NRX-101, a Rapid-Acting Anti-Depressant, Does Not Cause Neurotoxicity Following Ketamine Administration in Preclinical Models.

Agents that act at the N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have gained increasing attention as rapid-acting antidepressants; however, their use has been limited by potential neurotoxicity. Recent FDA guidance requires a demonstration of safety on histologic parameters prior to the initiation of human studies. D-cycloserine (DCS) is a partial NMDA agonist that, along with lurasidone, is being investigated as a treatment for depression. The current study was designed to investigate the neurologic safety profile of DCS. To this end, female Sprague Dawley rats (n = 106) were randomly divided into 8 study groups. Ketamine was administered via tail vein infusion. DCS and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with 3 different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E, silver, and Fluoro-Jade B stains. No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 (positive control) group. We conclude that NRX-101, a fixed-dose combination of DCS/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at supratherapeutic doses of DCS.

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial.

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

NRX-101 (D-Cycloserine + Lurasidone) Is Active against Drug-Resistant Urinary Pathogens In Vitro.

D-Cycloserine (DCS) is a broad-spectrum antibiotic that is currently FDA-approved to treat tuberculosis (TB) disease and urinary tract infection (UTI). Despite numerous reports showing good clinical efficacy, DCS fell out of favor as a UTI treatment because of its propensity to cause side effects. NRX-101, a fixed-dose combination of DCS and lurasidone, has been awarded Qualified Infectious Disease Product and Fast Track Designation by the FDA. In this study, we tested NRX-101 against the urinary tract pathogens Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii in cation-adjusted Mueller-Hinton broth (caMHB) and artificial urine media (AUM). Several strains were multidrug resistant. Test compounds were serially diluted in broth/media. Minimum inhibitory concentration (MIC) was defined as the lowest concentration of the test compound at which no bacterial growth was observed. DCS exhibited antibacterial efficacy against all strains tested while lurasidone did not appreciably affect the antibacterial action of DCS in vitro. In AUM, the MICs ranged from 128 to 512 mcg/mL for both DCS and NRX-101. In caMHB, MICs ranged from 8 to 1024 mcg/mL for NRX-101 and 32 to 512 mcg/mL for DCS alone. Our data confirm that DCS has antibacterial activity against reference and drug-resistant urinary pathogens. Furthermore, lurasidone does not interfere with DCS's antimicrobial action in vitro. These results support the clinical development of NRX-101 as a treatment for complicated urinary tract infections.

D-cycloserine is not susceptible to self-administration using an intravenous self-administration model in male ketamine-habituated Sprague-Dawley rats.

OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested for its efficacy in substituting for ketamine in ketamine-dependent rats. METHODS: A standard intravenous self-administration study was conducted in male adult Sprague-Dawley rats to study abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to the intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15 mg/kg per lever press. RESULTS: S-ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in self-administration at any of the test doses. The self-infusion behavior of DCS was similar to control (saline). CONCLUSION: D-cycloserine, a partial agonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies, has no apparent potential for abuse liability in a standard rodent self-administration model.

NRX-101 (D-cycloserine plus lurasidone) vs. lurasidone for the maintenance of initial stabilization after ketamine in patients with severe bipolar depression with acute suicidal ideation and behavior: a randomized prospective phase 2 trial.

