Drugs

Bannwarth, Bernard; Kostine, Marie

doi: 10.1007/s40265-017-0781-6pmid: 28660479

Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of ‘class-specific effects’. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti-inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis.

Ahluwalia, Jusleen; Udkoff, Jeremy; Waldman, Andrea; Borok, Jenna; Eichenfield, Lawrence

doi: 10.1007/s40265-017-0784-3pmid: 28681318

Phosphodiesterase 4 (PDE4) is a cyclic AMP degrading enzyme in leukocytes. Several decades ago, increased PDE activity was demonstrated in patients with atopic dermatitis (AD). Currently, several PDE4 inhibitors in both topical and oral formulation have been developed to target the inflammatory cascade of AD. This review shows the pathogenic rationale behind these inhibitors, and discusses multiple PDE4 inhibitors that are under evaluation or in the market. PDE4 inhibitors may be considered as favorable agents in the repertoire of current interventions for AD.

Poulakou, Garyphallia; Matthaiou, Dimitrios K.; Nicolau, David P.; Siakallis, Georgios; Dimopoulos, George

doi: 10.1007/s40265-017-0787-0pmid: 28741229

Positive experience with inhaled antibiotics in pulmonary infections of patients with cystic fibrosis has paved the way for their utilization in mechanically ventilated, critically ill patients with lower respiratory tract infections. A successful antibiotic delivery depends upon the size of the generated particle and the elimination of drug impaction in the large airways and the ventilator circuit. Generated droplet size is mainly affected by the type of the nebulizer employed. Currently, jet, ultrasonic, and vibrating mesh nebulizers are marketed; the latter can deliver optimal antibiotic particle size. Promising novel drug-device combinations are able to release drug concentrations of 25- to 300-fold the minimum inhibitory concentration of the targeted pathogens into the pulmonary alveoli. The most important practical steps of nebulization include pre-assessment and preparation of the patient (suctioning, sedation, possible bronchodilation, adjustment of necessary ventilator settings); adherence to the procedure (drug preparation, avoidance of unnecessary tubing connections, interruption of heated humidification, removal of heat-moisture exchanger); inspection of the procedure (check for residual in drug chamber, change of expiratory filter, return sedation, and ventilator settings to previous status); and surveillance of the patient for adverse events (close monitoring of the patient and particularly of peak airway pressure and bronchoconstriction). Practical aspects of nebulization are very important to ensure optimal drug delivery and safe procedure for the patient. Therefore, the development of an operational checklist is a priority for every department adopting this modality.

Santamato, Andrea; Panza, Francesco

doi: 10.1007/s40265-017-0786-1pmid: 28726023

Spasticity with muscle paresis and loss of dexterity is a common feature of upper motor neuron syndrome due to injuries or the pyramidal tract in several neurological conditions. Botulinum toxin type A has been considered the gold standard treatment for spasticity and movement disorders, with efficacy, reversibility, and low prevalence of complications. During the last 30 years, thousands of studies of its use have been performed, but few guidelines are available. Therefore, there is great variability in both the doses and intervals of administration and the approaches taken by clinicians with considerable experience in spasticity and movement disorder treatment. In the present review article, we provide a short overview of the benefits and risks of non-approved injection regimens and doses for botulinum toxins, focusing on the treatment of post-stroke spasticity, where there is great interest in the potential for increasing the number of treatment/years and the dose of botulinum toxin treatment for subjects with upper and lower limb spasticity. However, many doubts exist regarding antibody development and possible adverse effects.

