Acorda Data on Inhaled Levodopa Therapy CVT-301 Recognized in Blue Ribbon Highlights Session at International Congress of Parkinson's Disease and Movement Disorders ARDSLEY, N.Y.--(BUSINESS WIRE)-- Acorda Therapeutics, Inc. (Nasdaq:ACOR) today announced that data from aPhase 2b clinical trial of CVT-301, an inhaled levodopa (L-dopa) under development for the episodic treatment ofOFF episodes associated with Parkinson's disease (PD), was included in the Blue Ribbon Highlights Session of the19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Selected by a panel of experts,the Blue Ribbon Highlights Session provided a critical review of the best poster presentations, highlightingrelevance, novelty and quality of both clinical data and basic research. "Inhaled Levodopa (CVT-301) Provides RapidImprovement of OFF States in Parkinson's Disease" was one of only 19 posters selected from among the almost1,500 poster presentations at this year's conference.
Bloodmed.comBritish Journal of Haematology, 2003, 120, 177–186 THE ROLE OF HYDROXYUREA IN SICKLE CELL DISEASE Although the molecular basis for the sickling disorders was ism by which hydroxyurea induces HbF is still unclear.
identified more than 50 years ago (reviewed in Weatherall Unlike several of the other HbF-inducing agents, such as 2001), progress towards definitive therapy for sickle cell 5-azacytidine and butyrates, hydroxyurea does not appear disease (SCD) has been frustratingly slow. Until the mid- to directly modulate globin gene expression by altering 1990s, treatment was almost entirely supportive with no methylation or binding to transcriptionally active elements.
clinically useful drugs available to prevent or reverse the That hydroxyurea is a ribonucleotide reductase inhibitor polymerization of HbS. However, a number of key observa- and arrests cells in S-phase as a result of impairment of DNA tions about the role of HbF (Stevens et al, 1981; de Simone replication is well known. It may therefore increase HbF et al, 1982, Platt et al, 1984, 1991; Veith et al, 1985; indirectly by killing rapidly dividing late erythroid cells, Noguchi et al, 1993) led, in 1995, to the publication of a causing recruitment of more primitive erythroid precursors crucially important study in which a new therapeutic agent, which in turn produce high levels of HbF, or by acting hydroxyurea, was heralded as a major breakthrough in the directly on the primitive precursors thereby stimulating HbF management of SCD (Charache et al, 1995; Schechter & production (Kolata, 1984). However, even in the early Rodgers, 1995). The initial clinical trials of hydroxyurea in trials, it was clear that induction of HbF was unlikely to SCD were stopped early as a result of outstanding results in explain all the clinical effects of hydroxyurea; treatment was the treatment arm and the drug was rapidly licensed in the often associated with clinical improvement well before any USA for the treatment of patients with severe SCD. Since detectable laboratory rise in HbF and the level of HbF did then, hydroxyurea has been used successfully in a variety of not always predict response, other variables such as situations in SCD, including new studies in very young neutrophil counts and mean cell volume (MCV) often being children (Wang et al, 2001). However, doubts remain both more strongly correlated with reduction in symptoms about its efficacy and safety in the long term.
(Charache et al, 1995).
This review aims to outline current information about the mechanisms of action of hydroxyurea in SCD, its clinical Effects of hydroxyurea on red cell–endothelial cell interactions efficacy in sickling disorders, the approaches to monitoring An important experimental observation is that within treatment and to update the evidence about its short-term 2 weeks of commencing hydroxyurea therapy, prior to and long-term toxicity.
any rise in HbF, sickle erythrocytes show reduced adhesionto endothelial cells under low shear flow conditions (Bridgeset al, 1996). Other investigators have shown that hydroxy- MECHANISMS OF ACTIONS OF urea reduces adhesion molecule expression on sickle eryth- HYDROXYUREA (TABLE I) rocytes, including very late activation antigen-4 and CD36 The principal rationale for treatment with hydroxyurea is its (Styles et al, 1997). Erythrocytes from hydroxyurea treated ability to induce HbF (Letvin et al, 1984). However, patients also show reduced adhesion in vitro to thrombo- hydroxyurea appears to exert its beneficial effects in SCD spondin and laminin (Hillery et al, 2000). As transit times via a number of additional mechanisms, including modifi- through hypoxic postcapillary venules are critical in cation of red cell–endothelial cell interactions and the promotion of sickling and microvascular occlusion, any rheological properties of HbS-containing red cells and via its reduction in sickle–endothelial adhesion would be predicted myelosuppressive effects, particularly on neutrophils.
to have a beneficial effect.
Effects of hydroxyurea on sickle red cell rheology The increase in HbF induced by hydroxyurea appears to Other rheological properties of sickle erythrocytes may also interfere with HbS polymerization both by preventing be important, including erythrocyte hydration status and effective contact between adjacent HbS molecules and also whole cell deformability, both of which can be increased by by forming mixed hybrids with HbS that have greater hydroxyurea (Ballas et al, 1989). An animal model of sickle solubility than HbS polymers. However, the exact mechan- cell disease, the transgenic sickle (SAD) mouse, has beenused to investigate these properties further. Hydroxyureacauses increased cellular potassium levels and reducederythrocyte density. Subsequent exposure to chronic hyp- Correspondence: Professor Irene Roberts, Department of Haema- oxia led to reduced cellular dehydration compared with tology, Faculty of Medicine Imperial College, Hammersmith Campus, untreated animals (de Franceschi et al, 1999). Human Du Cane Road, London W12 0NN, UK. E-mail: [email protected] studies have not always shown consistent results with 2003 Blackwell Publishing Ltd Table I. Mechanisms of action of hydroxyurea in SCD.
