Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit.

BACKGROUND: Epigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis (AR). Our aim was to examine genome-wide epigenetic changes induced by controlled pollen exposure in the environmental exposure unit (EEU). METHODS: 38 AR sufferers and eight nonallergic controls were exposed to grass pollen for 3 hours on two consecutive days. We interrogated DNA methylation at baseline and 3 hours in peripheral blood mononuclear cells (PBMCs) using the Infinium Methylation 450K array. We corrected for demographics, cell composition, and multiple testing (Benjamini-Hochberg) and verified hits using bisulfite PCR pyrosequencing and qPCR. To extend these findings to a clinically relevant tissue, we investigated DNA methylation and gene expression of mucin 4 (MUC4), in nasal brushings from a separate validation cohort exposed to birch pollen. RESULTS: In PBMCs of allergic rhinitis participants, 42 sites showed significant DNA methylation changes of 2% or greater. DNA methylation changes in tryptase gamma 1 (TPSG1), schlafen 12 (SLFN12), and MUC4 in response to exposure were validated by pyrosequencing. SLFN12 DNA methylation significantly correlated with symptoms (P < 0.05), and baseline DNA methylation pattern was found to be predictive of symptom severity upon grass allergen exposure (P = 0.029). Changes in MUC4 DNA methylation in nasal brushings in the validation cohort correlated with drop in peak nasal inspiratory flow (Spearman's r = 0.314, P = 0.034), and MUC4 gene expression was significantly increased (P < 0.0001). CONCLUSION: This study revealed novel and rapid epigenetic changes upon exposure in a controlled allergen challenge facility, and identified baseline epigenetic status as a predictor of symptom severity.

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial.

BACKGROUND: Toll-like receptor 7 (TLR7) stimulation in the airways may reduce responses to aeroallergens by induction of type 1 interferons (IFNs). GSK2245035 is a novel selective TLR7 agonist in pharmaceutical development. OBJECTIVE: Assessment of safety, pharmacodynamics and nasal allergic reactivity following repeated weekly intranasal (i.n.) GSK2245035. METHODS: This randomized, double-blind, placebo-controlled study (TL7116958) was conducted over two pollen seasons (2013-2014) and follow-up study (204509) conducted 1 year later. Participants with allergic rhinitis (n=42) were randomized to receive eight weekly doses of i.n. GSK2245035 (20 ng [2014 Cohort; n=14] or 80 ng [2013 Cohort; n=14]) or placebo (n=14). Adverse events (AEs) including cytokine release syndrome AEs (CytoRS-AEs) and nasal symptoms were assessed. Nasal and serum IFN-inducible protein 10 (IP-10) were measured after doses 1 and 8, then 1 (follow-up visit [FUV] 1) and 3 (FUV2) weeks after final dose. Nasal allergen challenges (NACs) and allergic biomarker assessment (nasal, serum) were conducted at baseline, FUV1, FUV2 and at a FUV 1 year after final dose (FUV3; 2014 Cohort only). A Bayesian framework enabled probability statements for mean effect sizes. RESULTS: GSK2245035 induced CytoRS-AEs (most commonly headache, median duration <1 day) in 93% of participants at 80 ng, while AE incidence at 20 ng was similar to placebo. There was no evidence of nasal inflammation. Dose-related increases in nasal and serum IP-10 were observed 24 hours after doses 1 and 8 (>95% certainty). Both doses showed a trend in reducing total nasal symptom score 15 minutes post-NAC at FUV1 and FUV2, but there was no reduction evident at FUV3. Nasal levels of selected allergic biomarkers demonstrated trends for reductions at FUV1, FUV2 and FUV3. CONCLUSIONS AND CLINICAL RELEVANCE: Weekly i.n. GSK2245035 20 ng was well tolerated and reduced allergic reactivity to nasal challenge for 3 weeks post-treatment.

Let's Talk Period! Preliminary results of an online bleeding awareness knowledge translation project and bleeding assessment tool promoted on social media.

