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Glatiramer acetate (Copaxone®) is a synthetic analogue of the multiple sclerosis (MS)-associated antigen, myelin basic protein. Although its exact mechanisms of action in MS remain to be fully elucidated, the key mechanisms of action of glatiramer acetate appear to be modulation of the inflammatory response and neuroprotective and/or neuroregenerative effects. Subcutaneous glatiramer acetate is indicated for the treatment of adult patients with relapsing-remitting MS (RRMS) and the treatment of patients who have experienced a well-defined first clinical episode and have magnetic resonance imaging (MRI) features consistent with MS or have been determined to be at high risk of developing clinically definite MS (CDMS). In clinical trials in patients with RRMS, glatiramer acetate reduced the frequency of relapses and reduced the burden and activity of disease on MRI, was more effective than placebo and showed generally similar efficacy to subcutaneous interferon (IFN) β-1a and IFNβ-1b. Furthermore, the beneficial effects of glatiramer acetate were sustained during up to 15 years of treatment in an extension study. In patients with clinically isolated syndrome (CIS), glatiramer acetate significantly delayed the onset of CDMS compared with placebo. The drug was generally well tolerated in these patient populations, with injection-site reactions being the most commonly occurring adverse events. Therefore, glatiramer acetate remains a valuable first-line option in the treatment of RRMS and is an option for delaying the onset of CDMS in patients with CIS. © 2013 Springer International Publishing Switzerland.

A new single-tablet, fixed-dose formulation consisting of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI); cobicistat, a pharmacokinetic enhancer; emtricitabine, a nucleoside reverse transcriptase inhibitor; and tenofovir disoproxil fumarate (tenofovir DF), a nucleotide reverse transcriptase inhibitor (elvitegravir/cobicistat/emtricitabine/tenofovir DF 150 mg/150 mg/200 mg/300 mg; Stribild®) is available in some countries for the once-daily treatment of HIV-1 infection in antiretroviral therapy-naïve adults. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is the first INSTI-based single-tablet regimen available for the complete initial treatment of adults with HIV-1 infection. In two large, randomized, double-blind, phase III trials, once-daily treatment with elvitegravir/cobicistat/emtricitabine/ tenofovir DF was effective in reducing plasma HIV-1 RNA levels to <50 copies/mL at the week 48 assessment and showed virological efficacy noninferior to that of the efavirenz/emtricitabine/tenofovir DF single-tablet regimen or a once-daily regimen of atazanavir plus ritonavir (ritonavir-boosted atazanavir) plus the fixed-dose combination of emtricitabine/tenofovir DF. Elvitegravir/cobicistat/emtricitabine/tenofovir DF also showed durable efficacy in terms of achieving sustained suppression of HIV-1 RNA levels to <50 copies/mL for up to 144 weeks in both of the phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is an important addition to the group of simplified once-daily single-tablet regimens currently available for the effective treatment of HIV-1 infection in antiretroviral therapy-naïve patients and is among the preferred regimens recommended for use as initial treatment. It offers advantages over more complex multiple-tablet regimens that may impair treatment adherence, which is fundamental to the successful management of HIV-1 infection. © 2013 Springer International Publishing Switzerland.

QVA149 (indacaterol/glycopyrronium) [Xoterna® Breezhaler®, Ultibro® Breezhaler®] is an inhaled fixed-dose combination of indacaterol (a long-acting selective β2-adrenergic receptor agonist [LABA]) and glycopyrronium (a long-acting muscarinic receptor antagonist [LAMA]) that has been approved in the EU and Japan for the symptomatic control of chronic obstructive pulmonary disease (COPD) in adults. In phase III studies, QVA149 significantly improved bronchodilation versus indacaterol, glycopyrronium or tiotropium alone and the LABA/inhaled corticosteroid fixed-dose combination salmeterol/fluticasone. These improvements in lung function, which were rapid in onset and maintained during long-term treatment, were generally associated with significant improvements in dyspnoea, health status, COPD exacerbation risk, patient symptoms, and rescue medication use. The SHINE and ILLUMINATE studies in low (exacerbation) risk patients with moderate to severe disease suggest that QVA149 may offer more symptomatic relief than tiotropium and salmeterol/fluticasone. Similarly, the SPARK study in high (exacerbation) risk patients with severe or very severe disease showed that QVA149 was more effective than glycopyrronium in preventing moderate to severe exacerbations, and suggests that QVA149 may offer more symptomatic relief than LAMA monotherapy. Another phase III study comparing QVA149 with salmeterol/fluticasone in high-risk patients with moderate to very severe disease (FLAME) is ongoing. QVA149 is generally well tolerated, with no new safety signals identified compared with its monocomponents. Bronchodilators remain central to the symptomatic management of COPD. When dual bronchodilation is indicated, QVA149 offers the convenience of two bronchodilators in a single inhaler coupled with a simple, once-daily dosing regimen that may encourage better treatment adherence. Therefore, it is a valuable option in the treatment of COPD. © 2014 Springer International Publishing.