Increase in haemoglobin F Interferes with HbS polymerization Reduced red cell–endothelial interactions Reduced adhesion under low shear flowReduced VLA-4 and CD36 expression on sickle erythrocytesReduced adhesion to thrombospondin and laminin Improved red cell rheology Improved erythrocyte hydration statusIncreased whole cell deformabilityReduced red cell density Reduced neutrophil counts? leads to reduced pro-inflammatory mediators Nitric oxide release, leading to vaso-dilatation and? reduced platelet activation respect to cell hydration, although there appears to be an efficacy. In these studies, using small numbers of patients alteration in the density profile with a reduction in both with homozygous SCD, hydroxyurea consistently led to low-density reticulocytes and high-density sickle cells increases in the number of erythrocytes and reticulocytes (Charache et al, 1987; Orringer et al, 1991).
containing HbF (F cells and F reticulocytes respectively), inthe overall percentage of HbF, and in the MCV. Some studies Myelosuppressive effects of hydroxyurea also showed an increase in steady-state haemoglobin with Myelosuppressive effects of hydroxyurea may also be reductions in neutrophils and reticulocytes, improved red important in reduction of symptoms. The fall in neutrophil cell survival and improved red cell filterability (Rodgers et al, count appears especially important, and neutrophilia has 1993). These encouraging laboratory changes were accom- long been identified as a marker of severity in SCD (Platt panied by a lack of evidence of serious toxicity (Charache et al, 1994). Neutrophils release powerful pro-inflammatory et al, 1992) and led to the Multicenter Study of Hydroxy- mediators which are important in endothelial damage and urea in Sickle Cell Anemia (MSH) study (Charache et al, cytokine release, both of which trigger sickling (Noguchi et al, 1993). Neutrophils may also contribute to slow transittime via their adhesive properties and an increase in whole The Multicenter Study of Hydroxyurea in Sickle Cell Anemia blood viscosity. Evidence that hydroxyurea may modulate This study ran from January 1992 until June 1994 neutrophil activation comes from a recent study by (Charache et al, 1995). The trial was stopped 10 months Benkerrou et al (2002), who showed that hydroxyurea early because of a significant reduction in events in the treatment in patients with SCD corrected the dysregulated hydroxyurea group. The study was a double-blind, rand- omized controlled trial of 299 patients with severe SCD increased hydrogen peroxide production characteristic of (defined as at least three painful crises per year) recruited neutrophil activation in SCD.
from 21 centres in the USA and Canada. All patients hadHbSS. Treatment was started at a dose of 15 mg ⁄ kg ⁄ d and Effects of hydroxyurea in SCD: other mechanisms escalated according to 2 weekly blood counts aiming for the Finally, it has been suggested that hydroxyurea may highest dose possible without myelosuppression (maximum mediate some of its effects via nitric oxide. Studies in rats tolerated dose; MTD). The results were impressive and showed that metabolism of hydroxyurea leads to nitric oxide release (Jiang et al, 1997). In humans, nitrosylhae- • reduced annual rate of crises (2Æ5 in the treatment arm vs moglobin can be detected in blood within 30 min of 4Æ5 in the placebo arm) P < 0Æ001 ingestion of hydroxyurea (Glover et al, 1999) and steady • increased median time interval to first crisis (3Æ0 vs state levels of nitric oxide metabolites can be detected 1Æ5 months) P ¼ 0Æ001 in hydroxyurea-treated subjects (Nahavandi et al, 2000, Gladwin et al, 2002). This leads to the possibility that some 4Æ6 months) P < 0Æ001 of the clinical effects are mediated by nitric oxide-induced • reduced incidence of acute chest syndrome (25 events vs vasodilatation or reduced platelet activation.
51 events) P < 0Æ001 • reduced transfusion requirements (48 events vs 73 events) P ¼ 0Æ001 CLINICAL EFFICACY OF HYDROXYUREA The MSH trial showed that hydroxyurea could ameliorate IN ADULTS WITH SCD the clinical course of SCD in some adults without serious Initial reports of the use of hydroxyurea in SCD emerged in short-term adverse effects and that the MTD was not always the 1980s (Platt et al, 1984; Veith et al, 1985). These early needed to achieve a clinical response. Although higher HbF studies focused on the ability of hydroxyurea to increase levels were associated with lower crisis rates, the association HbF and improve laboratory parameters rather than clinical was not statistically significant and neutrophil counts 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 appeared to have the most impact, being associated with hydroxyurea in children. A registry of European patients on lower crisis rates throughout the whole study (Charache, hydroxyurea has recently been established with the aim of 1997). In addition, the final HbF levels in the hydroxyurea addressing these important questions (Davies & Roberts- group did not differ markedly from their pretreatment levels Harwood, 1998).
(5% vs 9%) (Steinberg et al, 1997a) and overall neither theinitial HbF nor the phenotype of the X-linked F-cell Hydroxyurea and stroke in adults with SCD production locus (FCP locus) predicted outcome, although Hydroxyurea has many theoretical benefits in the treatment the Central African Republic globin haplotype was associ- and prevention of stroke. It lowers white cell count, ated with a reduced response.
improves steady-state haemoglobin and reduces the risk of Use of hydroxyurea was also shown to be cost effective, acute chest syndrome: all risk factors for stroke (Ohene- despite the rigorous monitoring used with 2 weekly clinic Frempong et al, 1998). It also leads to improved rheological visits and blood tests. Average annual costs were $16 810 properties of red cells and reduction in endothelial adhesion.
in the hydroxyurea group vs $22 020 in the placebo group The only theoretical disadvantage is the increased whole with the vast majority of cost being accounted for by blood viscosity secondary to the rise in steady-state haemo- inpatient admissions. This difference failed to reach statis- globin. Despite these promising properties, the MSH study tical significance. No account was taken of possible reduc- did not show a statistical reduction in stroke although the tions in long-term morbidity with treatment (Moore et al, numbers involved (two in treatment group and three in 2000). Follow-up data after 6–7 years showed that there placebo) were very small (Charache et al, 1995). It is had been 51 deaths, 21 in the hydroxyurea group and 30 in possible that hydroxyurea may have a role to play in the placebo group (P ¼ 0Æ13); although because of the patients coming off transfusion regimes, although prelim- unblinding and subsequent switch of many patients to the inary data in children suggest that this may be associated treatment arm, these data are difficult to interpret. Analysis with a significant risk of stroke recurrence (Ware et al, according to hydroxyurea usage rather than original 1999). However, as most patients are unwilling or unable treatment allocation suggests that the odds ratio for to continue transfusions lifelong, many clinicians recom- mortality during hydroxyurea use compared with no mend stopping transfusions once patients reach adulthood hydroxyurea use ranges from 0Æ59 (P ¼ 0Æ08) to 0Æ39 (Powars, 2000). Prospective randomized trials of hydroxy- (P ¼ 0Æ001), depending upon assumptions made about urea versus continuing transfusions will be required to patients with incomplete data. There was no difference in define the role of hydroxyurea in this setting.
the incidence of stroke in the hydroxyurea-treated patients.