INTRODUCTION: Undiagnosed bleeding disorders are common and can pose significant health risks, especially for women. Recently, a self-administered bleeding assessment tool (Self-BAT) was validated in von Willebrand disease. AIM: To increase awareness of undiagnosed bleeding disorders through the use of an informational website (http://letstalkperiod.ca) targeted at women in their reproductive years. METHODS: The Let's Talk Period website was built in consultation with a medical communications company and focus groups of women, with the aim of clearly presenting key messages around menstrual bleeding. The website was promoted through social media and local and national interviews. Upon completion of the online Self-BAT available at http://letstalkperiod.ca, the result is displayed to the user along with a recommendation to seek medical attention if the score is abnormal. RESULTS: During the initial 3-month period, there were 5158 page views from 64 countries. A total of 489 individuals, 95% female, completed the online Self-BAT. The mean Self-BAT score was 6, range 0-44. Abnormal Self-BAT scores were reported in 45% of the respondents, of whom 96% were female. The most commonly reported bleeding symptoms were menorrhagia (98%) and postpartum haemorrhage (82%). Bleeding symptoms were similar across different geographical areas. CONCLUSION: An online screening tool is an effective method of identifying individuals concerned with abnormal bleeding. A significant portion of the general population report experiencing symptoms of abnormal bleeding. In women, the most frequently reported bleeding symptoms were menorrhagia and postpartum haemorrhage.

Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future - an EAACI Position Paper.

BACKGROUND: Allergen exposure chambers (AECs) are clinical facilities allowing for controlled exposure of subjects to allergens in an enclosed environment. AECs have contributed towards characterizing the pathophysiology of respiratory allergic diseases and the pharmacological properties of new therapies. In addition, they are complementary to and offer some advantages over traditional multicentre field trials for evaluation of novel therapeutics. To date, AEC studies conducted have been monocentric and have followed protocols unique to each centre. Because there are technical differences among AECs, it may be necessary to define parameters to standardize the AECs so that studies may be extrapolated for driving basic immunological research and for marketing authorization purposes by regulatory authorities. METHODS: For this task force initiative of the European Academy of Allergy and Clinical Immunology (EAACI), experts from academia and regulatory agencies met with chamber operators to list technical, clinical and regulatory unmet needs as well as the prerequisites for clinical validation. RESULTS: The latter covered the validation process, standardization of challenges and outcomes, intra- and interchamber variability and reproducibility, in addition to comparability with field trials and specifics of paediatric trials and regulatory issues. CONCLUSION: This EAACI Position Paper aims to harmonize current concepts in AECs and to project unmet needs with the intent to enhance progress towards use of these facilities in determining safety and efficacy of new therapeutics in the future.

Haemopoietic processes in allergic disease: eosinophil/basophil development.

Haemopoietic myeloid progenitors contribute to the ongoing recruitment of pro-inflammatory cells, such as eosinophils and basophils (Eo/B), to target tissue sites in allergic diseases. It is apparent that the development of allergic inflammation is critically dependent on the ability of the bone marrow to support the proliferation, differentiation and mobilization of haemopoietic progenitors. The haemopoietic inductive microenvironment in the bone marrow is crucial for providing signals necessary for maintenance of progenitor populations at varying stages of lineage commitment and permitting these cells to circulate in the bloodstream. Progenitors demonstrate responsiveness to specific cytokines, which varies with stage of differentiation. Pro-inflammatory signals, Th2 cytokines in particular, generated following allergen challenge, can impact on haemopoietic progenitor differentiation and mobilization, leading to accelerated Eo/B production. Allergen inhalation by allergic asthmatics induces a time-dependent change in cytokine levels within the bone marrow compartment, influencing differentiation of Eo/B progenitors, as evidenced by the relationship between increased bone marrow IL-5 levels and Eo/B production. It is proposed that inhaled allergen induces trafficking of IL-5-producing T lymphocytes to the bone marrow, further promoting eosinophilopoiesis through IL-5R signalling. In this manner, Th2 lymphocyte trafficking from the airway may regulate events occurring in the bone marrow. Negative regulators of Eo/B differentiation, including Th1 cytokines, may prove to be important for restoring homeostasis. Eo/B progenitors are also altered in cord blood of infants at risk of atopy and asthma, offering a potential biomarker for, and raising the possibility that Eo/B progenitors are directly involved in the development of allergic disease. For example, changes in the expression of haemopoietic cytokine receptors on cord blood progenitor cells are associated with maternal allergic sensitization, atopic risk and its development, suggesting that haemopoietic processes underlying the allergic phenotype may begin to evolve in the perinatal period.

