Targeting the A3 adenosine receptor to treat hepatocellular carcinoma: anti-cancer and hepatoprotective effects.

The A3 adenosine receptor (A3AR) is over-expressed in human hepatocellular carcinoma (HCC) cells. Namodenoson, an A3AR agonist, induces de-regulation of the Wnt and NF-kB signaling pathways resulting in apoptosis of HCC cells. In a phase I healthy volunteer study and in a phase I/II study in patients with advanced HCC, namodenoson was safe and well tolerated. Preliminary evidence of antitumor activity was observed in the phase I/II trial in a subset of patients with advanced disease, namely patients with Child-Pugh B (CPB) hepatic dysfunction, whose median overall survival (OS) on namodenoson was 8.1 months. A phase II blinded, randomized, placebo-controlled trial was subsequently conducted in patients with advanced HCC and CPB cirrhosis. The primary endpoint of OS superiority over placebo was not met. However, subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed nonsignificant differences in OS/progression-free survival and a significant difference in 12-month OS (44% vs 18%, p = 0.028). Partial response was achieved in 9% of namodenoson-treated patients vs 0% in placebo-treated patients. Based on the positive efficacy signal in HCC CPB7 patients and the favorable safety profile of namodenoson, a phase III study is underway.

The Society of Toxicologic Pathology: Advances and Adventures in the First 50 Years.

The Society of Toxicologic Pathology (STP, https://www.toxpath.org/) was founded in North America in 1971 as a nonprofit scientific and educational association to promote the professional practice of pathology as applied to pharmaceutical and environmental safety assessment. In the ensuing 50 years, the STP has become a principal global leader in the field. Society membership has expanded to include toxicologic pathologists and allied scientists (eg, toxicologists, regulatory reviewers) from many nations. In addition to serving membership needs for professional development and networking, major STP outreach activities include production of articles and presentations designed to optimize toxicologic pathology procedures ("best practice" recommendations), communicate core principles of pathology evaluation and interpretation ("points to consider" and "opinion" pieces), and participation in international efforts to harmonize diagnostic nomenclature. The STP has evolved into an essential resource for academic, government, and industrial organizations that employ and educate toxicologic pathologists as well as use toxicologic pathology data across a range of applications from assessing product safety (therapies, foods, etc) to monitoring and maintaining environmental and occupational health. This article recapitulates the important milestones and accomplishments of the STP during its first 50 years.

Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults.

OBJECTIVE: To provide a management approach for adults with calcium channel blocker poisoning. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Following the Appraisal of Guidelines for Research & Evaluation II instrument, initial voting statements were constructed based on summaries outlining the evidence, risks, and benefits. DATA SYNTHESIS: We recommend 1) for asymptomatic patients, observation and consideration of decontamination following a potentially toxic calcium channel blocker ingestion (1D); 2) as first-line therapies (prioritized based on desired effect), IV calcium (1D), high-dose insulin therapy (1D-2D), and norepinephrine and/or epinephrine (1D). We also suggest dobutamine or epinephrine in the presence of cardiogenic shock (2D) and atropine in the presence of symptomatic bradycardia or conduction disturbance (2D); 3) in patients refractory to the first-line treatments, we suggest incremental doses of high-dose insulin therapy if myocardial dysfunction is present (2D), IV lipid-emulsion therapy (2D), and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism (2D); 4) in patients with refractory shock or who are periarrest, we recommend incremental doses of high-dose insulin (1D) and IV lipid-emulsion therapy (1D) if not already tried. We suggest venoarterial extracorporeal membrane oxygenation, if available, when refractory shock has a significant cardiogenic component (2D), and using pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block in the absence of myocardial dysfunction (2D) if not already tried; 5) in patients with cardiac arrest, we recommend IV calcium in addition to the standard advanced cardiac life-support (1D), lipid-emulsion therapy (1D), and we suggest venoarterial extracorporeal membrane oxygenation if available (2D). CONCLUSION: We offer recommendations for the stepwise management of calcium channel blocker toxicity. For all interventions, the level of evidence was very low.

CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study.

BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop.

BACKGROUND: Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists. METHODS: A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm. RESULTS: A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy. CONCLUSIONS: Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes.

Treatment of dry eye syndrome with orally administered CF101: data from a phase 2 clinical trial.

