Pan AMPK Activation Protects Tubules in Rat Ischemic Acute Kidney Injury.

Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.

Benzonatate Safety and Effectiveness: A Systematic Review of the Literature.

OBJECTIVE: To review the available literature regarding the treatment effects and efficacy of benzonatate needed to better inform patients, providers, and regulators evaluating its role in modern medical therapies. DATA SOURCES: Comprehensive literature searches were conducted in PubMed, Embase (Elsevier), Cochrane Library, and Scopus for original research articles evaluating the effectiveness, tolerability, and safety profile of benzonatate from January 1956 through August 2022. STUDY SELECTION AND DATA EXTRACTION: The identified studies were screened for relevance and then assessed for inclusion through a full-text review, data extraction, and quality assessment by multiple reviewers using the online software Covidence. DATA SYNTHESIS: The selection process resulted in 37 articles consisting of 21 cohort studies, 5 experimental studies, and 11 case studies and series. Initial clinical studies exploring potential therapeutic benefits collected data from very small populations and limited clinical settings. Safety is primarily assessed in terms of toxicity due to overdose or inappropriate use. Quality assessment raised concerns for high degrees of biases primarily related to the limited sample size, data collection, generalizability, and study design. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review reveals substantial limitations within existing evidence pertaining to the safety and clinical effectiveness of benzonatate and thus, a need for large observational studies or randomized trials to better characterize its role and value in modern medical practice. CONCLUSIONS: Rising safety concerns should bring closer scrutiny upon the prescription of benzonatate whose approval is founded upon evidence that would not stand up to current regulatory review.

Medical Outcomes of Acute Aspirin Single Substance Poisoning in Pediatric Patients.

BACKGROUND: A consensus guideline on salicylate poisoning recommends referring patients to the emergency department if they ingested 150 mg/kg of aspirin. The dose of aspirin associated with severe poisoning in pediatric patients has not been investigated. OBJECTIVE: This study aims to associate medical outcomes with aspirin overdoses in patients 5 years old and younger. METHODS: A retrospective review of data on pediatric patients with single substance aspirin exposures reported from poison centers across the country was conducted. The primary endpoint was to associate aspirin doses with medical outcomes. Secondary endpoints included evaluation of the signs, symptoms, and treatments of ingestion and their association with medical outcomes. RESULTS: There were 26 488 included exposures with aspirin exposures resulting in no effect (92.5%), minor effect (6.0%), moderate effect (1.4%), major effect (0.2%), and death (0.02%). There were 8921 cases with available weight-based dosing information. Median doses associated with no effect, minor effects, moderate effects, major effects, and death ranged between 28.4 and 40.9 mg/kg, 52.5 and 82.3 mg/kg, 132.1 and 182.3 mg/kg, 132.3 and 172.8 mg/kg, and 142.2 and 284.4 mg/kg, respectively. Minor effect and moderate effect exposures were more likely to have alkalinization documented compared to no effect exposures (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.41-2.17; OR = 1.79, 95% CI = 1.12-2.86). There was no difference in rates of alkalinization between minor and moderate exposures (OR = 1.02, 95% CI: 0.61-1.7). CONCLUSIONS AND RELEVANCE: Reevaluation of the current recommendation of 150 mg/kg for referral to a healthcare facility is necessary for pediatric acute salicylate overdoses.

Editorial Commentary: A Complex Network of Bony and Soft-Tissue Stabilizers-and Overall Limb Alignment-Determines Patellofemoral Stability.

Patellofemoral stability is maintained through a complex network of static and dynamic soft-tissue stabilizers, the osseous structure of the patella and trochlea, and overall limb alignment. Thus, determining the risk of recurrent patellar instability must account for as many of these factors as possible in the clinical decision-making process. The tibial tubercle-trochlear groove distance is the most common parameter used for this evaluation but may be limited because of methodologic issues and because this distance is an absolute value. Indices that incorporate other predisposing factors, including trochlear dysplasia, increase the accuracy of predicting recurrent patellar instability and can be used to generate a patient-specific treatment plan.