Hemopneumothorax in a COPD patient treated with noninvasive positive pressure ventilation: the risk of attendant anticoagulation.

Noninvasive positive pressure ventilation (NIPPV) modalities have been proven to be effective in the setting of exacerbations of chronic obstructive pulmonary disease (COPD). Reported complications include pneumothorax, increased work of breathing, gastric distension and air embolism. This case demonstrates that patients with severe COPD on anticoagulant therapy are potentially at risk for the serious complication of combined lung barotrauma and hemorrhage while on acute NIPPV therapy. This is the first reported case of hemopneumothorax complicating NIPPV therapy.

Metformin-associated lactic acidosis in a low risk patient.

Metformin is an oral hypoglycemic agent belonging to the class of biguanides that are commonly used in the treatment of type II diabetes mellitus. Lactic acidosis is a rare but severe adverse reaction that occurs primarily in patients with contraindications such as renal failure. The case of a 71-year-old woman with type II diabetes, in whom severe metformin-associated lactic acidosis was precipitated by acute renal failure in the absence of pre-existing chronic renal failure or other absolute contraindications to biguanide use, is presented. Aggressive correction of the acidosis and prolonged dialysis resulted in a favourable outcome despite severe acidosis. The present case report shows that metformin-associated lactic acidosis can occur in patients without pre-existing renal insufficiency. Metformin should be temporarily stopped when acute renal failure occurs or is anticipated.

Quality of life indices may be predictive of placebo and medication response to treatment for allergic rhinitis.

BACKGROUND: Quality of life (QOL) is known to be an important clinical endpoint in determining medication efficacy; however, the predictive value of QOL indices for response to medication or placebo has not been tested. OBJECTIVE: To determine whether a correlation between measures of QOL and response to medication/placebo exists in an evaluation of budesonide for allergic rhinitis. METHODS: Two hundred nine participants completed the 36-item short-form health QOL survey at screening for entry into a study examining the onset of action of budesonide in an allergen challenge system. During the treatment phase, symptom assessments were recorded hourly after dosing of double-blind medication. Participants were determined to be responders or nonresponders to study medication. A responder was defined as a participant who rated medication effectiveness as fair to excellent with regard to symptom relief, for three consecutive hourly assessments during the study day or one whose total symptom score decreased by > or =25% for three consecutive hourly assessments. Baseline QOL scores were compared between responders and nonresponders. RESULTS: Differences were noted among responders and nonresponders on the basis of whether budesonide or placebo was received. Ratings of general health perception, pain, physical function, and role limitation due to physical health were significantly lower among participants who responded to placebo, compared with placebo nonresponders. In addition, the overall physical health and 36-item short-form health survey averages were significantly lower. Differences between responders and nonresponders to budesonide did not reach statistical significance. CONCLUSIONS: Lower baseline QOL scores were associated with a clinically significant response to placebo in a trial of treatment for allergic rhinitis. QOL may be a factor in participant response to medication in clinical studies and, hence, a predictor of outcome.

Quality of life in women with urinary tract infections: is benign disease a misnomer?