OBJECTIVE: To explore the safety and efficacy of CF101, an A(3) adenosine receptor agonist, in patients with moderate to severe dry eye syndrome. DESIGN: Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study. PARTICIPANTS: Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. INTERVENTION: Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week posttreatment observation. MAIN OUTCOME MEASURES: An improvement of more than 25% over baseline at week 12 in one of the following parameters: (1) tear break-up time (BUT); (2) superficial punctate keratitis assessed by fluorescein staining results; and (3) Schirmer tear test 1 results. Clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements, and monitoring of adverse events. RESULTS: A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group. CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group. CONCLUSIONS: CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Management of beta-adrenergic blocker and calcium channel antagonist toxicity.

State-of-the-art therapy for beta-adrenergic receptor blocker and calcium channel antagonist toxicity is reviewed in the light of new insights into drug-induced shock. A brief discussion of pathophysiology, including cardiac, hemodynamic, and metabolic effects of cardiac drug toxicity, provides a foundation for understanding the basis of therapy. The major focus of this review is a critical evaluation of antidotal use of calcium, glucagon, catecholamines, insulin-euglycemia, and other novel therapies based on investigational studies and cumulative clinical experience.

Outcomes in Cardiac Arrest Patients due to Toxic Exposure Treated with Therapeutic Hypothermia.

The incidence and outcome of patients who undergo therapeutic hypothermia (TH) after toxin-induced cardiac arrest (TICA) is not previously described. Our study aimed to describe the incidence, epidemiologic characteristics, and outcomes of patients who experience TICA in a dedicated clinical pathway for post-cardiac arrest care between November 2007 and February 2013. All patients were treated in an evidence-based clinical pathway that included TH. Database and medical records were independently reviewed by investigators to ascertain TICA. TICA was defined as cardiac arrest (CA) directly and immediately caused by a xenobiotic exposure. All patients were enrolled at Carolinas Medical Center, an urban 874-bed teaching hospital that serves as a regional cardiac resuscitation center. All patients were adult victims of cardiac arrest who had obtained return of spontaneous circulation and were enrolled in a clinical pathway for post-cardiac arrest care that included TH. Three hundred eighty-nine patients underwent treatment following CA during the study period and 48 (12 %) were deemed TICA. Patients who suffered TICA were slightly younger, less likely to have an initial shockable rhythm, and less likely to receive bystander CPR as compared to non-toxic cases. TICA accounted for a significant proportion of patients in this study. Additional, larger studies are needed to fully elucidate the optimal role for TH in TICA.

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock.

Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising.

Brugada syndrome and "Brugada sign": clinical spectrum with a guide for the clinician.

BACKGROUND: Patients with the manifest Brugada syndrome have an inordinate risk of sudden death and are candidates for implantation of a defibrillator. The Brugada type electrocardiogram (ECG) abnormality (the "Brugada sign"), however, is known to be associated with a wide range of conditions, many of which may not pose such a threat. Clinicians need guidance in choosing a rational approach for the evaluation and treatment of patients with a finding of the Brugada sign. METHODS: A systematic literature search was performed to identify publications on the Brugada syndrome and the Brugada-type ECG abnormality, with special emphasis on analyzing outcomes data. In addition, the ECG database of our institution was reviewed for tracings consistent with the Brugada sign, and, when possible, clinical correlations were made. RESULTS: Patients with the Brugada sign and a family history of sudden death or a personal history of syncope are at a high risk of sudden death and therefore should be strongly considered for implantation of a defibrillator. In patients who are hospitalized and critically ill, the Brugada sign is frequently the result of severe hyperkalemia, drug toxicity, or right ventricular injury. In most individuals with no symptoms and without a family history of sudden death, the Brugada sign is likely a normal variant. CONCLUSIONS: Most patients with the Brugada sign can be risk-stratified with simple clinical tools. Specific testing for the Brugada syndrome should be reserved for questionable cases and for the research setting. A provisional diagnostic-therapeutic algorithm is offered as a means of assisting the clinician in the evaluation and treatment of patients with the Brugada sign.

Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment of copperhead snakebite.