None of the patients have developed malignancies and, HYDROXYUREA IN CHILDREN although the incidence of acute chest syndrome wasreduced by hydroxyurea, pulmonary disease was the The use of hydroxyurea in children potentially brings the commonest cause of death (Steinberg et al, 1999).
greatest rewards in terms of prevention of end organdamage but also carries greater potential risks (Vichinsky, Other trials of hydroxyurea in adults with SCD 1997). The possibility of adverse effects on growth and A Cochrane review looking at the use of hydroxyurea in development, and the risks of secondary malignancy in SCD was published in February 2001 (Davies & Olujo- groups exposed to the drug for long periods led to caution.
hungbe 2001). Twenty randomized or quasi-randomized However, a number of promising phase I ⁄ II studies, trials comparing hydroxyurea with placebo, standard showing profound and sustained increases in HbF without therapy or other interventions were found. Only two of serious adverse events, led to larger scale trials (Scott et al, these, the MSH study and the Belgian paediatric trial (see 1996; Kinney et al, 1999). The published studies of below), were assessable. Problems with study design or data hydroxyurea therapy in children with SCD are summarized excluded the other 18. Despite these methodological in Table II.
concerns, none of the published data conflict in anysubstantive way with the MSH findings. The vast majority Evidence of efficacy report increases in HbF, MCV and steady-state haemoglobin Of the published studies, only four have focused on along with clinical improvement in the number of painful measures of clinical improvement in the severity of SCD crises, hospital attendance rates and acute chest syndrome (Ferster et al, 1996, 2001; Jayabose et al, 1996; Koren et al, (el-Hazmi et al, 1992; Kutlar et al, 2000). Studies from the 1999) while the other studies have mainly assessed developing world suggested hydroxyurea was no less laboratory parameters of response and safety. The Belgian effective in these populations (Lima et al, 1997; el-Alfy paediatric trial of hydroxyurea in severe SCD first reported in 1996 (Ferster et al, 1996), with the 5-year follow-up in While these studies have been useful in establishing the 2001 (Ferster et al, 2001). The first study included 25 clinical effectiveness of hydroxyurea, they leave a number of children (mean age 9 years) in a single-blind crossover unanswered questions including: the optimum dose and design with 6 months hydroxyurea (20–25 mg ⁄ kg ⁄ d) and schedule, the potential for prospective identification of 6 months placebo. The follow-up study described 93 responders and non-responders to avoid exposure to a patients (median age 7 years), including a small number potentially toxic drug, the impact of treatment on long-term of adults, who had a median follow-up of 3Æ5 years. There organ damage, morbidity and mortality, and the safety of was evidence in both studies of a reduction in hospital 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 admissions and days spent in hospital, and evidence of a reduced frequency of acute chest syndrome. Significant increases in HbF and MCV with reduction in white cell and reticulocyte counts were also seen. MTD was not needed for efficacy and no important adverse events were noted.
Similar beneficial results with hydroxyurea have been reported in the other clinical studies in children (Jayabose et al, 1996; Koren et al, 1999).
In all the studies to date, growth and development appear to be unaffected (Rogers, 1997; Wang et al, 2002) even in children under school age (Hoppe et al, 2000) and in infants (Wang et al, 2001). However, there is no evidence that hydroxyurea prevents stroke or the recurrence of strokein children. The largest study included 16 children, three of whom suffered a recurrent stroke within 16 weeksof changing from regular transfusions to hydroxyurea,although the dose and duration of hydroxyurea therapymay have contributed to these worrying results (Ware et al,1999).
Use of hydroxyurea in very young children to prevent organ dysfunction The development of end organ damage is closely associated with morbidity and mortality in SCD (Platt et al, 1994). This damage often starts early with evidence of splenic dysfunc- tion by 6 months of age. This raises the possibility that hydroxyurea might be able to exert a significant disease- modifying effect if given to very young children with SCD.
An early report suggested that hydroxyurea use in two young adults with sickle cell disease had led to reversal of splenic dysfunction (Claster & Vichinsky, 1996). This wasnot confirmed by a trial in older children (12 ± 1Æ2 years)perhaps because splenic auto-infarction may well haveoccurred by this age (Olivieri & Vichinsky, 1998). However,in a 2-year pilot trial of hydroxyurea (20 mg ⁄ kg ⁄ d) in 28children aged 6–28 months (median 15 months) with HbSS and Sbthalassaemia, Wang et al (2001) reported a lower frequency of functional asplenia (47%) compared with the expected frequency from historical data of 80% as assessed by radionucleotide scanning. While this may indicate aclinical benefit of hydroxyurea in very young children withSCD, this study also showed that hydroxyurea is clearly notenough on its own to completely prevent the majorcomplications of the disease at this age. Two of the 28children in this study had neurological events, three had acute chest syndrome and two had splenic sequestration despite hydroxyurea treatment. These results emphasize the still considerable as to its role in young children; a randomized controlled trial would seem DOSE AND MONITORING OF HYDROXYUREA The dose of hydroxyurea needed for maximal clinical benefit appears not to be the same as the MTD. Although with adverse clinical events in the form of invasive infection or bleeding, it seems prudent to minimize doses to reduce the risk of long-term toxicity, including secondary 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 malignancies. Hydroxyurea is available as capsules of occasional reports of aplasia lasting several weeks or 500 mg and syrup can be made up for paediatric use months (Vichinsky & Lubin, 1994). As far as we are aware, (generally 100 mg ⁄ ml) but is not widely available com- there has never been a documented episode of life- threatening infection associated with hydroxyurea-induced The MSH study started patients at 10–15 mg ⁄ kg once daily. Blood tests for full blood count, renal and liverfunction, along with HbF level were taken every 2 weeks.