Oral aripiprazole (Abilify®) is an atypical antipsychotic agent that is approved worldwide for use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique receptor binding profile as it exhibits both partial agonist activity at dopamine D2 receptors and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.In several well designed, randomized, clinical trials of 46 weeks duration, aripiprazole provided symptomatic control for patients with acute, relapsing schizophrenia or schizoaffective disorder. Furthermore, following 26 weeks treatment, the time to relapse was significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole compared with those receiving placebo.Using a variety of efficacy outcomes, aripiprazole showed a mixed response when evaluated against other antipsychotic agents in randomized clinical trials. Longer-term data showed that improvements in remission rates and response rates favoured aripiprazole over haloperidol, although, the time to failure to maintain a response was not significantly different between the treatment arms. On the other hand, improvements in positive and negative symptom scores mostly favoured olanzapine over aripiprazole, although, the time to all-cause treatment discontinuation was not significantly different between the two treatments.Several open-label, switching trials showed that aripiprazole provided continued control of symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of efficacy outcomes or quality-of-life scores, longer-term treatment generally favoured patients switched to receive aripiprazole compared with standard-of-care oral antipsychotics.Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more cost-effective treatment option compared with other atypical antipsychotics.In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative for the acute and long-term management of patients with schizophrenia. © 2012 Adis Data Information BV.

Canagliflozin (Invokana™) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, canagliflozin reduces renal glucose reabsorption, thereby increasing urinary glucose excretion and reducing blood glucose levels. Several randomized placebo- or active comparator-controlled trials of 26-52 weeks' duration (plus extension phases) have shown that canagliflozin improves glycaemic control when used as monotherapy or as add-on therapy to metformin and/or other antihyperglycaemic agents, including insulin, in patients with type 2 diabetes. In addition to achieving reductions from baseline in glycosylated haemoglobin, canagliflozin also showed beneficial effects for other endpoints including reductions from baseline in fasting plasma glucose levels and bodyweight. Canagliflozin has a low risk of hypoglycaemia and was generally well tolerated in clinical trials. The most frequently reported adverse events with canagliflozin are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment, and prescribing information should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Canagliflozin has modest effects on the serum lipid profile, some beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others not (increased low-density lipoprotein cholesterol). Most patients treated with canagliflozin also have a modest reduction in blood pressure. The overall effect of canagliflozin on the risk of cardiovascular disease is unknown and will be evaluated in the ongoing CANVAS trial; preliminary cardiovascular safety data suggest no increased risk. Thus, with its unique mechanism of action that is independent of insulin secretion and action, canagliflozin is a useful addition to the therapeutic options available for the management of type 2 diabetes, particularly by providing complementary treatment when used as add-on therapy. © 2014 Springer International Publishing Switzerland.

