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Wolters Kluwer N.V. is a global information services and publishing company. The company provides products and services for professionals in the health, tax, accounting, corporate, financial services, legal and regulatory sectors. Wolters Kluwer has annual revenues of €3.4 billion, employs approximately 18,000 people worldwide and maintains operations across Europe, North America, Asia Pacific and Latin America. Wolters Kluwer is headquartered in Alphen aan den Rijn, Netherlands. Its shares are quoted on the Euronext Amsterdam and are included in the AEX index and Euronext 100 index. The CEO and Chairman of the Executive Board is Nancy McKinstry.Wolters Kluwer formed under its present name in 1987 when Kluwer Publishers merged with Wolters Samson as a defensive move against an attempted hostile takeover of Kluwer Publishers by Elsevier. In 2003 Wolters Kluwer sold Kluwer Academic Publishers to two private equity funds who shortly after merged with BertelsmannSpringer to form Springer Science+Business Media. Wolters Kluwer Education, was sold to Bridgepoint Capital for 700 million euros in March 2007, who renamed it Infinitas Learning. Wikipedia.


Plerixafor (Mozobil®) is a CXCR4 chemokine receptor antagonist that is indicated for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize stem cells to the peripheral blood for collection and subsequent autologous stem-cell transplantation in patients who have non-Hodgkins lymphoma (NHL) or multiple myeloma (MM) US and in patients who have lymphoma or MM and are poor mobilizers (EU). This article reviews the clinical efficacy and tolerability of subcutaneous plerixafor for stem-cell mobilization in patients with lymphoma or MM, as well as summarizing its pharmacological properties. Pharmacoeconomic analyses of plerixafor and decision-making algorithms intended to optimize its use are also discussed.Plerixafor plus G-CSF mobilized stem cells more efficiently than placebo plus G-CSF in adults with NHL or MM, according to the results of two randomized, double-blind, multicentre trials. In these trials, significantly more plerixafor plus G-CSF recipients than placebo plus G-CSF recipients reached primary apheresis targets in significantly fewer apheresis days. In the trial in patients with NHL, significantly more plerixafor plus G-CSF than placebo plus G-CSF recipients proceeded to transplantation.Results of compassionate-use studies in patients with lymphoma or MM demonstrated that plerixafor plus G-CSF successfully mobilized stem cells in the majority of patients who were poor mobilizers (i.e. sufficient CD34 cells had not been collected during apheresis or apheresis had not occurred because of low peripheral blood CD34 cell counts). Results of compassionate-use studies and additional studies in patients with lymphoma or MM also demonstrated that plerixafor plus G-CSF successfully mobilized stem cells in predicted poor mobilizers, such as heavily pretreated patients considered to be at high risk of mobilization failure. In addition, a small study showed mobilization with pre-emptive plerixafor to be effective.Subcutaneous plerixafor was generally well tolerated during stem-cell mobilization in patients with NHL or MM; the most commonly occurring treatment-related adverse events in plerixafor plus G-CSF recipients included injection-site reactions and gastrointestinal adverse events.Preliminary results of a US cost-effectiveness analysis suggest that plerixafor plus G-CSF is a cost-saving option compared with cyclophosphamide plus G-CSF. A retrospective US cost analysis found no significant difference between plerixafor plus G-CSF and cyclophosphamide plus G-CSF recipients in the median total cost of initial mobilization, suggesting that the cost of plerixafor may be offset by increased utilization of other resources in patients receiving alternative mobilization regimens. Additional cost analyses examined the use of pre-emptive plerixafor; institutions have developed decision-making algorithms, mainly relating to the use of pre-emptive plerixafor, to help optimize its use.In conclusion, plerixafor is a valuable stem-cell mobilizer for use in combination with G-CSF in patients with lymphoma or MM, particularly in patients who are poor mobilizers or predicted poor mobilizers. © 2011 Adis Data Information BV. All Rights Reserved.