Skin, gastrointestinal and renal The dose was increased by 5 mg ⁄ kg ⁄ d every 12 weeks in Cutaneous side-effects include nail hyperpigmentation, the absence of bone marrow suppression (neutrophil which is common, and increased skin pigmentation, count < 2 · 109 ⁄ l, haemoglobin < 4Æ5 g ⁄ dl, reticulocytes especially on the palms and soles (O'Branski et al, 2001).
or platelets < 80 · 109 ⁄ l). Once bone marrow suppression Patients should be warned of this potential side-effect as it had occurred, the dose was restarted at 2Æ5 mg ⁄ kg ⁄ d less can be quite distressing. Hydroxyurea is associated with than the toxic dose and this was defined as the MTD. Most development of leg ulcers in myeloproliferative diseases and patients achieved a dose of 20–25 mg ⁄ kg ⁄ d although some some studies have quoted rates of up to 30% in SCD patients tolerated 35 mg ⁄ kg ⁄ d. Some patients, however, showed on hydroxyurea, but the role of hydroxyurea is unclear as toxicity at levels of only 2Æ5 mg ⁄ kg ⁄ d.
90% of these patients had a prior history of ulcers (Chaine Most studies in children have used doses of approximately et al, 2001). In the MSH study, 32% of patients had leg 20 mg ⁄ kg ⁄ d. Unfortunately, there have been few studies ulcers at enrolment and new ulcers developed with equal looking at alternative dosing regimes. In general, our frequency in treatment and placebo groups (Charache et al, practice is to start at a dose of 15–20 mg ⁄ kg ⁄ d. Full blood 1995). Nausea, rash and other gastrointestinal upsets have count (FBC), including reticulocytes, HbF level, renal and been described with hydroxyurea (de Montalembert et al, liver function tests, are performed prior to commencing 1999) but, in randomized trials, are no commoner than treatment. FBC and reticulocytes should be repeated at with placebo (Charache et al, 1995). Hydroxyurea is renally 2 weeks and then at 2–4 week intervals during the initial excreted and small increases in creatinine are sometimes phases of treatment. Renal and liver function should be seen on treatment. Renal function should be monitored; checked at least monthly. Once the patient is well estab- dose reductions are needed in patients with renal failure.
lished on a stable dose, monthly blood counts should suffice.
The interval between counts should never exceed 6 weeks.
Pregnancy and teratogenicity Caution should be taken in issuing repeat prescriptions Studies in rats showed an increase in post-implantation without a recent blood count and supply should probably losses, and reduced fetal and placental weights (Spencer not exceed 4–6 weeks worth at any one time. Patients are et al, 2000). Despite strict instructions to take contraceptive asked to report any fever, sore mouth or other worrying precautions for both men and women patients on treat- symptoms and have a blood count done in these circum- ment, there have been a number of pregnancies in stances. When monitoring the response to hydroxyurea, the published studies. More than 14 cases have now been effect on clinical well-being is probably more important than described: three pregnancies were terminated electively, one any absolute increase in HbF levels. Patients that fail to infant was stillborn in a mother with eclampsia and the respond clinically to 20 mg ⁄ kg ⁄ d can have their dose other 10 resulted in healthy live-born infants with no escalated as long as there is no evidence of marrow congenital abnormalities (Byrd et al, 1999). Patients on hydroxyurea should be advised as to the theoretical risks of Although most cases of poor response are due to com- pregnancy and those wishing to conceive should stop pliance (Steinberg et al, 1997a), there appear to be some treatment 3–6 months before switching to unprotected individuals who are biologically resistant to hydroxyurea (Yang et al, 1997). Addition of erythropoietin has helpedin a small number of cases (el-Hazmi et al, 1995). Because of concerns about long-term toxicity, it is probably wise to The Polycythemia Study Group showed a trend towards withdraw treatment in any patient who has had no increased second malignancies after 8 years in a small study of 51 patients treated with hydroxyurea (9Æ8% vs 3Æ7% in 3–6 months of treatment. It is worth noting that labor- historical control group; P ¼ 0Æ1) (Fruchtman et al, 1997).
atory methods for measurement of HbF have generally A larger study of 150 patients with polycythaemia rubra been developed to measure fairly low levels. It is import- vera diagnosed before the age of 65 showed an actuarial ant to ensure that the method used is reliable at higher risk of leukaemia of about 10% by the 13th year of HbF concentrations (Epstein et al, 1996; Schultz, 1999).
treatment and a 15% rate of other cancers, although thiswas only slightly greater than the expected rate of 11Æ5% inpatients of this age group (Najean & Rain, 1997). A more LONG-TERM TOXICITY AND SAFETY suitable comparison group might be young patients with erythrocytosis secondary to inoperable congenital heart disease; a study of 64 patients treated with hydroxyurea for The commonest side-effect is dose-dependent myelosuppres- 2–15 years showed no increase in malignancy (Triadou sion. Although this is usually transient, there have been et al, 1994). Initial pilot studies of hydroxyurea showed that 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 Table III. Patients with SCD who have developed malignancies while on treatment withhydroxyurea.
hydroxyurea treatment Ferster et al (2001) Raunch et al (1999) Hodgkin's lymphoma Moschovi et al (2001) AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome.
some adults had pre-existing chromosomal breaks in similar advantages of treatment in other sickling conditions peripheral blood leucocytes but there was no progression especially sickle b-thalassaemia (Voskaridou et al, 1995; through treatment and no difference from HbSS and HbAA Loukopoulos et al, 2000; Rigano et al, 2001). Theoretically controls (Charache et al, 1987). More worrying are experi- hydroxyurea may be even more effective in this group of mental studies of acquired DNA mutations in children disorders than in HbSS as HbF production has the added treated for between 7 and 30 months that showed an advantage of mopping up excess a-chains responsible for increased mutation rate as measured by the VDJ recombi- some of the ineffective erythropoiesis. Results in HbSC nation assay. Although this was significantly greater than disease are more difficult to interpret. An initial study of six with control children (P ¼ 0Æ04), it was still within the patients showed an increase in haemoglobin levels and normal range for age (Hanft et al, 2000).