Veerman, Selene; Schulte, Peter; Haan, Lieuwe

doi: 10.1007/s40265-017-0789-ypmid: 28776162

Negative symptoms (such as amotivation and diminished expression) associated with schizophrenia are a major health concern. Adequate treatment would mean important progress with respect to quality of life and participation in society. Distinguishing primary from secondary negative symptoms may inform treatment options. Primary negative symptoms are part of schizophrenia. Well-known sources of secondary negative symptoms are psychotic symptoms, disorganisation, anxiety, depression, chronic abuse of illicit drugs and alcohol, an overly high dosage of antipsychotic medication, social deprivation, lack of stimulation and hospitalisation. We present an overview of reviews and meta-analyses of double-blind, controlled randomised trials, in which the efficacy of pharmacological and non-pharmacological interventions for negative symptoms was assessed. Unfortunately, there have been very few clinical trials focusing on primary negative symptoms and selecting chronically ill patients with predominant persistent negative symptoms. An important limitation in many of these studies is the failure to adequately control for potential sources of secondary negative symptoms. At present, there is no convincing evidence regarding efficacy for any treatment of predominant persistent primary negative symptoms. However, for several interventions there is short-term evidence of efficacy for negative symptoms. This evidence has mainly been obtained from studies in chronically ill patients with residual symptoms and studies with a heterogeneous study population of patients in both the acute and chronic phase. Unfortunately, reliable information regarding the distinction between primary and secondary negative symptoms is lacking. Currently, early treatment of psychosis, add-on therapy with aripiprazole, antidepressants or topiramate, music therapy and exercise have been found to be useful for unspecified negative symptoms. These interventions can be considered carefully in a shared decision-making process with patients, and are promising enough to be examined in large, well-designed long-term studies focusing on primary negative symptoms. Future research should be aimed at potential therapeutic interventions for primary negative symptoms since there is a lack of research in this field.

Schuller, Y.; Hollak, C.; Gispen-de Wied, C.; Stoyanova-Beninska, V.; Biegstraaten, M.

doi: 10.1007/s40265-017-0788-zpmid: 28752290

Syed, Yahiya

doi: 10.1007/s40265-017-0795-0pmid: 28791622

Lenalidomide (Revlimid®) is an immunomodulatory drug with multiple mechanisms of action against multiple myeloma. It is a thalidomide analogue, with improved potency and reduced toxicity compared with thalidomide. In the EU and USA, lenalidomide monotherapy is indicated for the maintenance treatment of patients with newly diagnosed multiple myeloma who have undergone autologous stem-cell transplantation (ASCT). In the pivotal, phase 3 IFM 2005-02 and CALGB 100104 trials, lenalidomide maintenance therapy after ASCT administered until disease progression significantly prolonged progression-free survival (PFS; primary endpoint) relative to placebo in patients with newly diagnosed multiple myeloma. These results are generally supported by those of the phase 3 GIMEMA and Myeloma XI trials. Lenalidomide maintenance therapy significantly prolonged overall survival in CALGB 100104 but not in IFM 2005-02. However, a meta-analysis of patient-level data from IFM 2005-02, CALGB 100104 and GIMEMA showed an overall survival benefit with this therapy. Lenalidomide maintenance therapy had a manageable tolerability profile in the pivotal trials. Grade 3/4 haematological adverse events and grade 3 nonhaematological adverse events were more common with lenalidomide than with placebo. Lenalidomide increased the risk of a second primary cancer, but the survival benefits outweigh this risk. In conclusion, lenalidomide maintenance therapy after ASCT until disease progression prolongs PFS and overall survival in patients with newly diagnosed multiple myeloma. Therefore, lenalidomide offers a valuable maintenance treatment option for this population.

Markham, Anthony

doi: 10.1007/s40265-017-0790-5pmid: 28748399

Delafloxacin (Baxdela™) is a fluoroquinolone antibacterial with activity against both gram-positive and gram-negative pathogens being developed by Melinta Therapeutics. The drug is being investigated or considered as a treatment for various bacterial infections and in June 2017 received approval in the USA for the treatment of acute bacterial skin and skin structure infections. This article summarizes the milestones in the development of delafloxacin leading to this first global approval for the treatment of acute bacterial skin and skin structure infections.

Markham, Anthony

doi: 10.1007/s40265-017-0800-7pmid: 28819723

Guselkumab (Tremfya™) is a human monoclonal IgG1λ antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.