Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment.

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.

Implementing the Collaborative Care Model as Part of a Countywide Initiative.

This column describes the planning and implementation of an integrated behavioral health project which was facilitated and endorsed by a developing accountable health community, the Washtenaw Health Initiative (WHI). The WHI is a voluntary countywide coalition of academic, community, health system, and county government agencies dedicated to improving access to high-quality health care for low-income, uninsured, and Medicaid populations. When lack of access to mental health services was identified as a pressing concern, the WHI endorsed pilot testing of collaborative care, an evidence-based treatment model, in county safety-net clinics. Challenges, outcomes, and relevance of this initiative to other counties or regional entities are discussed.

Cytokines: The Good, the Bad, and the Deadly.

Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon ß reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

Administration of supplemental L-tyrosine with phenelzine: a clinical literature review.

The subject of this literature review is the alleged relationship between L-tyrosine, phenelzine, and hypertensive crisis. Phenelzine (Nardil(®)) prescribing information notes: "The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take […] L-tyrosine […]". Interest in the scientific foundation of this claim was generated during routine patient care. A comprehensive literature search of Google Scholar and PubMed revealed no reported cases of hypertensive crisis associated with concomitant administration of L-tyrosine and phenelzine. Review of current US Food and Drug Administration nutritional guidelines relating to ongoing phenelzine studies reveals no mention and requires no consideration of L-tyrosine ingestion in combination with phenelzine. This paper is intended to provide an objective review of the science to then allow the reader to formulate the final opinion.

Proteasome inhibitors in the treatment of multiple myeloma.

Proteasome inhibition has been shown to be an effective strategy for the treatment of multiple myeloma, as demonstrated by the clinical activity of the first-in-class agent bortezomib. Recently, the second-generation proteasome inhibitor carfilzomib has been approved in the USA in the relapsed and refractory setting, and several other investigational agents are in clinical development, including MLN9708, marizomib, oprozomib and delanzomib. Here, the authors provide a comprehensive review of the key role of proteasome inhibitors in the myeloma treatment pathway, and highlight the similarities and differences in pharmacology, routes of administration, and efficacy and safety profiles between bortezomib, carfilzomib and investigational agents. The authors also evaluate the potential for further improving myeloma treatment through the ongoing development of novel proteasome inhibitors.

Cognitive rehabilitation in traumatic brain injury.

OPINION STATEMENT: Traumatic brain injury (TBI) is a major public health problem with neurobehavioral sequelae contributing to the long-term disability that is often associated with the moderate to severe levels of injury. Rehabilitation of cognitive skills is central to encouraging the full participation of the individual in home, vocational, and social roles. The review of available evidence points to four major recommendations for the rehabilitation of cognition following brain injury: 1) Access to subacute rehabilitation that is holistic in nature and involves a multidisciplinary or transdisciplinary team to work in an integrated fashion to support physical, cognitive, and social skill retraining is vital to support positive outcome following TBI. The collaborative effort of these individuals allows for continual reinforcement and evaluation of treatment goals and will often involve the family and/or important others in the individual's life to prepare for community re-entry. 2) Trials of medication, especially methylphenidate, to assist individuals with significant attention and memory impairment appear well supported by the available evidence. Though some data suggest that the use of cholinesterase inhibitors may be of use for individuals with memory impairments, there is less support for this practice and there are indications that it may worsen the behavioral sequelae of the injury. 3) Randomized controlled trials demonstrate the utility of specific rehabilitation approaches to attention retraining and retraining of executive functioning skills. Future research is needed on rehabilitation techniques in other domains of cognition. 4) Training in the use of supportive devices (either a memory book or more technologically enhanced compensatory devices) to support the individual's daily activities remains central to the independent function of the individual in the community. Though emerging treatments (eg, virtual reality environments) show relative degrees of promise for inclusion in the rehabilitation of the individual with TBI, these need further evaluation in systematic trials.

Approaching death: a phenomenologic study of five older adults with advanced cancer.

PURPOSE/OBJECTIVES: To explore the lived experience and the associated meaning of approaching death among older adults with advanced cancer. RESEARCH APPROACH: A phenomenologic inquiry. SETTING: Urban cancer center. PARTICIPANTS: 5 individuals diagnosed with advanced cancer who were 65 years or older. METHODOLOGIC APPROACH: A series of semistructured interviews were tape-recorded, transcribed verbatim, analyzed, and developed into narrative summations. FINDINGS: The study elucidated the experience of approaching death from advanced cancer. The insightful and compelling narratives of five individuals' experiences suggest that genuine caring, compassionate honesty from trusted healthcare professionals, cautious hopefulness maintained by patients and their loved ones, unquestioned faith, an involvement in desired life activities, and positive interactions within the healthcare system and in personal relationships were meaningful to participants. CONCLUSIONS: Knowledge developed from dying patients allows for an awareness that moves beyond assumption toward an in-depth understanding that can enable healthcare professionals to design meaningful care for these individuals. INTERPRETATION: Knowledge gained directly from patients' experiences of what is meaningful and helpful as death approaches can guide effective interventions to improve palliative care practices and enhance overall quality of life while living with an incurable illness. Nurses have the ability to contribute meaningfully to patients facing death by relating to them with genuine care that acknowledges their humanity, conveying information with a compassionate honesty that recognizes the impact it will hold for patients and their loved ones, supporting patients' faith and cautious hopes, assisting patients in enjoying an active involvement in life within their limitations, and providing a safe and trusting environment in which to receive care.

Adverse effects of subthalamic nucleus DBS in a patient with multiple system atrophy.

A 59-year-old woman with levodopa-responsive parkinsonism complicated by motor fluctuations and generalized levodopa dyskinesia underwent bilateral subthalamic deep brain stimulation (STN DBS) 7 years after symptom onset. DBS improved levodopa-responsive upper extremity bradykinesia but aggravated speech, swallowing, and gait. Motor fluctuations were not improved and levodopa dose remained unchanged. Pulse generators were turned off. Clinical features and brain MRI in this case were indicative of multiple system atrophy (MSA). STN DBS is not recommended for patients with MSA.