Oral fingolimod (Gilenya™), a sphingosine 1-phosphate (S1P) receptor agonist, is the first oral agent and the first in a novel class of disease-modifying therapies (DMTs) to be approved for use in the US for the treatment of relapsing forms of multiple sclerosis (MS). In the EU, fingolimod is approved for use as a single-agent DMT in selected patients with highly-active, relapsing-remitting (RR) MS. This article reviews the pharmacological properties and clinical use of the drug in patients with RRMS.Fingolimod is rapidly converted in vivo to the active moiety S-fingolimod-phosphate, which binds with high affinity to S1P receptors, thereby sequestering lymphocytes in the lymph nodes and preventing their egress into the peripheral circulation. As a consequence, there is a reduction in the infiltration of autoaggressive lymphocytes into the CNS. Fingolimod-phosphate also acts as a functional antagonist, as its binding to S1P receptors results in their internalization and degradation, thereby downregulating S1P receptors on the lymphocyte cell surface. Since fingolimod crosses the blood:brain barrier, it also potentially acts at S1P receptors on neural cells in the CNS to mitigate neuropathological processes associated with MS.In large multinational trials in adult patients with RRMS, oral fingolimod 0.5mgday was more effective than oral placebo (FREEDOMS) and recommended dosages of intramuscular interferon-β (IFNβ)-1a (TRANSFORMS) in reducing the annualized relapse rate and was also generally more effective at slowing progression of neurological disability and at reducing the burden and activity of disease. Fingolimod was generally well tolerated in these trials of up to 2 years duration, with most adverse events being manageable and of mild to moderate severity; there were two deaths from opportunistic infections, albeit these occurred with fingolimod 1.25mgday (higher than the recommended dosage). Limited long-term data indicated that no new safety concerns had arisen after 5 years of fingolimod treatment. However, further clinical experience is required to fully determine the long-term safety profile of fingolimod, particularly with regard to any potentially serious or life-threatening adverse events. In the absence of robust pharmacoeconomic studies and of head-to-head trials comparing fingolimod with other formulations of IFNβ and glatiramer acetate, the relative position of fingolimod with respect to other DMTs remains to be fully determined. In the meantime, given its convenient once-daily oral treatment regimen and better efficacy than intramuscular IFNβ-1a, fingolimod is a valuable emerging option for the treatment of adult patients with relapsing forms of MS. © 2011 Adis Data Information BV. All rights reserved.


Aripiprazole (Abilify®) is an atypical antipsychotic indicated for the treatment of mania associated with bipolar I disorder. It is unique in its class, as it is a partial agonist of dopamine D2 and D3, and serotonin 5-HT1A receptors and a modest antagonist of 5-HT2A receptors. This article reviews the pharmacological properties, clinical efficacy and tolerability of oral aripiprazole in the management of mania associated with bipolar I disorder in adults.In well designed clinical trials in patients with recent manic or mixed episodes associated with bipolar I disorder, oral aripiprazole monotherapy or adjunctive therapy to lithium or valproate improved symptoms of mania following short-term (≤12 weeks) or maintenance (≤100 weeks) treatment. In addition, maintenance treatment with aripiprazole (as monotherapy or adjunctive therapy) prevented the recurrence of any mood episodes or manic episodes (but not depressive episodes) in patients who had previously been stabilized and maintained on aripiprazole.Aripiprazole was generally well tolerated in these studies and was associated with a low risk of prolactin elevation, corrected QT interval prolongation and metabolic disturbances. Extrapyramidal symptoms occurred in up to 28 of aripiprazole recipients, but after longer-term treatment (≤100 weeks), symptom severity did not differ significantly from that in placebo recipients. Aripiprazole treatment generally did not increase bodyweight to a clinically relevant extent; however, more patients receiving aripiprazole monotherapy than placebo had clinically significant bodyweight gain during 100 weeks treatment.Additionally, in a comparative trial, aripiprazole monotherapy was at least as effective as haloperidol monotherapy in terms of improving symptoms of mania, but had the advantage of a lower incidence of some adverse events, such as extrapyramidal symptom-related adverse events. Further trials comparing aripiprazole with other agents, including atypical antipsychotics, would help to definitively position aripiprazole relative to these agents.Current guidelines recommend aripiprazole as a first-line option (as monotherapy or adjunctive therapy) for the short-term treatment of mania associated with bipolar I disorder, and as a first-line (as monotherapy) or second-line (as adjunctive therapy) option for preventing the recurrence of mood episodes during longer-term therapy. © 2012 Adis Data Information BV. All rights reserved.