Time to Peak International Normalized Ratio Rise in Acute and Acute-on-Chronic Warfarin Overdoses.

ABSTRACT: Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment.

Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome.

A novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.

Impact of a drug safety communication on the severity of benzonatate exposures reported to poison centers.

PURPOSE: Identify if publication of the 2010 drug safety communication (DSC) regarding benzonatate was associated with a decrease in the incidence of severe benzonatate poisonings reported to United States poison centers. METHODS: This retrospective database study utilized the National Poison Data System to compare the incidence of severe benzonatate poisonings before and after the publication of a drug safety communication. We utilized interrupted time series analysis to compare 2000-2010 (pre-DSC) to 2012-2019 (post-DSC). RESULTS: There were 18 619 benzonatate exposures reported to US poison centers during the time period covered and 11 554 exposures were included. There was an increase in exposures throughout the time period. There was no difference in the incidence of severe outcomes in the two time periods. In the pre-DSC era, rates of severe outcomes increased by 0.4% per year followed by an immediate non-significant drop of 2.9% in incidence of severe outcomes (P = .15). Finally, the slope of severe outcomes in the post-DSC era showed an increase of 0.3% per year, which was not significantly different from the pre-DSC era (P = .78). CONCLUSION: Publication of a Drug Safety Communication regarding the risks of benzonatate did not result in a decrease in the proportion of severe benzonatate poisoning reported to US poison centers. Deaths and other severe outcomes continued to occur at a similar rate after the publication.

Editorial Commentary: Preoperative Exercise, Workers' Compensation, Diabetes, Lateral Extra-Articular Tenodesis, and Return to Sport Determine Patient Satisfaction After Anterior Cruciate Ligament Reconstruction.

Patient-reported outcome measures (PROMs) have been developed and used as the primary determinant of successful patient-centered results. The patient acceptable symptomatic state delineates an absolute value for PROMs indicating that patients are satisfied with their outcome. When this metric is used for anterior cruciate ligament reconstruction, patients reach a satisfactory outcome at between 6 and 8 months postoperatively, and more than 90% reach a satisfactory outcome at 12 months. Preoperative variables such as preoperative exercise, Workers' Compensation, and diabetes impact patient outcomes, whereas preoperative PROMs and use of the anteromedial portal technique for femoral tunnel drilling have a limited impact on satisfaction. Iliotibial band tenodesis shows a large impact on satisfactory outcomes; however, this result may be affected by patient demographic issues (selection bias). Ultimately, a "satisfactory" outcome is a very general term and may not necessarily apply to active athletes desiring a return to competitive sport. Thus, the patient acceptable symptomatic state should be interpreted in combination with a surgeon's experience. Ultimately, the success of a surgical procedure could be determined, in large part, based on the patient's individual preoperative expectations.

Environmental Sampling for Severe Acute Respiratory Syndrome Coronavirus 2 During a COVID-19 Outbreak on the Diamond Princess Cruise Ship.

During a COVID-19 outbreak on the Diamond Princess cruise ship we sampled environmental surfaces after passengers and crew vacated cabins. SARS-CoV-2 RNA was detected in 58 of 601 samples (10%) from case cabins 1-17 days after cabins were vacated but not from noncase cabins. There was no difference in detection proportion between cabins of symptomatic (15%, 28/189; cycle quantification [Cq], 29.79-38.86) and asymptomatic cases (21%, 28/131; Cq, 26.21-38.99). No SARS-CoV-2 virus was isolated from any of the samples. Transmission risk of SARS-CoV-2 from symptomatic and asymptomatic patients may be similar and surfaces could be involved in transmission.

Targeting Enteropeptidase with Reversible Covalent Inhibitors To Achieve Metabolic Benefits.

Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (k inact/KI) of 1.5 × 104 M-1s-1 High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 Å, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT: Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.

Amino acids are sensitive glucagon receptor-specific biomarkers for glucagon-like peptide-1 receptor/glucagon receptor dual agonists.

