Correction to: Cladribine Tablets: In Relapsing-Remitting Multiple Sclerosis.

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Olmesartan medoxomil in children and adolescents with hypertension†: profile report.

†Adapted and reproduced from the original article published in Drugs 2010; 70 (18): 2439-47.

Botulinum toxin A (Dysport®): in dystonias and focal spasticity.

Dysport®, a formulation of botulinum toxin A, blocks acetylcholine release at neuromuscular junctions causing denervation and temporary muscle paralysis. It is used to treat several medical conditions, including dystonias and focal spasticity. Subcutaneous Dysport® was effective in improving functional disability in adults with blepharospasm in a placebo-controlled trial with 16 weeks' follow-up, and in adults with hemifacial spasm in case series. Similarly, intramuscular Dysport® was effective in improving symptoms of cervical dystonia in adults, focal spasticity in adults with post-stroke upper limb spasticity and dynamic equinus spasticity in paediatric patients with cerebral palsy in placebo-controlled trials with up to 20 weeks' follow-up. However, in two 12-week, placebo-controlled trials in adults with focal lower limb spasticity (spastic equinovarus deformity after stroke and hip adductor spasticity associated with multiple sclerosis) intramuscular Dysport® had limited efficacy. Available longer-term data indicated that Dysport® treatment was effective over several treatment cycles in patients with cervical dystonia or upper limb spasticity. Dysport® was generally well tolerated in patients with dystonias or focal spasticity. Most adverse events were mild to moderate and transient.

Denosumab: in the prevention of skeletal-related events in patients with bone metastases from solid tumours.

Denosumab, a fully human monoclonal antibody, binds to the receptor activator of nuclear factor-κB ligand (RANKL) and thereby inhibits RANKL-mediated bone resorption. In various individual countries, subcutaneous denosumab is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumours (featured indication), and/or for the treatment of postmenopausal osteoporosis and/or of cancer treatment-induced bone loss in prostate or breast cancer patients. In three, pivotal, double-blind, multinational trials in adult patients with cancer-related bone metastases (total n > 5700), including trials in patients with advanced breast or prostate cancer, subcutaneous denosumab (120 mg every 4 weeks) was shown to be noninferior to intravenous zoledronic acid (4 mg every 4 weeks), as determined by the median time to first on-study skeletal-related event (primary endpoint) at the time of the primary analysis (≈34 or 41 months). Denosumab treatment was superior to zoledronic acid in terms of the primary endpoint in two trials in patients with breast cancer or prostate cancer, based on secondary superiority analyses. In a third trial in patients with solid tumours excluding breast or prostate cancer, superiority of denosumab treatment versus zoledronic acid treatment was not demonstrated. The tolerability profile of denosumab was manageable in patients with bone metastases from solid tumours. Osteonecrosis of the jaw occurred in 1.8% and 1.3% of patients in the denosumab and zoledronic acid groups during the primary treatment phase; the incidence after approximately 4 additional months of denosumab treatment was 2.2%.

Erlotinib: as maintenance monotherapy in non-small-cell lung cancer.

Erlotinib is a low molecular weight, orally active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Inhibition of EGFR tyrosine kinase results in the disruption of processes involved in cancer growth and development, including cell migration, proliferation, angiogenesis, and apoptosis. In the well designed, phase III SATURN study, oral erlotinib 150 mg/day as maintenance treatment prolonged progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) who had not progressed after four cycles of first-line platinum doublet chemotherapy. PFS was significantly longer with erlotinib than with placebo in patients who were analyzable for PFS and in the subgroup of these patients with EGFR immunohistochemistry-positive tumors (co-primary endpoints). The improvement in PFS was independent of several baseline and clinical characteristics, including histology, smoking status, and EGFR mutation status, although a greater treatment benefit was observed in patients with tumors bearing EGFR-activating mutations than in those with wild-type EGFR tumors. Overall survival in the SATURN study was significantly longer with erlotinib than with placebo in the intent-to-treat population, in patients with EGFR immunohistochemistry-positive tumors, and in patients with wild-type EGFR tumors. Median overall survival had not yet been reached in patients with tumors bearing EGFR-activating mutations. Oral erlotinib as maintenance therapy was generally well tolerated in patients with NSCLC in the SATURN study and had a tolerability profile generally similar to that observed in a trial of erlotinib monotherapy as second-line treatment in patients with NSCLC.

Cladribine tablets: in relapsing-remitting multiple sclerosis.

Cladribine, an immunosuppressant that selectively reduces peripheral lymphocyte levels, has potential as an oral therapy for relapsing-remitting multiple sclerosis. An oral (tablet) formulation is being investigated in clinical trials. In the large, well designed, phase III CLARITY trial, short-course treatment with oral cladribine (cumulative dose of 3.5 or 5.25 mg/kg) resulted in a significantly greater reduction in annualized relapse rates at 96 weeks compared with placebo in patients with relapsing-remitting multiple sclerosis. Improvements in the annualized relapse rate with oral cladribine were independent of key baseline patient characteristics which included age, sex, previous treatment with disease-modifying drugs and the number of relapses in the previous 12 months. In addition, a significantly higher proportion of patients were relapse-free at 96 weeks and there were significant reductions in the risk of 3-month sustained progression of disability in cladribine recipients compared with placebo recipients. The mean numbers of brain lesions on magnetic resonance imaging were also significantly reduced with cladribine compared with placebo in the CLARITY trial. Lymphocytopenia, herpes zoster infections and neoplasms (including malignancies) were more common in cladribine than placebo recipients.

Olmesartan medoxomil: in children and adolescents with hypertension.

