Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Snakebites and climate change in California, 1997-2017.

BACKGROUND: Climate change effect on flora and fauna has been scientifically documented, but the effect on North American venomous snakebites is unknown. The objectives were to examine Californian snakebite incidence and correlate with weather patterns and climate changes. METHODS: A retrospective analysis of snakebites reported to the Californian Poison Control System from 1 September 1997 to 30 September 2017. Venomous snakebite reports were aggregated by caller zip code, and correlated per county with weather data, air temperature, precipitation, population data, eco-regions, and land characteristics. Time series decomposition by seasonality and trend, regression, and autocorrelation were used to assess association between climate variables and incidence. RESULTS: There were 5365 reported venomous snakebites during the study period, with a median age of 37 years (22-51) with 76% male (p < .001, 95% CI 75.6-77.9%). Most snakebite outcomes were coded as minor (1363, 25%) or moderate (2607, 49%), with three deaths. Adjusted for population, the annualized incidence of snakebites statewide slightly decreased (rho = -0.11, p = .65). The snakebite incidence per million people rose after a period of no drought and declined during drought (r = -0.41, p ≪ .01). Snakebite incidence decreased by 6-month prior drought (-3.8% for each 10% increase in drought), and increased by 18-month prior precipitation (+3.9% for each 10% increase in precipitation). CONCLUSIONS: Patterns of precipitation and drought had a significant and predictive effect on snakebites in California over a 20-year period. Snakebite incidence decreased following drought, and increased after precipitation.

Butanediol Conversion to Gamma-Hydroxybutyrate Markedly Reduced by the Alcohol Dehydrogenase Blocker Fomepizole.

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO.

Racial disparities across provider specialties in opioid prescriptions dispensed to medicaid beneficiaries with chronic noncancer pain.

OBJECTIVE: Chronic pain affects both psychological and physical functioning, and is responsible for more than $60 billion in lost productivity annually in the United States. Although previous studies have demonstrated racial disparities in opioid treatment, there is little evidence regarding disparities in treatment of chronic noncancer pain (CNCP) and the role played by physician specialty in these disparities. DESIGN: A retrospective cohort study. SETTING: We analyzed North Carolina Medicaid claims data, from July 1, 2009 to May 31, 2010, to examine disparities by different provider specialties in beneficiaries' dispensed prescriptions for opioids. SUBJECTS: The population included white and black North Carolina Medicaid beneficiaries with CNCP (N = 75,458). METHODS: We used bivariate statistics and logistic regression analysis to examine race-based discrepancies in opioid prescribing by physician specialty. RESULTS: Compared with white beneficiaries with CNCP (N = 49,197), black beneficiaries (N = 26,261) were less likely (odds ratio [OR] 0.91 [confidence interval {CI}: 0.88-0.94]) to fill an opioid prescription. Our hypothesis was partially supported: we found that race-based differences in beneficiaries' dispensed opioid prescriptions were more prominent in certain specialties. In particular, these differences were most salient among patients of specialists in obstetrics and gynecology (OR 0.78 [CI: 0.67-0.89]) and internal medicine (OR 0.86 [CI: 0.79-0.92]), as well as general practitioners/family medicine physicians (OR 0.91 [CI: 0.85-0.97]). CONCLUSIONS: Our findings suggest that, in our study population, black beneficiaries with CNCP are less likely than whites to fill prescriptions for opioid analgesics as a function of their provider's specialty. Although race-based differences in patients filling opioid prescriptions have been noted in previous studies, this is the first study that clearly demonstrates these disparities by provider specialty.

Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses.