MCV, and a decrease in reticulocytes and bilirubin on There have now been four reported cases of malignancy treatment but no statistically significant change in HbF in sickle cell patients on hydroxyurea (Table III). Patients 1 levels (Steinberg et al, 1997b). A more recent trial in six and 4 are likely to be unrelated to treatment, given the time children with HbSC showed a significant rise in HbF and a course and type of malignancy. Cases 2 and 3 are more good clinical response with a marked reduction in hospital doubtful. It is difficult to judge risk as the denominator in admission rates (Miller et al, 2001). It is unlikely that these terms of total number of sickle cell patients on hydroxyurea patients are intrinsically resistant to hydroxyurea and is unknown. The earliest large-scale recruitment to trials therefore there seems no reason to deny severely affected began in 1992 so we have now accumulated 10 years individuals a trial of therapy. Case reports documenting worth of experience. The risk appears small but continued beneficial effects of hydroxyurea in HbSD-Punjab and HbSO- caution is needed (Ho & Murgo, 1995; Silver, 1995; Arab disease can also be found (Rogers, 1997; Udden et al, de Montalembert & Davies 2001).
HYDROXYUREA FOR SICKLING DISORDERS Based on the evidence reviewed above, hydroxyurea plays Initial studies were confined to patients with homozygous an important role in the management of a number of sickle cell disease. Smaller scale studies have confirmed complications of SCD. This is summarized in Table IV.
Table IV. The role of hydroxyurea in SCD.
Evidence for hydroxyurea Treatment of choice in severely affected adult patients (‡3 hospital admissions per year).
vaso-occlusive crises Probably similar efficacy in children but concerns surrounding long-term toxicity so reserve for patientswith severe disease despite intensive supportive care.
Proven reduction in acute chest syndrome in adults and supportive evidence in children.
Should be the treatment of choice in all patients with ‡ 2 episodes in preceding 1–2 years.
No evidence that hydroxyurea can reduce the incidence of first or recurrent strokes.
May have a role in patients coming off transfusion programmes.
Need controlled clinical trials to establish role.
No evidence for prevention or treatment of leg ulcers, priapism, osteonecrosis, splenic or hepatic sequestration.
Need to test in controlled clinical trials.
Insufficient data to comment on prevention of organ dysfunction, needs larger trials with prolonged follow-up.
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 Recurrent vaso-occlusive crises Benkerrou, M., Delarche, C., Brahimi, L., Fay, M., Vilmer, E., Elion, For the majority of adults with SCD, hydroxyurea can be J., Gougerot-Pocidalo, M.-A. & Elbim, C. (2002) Hydroxyurea recommended as the treatment of choice for preventing corrects the dysregulated L-selectin expression and increased vaso-occlusive crises in patients who have frequent, debi- H2O2 production of polymorphonuclear neutrophils frompatients with sickle cell anemia. Blood, 99, 2297–2303.
litating vaso-occlusive crises especially where these lead to Bridges, K.R., Barabino, G.D., Brugnara, C., Cho, M.R., Christoph, ‡ 3 hospital admissions per year or to excessive time lost G.W., Dover, G., Ewenstein, B.M., Golan, D.E., Guttmann, C.R., from work or higher education. Close monitoring for Hofrichter, J., Mulkern, R.V., Zhang, B. & Eaton, W.A. (1996) A toxicity is essential and this, or worries about possible multiparameter analysis of sickle erythrocytes in patients long-term toxicity, may lead many patients to decline this undergoing hydroxyurea therapy. Blood, 88, 4701–4710.
option. Unfortunately, there are as yet no other pharmaco- Byrd, D.C., Pitts, S.R. & Alexander, C.K. (1999) Hydroxyurea in two logical agents available with equivalent efficacy and the pregnant women with sickle cell anemia. Pharmacotherapy, 19, risks associated with chronic transfusion make this an unattractive approach for vaso-occlusive crises. For children Chaine, B., Neonato, M.G., Girot, R. & Aractingi, S. (2001) Cuta- with recurrent painful crises, every attempt should be made neous adverse reactions to hydroxyurea in patients with sicklecell disease. Archives of Dermatology, 137, 467–470.
to educate and support the family about the best ways to Charache, S. (1997) Mechanism of action of hydroxyurea in the prevent and cope with recurrent crises, as this will often be management of sickle cell anemia in adults. Seminars in Hema- sufficient to reduce the frequency of hospital admissions.
tology, 34, 15–21.
Psychologists with special expertise in SCD are often very Charache, S., Dover, G.J., Moyer, M.A. & Moore, J.W. (1987) valuable in more severe cases. Hydroxyurea should be Hydroxyurea-induced augmentation of fetal hemoglobin pro- reserved for children who have ongoing problems even after duction in patients with sickle cell anemia. Blood, 69, 109–116.
these intensive supportive measures have been explored.
Charache, S., Dover, G.J., Moore, R.D., Eckert, S., Ballas, S.K., Koshy, M., Milner, P.F., Orringer, E.P., Phillips, G.J. & Platt, O.S.
Recurrent acute chest syndrome (1992) Hydroxyurea: effects on hemoglobin F production in Given the mortality and morbidity associated with acute patients with sickle cell anemia. Blood, 79, 2555–2565.
Charache, S., Terrin, M.L., Moore, R.D., Dover, G.J., Barton, F.B., chest syndrome in SCD and the clear cut evidence of a Eckert, S.V., McMahon, R.P. & Bonds, D.R. (1995) Effect of reduced incidence of acute chest syndrome in patients on hydroxyurea on the frequency of painful crises in sickle cell hydroxyurea, this should be the treatment of choice to anemia. Investigators of the Multicenter Study of Hydroxyurea prevent recurrence for all patients, adults and children, who in Sickle Cell Anemia. New England Journal of Medicine, 332, have suffered more than one episode of acute chest syndrome in the preceding 1–2 years. There is no evidence Claster, S. & Vichinsky, E. (1996) First report of reversal of organ of benefit of transfusion in this setting and stem cell dysfunction in sickle cell anemia by the use of hydroxyurea: transplantation should be reserved for children who have splenic regeneration. Blood, 88, 1951–1953.
failed to respond to, or are unable to take, hydroxyurea.
Davies, S. & Olujohungbe, A. (2001) Hydroxyurea for sickle cell disease (Cochrane Review). In: The Cochrane Library, Issue 32002. Update Software, Oxford.