STUDY OBJECTIVE: Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) effectively treats patients bitten by rattlesnakes. The copperhead snake (Agkistrodon contortrix) caused 37% of venomous snakebites reported to US poison centers in 2001 and is the major envenomating reptile in the southeastern United States. FabAV has not been tested in human beings envenomated by copperhead snakes. METHODS: In this preliminary study, we performed a retrospective chart review of all copperhead snake envenomations reported to the Carolinas Poison Center that were treated with FabAV. Progression of limb swelling, coagulopathy, and hemodynamic status before and after FabAV administration, adverse effects of FabAV therapy, and recurrence phenomena were recorded. RESULTS: Of approximately 400 copperhead envenomation cases reported to the poison center during the study period, 32 received FabAV and were included. Most patients had moderate envenomation. The median time to FabAV administration was 4.0 hours. The median time to achieve initial control was 1.0 hour, with a median dose of 4 vials of FabAV. A rapid initial response, defined as cessation of the progression of local tissue injury within 4 hours of FabAV administration, occurred in 28 cases (88%; 95% confidence interval [CI] 76% to 99%). Four cases (13%; 95% CI 1% to 24%) were considered treatment failures. Recurrent swelling occurred in 6 cases (19%; 95% CI 5% to 32%). The incidence of recurrent swelling was not reduced by administration of repeated doses of antivenom on a planned schedule. One patient developed late-onset coagulopathy. One minor allergic reaction was observed. CONCLUSION: In this select group of patients bitten by copperhead snakes, local tissue effects of envenomation halted promptly after FabAV treatment in most cases. Treatment failures occurred, and recurrence of swelling and defibrination syndrome was sometimes problematic. Time to return to work and long-term limb function were not assessed. A controlled trial with long-term follow-up is needed to define the role of FabAV treatment for copperhead envenomation.

Gamma hydroxybutyric acid (GHB) intoxication.

Gamma hydroxybutyric acid (GHB) is a naturally occurring analog of gamma-aminobutyric acid (GABA) that has been used in research and clinical medicine for many years. In the past decade it has become very popular as a dietary supplement and recreational drug. Acute overdose leads to profound alteration of mental status and variable amounts of respiratory depression. With proper management, most patients recover fully within six hours. However, respiratory arrest and death have been reported in severe GHB intoxication. In addition to acute overdose, there is a GHB withdrawal syndrome that is similar to sedative/hypnotic and ethanol withdrawal. Recently several congeners of GHB, gamma butyrolactone and 1,4-butanediol, have emerged as drugs of abuse and show toxidromes similar to GHB. Emergency physicians should be familiar with the presentation and management of GHB-related emergencies.

Is nurse interpretation of the ECG QRS width reliable?

Electrocardiogram (ECG) data are critical in formulating management strategies following sodium channel antagonist overdose. Poison centers frequently rely on verbal reports of the ECG obtained from bedside nurses. No previous study has addressed the quality of ECG data obtained in this manner. Therefore, we sought to test the ability of nurses to recognize and measure a widened QRS complex, the hallmark of myocardial sodium channel toxicity. Thirty-six emergency department and critical care nurses employed at a tertiary care hospital participated in this prospective study. The study subjects were divided into three groups and asked to interpret 12 ECGs (five normal and seven wide QRS). For each ECG, participants (1) determined if the QRS was narrow or wide and (2) measured the QRS duration. The groups differed in delivery of instruction regarding QRS measurement. Group 1 received visual instructions; group 2 received scripted verbal instructions, and group 3 served as controls, receiving no specific QRS measurement instructions. The nurse data was compared with physician interpretation (consensus of three physicians). Between-group analysis tested for impact of potential real-time educational intervention. Overall, the nurses identified a wide QRS complex most of the time (77%), but had difficulty in accurately measuring the QRS duration (44%). Real-time visual or verbal instruction did not improve accuracy (p = NS between groups). The results suggest that verbal ECG data from nurse callers is not sufficient to make an accurate clinical assessment in the setting of sodium channel poisoning.

Rapid induction of colonic adenocarcinoma in mice exposed to benzo[a]pyrene and dextran sulfate sodium.

Previously, we reported that the mutation frequency was markedly increased in the colon after the oral treatment of mice with an environmental mutagen/carcinogen, benzo[a]pyrene (BP); however this was not followed by tumor development. The reasons for this are as yet unresolved. The purpose of the present study is to explore the mechanisms why a high frequency of mutations induced by BP in the colon is not associated with subsequent tumor development. We show in this study that oral administration of BP to CD2F(1) mice at 125 mg/kg/day for 5 days can lead to adenocarcinomas in the mouse colon both at Weeks 4 (5/8 mice) and 11 (100% of mice), but only in the presence of inflammation induced by 4% dextran sulfate sodium (DSS) in the drinking water for up to 2 weeks. These data indicate that, in this DSS model, BP induced mutagenic events lead to tumors in the mouse colon, a tissue which is not a BP target organ. DSS-induced inflammation in a tissue primed with mutagenic risk is a key to the induction of tumors in this model. This study provides a novel, rapid and useful colon carcinogenesis model (BP/DSS model).

Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial.

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS: . Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.