BACKGROUND: Despite >20 years of studies investigating the characteristics of patients seeking or receiving opioid analgesics, research characterizing factors associated with physicians' opioid prescribing practices has been inconclusive, and the role of practitioner specialty in opioid prescribing practices remains largely unknown. OBJECTIVE: To examine the relationships between physicians' and other providers' primary specialties and their opioid prescribing practices among patients with chronic noncancer pain (CNCP). METHODS: Prescriptions for opioids filled by 81,459 Medicaid patients with CNCP in North Carolina (USA), 18 to 64 years of age, enrolled at any point during a one-year study period were examined. χ2 statistics were used to examine bivariate differences in prescribing practices according to specialty. For multivariable analyses, maximum-likelihood logistic regression models were used to examine the effect of specialty on prescribing practices, controlling for patients' pain diagnoses and demographic characteristics. RESULTS: Of prescriptions filled by patients with CNCP, who constituted 6.4% of the total sample of 1.28 million individuals, 12.0% were for opioids. General practitioner/family medicine specialists and internists were least likely to prescribe opioids, and orthopedists were most likely. Across specialties, men were more likely to receive opioids than women, as were white individuals relative to other races/ethnicities. In multivariate analyses, all specialties except internal medicine had higher odds of prescribing an opioid than general practitioners: orthopedists, OR 7.1 (95% CI 6.7 to 7.5); dentists, OR 3.5 (95% CI 3.3 to 3.6); and emergency medicine physicians, OR 2.7 (95% CI 2.6 to 2.8). CONCLUSIONS: Significant differences in opioid prescribing practices across prescriber specialties may be reflective of differing norms concerning the appropriateness of opioids for the control of chronic pain. If so, sharing these norms across specialties may improve the care of patients with CNCP.

Multidisciplinary intervention decreases the use of opioid medication discharge packs from 2 urban EDs.

INTRODUCTION: Prescription opioid overdoses and deaths constitute a public health epidemic, and recent studies show that emergency department (ED) prescribers may contribute to this crisis. We hypothesized that a multidisciplinary educational intervention would decrease ED opioid packs dispensed at discharge. METHODS: This prospective study implemented a "bundle" of interdisciplinary educational modalities: lectures, journal clubs, case discussions, and an electronic medical record decision support tool. Implementation occurred in 2 urban EDs in the same health system at different times ("affiliate," September 2011; "primary," January 2012) to better distinguish its effects. The primary outcome was preintervention/postintervention change in opioid discharge packs dispensed to all patients treated and discharged through August 2012 and was assessed by 2-way analysis of variance. The secondary outcome was bivariate analysis (using Fisher exact test) of change in opioid dispensing among patients with known risk factors for prescription opioid dependence: age less than 65 years, history of substance abuse, chronic pain, or psychiatric disorders. RESULTS: A total of 71,512 and 45,746 patients were evaluated and discharged from primary and affiliate EDs, respectively. Orders for opioid discharge packs decreased from 13.9% to 8.4% and 4.7% to 1.9% at the primary and affiliate hospitals (P < .0001). Dispensing among individuals at risk for opioid dependence at the primary ED decreased from 21.8% to 13.9%. CONCLUSIONS: A staged, multidisciplinary intervention targeting nurses, residents, nurse practitioners, and attending physicians was associated with decreased orders for opioid discharge packs in 2 urban EDs. Opioid discharge pack orders decreased slightly more among patients with risk factors for prescription opioid dependence.

Beau's Lines After Cardiac Arrest.

A 34-year-old man with uncontrolled hypertension suffered a ventricular fibrillation cardiac arrest from an obstructive left anterior descending artery occlusion. He was defibrillated more than 10 times before achieving return of spontaneous circulation. He was comatose after his arrest and was treated with therapeutic hypothermia, and a bare metal stent was placed in his obstructed coronary artery with restoration of excellent postobstruction blood flow. His postarrest course was complicated by cardiogenic shock; prolonged ventilator-dependent respiratory failure requiring tracheostomy; tracheobronchitis, with cultures positive for methicillin-resistant Staphylococcus aureus (MRSA); and an extended period of agitation and delirium. Thirty-four days after his arrest, his mental status started to improve rapidly. His delirium resolved, he became oriented and lucid, and he was able to be discharged to a rehabilitation facility on hospital day 41, with an excellent prognosis and close follow-up in primary care, cardiology, tracheostomy, and coumadin clinics. He returned to the emergency department 65 days later with the complaint of intermittent chest pain of 4 days' duration. Upon physical examination he was found to have Beau's lines on his fingernails. He was admitted to the hospital for a rule-out myocardial infarction workup, which was uneventful. He was discharged to home in good condition 2 days later.

Windmills and pill mills: can PDMPs tilt the prescription drug epidemic?

Prescription drug monitoring programs (PDMPs) are state-based registries of prescriptions for specific controlled substances. This overview will describe the history and funding of these databases, address those characteristics thought to be of greatest utility for PDMPs and review current literature regarding PDMP effectiveness and their potential limitations. Although more extensive research on PDMP outcomes is needed, these databases are an essential component in ongoing efforts to establish safe and compassionate prescription opioid stewardship.