Lyseng-Williamson K.A.,Adis
Drugs | Year: 2014

Miglustat (Zavesca®, Brazaves®), a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis, is the only disease-specific drug approved for the treatment of progressive neurological manifestations of Niemann-Pick disease type C (NP-C) in adult and paediatric patients. NP-C is a rare, autosomal-recessive lipid storage disorder characterized by impaired intracellular lipid trafficking and progressive neurological symptoms leading to premature death. In a randomized clinical trial, long-term extension studies and a retrospective observational cohort study, treatment with oral miglustat stabilized key neurological manifestations of NP-C (including horizontal saccadic eye movement peak velocity, ambulation, manipulation, language and swallowing) in paediatric and adult patients with the disease. The therapeutic effects of miglustat in stabilizing or slowing disease progression have been confirmed in other reports in the clinical experience setting. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects (e.g. diarrhoea, flatulence and abdominal pain/discomfort) and weight loss, which usually occur during initial therapy and are generally manageable. In the absence of a cure, miglustat is a valuable agent to reduce the progression of clinically relevant neurological symptoms in paediatric and adult patients with NP-C, which is considered a significant achievement in the treatment of this disease. © 2013 Springer International Publishing Switzerland.

The dipeptidyl peptidase-4 inhibitor vildagliptin (Galvus®) is approved for use as monotherapy and combination therapy in type 2 diabetes mellitus. A fixed-dose combination of vildagliptin/metformin (Eucreas®) is also available. This article reviews the clinical efficacy and tolerability of vildagliptin in the treatment of type 2 diabetes, as well as summarizing its pharmacological properties. Results of randomized controlled trials demonstrated that oral vildagliptin improved glycaemic control when administered as monotherapy, as dual therapy in combination with metformin, a sulfonylurea or a thiazolidinedione, as triple therapy in combination with metformin plus a sulfonylurea, and in combination with insulin with or without metformin. Improvements in glycaemic control were also seen with vildagliptin in elderly patients with type 2 diabetes and in patients with type 2 diabetes and moderate or severe renal impairment. Vildagliptin was generally well tolerated in patients with type 2 diabetes, was weight neutral and was associated with a low risk of hypoglycaemia, reflecting its glucose-dependent mechanism of action. Thus, oral vildagliptin is a useful option as monotherapy or as add-on therapy for patients with type 2 diabetes. © 2014 Springer International Publishing Switzerland.

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin®) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving.In direct comparisons with other marketed agents, tranexamic acid was at least as effective as ε-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent. © 2012 Adis Data Information BV. All rights reserved.

Dapagliflozin (Forxiga®) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a reduction in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action.A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10mgday for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated haemoglobin values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycaemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clinical trials, dapagliflozin was associated with reductions in body weight that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to ≈2 years.Dapagliflozin was generally well tolerated in clinical trials of 24 or 52 weeks duration and in extension studies of up to ≈2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycaemia, especially when used alone or in combination with metformin, although the incidence of hypoglycaemic events reported with dapagliflozin in clinical trials varied depending on the background therapy. Longer-term tolerabilitysafety data with dapagliflozin are awaited with interest.In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addition to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy. Adis © 2012 Springer International Publishing AG. All rights reserved.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil (Zinforo™, Teflaro®), is an advanced-generation, parenteral cephalosporin with broad-spectrum antibacterial activity in vitro against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Streptococcus pneumoniae and Gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis, but not Pseudomonas aeruginosa. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for drug-resistant Gram-positive organisms, including MRSA, as well as for Gram-negative respiratory pathogens. In pivotal phase III studies, intravenous ceftaroline fosamil demonstrated noninferiority to intravenous vancomycin plus aztreonam in patients hospitalized with complicated skin and soft tissue infections (cSSTIs) and intravenous ceftriaxone in patients hospitalized with community-acquired pneumonia (CAP) [Pneumonia Outcomes Research Team (PORT) risk class III or IV]; however, patients with CAP admitted to the intensive care unit were not evaluated. Ceftaroline fosamil was generally well tolerated in these trials, with an adverse event profile similar to that of other cephalosporins. Diarrhoea was the most commonly reported adverse event; however, the risk of Clostridium difficile-associated diarrhoea with ceftaroline fosamil appeared to be low. Potential limitations of the drug include the lack of an oral formulation and the requirement for twice-daily administration. Nonetheless, ceftaroline fosamil represents an attractive option (either alone or in combination with other agents) for the initial empirical treatment of patients hospitalized with cSSTIs (including those with suspected MRSA infection) or CAP (PORT risk class III or IV) who require intravenous antimicrobial therapy. As with all antibacterial agents, ceftaroline fosamil should be used in accordance with good antimicrobial stewardship. © 2013 Springer International Publishing Switzerland.

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