Other SCD-related complications Davies, S.C. & Roberts-Harwood, M. (1998) European register of There is no evidence yet that hydroxyurea is able to prevent patients with sickle cell disease treated with hydroxyurea is being first or recurrent strokes, splenic ⁄ hepatic sequestration, set up. British Medical Journal, 317, 541–542.
priapism, osteonecrosis, or leg ulcers. It is also unclear Epstein, N., Epstein, M., Boulet, A., Fibach, E. & Rodgers, G.P.
whether hydroxyurea given early in life is able to preserve (1996) Monoclonal antibody-based methods for quantitation of splenic function. Given the known and possible toxicity of hemoglobins: application to evaluating patients with sickle cell hydroxyurea, its use in these complications of SCD should anemia treated with hydroxyurea. European Journal of Haema- be investigated within the context of controlled clinical tology, 57, 17–24.
Ferster, A., Vermylen, C., Cornu, G., Buyse, M., Corazza, F., Devalck, C., Fondu, P., Toppet, M. & Sariban, E. (1996) Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial.
Department of Haematology, Blood, 88, 1960–1964.
Great Ormond Street Hospital Ferster, A., Tahriri, P., Vermylen, C., Sturbois, G., Corazza, F., for Sick Children, and Fondu, P., Devalck, C., Dresse, M.F., Feremans, W., Hunninck, 2Department of Haematology, K., Toppet, M., Philippet, P., Van Geet, C. & Sariban, E. (2001) Hammersmith and St Mary's Five years of experience with hydroxyurea in children and young Hospitals, Imperial College Faculty adults with sickle cell disease. Blood, 97, 3628–3632.
of Medicine, London, UK de Franceschi, L., Brugnara, C., Rouyer-Fessard, P., Jouault, H. & Beuzard, Y. (1999) Formation of dense erythrocytes in SAD miceexposed to chronic hypoxia: evaluation of different therapeutic regimens and of a combination of oral clotrimazole and mag-nesium therapies. Blood, 94, 4307–4313.
el-Alfy, M.S. (2000) Hydroxyurea in children with sickle cell ane- Fruchtman, S.M., Mack, K., Kaplan, M.E., Peterson, P., Berk, P.D. & mia, should it be a life long treatment? Blood, 96, 16b.
Wasserman, L.R. (1997) From efficacy to safety: a Polycythemia Ballas, S.K., Dover, G.J. & Charache, S. (1989) Effect of hydroxyurea Vera Study group report on hydroxyurea in patients with poly- on the rheological properties of sickle erythrocytes in vivo.
American Journal of Hematology cythemia vera. Seminars in Hematology, 34, 17–23.
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 Gladwin, M.T., Shelhamer, J.H., Ognibene, F.P., Pease-Fye, M.E., the experience of a single center in Greece. Blood Cells Molecules Nichols, J.S., Link, B., Patel, D.B., Jankowski, M.A., Pannell, L.K., and Diseases, 26, 453–466.
Schechter, A.N. & Rodgers, G.P. (2002) Nitric oxide donor Maier-Redelsperger, M., de Montalembert, M., Flahault, A., properties of hydroxyurea in patients with sickle cell disease.
Neonato, M.G., Ducrocq, R., Masson, M.P., Girot, R. & Elion, J.
British Journal of Haematology, 116, 436–444.
(1998) Fetal hemoglobin and F-cell responses to long-term Glover, R.E., Ivy, E.D., Orringer, E.P., Maeda, H. & Mason, R.P.
hydroxyurea treatment in young sickle cell patients. The French (1999) Detection of nitrosyl hemoglobin in venous blood in the Study Group on Sickle Cell Disease. Blood, 91, 4472–4479.
treatment of sickle cell anemia with hydroxyurea. Molecular Miller, M.K., Zimmerman, S.A., Schultz, W.H. & Ware, R.E. (2001) Pharmacology, 55, 1006–1010.
Hydroxyurea therapy for pediatric patients with hemoglobin SC Hanft, V.N., Fruchtman, S.R., Pickens, C.V., Rosse, W.F., Howard, disease. Journal of Pediatric Hematology and Oncology, 23, 306–308.
T.A. & Ware, R.E. (2000) Acquired DNA mutations associated de Montalembert, M. & Davies, S.C. (2001) Is hydroxyurea leuke- with in vivo hydroxyurea exposure. Blood, 95, 3589–3593.
mogenic in children with sickle cell disease? Blood, 98, 2878– el-Hazmi, M.A., Warsy, A.S., al-Momen, A. & Harakati, M. (1992) Hydroxyurea for the treatment of sickle cell disease. Acta Hae- de Montalembert, M., Belloy, M., Bernaudin, F., Gouraud, F., matologica, 88, 170–174.
Capdeville, R., Mardini, R., Philippe, N., Jais, J.P., Bardakdjian, J., el-Hazmi, M.A., al-Momen, A., Warsy, A.S., Kandaswamy, S., Ducrocq, R., Maier-Redelsperger, M., Elion, J., Labie, D. & Girot, Huraib, S., Harakati, M. & al-Mohareb, F. (1995) The pharma- R. (1997) Three-year follow-up of hydroxyurea treatment in cological manipulation of fetal haemoglobin: trials using hydro- severely ill children with sickle cell disease. The French Study Group on Sickle Cell Disease. Journal of Pediatric Hematology and Haematologica, 93, 57–61.
Oncology, 19, 313–318.
Hillery, C.A., Du M.C., Wang, W.C. & Scott, J.P. (2000) Hydro- de Montalembert, M., Begue, P., Bernaudin, F., Thuret, I., Bachir, D.
xyurea therapy decreases the in vitro adhesion of sickle ery- & Micheau, M. (1999) Preliminary report of a toxicity study of throcytes to thrombospondin and laminin. British Journal of hydroxyurea in sickle cell disease. French Study Group on Sickle Haematology, 109, 322–327.
Cell Disease. Archives of Diseases in Childhood, 81, 437–439.
Ho, P.T. & Murgo, A.J. (1995) Hydroxyurea and sickle cell crisis.
Moore, R.D., Charache, S., Terrin, M.L., Barton, F.B. & Ballas, S.K.
New England Journal of Medicine, 333, 1008.
(2000) Cost-effectiveness of hydroxyurea in sickle cell anemia.
Hoppe, C., Vichinsky, E., Quirolo, K., van Warmerdam, J., Allen, K.