AIM: The aim of this study was to evaluate amino acids as glucagon receptor (GCGR)-specific biomarkers in rodents and cynomolgus monkeys in the presence of agonism of both glucagon-like peptide-1 receptor (GLP1R) and GCGR with a variety of dual agonist compounds. MATERIALS AND METHODS: Primary hepatocytes, rodents (normal, diet-induced obese and GLP1R knockout) and cynomolgus monkeys were treated with insulin (hepatocytes only), glucagon (hepatocytes and cynomolgus monkeys), the GLP1R agonist, dulaglutide, or a variety of dual agonists with varying GCGR potencies. RESULTS: A long-acting dual agonist, Compound 2, significantly decreased amino acids in both wild-type and GLP1R knockout mice in the absence of changes in food intake, body weight, glucose or insulin, and increased expression of hepatic amino acid transporters. Dulaglutide, or a variant of Compound 2 lacking GCGR agonism, had no effect on amino acids. A third variant with ~31-fold less GCGR potency than Compound 2 significantly decreased amino acids, albeit to a significantly lesser extent than Compound 2. Dulaglutide (with saline infusion) had no effect on amino acids, but an infusion of glucagon dose-dependently decreased amino acids on the background of GLP1R engagement (dulaglutide) in cynomolgus monkeys, as did Compound 2. CONCLUSIONS: These results show that amino acids are sensitive and translatable GCGR-specific biomarkers.

Development of a Tool to Predict Risk of Behavioral Health Evacuation From Combat.

In the present study, we examined administrative data on 667,437 deployments of at least 30 days duration to Iraq and Afghanistan from 2011 through the end of 2016 to determine risk factors for evacuation from the combat zone for behavioral health reasons. Demographic data, military-specific data, responses on predeployment mental health assessments, and presence of previous treatment for psychiatric conditions were entered into a logistic regression based on expert determination, distinguishing the 2,133 behavioral health evacuations from those deployments that either did not end in evacuation or included evacuations for reasons other than behavioral health. The model, derived from a random half of the sample (training set), was verified on the other half (validation set). Predictor variables used in the model were calendar year; gender; age; rank; marital status; parental status; number of prior war zone deployments; branch of service; screens for symptoms of posttraumatic stress disorder, depression, and hazardous alcohol use on the predeployment mental health assessment; and prior substance- and non-substance-related behavioral health diagnoses. Odds ratios (range: 1.05-3.85) for selected variables that contributed to the model were used to assign risk scores in the Behavioral Health Evacuation Risk Tool, which can aid predicting which service members are more likely to be evacuated from combat for behavioral health reasons, thus indicating where resources can be allocated for behavioral health referrals and war zone care.

Editorial Commentary: My Harvested Hamstring Autograft Is Too Small. Now What?

A harvested hamstring autograft that is too small is a technical challenge for an effective anterior cruciate ligament reconstruction. One potential solution is to assemble the graft differently to maximize the diameter and length of the graft. Compared with the traditional, all-inside, 4-strand graft preparation, alternative graft constructs could be further explored and evaluated.

Characterization of intentional-abuse venlafaxine exposures reported to poison control centers in the United States.

Background: Venlafaxine use to achieve an amphetamine-like high has been described but data regarding the epidemiology and clinical effects are sparse. Objectives: Describe the prevalence and toxicity of venlafaxine abuse reported to US poison control centers. Methods: This was a retrospective review of venlafaxine exposures reported to the National Poison Data System (NPDS) from 2000 to 2016. Inclusion criteria were: age 12 years and older, reason for exposure intentional-abuse, and either single-substance exposure or venlafaxine was the first substance. The primary outcome was prevalence of intentional-abuse of venlafaxine. Secondary outcomes characterized demographics, geographic distribution, toxicity, and outcomes. Results: Intentional-abuse accounted for 752 of 85,621 venlafaxine exposures. Overall prevalence was 87.8 intentional-abuse exposures/10,000 venlafaxine exposures reported to NPDS (range, 59.3-117.6/10,000). Prevalence decreased from 107/10,000 in 2000 to 59.3/10,000 in 2016. Median age was 23 years and 50% were female. Primary route was ingestion (90.8%) with 4.7% using venlafaxine via inhalation/intranasal insufflation, and 3.7% both routes. There were 227 venlafaxine-only exposures; 54.0% were treated/released from the emergency department, 20% were admitted for medical management, 9.0% to a psychiatric facility, and 17.0% managed at home. Known medical outcomes for single-substance exposures were: no effect (24.0%), minor (39.0%), moderate (33.0%), and major (4.0%); no deaths occurred. Most frequent clinical effects were tachycardia (33.9%), drowsiness (20.7%), and agitation (11.5%). Conclusion: The prevalence of venlafaxine abuse reported to poison control centers has decreased. Medical outcomes are usually not serious. Clinicians should be aware that non-medical use is possible but infrequently reported to poison control centers.

Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes.

The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.

Metoclopramide induced pheochromocytoma crisis.

Metoclopramide (MCP) is a commonly used anti-emetic in the emergency department (ED). Its use is generally well tolerated; although infrequent adverse reactions such as extrapyramidal reactions or tardive dyskinesia are reported. However, many ED providers are not familiar with the potentially life-threatening hypertensive emergency that can be precipitated by MCP administration in patients with pheochromocytoma. A previously healthy 36-year-old woman presented to the ED with headache and nausea. She developed acute hypertensive emergency (acute agitation, worsening headache, chest pain and wide complex tachycardia) when her blood pressure (BP) increased to 223/102mmHg (initial BP, 134/86mmHg) after receiving intravenous MCP. Her hospital course was complicated by multi-organ injury, including acute respiratory distress syndrome requiring venous-venous extracorporeal membrane oxygenation, non-ST elevation myocardial infarction, cardiogenic shock, acute liver failure, and oliguric kidney injury requiring continuous renal replacement therapy. CT scan showed previously undiagnosed large right adrenal mass (5.9cm). The diagnosis of pheochromocytoma was confirmed after adrenalectomy. Drug-induced acute pheochromocytoma crisis is a rare event. Early recognition and appropriate blood pressure management with clevidipine, nicardipine, or phentolamine is essential.

Interrater reliability of electrodiagnosis in neonatal brachial plexopathy.

INTRODUCTION: We investigated interrater reliability of overall assessment of nerve root lesions by electrodiagnostic testing (EDX) in neonatal brachial plexus palsy (NBPP). METHODS: Two blinded, board-certified reviewers retrospectively reviewed de-identified EDX data from 37 infants with NBPP for 2005-2012. Only nerve conduction and electromyography needle data were included. The examiners independently assigned 1 of 4 nerve root lesion categories: (1) pre-ganglionic lesion (avulsion), (2) post-ganglionic lesion (rupture), (3) normal, or (4) "unable to determine." Simple percentage agreement, the Cohen kappa statistic representing interrater reliability for each nerve root (C5-T1), and overall kappa between examiners were evaluated. RESULTS: Interrater reliabilities were substantial to almost perfect for each nerve root except C5. Considering all nerve roots, overall interrater reliability was substantial (kappa = 0.62); simple percentage agreement was 75% (138/185). CONCLUSIONS: Interrater reliability of nerve root assessment by EDX for infants with NBPP was high for C6-T1 root levels, but less reliable for C5 because of technical factors. Muscle Nerve 55: 69-73, 2017.

Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists.

A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.

Potential drug interaction with opioid agonist in the setting of chronic low-dose opioid antagonist use.

Low dose naltrexone (LDN) has been evaluated in several small studies for the treatment of inflammatory conditions. It is thought to work through modulation of inflammatory mediators and upregulation of endogenous opioid receptors. This may hypersensitize patients to exogenous opioids. Drug-drug interaction screening tools built into electronic health records and other services identify the interaction as risk of opioid withdrawal rather than hypersensitivity. We present a case of a drug-drug interaction in a patient who was receiving LDN treatment of multiple sclerosis. The patient received a single dose of oxycodone 5mg that resulted in obtundation unresponsive to painful stimuli necessitating the administration of naloxone boluses and infusion along with admission to the intensive care unit for 1 night. The patient responded well to naloxone therapy. He was discharged in satisfactory condition.