USING THE COMPASS-EZ AND DUAL DIAGNOSIS CAPABILITY IN ADDICTION TREATMENT (DDCAT) INDEX TO IMPROVE OUTCOMES: RECOVERING, RENEWING, AND RESTORING LIVES

Background: More than two decades of research mounts clear demonstration that providing an integrated, concurrent delivery of mental health and substance abuse treatment to persons with co-occurring substance use and psychiatric illness (also known as ‘dual diagnosis’ [DD]) renders best outcomes; yet, most persons suffering from these disorders do not receive such integrated interventions and most community-based behavioral health agencies are not prepared to provide it. Aims: To investigate the dual use of COMPASS-EZ and DDCAT instruments to (1) evaluate the current dual diagnosis capability of a community-based behavioral health agency; and (2) to develop and implement evidence-based recommendations to increase the agency’s dual diagnosis capabilities. Methods: A quality improvement (QI) initiative utilizing dual instruments to assess 22 programmatic domains of care and address the co-occurring capabilities of a single addiction treatment center for pregnant and postpartum women. Results: With all conditions met, focused quality improvements developed in policy for clinical documentation (recordkeeping), discharge planning, and staff competency assessment yield a prospective increase in DD-capability scores for the following COMPASS-EZ domains and agency overall: Program Policies [4.33 to 5.00], Screening and Identification [4.00 to 4.33], Integrated Discharge/Transition Planning [4.00 to 5.00], Program Collaboration and Partnership [4.20 to 5.00], and General Staff Competencies and Training [3.50 to 4.67]; total agency DD-capability score returned a prospective increase of 4.50 to 4.77. Conclusions: Findings suggest that across domains of care, community behavioral health agencies can continue to increase critical capabilities for patients with dual diagnosis through policy development. The collective application of one or more independent instruments proves useful to guide and measure the efficacy of quality improvement efforts.Doctor of Nursing Practic

Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1

The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels

Pharmacological Validation of an Inward-Rectifier Potassium (Kir) Channel as an Insecticide Target in the Yellow Fever Mosquito <i>Aedes aegypti</i>

<div><p>Mosquitoes are important disease vectors that transmit a wide variety of pathogens to humans, including those that cause malaria and dengue fever. Insecticides have traditionally been deployed to control populations of disease-causing mosquitoes, but the emergence of insecticide resistance has severely limited the number of active compounds that are used against mosquitoes. Thus, to improve the control of resistant mosquitoes there is a need to identify new insecticide targets and active compounds for insecticide development. Recently we demonstrated that inward rectifier potassium (Kir) channels and small molecule inhibitors of Kir channels offer promising new molecular targets and active compounds, respectively, for insecticide development. Here we provide pharmacological validation of a specific mosquito Kir channel (<i>Ae</i>Kir1) in the yellow fever mosquito <i>Aedes aegypti</i>. We show that VU590, a small-molecule inhibitor of mammalian Kir1.1 and Kir7.1 channels, potently inhibits <i>Ae</i>Kir1 but not another mosquito Kir channel (<i>Ae</i>Kir2B) in vitro. Moreover, we show that a previously identified inhibitor of <i>Ae</i>Kir1 (VU573) elicits an unexpected agonistic effect on <i>Ae</i>Kir2B in vitro. Injection of VU590 into the hemolymph of adult female mosquitoes significantly inhibits their capacity to excrete urine and kills them within 24 h, suggesting a mechanism of action on the excretory system. Importantly, a structurally-related VU590 analog (VU608), which weakly blocks <i>Ae</i>Kir1 in vitro, has no significant effects on their excretory capacity and does not kill mosquitoes. These observations suggest that the toxic effects of VU590 are associated with its inhibition of <i>Ae</i>Kir1.</p></div