Investigators of the Multicenter Study of Hydroxyurea in Sickle & Styles, L. (2000) Use of hydroxyurea in children ages 2–5 years Cell Anemia. American Journal of Hematology, 64, 26–31.
with sickle cell disease. Journal of Pediatric Hematology and Moschovi, M., Psychou, F., Menegas, D., Tsangaris, G.T., Tzortzatou- Oncology, 22, 330–334.
Stathopoulou, F. & Nikolaidou, P. (2001) Hodgkin's disease in a Jayabose, S., Tugal, O., Sandoval, C., Patel, P., Puder, D., Lin, T. & child with sickle cell disease treated with hydroxyurea. Pediatric Visintainer, P. (1996) Clinical and hematologic effects of Hematology and Oncology, 18, 371–376.
hydroxyurea in children with sickle cell anemia. Journal of Nahavandi, M., Wyche, M.Q., Perlin, E., Tavakkoli, F. & Castro, O.
Pediatrics, 129, 559–565.
(2000) Nitric Oxide Metabolites in Sickle Cell Anemia Patients Jiang, J., Jordan, S.J., Barr, D.P., Gunther, M.R., Maeda, H. & Mason, after Oral Administration of Hydroxyurea: Hemoglobinopathy.
R.P. (1997) In vivo production of nitric oxide in rats after Hematology, 5, 335–339.
administration of hydroxyurea. Molecular Pharmacology, 52, Najean, Y. & Rain, J.D. (1997) Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the Kinney, T.R., Helms, R.W., O'branski, E.E., Ohene-Frempong, K., age of 65 years. Blood, 90, 3370–3377.
Wang, W., Daeschner, C., Vichinsky, E., Redding-Lallinger, R., Noguchi, C.T., Schechter, A.N. & Rodgers, G.P. (1993) Sickle cell Gee, B., Platt, O.S. & Ware, R.E. (1999) Safety of hydroxyurea in disease pathophysiology. Bailliere's Clinical Haematology, 6, 57–91.
children with sickle cell anemia: results of the HUG-KIDS study, a O'Branski, E.E., Ware, R.E., Prose, N.S. & Kinney, T.R. (2001) Skin phase I ⁄ II trial. Pediatric Hydroxyurea Group. Blood, 94, 1550– and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. Journal of the American Academy of Der- Kolata, G. (1984) Globin gene studies create a puzzle. Science, 223, matology, 44, 859–861.
Ohene-Frempong, K., Weiner, S.J., Sleeper, L.A., Miller, S.T., Koren, A., Segal-Kupershmit, D., Zalman, L., Levin, C., Abu, H.M., Embury, S., Moohr, J.W., Wethers, D.L., Pegelow, C.H. & Gill, Palmor, H., Luder, A. & Attias, D. (1999) Effect of hydroxyurea in F.M. (1998) Cerebrovascular accidents in sickle cell disease: rates sickle cell anemia: a clinical trial in children and teenagers with and risk factors. Blood, 91, 288–294.
severe sickle cell anemia and sickle cell beta-thalassemia. Pedia- Olivieri, N.F. & Vichinsky, E.P. (1998) Hydroxyurea in children tric Hematology and Oncology, 16, 221–232.
with sickle cell disease: impact on splenic function and com- Kutlar, A., Woods, K.F., Clair, B., Daitch, L., Milner, P.F. & Samuels, pliance with therapy. Journal of Pediatric Hematology and Oncol- B.J. (2000) Long term use of hydroxyurea in adults with sickle ogy, 20, 26–31.
cell disease: a large single centre experience. Blood, 96, 10a.
Orringer, E.P., Blythe, D.S., Johnson, A.E., Phillips, G.J., Dover, G.J.
Letvin, N.L., Linch, D.C., Beardsley, G.P., McIntyre, K.W. & Nathan, & Parker, J.C. (1991) Effects of hydroxyurea on hemoglobin F D.G. (1984) Augmentation of fetal-hemoglobin production in and water content in the red blood cells of dogs and of patients anemic monkeys by hydroxyurea. New England Journal of Medi- with sickle cell anemia. Blood, 78, 212–216.
cine, 310, 869–873.
Oury, A.P., Hoyoux, C., Dresse, M.F. & Chantraine, J.M. (1997) Lima, C.S., Arruda, V.R., Costa, F.F. & Saad, S.T. (1997) Minimal Sickle cell anemia in children: value of hydroxyurea in severe doses of hydroxyurea for sickle cell disease. Brazilian Journal of forms. Archives of Pediatrics, 4, 839–844.
Medical and Biological Research, 30, 933–940.
Platt, O.S., Orkin, S.H., Dover, G., Beardsley, G.P., Miller, B. & Loukopoulos, D., Voskaridou, E., Kalotychou, V., Schina, M., Nathan, D.G. (1984) Hydroxyurea enhances fetal hemoglobin Loutradi, A. & Theodoropoulos, I. (2000) Reduction of the clin- production in sickle cell anemia. Journal of Clinical Investigation, ical severity of sickle cell ⁄ beta-thalassemia with hydroxyurea: 74, 652–656.
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186 Platt, O.S., Thorington, B.D., Brambilla, D.J., Milner, P.F., Rosse, Styles, L.A., Lubin, B., Vichinsky, E., Lawrence, S., Hua, M., Test, S.
W.F., Vichinsky, E. & Kinney, T.R. (1991) Pain in sickle cell & Kuypers, F. (1997) Decrease of very late activation antigen-4 disease. Rates and risk factors. New England Journal of Medicine, and CD36 on reticulocytes in sickle cell patients treated with 325, 11–16.
hydroxyurea. Blood, 89, 2554–2559.
Platt, O.S., Brambilla, D.J., Rosse, W.F., Milner, P.F., Castro, O., Steinberg, M.H. & Klug, P.P. (1994) Mortality in sickle cell dis- Deschamps, A., Casadevall, N., Dunda, O., Ducrocq, R., Elion, J., ease. Life expectancy and risk factors for early death. New Eng- Girot, R. & Labie, D. (1994) Fetal haemoglobin variations fol- land Journal of Medicine, 330, 1639–1644.
lowing hydroxyurea treatment in patients with cyanotic con- Powars, D.R. (2000) Management of cerebral vasculopathy in genital heart disease. Nouvelle Review of French Hematology, 36, children with sickle cell anaemia. British Journal of Haematology, 108, 666–678.
