Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures

Wang, Guosu; Franklin, Richard A.; Hong, Ying

doi:10.1038/sj.bjp.0706341

Cited by 39 publications

(36 citation statements)

References 23 publications

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“…Also tested in PDE4D (390 nM) . Anagrelide (13); zardaverine (14); CDP 840 (15); trequinsin (16); piclamilast (17); YM 976 (18); cilostamide (19, 20); milrinone (21); (R)-(−)-rolipram (22); Ro 20-1724 (23); cilostazol (24); siguazodan (21); RS 25344 (25); ICI 63197 (26) .…”

Section: Resultsunclassified

Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient

et al. 2017

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Costello syndrome (CS) patients suffer from a very high 10% incidence of embryonal rhabdomyosarcoma (ERMS). As tools to discover targeted therapeutic leads, we used a CS patient-derived ERMS cell line (CS242 ERMS) harboring a homozygous p.G12A mutation in HRAS, and a control cell line derived from the same patient comprising non-malignant CS242 fibroblasts with a heterozygous p.G12A HRAS mutation. A library of 2,000 compounds with known pharmacological activities was screened for their effect on CS242 ERMS cell viability. Follow-up testing in a panel of cell lines revealed that various compounds originally developed for other indications were remarkably selective; notably, the phosphodiesterase (PDE) inhibitor zardaverine was at least 1,000-fold more potent in CS242 ERMS than in the patient-matched non-malignant CS242 fibroblasts, other ERMS, or normal fibroblasts. Chronic treatment with zardaverine led to the emergence of resistant cells, consistent with CS242 ERMS comprising a mixed population of cells. Many PDE inhibitors in addition to zardaverine were tested on CS242 ERMS, but almost all had no effect. Interestingly, zardaverine and analogs showed a similar cytotoxicity profile in CS242 ERMS and cervical carcinoma-derived HeLa cells, suggesting a mechanism of action common to both cell types that does not require the presence of an HRAS mutation (HeLa contains wild type HRAS). Two recent studies presented possible mechanistic explanations for the cytotoxicity of zardaverine in HeLa cells. One revealed that zardaverine inhibited a HeLa cell-based screen measuring glucocorticoid receptor (GR) activation; however, using engineered HeLa cells, we ruled out a specific effect of zardaverine on signaling through the GR. The second attributed zardaverine toxicity in HeLa cells to promotion of the interaction of phosphodiesterase 3A and the growth regulatory protein Schlafen 12. We speculate that this work may provide a possible mechanism for zardaverine action in CS242 ERMS, although we have not yet tested this hypothesis. In conclusion, we have identified zardaverine as a potent cytotoxic agent in a CS-derived ERMS cell line and in HeLa. Although we have ruled out some possibilities, the mechanism of action of zardaverine in CS242 ERMS remains to be determined.

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Section: Resultsunclassified

Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient

et al. 2017

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“…This activity led to the registration of anagrelide as an agent for lowering platelet count in patients with myeloproliferative disorders. The mechanism of this activity has not been characterized as yet but appears to act at the megakaryocyte level -inhibiting platelet production [106].…”

Section: Clinical History Of Pde3 Inhibitorsmentioning

confidence: 99%

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Thompson¹,

Manganiello²,

Degerman

2007

CTMC

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The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.

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“…In vitro studies have shown that anagrelide is metabolized by cytochrome P450 (CYP) 1A2 and produces the active metabolite 6,7-dichloro-3-hydroxy-1,5-dihydro-imidazol[2,1-b] quinazolin-2-one (3-hydroxyanagrelide) [4, 5]. Caffeine is a known substrate of CYP1A2 [6] and the possible effects of the constituents of a normal high-fat breakfast with coffee on the rate and extent of absorption of anagrelide, as well as the rate and extent of formation of the active metabolite, was considered worthy of investigation.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Safety of Anagrelide in Healthy Subjects: Effects of Caffeine and Food Intake on Pharmacokinetics and Adverse Reactions

Martínez‐Sellés

Datino

Figueiras-Graillet

et al. 2012

Clinical Drug Investigation

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BackgroundEssential 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.ObjectivesThe 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 intakeMethodsThirty-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.ResultsTime to maximum (peak) plasma concentration (Cmax) 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 Cmax 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).ConclusionWe 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.

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Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures

Cited by 39 publications

References 23 publications

Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient

Cytotoxicity of Zardaverine in Embryonal Rhabdomyosarcoma from a Costello Syndrome Patient

Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Cardiovascular Safety of Anagrelide in Healthy Subjects: Effects of Caffeine and Food Intake on Pharmacokinetics and Adverse Reactions

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