Olmesartan medoxomil is an orally administered angiotensin II receptor antagonist, selective for the angiotensin II type 1 receptor, which has established antihypertensive efficacy in adults. In children and adolescents with hypertension (n = 302), oral olmesartan medoxomil significantly and dose-dependently reduced seated systolic blood pressure (BP) and seated dystolic BP from baseline (the primary endpoint) in a 3-week, dose-response period in a well designed phase II/III clinical trial. Patients received olmesartan medoxomil high dose (20 or 40 mg once daily depending on bodyweight) or low dose (2.5 or 5.0 mg once daily depending on bodyweight). The response was significant for both cohorts, which were stratified by race (cohort A was mixed race [62% White] and cohort B was 100% Black). In addition, BP control was maintained in olmesartan recipients relative to placebo recipients in cohort A and the combined cohort A + B, but not for patients in cohort B, during a placebo-controlled withdrawal period of this trial. Oral olmesartan medoxomil was generally well tolerated in children and adolescents with hypertension. The majority of adverse events were of mild to moderate intensity.

Denosumab: in cancer treatment-induced bone loss.

Denosumab is a fully human monoclonal IgG(2) antibody that binds to receptor activator of nuclear factor-κB ligand (RANKL) and inhibits bone resorption due to RANKL-mediated osteoclastogenesis. In Europe, subcutaneous denosumab is indicated for cancer treatment-induced bone loss in men with prostate cancer and in postmenopausal women with breast cancer. In a large (n= 1468), well designed, multinational, phase III trial in adult patients with prostate cancer who were receiving androgen-deprivation therapy, bone mineral density (BMD) at the lumbar spine was significantly improved from baseline after 24 (primary endpoint) and 36 months of treatment with subcutaneous denosumab (60 mg once every 6 months), relative to that with placebo. Moreover, the risk of new vertebral fracture was significantly reduced by 62% in the denosumab group compared with the placebo group. In breast cancer patients receiving aromatase inhibitor therapy (n =252), subcutaneous denosumab (60 mg once every 6 months) significantly improved BMD at the lumbar spine from baseline after 12 (primary endpoint) and 24 months of treatment relative to placebo in a pivotal phase III trial. There were significant improvements in BMD at all skeletal sites, including the lumbar spine, total hip, and femoral neck, after 24 and 36 months' denosumab treatment in prostate cancer patients and after 12 and 24 months' treatment in breast cancer patients. In general, these improvements occurred irrespective of baseline characteristics, including age, duration of hormone ablation therapy, and baseline BMD. Denosumab treatment was generally well tolerated for up to 24 months in breast cancer patients and for up to 36 months in prostate cancer patients.

Guanfacine extended-release: in attention deficit hyperactivity disorder.

Guanfacine, an alpha(2A)-adrenoceptor agonist, is available in the US as an extended-release (ER) tablet for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents (aged 6-17 years). In two large, randomized, double-blind, placebo-controlled trials of 8 and 9 weeks' duration, guanfacine ER (1-4 mg once daily) was effective in reducing the symptoms of ADHD (hyperactivity, impulsivity and inattention) in children and adolescents. There were significant reductions (denoting improvements) from baseline in ADHD rating scale IV (ADHD-RS-IV) total scores (the primary endpoint), compared with placebo. Oppositional symptoms were also significantly reduced from baseline in children with ADHD with oppositional symptoms who received guanfacine ER in a randomized, double-blind, placebo-controlled trial. Improvements in ADHD symptoms were sustained over 24 months in two noncomparative, open-label extension trials in children and adolescents who received guanfacine ER at an optimized dosage of 1-4 mg/day. Guanfacine ER was relatively well tolerated in clinical trials in children and adolescents. The most common treatment-emergent adverse events were somnolence-related, and tended to resolve over time.

Synthesis of fluorescein-labelled O-mannosylated peptides as components for synthetic vaccines: comparison of two synthetic strategies.

Mannose-binding proteins on the surface of antigen-presenting cells (APCs) are capable of recognizing and internalizing foreign agents in the early stages of immune response. These receptors offer a potential target for synthetic vaccines, especially vaccines designed to stimulate T cells. We set out to synthesize a series of fluorescein-labelled O-mannosylated peptides using manual solid phase peptide synthesis (SPPS) on pre-loaded Wang resin, in order to test their ability to bind mannose receptors on human APCs in vitro. A flexible and reliable method for the synthesis of fluorescein-labelled O-mannosylated glycopeptides was desired in order to study their lectin-binding properties using flow cell cytometry. Two synthetic strategies were investigated: incorporation of a fluorescein label into the peptide chain via a lysine side chain epsilon-amino group at the final stage of standard Fmoc solid phase peptide synthesis or attachment of the fluorescein label to the N(alpha)-amino group of a lysine with further incorporation of a mannosylated peptide unit through the side chain N(epsilon)-amino group. The latter strategy proved more effective in that it facilitated SPPS by positioning the growing mannosylated peptide chain further removed from the fluorescein label.

A comparative study of different glycosylation methods for the synthesis of D-mannopyranosides of Nalpha-fluorenylmethoxycarbonyl-trans-4-hydroxy-L-proline allyl ester.

The synthesis of Nalpha-fluorenylmethoxycarbonyl-trans-4-hydroxy-4-O-[(2,3,4,6-tetra-O-acetyl)-alpha-d-mannopyranosyl]-l-proline allyl ester and Nalpha-fluorenylmethoxycarbonyl-trans-4-hydroxy-4-O-[(2,3,4,6-tetra-O-benzoyl)-alpha-d-mannopyranosyl]-l-proline allyl ester is described. Glycosylation using Königs-Knorr conditions with a benzoyl protected glycosyl donor provided the optimum method. Removal of the allyl ester gave two mannosylated building blocks suitable for solid phase glycopeptide synthesis.