Udden, M.M., Lo, M.N. & Sears, D.A. (1999) Successful hydro- Raunch, A., Borromeo, M., Ghafoor, A., Khoyratty, B. & Mahesh- xyurea treatment of a patient with SD hemoglobinopathy.
wari, J. (1999) Leukemogenesis of hydroxyurea in the treatment American Journal of Hematology, 60, 84–85.
of sickle cell anemia. Blood, 94, 415a.
Veith, R., Galanello, R., Papayannopoulou, T. & Stamatoyanno- Rigano, P., Rodgers, G.P., Renda, D., Renda, M.C., Aquino, A. & poulos, G. (1985) Stimulation of F-cell production in patients Maggio, A. (2001) Clinical and hematological responses to with sickle-cell anemia treated with cytarabine or hydroxyurea.
hydroxyurea in Sicilian patients with Hb S ⁄ beta-thalassemia.
New England Journal of Medicine, 313, 1571–1575.
Hemoglobin, 25, 9–17.
Vichinsky, E.P. (1997) Hydroxyurea in children: present and Rodgers, G.P., Dover, G.J., Uyesaka, N., Noguchi, C.T., Schechter, future. Seminars in Hematology, 34, 22–29.
A.N. & Nienhuis, A.W. (1993) Augmentation by erythropoietin Vichinsky, E.P. & Lubin, B.H. (1994) A cautionary note regarding of the fetal-hemoglobin response to hydroxyurea in sickle cell hydroxyurea in sickle cell disease. Blood, 83, 1124–1128.
disease. New England Journal of Medicine, 328, 73–80.
Voskaridou, E., Kalotychou, V. & Loukopoulos, D. (1995) Clinical Rogers, Z.R. (1997) Hydroxyurea therapy for diverse pediatric and laboratory effects of long-term administration of hydro- populations with sickle cell disease. Seminars in Hematology, 34, xyurea to patients with sickle-cell ⁄ beta-thalassaemia. British Journal of Haematology, 89, 479–484.
Schechter, A.N. & Rodgers, G.P. (1995) Sickle cell anemia: basic Wang, W.C., Wynn, L.W., Rogers, Z.R., Scott, J.P., Lane, P.A. & research reaches the clinic. New England Journal of Medicine, 332, Ware, R.E. (2001) A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. Journal of Pediatrics, 139, Schultz, J.C. (1999) Comparison of radial immunodiffusion and alkaline cellulose acetate electrophoresis for quantitating eleva- Wang, W.C., Helms, R.W., Lynn, H.S., Redding-Lallinger, R., Gee, ted levels of fetal hemoglobin (HbF): application to evaluating B.E., Ohene-Frempong, K., Smith-Whitley, K., Waclawiw, M.A., patients with sickle cell disease treated with hydroxyurea. Journal Vichinsky, E.P., Styles, L.A., Ware, R.E. & Kinney, T.R. (2002) of Clinical and Laboratory Analysis, 13, 82–89.
Effect of hydroxyurea on growth in children with sickle cell Scott, J.P., Hillery, C.A., Brown, E.R., Misiewicz, V. & Labotka, R.J.
anemia: Results of the HUG-KIDS study. Journal of Pediatrics, (1996) Hydroxyurea therapy in children severely affected with 140, 225–229.
sickle cell disease. Journal of Pediatrics, 128, 820–828.
Ware, R.E., Zimmerman, S.A. & Schultz, W.H. (1999) Hydroxyurea Silver, R.T. (1995) Hydroxyurea and sickle cell crisis. New England as an alternative to blood transfusions for the prevention of Journal of Medicine, 333, 1008–1009.
recurrent stroke in children with sickle cell disease. Blood, 94, de Simone, J., Heller, P., Hall, L. & Zwiers, D. (1982) 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Pro- Ware, R.E., Eggleston, B., Redding-Lallinger, R., Wang, W.C., ceedings of the National Academy of Sciences of the United States of Smith-Whitley, K., Daeschner, C., Gee, B., Styles, L.A., Helms, America, 79, 4428–4431.
R.W., Kinney, T.R. & Ohene-Frempong, K. (2002) Predictors of Spencer, F., Chi, L. & Zhu, M.X. (2000) Hydroxyurea inhibition of fetal hemoglobin response in children with sickle cell anemia cellular and developmental activities in the decidualized and receiving hydroxyurea therapy. Blood, 99, 10–14.
pregnant uteri of rats. Journal of Applied Toxicology, 20, 407–412.
Weatherall, D. (2001) Towards molecular medicine: reminiscences Steinberg, M.H., Lu, Z.H., Barton, F.B., Terrin, M.L., Charache, S. & of the haemoglobin field, 1960–2000. British Journal of Haema- Dover, G.J. (1997a) Fetal hemoglobin in sickle cell anemia: tology, 115, 729–738.
determinants of response to hydroxyurea. Multicenter Study of Wilson, S. (2000) Acute leukemia in a patient with sickle-cell Hydroxyurea. Blood, 89, 1078–1088.
anemia treated with hydroxyurea. Annals of Internal Medicine, Steinberg, M.H., Nagel, R.L. & Brugnara, C. (1997b) Cellular effects 133, 925–926.
of hydroxyurea in Hb SC disease. British Journal of Haematology, Yang, Y.M., Pace, B., Kitchens, D., Ballas, S.K., Shah, A. & Baliga, 98, 838–844.
B.S. (1997) BFU-E colony growth in response to hydroxyurea: Steinberg, M.H., Barton, F.B., Castro, O., Koshy, M., Eckman, J. & correlation between in vitro and in vivo fetal hemoglobin Terrin, M. (1999) Risks and benefits of hydroxyurea in adult induction. American Journal of Hematology, 56, 252–258.
sickle cell anemia. Effects at 6- to 7-years. Blood, 94, 644a.
Stevens, M.C., Hayes, R.J., Vaidya, S. & Serjeant, G.R. (1981) Fetal Keywords: sickle cell anaemia, antisickling agents, hydroxy- hemoglobin and clinical severity of homozygous sickle cell dis- ease in early childhood. Journal of Pediatrics, 98, 37–41.
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
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