BACKGROUND: We tested the hypothesis that, after initial improvement with intravenous ketamine in patients with bipolar disorder (BD) with severe depression and acute suicidal thinking or behavior, a fixed-dose combination of oral D-cycloserine (DCS) and lurasidone (NRX-101) can maintain improvement more effectively than lurasidone alone. METHODS: This was a multi-center, double-blind, twostage, parallel randomized trial. Adult BD patients with depression and suicidal ideation or behavior were infused with ketamine or saline (Stage 1); those who improved were randomized to a fixed-dose combination of DCS and lurasidone vs. lurasidone alone (Stage 2) to maintain the improvement achieved in Stage 1. Depression was measured by the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thinking and behavior was measured by the Columbia Suicide Severity Rating Scale (C-SSRS); global improvement was measured by the clinical global severity scale (CGI-S). CLINICALTRIALS: gov NCT02974010; Registered: November 22, 2016. RESULTS: Thirty-seven patients were screened and 22 were enrolled, randomized, and treated. All 22 patients treated in Stage 1 (17 with ketamine and 5 with saline) were enrolled into Stage 2, and 11 completed the study. The fixed-dose combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvement in depression (MADRS LMS Δ-7.7; p = 0.03) and reducing suicidal ideation, as measured by C-SSRS (Δ-1.5; p = 0.02) and by CGI-SS (Δ-2.9; p = 0.03), and with a non-statistically significant decrease in depressive relapse (0% vs. 40%; p = 0.07). This sequential treatment regimen did not cause any significant safety events and demonstrated improvements in patient-reported side effects. CONCLUSIONS: Sequential treatment of a single infusion of ketamine followed by NRX-101 maintenance is a promising therapeutic approach for reducing depression and suicidal ideation in patients with bipolar depression who require hospitalization due to acute suicidal ideation and behavior. On the basis of these findings, Breakthrough Therapy Designation was awarded, and a Special Protocol Agreement was granted by the FDA for a registrational trial.

Brief Report: Rapid Clinical Recovery From Critical Coronavirus Disease 2019 With Respiratory Failure in a Pregnant Patient Treated With IV Vasoactive Intestinal Peptide.

BACKGROUND: Aviptadil, a synthetic form of human vasoactive intestinal peptide, has entered clinical trials to treat critical coronavirus disease 2019 pneumonia with respiratory failure. Vasoactive intestinal peptide protects the lung against a broad array of injuries by binding to the vasoactive intestinal peptide receptor 1 receptor of alveolar type II cells, the cells that severe acute respiratory syndrome coronavirus 2 binds to. As the role of Aviptadil in treating pregnant patients with critical coronavirus disease 2019 pneumonia is unknown, the authors report successful treatment in such a patient who is ineligible for phase 3 trials of Aviptadil. CASE SUMMARY: Under an open-label Food and Drug Administration-approved Expanded Access Protocol NCT04453839, a 32-year-old female patient Gravida 6 Para 4 at 27-week gestation, body mass index 42.5 kg/m2, admitted to the ICU of a quaternary care hospital with critical coronavirus disease 2019 was treated in January 2021 and followed for 4 months post-ICU admission. Standard of care included remdesivir, methylprednisolone, enoxaparin, and inhaled epoprostenol. In addition, the patient received three successive 12-hour IV infusions of Aviptadil at 50/100/150 pmol/kg/hr escalating doses, per randomized clinical trial NCT04311697. Human subjects' protection was overseen by the Institutional Review Board of the Houston Methodist Hospital. The patient was enrolled in the treatment and was given informed consent approved by the Food and Drug Administration and the Institutional Review Board. Data on the patient was incorporated based on her consent for de-identified data to be used in research given at the time of hospital admission in a manner approved by the Institutional Review Board (PRO00025607). Baseline inflammatory markers, arterial blood gases, radiologic imaging, oxygen requirements, Pao2/Fio2, continuous fetal monitoring at baseline, throughout the patient's treatment with the investigational drug, and throughout the patient's hospital course. CONCLUSION: The rapid clinical improvement seen in this patient treated with IV vasoactive intestinal peptide is consistent with the theory that vasoactive intestinal peptide protects the alveolar type II cell, ameliorates cytokine storm, and improves oxygenation in acute lung injury. This specific role of vasoactive intestinal peptide in the lung may be vital to combating the lethal effects of severe acute respiratory syndrome coronavirus 2 infection. In addition, the role of vasoactive intestinal peptide in the human maternal-fetal interface suggests that vasoactive intestinal peptide is a safe treatment of severe coronavirus disease 2019 respiratory failure during pregnancy.

Association Between Eliminating Water From Surgical Hand Antisepsis at a Large Ophthalmic Surgical Hospital and Cost.