BACKGROUND: The objective of this study was to undertake an exploratory evaluation of quality-of-life indicators for women suffering from urinary tract infections. METHODS: The RAND 36-Item Health Survey 1.0 (SF-36) was administered to 47 women with a diagnosed urinary tract infection who were being cared for in the Family Medicine Center, Student Health Services, or Urology Outpatient Clinic. A control population of 71 women was obtained from the female members of an undergraduate geography class, a community basketball league, and a local women's choir. RESULTS: All subsections of the SF-36 quality-of-life indices were significantly decreased in the subject population compared with the control population (lower score indicates lower quality of life): patient general health perception (63.3 vs 78.9, P < .001) physical functioning (76.6 vs 87.6, P = .012), role limitation owing to physical health (53.8 vs 93.0, P < .001) and emotional health (67.4 vs 88.3, P < .001), vitality (43.0 vs 64.9, P < .001), emotional well-being (64.4 vs 80.2, P < .001), pain (58.7 vs 91.5, P < .001), and social functioning (60.4 vs 90.4. P < .001). CONCLUSION: Suffering from an urinary tract infection has a detrimental influence on patient quality of life. The effect of urinary tract infections on women and their perception of quality of life have not been hitherto reported in the medical literature. The significant findings in this study call into question whether acute, non-life-threatening illness should be regarded as benign.

Coronary angiographic findings and troponin T in patients with unstable angina pectoris.

This study sought to identify differences in coronary anatomic pathology in patients with unstable angina and elevated versus nonelevated serum troponin T values. Previous studies have shown a worse prognosis in unstable angina patients with elevated serum troponin T values. Consecutive patients (n = 117) with Braunwald class IIIB angina were included in the study. Serum samples for troponin T were obtained at admission and every 6 to 8 hours for 18 to 24 hours. Acute myocardial infarction was excluded by routine creatine kinase measurements. All patients underwent coronary angiography before discharge. Cardiac events including cardiac death and myocardial infarction were recorded. Two thirds of the patients with unstable angina had no increase in serum troponin T (<0.1 microg/L) (n = 80). They had a lower incidence of 3-vessel disease (26% vs 46%, p <0.001), left main disease (5% vs 16%, p = 0.04), visible thrombus (4% vs 22%, p = 0.006), and less severe stenosis of the culprit artery (65% vs 84%, p <0.004) than patients with elevated serum troponin T values (> or =0.1 microg/L) (n = 37). The 1-year cardiac event rate was 0% versus 19% in patients with troponin T values <0.1 microg/L compared with patients with serum troponin T values > or =0.1 microg/L (p <0.0001). It was concluded that patients with unstable angina and no release of troponin T have less severe coronary artery disease, and have an excellent prognosis. It is suggested that these patients may be managed more conservatively and without invasive evaluation before discharge.

Onset of action of intranasal budesonide (Rhinocort aqua) in seasonal allergic rhinitis studied in a controlled exposure model.

BACKGROUND: Intranasal budesonide aqueous nasal spray (BANS) is recognized as an efficacious treatment for seasonal allergic rhinitis (SAR), but the time to onset of action is not known. OBJECTIVE: The primary objective was to evaluate the time at which the onset of action of BANS in the symptomatic relief of seasonal allergic rhinitis becomes evident within 12 hours after a single dose in a controlled ragweed pollen exposure setting. METHODS: The study was of a double-blind, randomized, parallel-group design, testing BANS (64 microgram and 256 microgram) and placebo on ragweed-sensitive subjects with symptoms for at least 1 year by using a controlled pollen challenge system (Environmental Exposure Unit). The efficacy variables were the combined nasal score (the sum of blocked nose, runny nose, and sneezing-itchy nose), individual nasal symptoms, overall evaluation of treatment efficacy reported by participants on diaries, and peak nasal inspiratory flow (PNIF). RESULTS: A total of 217 participants were treated with BANS or placebo. At 7 to 12 hours, BANS was better than placebo in reducing combined nasal and blocked nose symptoms. For PNIF, the time to onset of action was shortest for 256 microgram of BANS relative to placebo (3 hours, P =.003). BANS 64 microgram was better than placebo in reducing the individual scores of blocked nose, runny nose, and sneezing-itchy nose from 3 to 5 hours after administration. Treatment efficacy was higher for those receiving BANS compared with placebo starting at 5 hours. All treatments were well tolerated, and no specific adverse events occurred. CONCLUSIONS: The onset of action of intranasal BANS was 7 hours according to combined nasal and blocked nose symptom scores. Evidence of earlier response was observed at 3 hours for runny nose and PNIF.