Supraventricular tachyarrhythmia (including atrial fibrillation), hypertension and tachycardia in the perioperative setting, and acute ischaemic heart disease are generally agreed to require rapid attention and treatment. Prolonged tachyarrhythmia or hypertension can result in significant morbidity, such as cerebrovascular events, myocardial infarction and other end-organ damage. This article reviews the clinical efficacy and tolerability of intravenous infusions of esmolol for the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension, and provides an overview of the pharmacological properties of the drug.Esmolol, a cardioselective β-blocker, has been proven effective in the control of elevated haemodynamic parameters in patients with supraventricular tachyarrhythmia, hypertension and tachycardia in the perioperative setting, and acute ischaemic heart disease, as well as being associated with a reduced risk of some clinical sequelae to increased haemodynamic parameters. Esmolol is, moreover, generally well tolerated; while it is associated with an increased risk of hypotension, this is rapidly reversible.Definitive conclusions on the efficacy of esmolol are difficult to reach, as most trials investigating esmolol have limitations such as small patient populations, and few studies investigate the same parameters. Ideally, several further studies would be beneficial; however, as esmolol is a well established, older drug, these are less likely to occur.Despite this, esmolol, as a fast-acting, rapidly reversible, easily titratable β-blocker, is an established option for the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension. © 2012 Adis Data Information BV. All rights reserved.


The anticholinergic agent tiotropium bromide (Spiriva®) is a long-acting bronchodilator that is indicated for the treatment of chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of tiotropium bromide inhalation powder, administered using the HandiHaler® device, in patients with COPD, as well as reviewing its pharmacological properties and the results of pharmacoeconomic analyses. Shorter-term placebo-controlled trials in patients with COPD demonstrated significantly higher trough forced expiratory volume in 1 second (FEV1) responses with tiotropium bromide than with placebo, confirming it has a duration of action of ≥24 hours and is suitable for once-daily administration. Lung function improved to a greater extent with tiotropium bromide than with ipratropium bromide or, in most instances, salmeterol. Indacaterol was shown to be noninferior to tiotropium bromide in terms of the trough FEV1 response. The large, 4-year UPLIFT® trial did not show a significant reduction in the annual rate of decline in FEV1 with tiotropium bromide versus placebo in patients with COPD, although subgroup analyses demonstrated a significantly lower rate of decline with tiotropium bromide than with placebo in some patient groups (e.g. patients with moderate COPD, patients aged ≥50 years, patients not receiving maintenance therapy at baseline). Tiotropium bromide prevented exacerbations in patients with COPD, with a significantly lower exacerbation rate and a significantly longer time to first exacerbation seen with tiotropium bromide than with placebo or salmeterol. Exacerbation rates did not significantly differ between patients receiving tiotropium bromide and those receiving salmeterolfluticasone propionate. Tiotropium bromide also had beneficial effects on health-related quality of life (HR-QOL) and other endpoints, such as dyspnoea and rescue medication use. Combination therapy with tiotropium bromide plus formoterol with or without budesonide improved lung function to a significantly greater extent than tiotropium bromide alone in patients with COPD. In addition, exacerbation rates were lower and HR-QOL was improved with tiotropium bromide plus budesonideformoterol versus tiotropium bromide alone. Although the addition of salmeterolfluticasone propionate to tiotropium bromide did not reduce the COPD exacerbation rate, it did improve lung function and HR-QOL. Tiotropium bromide inhalation powder is generally well tolerated in patients with COPD, with anticholinergic adverse events (e.g. dry mouth, constipation, gastrointestinal obstruction, dysuria) among the most commonly reported adverse events. The UPLIFT® trial showed no significant difference between tiotropium bromide and placebo recipients in the risk of stroke, and the risk of serious cardiac adverse events (including congestive heart failure and myocardial infarction) was significantly lower with tiotropium bromide than with placebo. The absence of a detrimental effect on cardiovascular outcomes was supported by the results of a meta-analysis and pooled analyses. In addition, on-treatment mortality was lower with tiotropium bromide than with placebo in the UPLIFT® trial. Pooled analyses showed significantly lower cardiovascular mortality with tiotropium bromide than with placebo, with a meta-analysis demonstrating no significant difference between patients receiving tiotropium bromide and controls in cardiovascular mortality. Results of modelled pharmacoeconomic analyses conducted from a healthcare payer perspective in several developed countries suggest that tiotropium bromide is a cost-effective option in patients with COPD.In conclusion, tiotropium bromide inhalation powder is a useful option for the maintenance treatment of patients with COPD. © 2012 Adis Data Information BV. All rights reserved.

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