Importance: Alcohol-based surgical scrub is recommended for presurgical antisepsis by leading health organizations. Despite this recommendation, water-based scrub techniques remain common practice at many institutions. Objective: To calculate the potential financial savings that a large, subspecialty ophthalmic surgical center can achieve with a conversion to waterless surgical hand preparation. Design, Setting, and Participants: A review of accounting records associated with the purchase of scrubbing materials and water company invoices was conducted to assess direct costs attributable to water consumption and scrub materials for brushless, alcohol-based surgical scrub and water-based presurgical scrub. The flow rate of scrub sinks to estimate water consumption per year was tested. Savings associated with operating room (OR) and personnel time were calculated based on the prescribed scrub times for waterless techniques vs traditional running-water techniques. The study was conducted from January 5 to March 1, 2019. Main Outcomes and Measures: The primary outcomes for this study were the quantity of water consumed by aqueous scrubbing procedures as well as the cost differences between alcohol-based surgical scrub and water-based scrub procedures per OR per year. Results: Scrub sinks consumed 15.9 L of water in a 2-minute period, projecting a savings of 61 631 L and $277 in water and sewer cost per operating room per year. Alcohol-based surgical scrub cost $1083 less than aqueous soap applied from wall-mounted soap dispensers and $271 less than preimpregnated scrub brushes per OR per year in supply costs. The decrease in scrub time from adopting waterless scrub technique could save between approximately $280 000 and $348 000 per OR per year. Conclusions and Relevance: Adopting waterless scrub techniques has the potential for economic savings attributable to water. Savings may be larger for surgical facilities performing more personnel-intensive procedures.

The retinal oxysterol pathway: a unifying hypothesis for the cause of age-related macular degeneration.

PURPOSE OF REVIEW: To summarize recent findings implicating toxic agents resulting in photooxidation of cholesterol in the etiology of age-related macular degeneration. Understanding the role of these agents and the existing pathways for their neutralization may lead to novel therapeutic approaches. RECENT FINDINGS: The human eye is now known to produce significant quantities of 7-ketocholesterol and related substances as a direct result of photoreceptor function. These substances are highly toxic to retinal cells and the eye has been shown to be unique among human organs in expressing three separate enzymatic pathways that neutralize these agents. Drusen are recently shown to contain significant accumulations of 7-ketocholesterol, likely as a result of failure of these neutralization pathways. In addition to its direct tissue toxicity, which may trigger death of retinal pigment epithelium and photoreceptor cells, ketocholesterol is a potent attractor of macrophages and induces macrophages to express both vascular endothelial growth factor F and metalloproteinases. The role of the former in neovascularization is well understood, whereas the latter is capable of directly inducing breaks in Bruch's membrane. SUMMARY: The toxic role of 7-ketocholesterol and existing pathways for its neutralization may point the way to a unified theory that explains the cause of age-related macular degeneration and points towards novel therapeutic interventions.

Cost-effectiveness model for neovascular age-related macular degeneration: comparing early and late treatment with pegaptanib sodium based on visual acuity.

OBJECTIVE: To compare the cost-effectiveness of pegaptanib and usual care within three distinct cohorts of subfoveal neovascular age-related macular degeneration (NV-AMD) patients, that is, those with early, moderate, and late disease, using a comprehensive economic model. METHODS: A Markov framework was used to model lifetime movement of a subfoveal NV-AMD cohort through health states based on visual acuity. The model takes a US payer perspective of patients over the age of 65 years. Clinical efficacy was based on published results for the 0.3 mg pegaptanib and usual care groups. Expert interviews were conducted to determine adverse event treatment patterns and vision rehabilitation resource use. Incidence and costs of comorbidities such as depression and fractures associated with the effects of declining visual acuity were based on our previously published analysis of Medicare data. Transition probabilities were derived from published clinical trial data for each 3-month cycle. Utilities were derived from published sources. Three runs of the model were conducted with cohorts of newly diagnosed patients. Patients were classified as having early, moderate, or late NV-AMD defined as visual acuity in the better-seeing eye of 20/40 to more than 20/80, 20/80 to more than 20/200, and 20/200 to more than 20/400, respectively. Costs and outcomes were discounted 3.0% per annum. RESULTS: Incremental costs per vision-year gained and per quality-adjusted life-year (QALY) gained for early NV-AMD patients were approximately one-third those of patients with late disease ($15,279 vs. $57,230 and $36,282 vs. $132,381, respectively). On average, patients treated early with either pegaptanib or usual care incurred lower lifetime total direct costs than those treated later. Sensitivity analysis showed that base-case incremental costs per QALY gained for pegaptanib versus usual care were relatively robust. CONCLUSIONS: For patients with subfoveal NV-AMD, treatment with pegaptanib should be started as early as possible to maximize the clinical and economic benefits.