Impact on quality of life during an allergen challenge research trial.

BACKGROUND: Quality of life (QOL) issues resulting from participation in an allergy research trial, or indeed any clinical trial, is not documented in the medical literature. OBJECTIVE: To determine whether participating in a trial where allergic symptoms are induced has a significant impact on subjects' QOL, and to quantify extent and duration. METHODS: Subjects were recruited from a trial utilizing a controlled allergen environment to assess anti-allergic medications. A QOL survey (consisting of the Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ] & the SF-36) was completed at screening, on study day, and approximately 2 weeks post-study. Follow-up was sought from subjects' whose QOL was significantly worse than baseline. RESULTS: Of 219 trial participants, 206 completed both screening and study surveys; 141 returned at least one follow-up survey; and 136 constructed the final dataset. Mean overall scores at follow-up via RQLQ were significantly better than screening (P < .001). Significant decreases in QOL from baseline on study day occurred in social function on the SF-36 (P = .026) and in domains of sleep (P = .019), non-nasal symptoms (P = .05), ocular symptoms (P < .001), and nasal symptoms (P < .001) on the RQLQ. Average post-study follow-up was 17.1 days (range = 5 to 55 days). CONCLUSION: Subjects participating in a trial involving allergic symptom induction experienced a decrease of QOL in parameters specific to rhinoconjunctivitis and social function. Subjects' QOL returned to or improved over baseline within 2 1/2 weeks. Positive QOL findings are important to studies where symptoms are induced and also have relevance to standard Phase 3 drug trials.

Onset of action and efficacy of terfenadine, astemizole, cetirizine, and loratadine for the relief of symptoms of allergic rhinitis.

BACKGROUND: Terfenadine, astemizole, cetirizine, and loratadine are compared in their abilities to produce relief of symptoms of allergic rhinitis. OBJECTIVE: The aim of this study was to compare the onset of action and efficacy of the study medications. METHODS: 111 ragweed-sensitive subjects were primed with pollen in the Environmental Exposure Unit. Study entry required adequate symptoms over a 3 hour exposure to 5000 +/- 300 grains/m3 of ragweed pollen. On the test day, subjects were given a single dose of either terfenadine 60 mg (22), astemizole 10 mg (22), cetirizine 10 mg (23), loratadine 10 mg (22), or placebo (22) when sufficiently symptomatic after a 60-minute exposure. Allergen levels were maintained and symptoms recorded every 30 minutes. RESULTS: Proportions of subjects with clinically important relief were cetirizine, 69.6%; terfenadine, 54.5%; loratadine, 50.0%; astemizole, 40.9%; and placebo, 31.8% but differences weren't significant between treatment groups (P = .119). Survival curves for times to onset of clinically important relief for the four treatment groups were not different (P = .119). Subjects realizing definitive relief were cetirizine, 65.2%; terfenadine, 45.5%; loratadine, 31.8%; placebo, 27.3%; and astemizole, 22.7% (P = .023). Survival analysis of onset time for definitive relief found significant differences (P = .010). The ranking was cetirizine --> terfenadine --> loratadine --> astemizole (quickest to slowest). Global evaluation based on subject willingness to take the medication again yielded percentages: cetirizine, 82.6%; terfenadine, 66.7%; astemizole, 63.6%; loratadine, 40.9%; and placebo, 36.4% (P = .036). CONCLUSION: Cetirizine and terfenadine continuously ranked higher in terms of onset of action and efficacy, while loratadine and astemizole ranked lower. Significance was detected in definitive relief and relative efficacy.

