or "true ET" in clinical and laboratory features at presentation, JAK2 status, survival, thrombosis, major hemorrhage, or myelofibrotic transformation. These results show that histologic criteria described in the WHO classification are difficult to apply reproducibly and question the validity of distinguishing true ET from prefibrotic myelofibrosis on the basis of subjective morphologic criteria. This study was registered at http://isrctn.org as #72251782 and at http://eudract.emea.europa.eu/ as #2004-000245-38.
Topics: Adult; Antineoplastic Agents; Aspirin; Biopsy; Blood Cell Count; Drug Therapy, Combination; Hematology; Humans; Hydroxyurea; Megakaryocytes; Observer Variation; Pathology, Clinical; Platelet Aggregation Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Prospective Studies; Quinazolines; Thrombocytosis
PubMed: 17885079
DOI: 10.1182/blood-2007-05-091850