Navigating the Complex Web of Prescribing Amyloidosis Therapeutics: A Primer.

Advancement in the diagnosis and treatment of transthyretin amyloid cardiomyopathy has made great strides in recent years. Novel therapeutics for transthyretin amyloidosis such as tafamidis, patisiran, and inotersen have shown significant benefits in a not-so-rare disease but come with high listing price tags ranging from a quarter to more than a half million dollars per year. These costs create significant financial barriers for the majority of patients, especially those with existing Medicare insurance plans. Of 72 patients reviewed, 67% were Medicare beneficiaries. Financial assistance was explored for the majority, and 37 (51%) patients with Medicare Part D received financial assistance that reduced their copayments to $0. Only one-third of our patients were able to afford these medications without any forms of financial assistance. Of these patients, 4 (6%) had the highest copayments ranging from $13 000 to $15 000 per year. To navigate the complexities of prescribing and affordability in amyloidosis, a multidisciplinary team including a dedicated clinical pharmacist is crucial in guaranteeing patients' success to secure these novel therapeutics. In this article, we discuss our experiences with prescribing, acquiring insurance authorizations, and financing these life-saving medications based on patient-specific insurance plans and socioeconomic status.

Clinical management of amyloid cardiomyopathy.

Clinical heart failure, restrictive cardiomyopathy, and arrhythmias are hallmark features of amyloid cardiomyopathy. In contrast to the advancements in targeted therapies, there is a general lack of evidence-based practice guidelines for clinical management of amyloid cardiomyopathy. In this review, we review the role of routine medical therapy in amyloid cardiomyopathy, from heart failure management to orthostatic hypotension, atrial arrhythmias, thromboembolic complications, and prevention of sudden death. We conclude by discussing approaches to patients with end-stage disease.

Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats.

Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45-58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood.

GABAergic Signaling within a Limbic-Hypothalamic Circuit Integrates Social and Anxiety-Like Behavior with Stress Reactivity.

The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.