Onset of action, efficacy, and safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an environmental exposure unit.

BACKGROUND: Fexofenadine hydrochloride is the active acid metabolite of terfenadine. Fexofenadine's anti-allergic properties require confirmation in a clinical setting. OBJECTIVE: The purpose of this study was to characterize the time to onset of clinically important relief of symptoms of allergic rhinitis in subjects taking single doses of either 60 mg or 120 mg fexofenadine HCl, or placebo, after exposure to ragweed pollen in a controlled environment. Other objectives were to assess the efficacy and safety of single doses of fexofenadine HCl. METHODS: One hundred forty-six ragweed-sensitive subjects were primed in the off-season with ragweed pollen in the environmental exposure unit. One hundred thirty-six subjects who adequately responded to priming entered a single-dose placebo phase. Placebo-responders were disqualified from the study, leaving 99 subjects with adequate symptoms to be randomized and given a single dose of either fexofenadine HCl 120 mg (33), 60 mg (33) or placebo (33), after 60 minutes of allergen exposure. Exposure continued over five hours and subjects recorded symptoms every 20 minutes. This study was of a randomized, placebo-controlled, double-blind, parallel design. RESULTS: Median time to onset for relaxed criteria clinically important relief was 60 minutes for both fexofenadine treatment groups, and 100 minutes for placebo (P = .018). The proportion with relief was 82% at 60 mg, 85% at 120 mg, and 64% for placebo. Treated groups had reductions in symptom scores double that of placebo. CONCLUSIONS: Fexofenadine is safe and efficacious at single doses of 60 mg and 120 mg. Average time to onset was 60 minutes using controlled pollen exposure in an environmental exposure unit.

Cardiac and skeletal muscle myoglobin release after reperfusion of injured myocardium in dogs with systemic hypotension.

BACKGROUND: Myoglobin (Mb) is an intramyocardial protein that is released into the systemic circulation and rapidly cleared via the kidneys after myocardial injury. Arterial Mb concentration-time curves have been studied in humans and dogs in the setting of acute coronary artery occlusion, and the rate of rise of Mb is both sensitive and specific as an indicator of successful coronary artery reperfusion. Systemic hypotension may alter Mb kinetics and impact on the utility of this method by causing Mb release from ischemic skeletal muscle and by decreasing renal Mb clearance. This study was undertaken to determine whether analysis of Mb kinetics remains accurate in identifying coronary reperfusion in the setting of systemic hypotension. METHODS AND RESULTS: Eighteen chronically instrumented dogs were made hypotensive by being bled via a large-bore femoral artery catheter into a reservoir adjusted to maintain a constant mean arterial pressure of 50 mm Hg for 8 hours. After the first hour of hypotension, each dog was studied under one of the following three protocols: group 1, 2 hours of mid-left anterior descending artery (LAD) occlusion followed by 5 hours of unlimited reperfusion; group 2, 7 hours of mid-LAD occlusion without reperfusion; or group 3, 7 additional hours of hypotension alone. Systemic lactate extractions demonstrated a shift to anaerobic metabolism in skeletal muscle and confirmed that shock was established in all animals. Regional arteriovenous Mb differences in group 1 animals demonstrated release of large amounts of Mb from reperfused myocardium; in contrast, smaller amounts of Mb were released both from skeletal muscle rendered ischemic by hypotension and from myocardium rendered ischemic by coronary occlusion without reperfusion. In group 1 dogs, arterial Mb rose rapidly immediately after reperfusion, with peak Mb occurring 108 +/- 24 minutes (mean +/- SEM) after vessel reopening. In group 2 and group 3 dogs, arterial Mb rose more slowly, such that peak Mb was not reached within 8 hours in 11 of 12 animals. The linear rate of rise of arterial Mb over the first hour of reperfusion in group 1 dogs was 51 +/- 16 ng.mL-1.min-1. This slope was significantly greater than slopes determined over the same time period in dogs occluded and not reperfused (group 2, 1.2 +/- 0.6 ng.mL-1.min-1) and in those hypotensive alone (group 3, 0.8 +/- 0.5 ng.mL-1.min-1). All the slopes of group 2 and group 3 dogs fell below the range of slopes of group 1 dogs. In contrast to slopes of the Mb concentration-time curves, linear creatine kinase slopes were significantly less sensitive in predicting reperfusion. CONCLUSIONS: Analysis of plasma Mb kinetics allows early identification of coronary reperfusion after myocardial injury even in the presence of significant systemic hypotension.

