Oral Anticoagulants in DevelopmentEriksson, Bengt; Quinlan, Daniel
doi: 10.2165/00003495-200666110-00001pmid: 16906775
Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa.
Biological Therapy in the Management of Recent-Onset Crohn’s DiseaseLöwenberg, Mark; Peppelenbosch, Maikel; Hommes, Daniel
doi: 10.2165/00003495-200666110-00002pmid: 16906776
Crohn’s disease is a chronic inflammatory bowel disease that may involve any part of the gastrointestinal tract. Conventional therapy consists of corticosteroids, azathioprine or methotrexate, but the clinical management of Crohn’s disease is significantly hampered by adverse effects. With the introduction of biological agents (such as infliximab), the goals of therapy have advanced, including induction of remission with bowel healing as well as reduction in the rate of complications, surgeries and mortality. Current therapy for moderate to severe Crohn’s disease is based on ‘step-up’ algorithms, which initiate treatment with corticosteroids followed by immunomodulatory agents, and defer therapy with biological agents until patients become refractory to conventional therapeutics. Recently, it has been shown that induction therapy with infliximab and azathioprine in recent-onset Crohn’s disease (i.e. ‘top-down’ approach) is superior to current step-up algorithms to induce clinical remission. The underlying molecular mechanisms responsible for these differences in clinical outcome remain to be defined. Experimental studies have demonstrated that corticosteroids are able to induce impaired apoptosis of immune cells, including T cells and dendritic cells, resulting in loss of tolerance and subsequent autoimmunity. Further research will have to determine whether corticosteroid therapy augments the mechanism of loss of tolerance in Crohn’s disease, which could complicate future clinical management.
Targeting the Epidermal Growth Factor Receptor in the Treatment of Colorectal CancerDiasio, Robert; Fourie, Jeanne
doi: 10.2165/00003495-200666110-00003pmid: 16906777
The epidermal growth factor receptor (EGFR) is an important mediator of normal cellular processes such as growth, survival, differentiation and morphogenesis. Disturbances in the EGFR pathway have been associated with the development and progression of malignancy, including cellular proliferation, angiogenesis, invasion/metastasis and anti-apoptosis, as well as with resistance to chemotherapy and/or radiation therapy. As a result, this is an excellent rationale for treatment with EGFR-specific therapeutic agents. These agents may be EGFR-targeted antibodies or small molecules that inactivate the receptor tyrosine kinase. While only cetuximab has received US FDA approval for the treatment of colorectal cancer, numerous agents are currently in development and in clinical trials and constitute an area of intensive, ongoing research.
Pharmacological Approaches to the Management of Cognitive Dysfunction in SchizophreniaHarvey, Philip; McClure, Margaret
doi: 10.2165/00003495-200666110-00004pmid: 16906778
Cognitive dysfunction is a core feature of schizophrenia as deficits that are present in the majority of patients with schizophrenia frequently precede the onset of other symptoms and persist even after other symptoms have been effectively treated. The use of atypical antipsychotics has produced some small improvements, although the need for adjunctive treatment specifically targeting cognitive dysfunction is gaining widespread acceptance. Animal models and some small clinical trials have yielded results that are promising but not definitive. Psychosocial interventions have also met with some success in ameliorating some cognitive limitations. The mixed results of pharmacological interventions are most likely to be as a result of a combination of methodological flaws of many studies, poor outcome measures, dose administration effects and problems with the agents themselves.
Beclometasone Dipropionate/FormoterolDhillon, Sohita; Keating, Gillian
doi: 10.2165/00003495-200666110-00005pmid: 16906779
▴ A hydrofluoroalkane (HFA)-propelled pressurised metered-dose inhaler (pMDI) has been developed (using Modulite® technology) for a new fixed combination of beclometasone dipropionate/formoterol fumarate (BDP/formoterol) 100μg/6μg. Each actuation of the BDP/formoterol HFA pMDI 100μg/6μg delivers 86.4μg of BDP and 5μg of formoterol.
▴ BDP/formoterol HFA pMDI was associated with significantly higher morning peak expiratory flow (PEF) values than BDP administered alone via a chlorofluorocarbon (CFC) pMDI (including when BDP was administered at a higher dosage) in well designed trials in adults with mild to moderate or moderate to severe asthma.
▴ In terms of morning PEF values, BDP/formoterol HFA pMDI was noninferior to BDP plus formoterol administered via separate inhalers in well designed trials in adults with moderate to severe asthma.
▴ BDP/formoterol HFA pMDI was noninferior to fixed-combination budesonide/formoterol (the daily dosage of BDP was half that of budesonide) in terms of lung function, asthma symptoms and use of rescue medications in adults with moderate to severe asthma. BDP/formoterol HFA pMDI was also noninferior to, and had a faster onset of bronchodilation than, fixed-combination fluticasone propionate/salmeterol.
▴ BDP/formoterol 200μg/12μg per day or 400μg/ 24μg per day administered by the HFA pMDI was generally well tolerated. Moreover, a single high dose of BDP/formoterol (1000μg/60μg) was generally well tolerated in patients with asthma.
AdalimumabSimpson, Dene; Scott, Lesley
doi: 10.2165/00003495-200666110-00008pmid: 16906782
▴ Adalimumab, a fully human monoclonal antibody, is a tumour necrosis factor antagonist that has been investigated for efficacy in psoriatic arthritis, based on well-established use of the drug in rheumatoid arthritis.
▴ In well-controlled Phase III trials, adalimumab (40 mg administered subcutaneously every other week) has shown efficacy in adult patients with psoriatic arthritis who had an inadequate response to previous treatment with NSAIDs (24-week ADEPT trial; n = 313) or disease-modifying antirheumatic drugs (12-week study; n = 100).
▴ In these trials, adalimumab recipients experienced a significantly greater improvement in arthritis response (p < 0.001 in the ADEPT trial, and p ≤ 0.05 in the smaller study) than placebo recipients, as assessed by the ACR20, ACR50 and ACR70 response rates.
▴ There was radiographic evidence of progressive joint damage in the placebo group but not the adalimumab group at 24 weeks in the ADEPT trial, according to the mean total Sharp score modified for psoriatic arthritis.
▴ The signs and symptoms of psoriasis in patients with psoriatic arthritis were clinically and statistically more improved with adalimumab than with placebo, according to the PASI responses, at 12 and 24 weeks in the ADEPT trial (e.g. PASI50 rate 75% vs 12% at 24 weeks; p < 0.001).
▴ Adalimumab was generally well-tolerated in clinical trials of psoriatic arthritis; the adverse event profile appears to be similar to that associated with use of the drug in rheumatoid arthritis.