bl-4162a and Headache

Platelets play a central role in atherothrombotic events. We investigated the effect of a novel platelet-lowering agent, rafigrelide, on thrombus formation and characteristics. In this phase 1, open-label, non-randomised, single-sequence, crossover study, healthy male volunteers received rafigrelide for 14 days (Period 1). Following a ≥6-week washout period, they then received rafigrelide + acetylsalicylic acid (ASA) for 14 days (Period 2). Thrombus formation was assessed ex vivo using the Badimon perfusion chamber, and thrombus characteristics were assessed using thromboelastography. A total of 15 volunteers were enrolled in the study and were assigned to Panel A or Panel B, which had different schedules of assessments. In Panel A, after treatment with rafigrelide alone (Period 1), mean (± standard deviation) platelet count was reduced from 283 (± 17) × 10⁹/l at Day 1, to 125 (± 47) × 10⁹/l at Day 14 (n=6) and thrombus area reduced under high and low shear conditions. Reductions in thrombus area under high shear conditions correlated with reductions in platelet count (r²=0.11, p=0.022; n=12). Rafigrelide treatment prolonged clot formation time and reduced clot strength. The addition of ASA to rafigrelide (Period 2) had no additional effect on platelet count or thrombus area under high or low shear conditions. Similar results were seen in Panel B for all parameters. The most common adverse events (≥3 participants per period) were thrombocytopenia and headache. While confirming the platelet-lowering effects of rafigrelide, this early phase study also indicates that rafigrelide has antithrombotic properties under both high and low shear conditions.

Topics: Adult; Aspirin; Blood Coagulation; Blood Platelets; Cross-Over Studies; Drug Therapy, Combination; Headache; Humans; Imidazoles; Male; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Thrombelastography; Thrombocytopenia; Thrombosis

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.. 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. 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.. 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).. 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

Although anagrelide is widely used in the treatment of thrombocythemia in myeloproliferative diseases, there is currently limited information on the efficacy and toxicity of its long-term use. This prospective study investigated clinical toxicity and efficacy of anagrelide during two years of treatment.. A multicenter, open, phase II study of anagrelide treatment was performed by the Swedish Myeloproliferative Disorder Study Group. The study included 60 patients with thrombocythemia due to myeloproliferative disease, 42 with essential thrombocythemia (ET), 17 with polycythemia vera (PV) and one with myelofibrosis (MF).. Complete response (CR), defined as a platelet count <400x10(9)/L in symptomatic patients and < 600x10(9)/L in asymptomatic patients was achieved in 67% of the patients and partial response (PR) in 6%. The response rate was higher in patients with ET than in those with PV (p = 0.05). Primary treatment failure occurred in 27% due to lack of efficacy at a tolerable dose (n=13) or insufficient platelet response without side effects (n=3). In addition, another 14 patients withdrew from treatment before the end of the two-year period due to side effects. Side effects included palpitations (70%), headache (52%), nausea (35%), diarrhea or flatulence (33%), edema (22%) and fatigue (23%). Patients and doctors rated their satisfaction with the anagrelide treatment on a 10-grade scale from 7.6 at 3 months to >9 at 24 months. After two years, 50% (n=30) of the patients continued anagrelide treatment.. Side effects and toxic discontinuation rates were higher than in previous studies, probably because this is the first long-term prospective study of the feasibility and toxicity of anagrelide treatment. Nevertheless, anagrelide is a valuable alternative for treatment of thrombocythemia in myeloproliferative disorders for patients who tolerate the drug well.

Topics: Adult; Aged; Chronic Disease; Diarrhea; Dose-Response Relationship, Drug; Female; Headache; Heart Rate; Humans; Male; Middle Aged; Myeloproliferative Disorders; Nausea; Patient Compliance; Patient Dropouts; Platelet Aggregation Inhibitors; Prospective Studies; Quinazolines; Thrombocytosis

In Japan, anagrelide has been approved for use in patients with essential thrombocythemia. Here, the safety and efficacy of anagrelide was assessed in clinical practice as post-marketing surveillance. Subgroup analyses were conducted to compare patients (1) with or without a history of cytoreductive therapy (CRT), (2) <60 or ≥60 years of age, and (3) with an anagrelide starting dose of ≤0.5 mg/day or 1.0 mg/day.. Data were collected for all patients who received anagrelide, with an observation period of 12 months after treatment initiation.. Of the 648 patients, 54.3% experienced adverse drug reactions (ADRs). The most commonly reported ADRs were headaches, palpitations, and anemia. No significant difference was observed in overall ADRs across patient subgroups. A significantly higher incidence of headaches was observed in patients < 60 years versus those ≥ 60 years (P < 0.001). The incidence of anemia and serious ADRs were significantly higher in patients ≥ 60 years, and those with a history of CRT (P < 0.05). The discontinuation rate at 6 months was significantly lower in patients started at the lower anagrelide dose (P < 0.05). Platelet counts decreased in all analyzed groups.. This surveillance showed that anagrelide has a tolerable safety and efficacy profile.

Topics: Cytoreduction Surgical Procedures; Headache; Humans; Japan; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Quinazolines

A case of severe headache in a young woman is described. The headache was not associated with additional neurological findings. In peripheral blood extremely high count of platelets was found. Additional examinations supported the diagnosis of essential thrombocythemia (ET). As a first line treatment thrombocytapheresis was performed. The introduced hydroxyurea treatment was complicated with dysmenorrhea and neutropenia. It was the reason to the use anagrelide--a new antiplatelet drug--in the therapy of ET. The treatment with anagrelide was free of previously mentioned complications. After one year of observation the platelet count was still effectively reduced.

Topics: Adult; Combined Modality Therapy; Female; Fibrinolytic Agents; Headache; Humans; Plateletpheresis; Quinazolines; Thrombocytosis