Information technology and medical missteps: evidence from a randomized trial.

We analyze the effect of a decision support tool designed to help physicians detect and correct medical "missteps". The data comes from a randomized trial of the technology on a population of commercial HMO patients. The key findings are that the new information technology lowers average charges by 6% relative to the control group. This reduction in resource utilization was the result of reduced in-patient charges (and associated professional charges) for the most costly patients. The rate at which identified issues were resolved was generally higher in the study group than in the control group, suggesting the possibility of improvements in care quality along measured dimensions and enhanced diffusion of new protocols based on new clinical evidence.

Association between vision loss and higher medical care costs in Medicare beneficiaries costs are greater for those with progressive vision loss.

PURPOSE: To identify the cost to the Medicare program for patients with either stable or progressive vision loss and to estimate the impact on eye-related and non-eye related care. DESIGN: Retrospective cohort study. PARTICIPANTS: The study population was Medicare beneficiaries included in the standard 5% analytic sample and continuously enrolled from 1999 to 2003, excluding Medicare managed-care enrollees. METHODS: Vision loss was categorized as moderate loss, severe loss, and blindness, based on International Classification of Diseases 9, Clinical Modification codes. MAIN OUTCOME MEASURES: Average yearly cost of eye-related and non-eye related medical care during 1999 to 2003, in 2003 dollars. SECONDARY OUTCOMES: (1) depression, (2) injury, (3) skilled nursing facility (SNF) utilization, and (4) long-term care facility (LTC) admission. RESULTS: Compared with patients with normal vision, excess adjusted mean eye-related costs were 345 dollars, 407 dollars, and 237 dollars annually for those with moderate loss, severe loss, and blindness, respectively; annual excess non-eye related costs were 2193 dollars, 3301 dollars, and 4443 dollars, respectively. At each level of vision loss, those progressing from a presumably normal state at baseline incurred higher Medicare costs than those with that level of vision loss at baseline. Any degree of progressive vision loss was associated with an increased risk of depression, injury, SNF utilization, and LTC admission. Identifiable costs attributable to these complications explained 27% to 41% of the excess costs associated with vision loss. CONCLUSIONS: Medicare beneficiaries with coded diagnoses of vision loss incur significantly higher costs than those with normal vision, and approximately 90% of these costs are non-eye related medical costs. Extrapolating to the entire Medicare population, blindness and vision loss are associated with $2.14 billion in 2003 non-eye related medical costs. Preventing vision loss is not only a medical imperative but also an economic one.

Using a claims data-based sentinel system to improve compliance with clinical guidelines: results of a randomized prospective study.

OBJECTIVE: To demonstrate the potential effect of deploying a sentinel system that scans administrative claims information and clinical data to detect and mitigate errors in care and deviations from best medical practices. METHODS: Members (n = 39 462; age range, 12-64 years) of a midwestern managed care plan were randomly assigned to an intervention or a control group. The sentinel system was programmed with more than 1000 decision rules that were capable of generating clinical recommendations. Clinical recommendations triggered for subjects in the intervention group were relayed to treating physicians, and those for the control group were deferred to study end. RESULTS: Nine hundred eight clinical recommendations were issued to the intervention group. Among those in both groups who triggered recommendations, there were 19% fewer hospital admissions in the intervention group compared with the control group (P < .001). Charges among those whose recommendations were communicated were dollar 77.91 per member per month (pmpm) lower and paid claims were dollar 68.08 pmpm lower than among controls compared with the baseline values (P = .003 for both). Paid claims for the entire intervention group (with or without recommendations) were dollar 8.07 pmpm lower than those for the entire control group. In contrast, the intervention cost dollar 1.00 pmpm, suggesting an 8-fold return on investment. CONCLUSION: Ongoing use of a sentinel system to prompt clinically actionable, patient-specific alerts generated from administratively derived clinical data was associated with a reduction in hospitalization, medical costs, and morbidity.