Histamine mediates myocardial damage by an H1 mechanism independent of coronary blood flow.

Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.

Kinetics of myoglobin release and prediction of myocardial myoglobin depletion after coronary artery reperfusion.

To better define the usefulness of blood myoglobin measurements in evaluating the effectiveness of attempted thrombolysis, we studied the kinetics of myoglobin entry into and removal from the circulation after coronary artery reperfusion and the relation between directly measured depletion of myocardial myoglobin after coronary occlusion and reperfusion and the amount of depletion predicted from plasma myoglobin concentration-time curves. Initially, canine myoglobin was administered to 11 dogs by both bolus injection and 40-minute infusion, and the subsequent disappearance patterns of myoglobin from plasma monitored by radioimmunoassay. A monoexponential regression line (corresponding to a one-compartment model) and a biexponential regression line (corresponding to a two-compartment model) were determined for each set of washout data, the kinetic parameters were calculated, and the goodness of fit of each model was assessed. Results were similar after both methods of myoglobin administration. In five of 11 animals, the one-compartment model described the myoglobin kinetics better; in the other six animals, the two-compartment model was statistically superior, but values for the volume of distribution and elimination rate constant differed by only 10% from the one-compartment estimates. After bolus administration of myoglobin and with a one-compartment model, the volume of distribution of myoglobin was determined to be 1,601 +/- 77 (SEM) ml, representing 6.8 +/- 0.2% of total body weight; the elimination rate constant averaged 0.132 +/- 0.006/min and corresponded to a mean half-time of disappearance of 5.5 +/- 0.2 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Early noninvasive detection of successful reperfusion in patients with acute myocardial infarction.

Myoglobin (Mb) is a protein that enters rapidly and is rapidly cleared from plasma after coronary reperfusion. We sought to determine the accuracy with which a rapid rise in plasma [Mb] could predict successful coronary artery reopening in patients undergoing coronary arteriography in conjunction with attempted reperfusion in acute myocardial infarction. In 42 patients, plasma Mb levels were measured before and for at least 4 hours after attempted reperfusion. Thirty-five patients were successfully reperfused. In each, the plasma Mb level rose rapidly with peak [Mb] occurring at 111 +/- 8.1 (+/- SEM) minutes after application of therapy. In contrast, Mb levels rose more slowly in the seven patients who were not reperfused, with peak [Mb] occurring 360 +/- 61.4 minutes after attempted reperfusion. T25-100 (the time required for [Mb] to rise from 25% to 100% of peak value) was shorter in patients successfully reperfused (71 +/- 7.9 minutes) and longer (341 +/- 35.3 minutes) in patients in whom therapy was unsuccessful. A rapid rise in [Mb] after successful reperfusion was also evident by a more than 4.6-fold rise in [Mb] over the first 2 hours after reperfusion in all but five patients; in contrast, [Mb] rose by less than 4.6-fold over this same interval in every patient not successfully reperfused (sensitivity, 85%; specificity, 100%; predictive accuracy, 88%). We conclude that a rapid rise in plasma Mb level over the initial 2 hours after attempted reperfusion in acute myocardial infarction provides a useful index of successful reperfusion.