How to succeed in health information technology.

The United States is poised to move the debate over electronic information systems for health care beyond the question of whether to computerize to how to computerize. Developers should heed the experiences of those who have already attempted similar efforts in vertically integrated environments. A key lesson is that the expertise and design perspectives of IT professionals should be supplemented with practical input from the caregivers and administrators who will actually use these systems. The paper by Douglas Bell and colleagues offers a ray of hope, as these authors have begun their process by asking the user community exactly what it needs.

Validity and reliability of the Cataract TyPE Spec: an instrument for measuring outcomes of cataract extraction.

PURPOSE: To design and validate a survey instrument that measures vision-related functional status, which is appropriate for self-administration in a clinical practice and mail survey setting. DESIGN: Observational, validation study in sequential patients. METHODS: A prototype visual function instrument (the Cataract TyPE Spec) was developed based on focus group input and then validated in an outcomes study conducted among 1,823 patients who underwent cataract extraction performed by 22 surgeons at six centers in the United States. Reliability was determined by calculating Cronbach alpha for different types of administration (self-administration at the site of care and mailed survey) and across race and gender. Criterion validity was determined by correlating scores on the TyPE Spec with baseline measures and changes in visual acuity, overall rating of vision, and general quality of life. RESULTS: The instrument was internally valid (Chronbach alpha = 0.94), both on self-administration in the patient care setting and upon mailed survey administration and across patient race and gender. The TyPE Spec score was highly correlated with overall rating of vision (r =.54, P <.0001) and moderately correlated with Snellen acuity (r =.32, P <.0001), rating of vision in the better eye (r =.42, P <.0001), and quality of life, as measured by the physical component summary score of the SF-36 (r =.27, P <.001). Change in TyPE Spec similarly correlated with change in rating of vision overall, change in best-corrected Snellen acuity, and change in rating of vision in the operated eye. CONCLUSIONS: The cataract TyPE Spec instrument was found to be equally valid and internally consistent when administered in the patient care setting and by mail survey.

Objectives of teaching direct ophthalmoscopy to medical students.

PURPOSE: To propose the objectives of undergraduate training in direct ophthalmoscopy (DO). METHOD: Narrative review of the literature on (i) opinions about the expected proficiency from students in DO, and (ii) estimates of its diagnostic value. RESULTS: (i) Authorities disagree on the proficiency in DO that they expect from students. Textbooks of physical diagnosis differ in their coverage of DO. Surveys have indicated that US physicians expect students to be able to detect optic nerve head abnormalities. The Association of American Medical Colleges expects students to perform ophthalmoscopic examination and describe observations. The International Council of Ophthalmology expects students to recognize also diabetic and hypertensive retinopathies. The Association of University Professors in Ophthalmology requires that students recognize papilloedema, cholesterol emboli, glaucomatous cupping and macular degeneration. (ii) There is evidence that DO, even by ophthalmologists, is inadequate for screening for glaucoma, diabetic and hypertensive retinopathies. Two studies have suggested a limited value of DO in detecting clinical emergencies. CONCLUSIONS: The evidence that DO, even by ophthalmologists, is sub-optimal in detecting common abnormalities challenges existing the notions of training medical students. On pending the results of additional studies of the value of DO in detecting emergencies, we suggest that undergraduate teaching of DO should impart the following: (i) an ability to identify the red fundus reflex and optic disc; (ii) an ability to recognize signs of clinical emergencies in patients, mannequins or fundus photographs; and (iii) knowledge about, but not an ability to detect, other retinopathies.