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Introduction: Sternal intraosseous (IO) access has advantages over humeral and tibial access for fluid resuscitation in military medical settings due to superior flow rates and pharmacokinetics. However, the morphology of the young adult manubrial cortical and medullary bone as it relates to IO catheter tips of currently available FDA-approved IO access devices is unclear., Materials and Methods: Computed tomography manubrium images of active duty service members (N = 93) aged 18 to 30 were assessed by radiologists, including manubrial height, width, and cortical thickness, as well as total thickness and medullary thickness at the thickest (superior) and thinnest (inferior) parts of the manubrium. Inference regarding medullary or cortical IO catheter tip placement rates were made for FAST1 (5.5 mm catheter depth) and TALON (4.5 mm catheter depth) sternal IO devices. Data were analyzed using ANOVA, non-parametric, and correlational statistics at P < 0.05., Results: As inferred from case-specific CT-derived manubrium dimensions and maximal catheter tip penetration depths, both FAST1 and TALON would be placed in the target medullary space on 100% of opportunities if properly applied in the superior manubrium and on 99% of opportunities if properly applied in the inferior manubrium. Age was not significantly related to IO-relevant manubrial dimensions., Conclusions: Present findings suggest that both FAST1 and TALON sternal IO catheter tips can be successfully placed into the target medullary bone with high accuracy in male military members aged 18 to 30 who require rapid resuscitation., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Swimming-induced pulmonary edema (SIPE) is an incompletely understood condition that is often seen in U.S. special operations candidates participating in maritime qualification training courses. We present a case of two monozygotic twins with the simultaneous onset of acute respiratory distress during a crucible event of a maritime assessment and selection course. Subsequent pulmonary ultrasonography in both candidates showed wedge-shaped hyperechoic lines (B-lines) extending from the pleural interface into the interstitium. Chest radiography of both candidates revealed bilateral asymmetric hazy opacities consistent with SIPE. Both candidates recovered with supportive measures but were medically removed from training. Given the near-identical exposures of the candidates to the same ambient and water temperatures, duration of water submersion, magnitude of physical stressors, and viral colonization, this case study suggests that there may be underlying genetic factors, in addition to environmental factors, that predispose individuals to developing SIPE. Further benchtop and clinical research must be performed to identify potential genetic polymorphisms that contribute to the development of SIPE and to investigate safe interventions that address the underlying etiologies of SIPE pathophysiology., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Pulmonary barotrauma of ascent is a well-recognized risk of compressed air diving in the civilian and military diving communities. Chest imaging is a beneficial adjunct to clinical evaluation in screening select individuals for fitness to dive, evaluating dive-related injuries, and safely returning individuals to diving duty. We present a case of a 26-year-old male U.S. Navy Ensign and Basic Underwater Demolition/SEAL (BUD/S) candidate who experienced pulmonary barotrauma following two shallow dives to a maximum depth of 18 feet of seawater using the MK-25 100% oxygen rebreather. A chest radiograph showed a left upper lobe peripheral wedge-shaped opacity abutting the pleural surface. A subsequent computerized tomography (CT) scan of the chest showed multifocal areas of peripheral pulmonary hemorrhage associated with small pneumatoceles. Two months after the diving injury, chest CT showed resolution of the pulmonary hemorrhage and pneumatoceles. Diving-related pulmonary barotrauma occurs most often secondary to breath-holding on ascent by inexperienced divers and is one of the most common diving injuries seen in BUD/S candidates. The risk of pulmonary barotrauma may be decreased through adequate training and thorough medical screening to include assessing for symptoms of infection before every dive. In cases of acute pulmonary barotrauma, chest radiographs may be used to screen for thoracic injury. Chest CT with inspiratory and expiratory sequences should be used to screen dive candidates on a case-by-case basis and to evaluate lung injury and predisposing pulmonary conditions following pulmonary barotrauma., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Respiratory complications such as swimming-induced pulmonary edema (SIPE) are a common feature of United States Navy Special Warfare (NSW) training., Research Question: This study was designed to evaluate the incidence and clinical features of SIPE seen in this population., Study Design and Methods: A prospective, observational review of all NSW candidates over a 15-month period was designed. Baseline height, weight, and ECG data were obtained. Candidates with respiratory issues were evaluated with a two-view chest radiograph and ECG while symptomatic and were closely followed up. The chest radiograph and clinical data were then independently reviewed., Results: A total of 2,117 NSW candidates participated in training during the study period, with 106 cases of SIPE identified (5.0%). Ten additional cases of SIPE were repeat episodes in candidates already diagnosed. Forty-four cases of pneumonia were identified (no repeat cases). The majority had cough (90.4%), frothy-pink sputum (35.6%), and hemoptysis (23.7%). Overall, 80.1% of candidates had an oxygen saturation ≥ 90%. Physical examination findings were variable: crackles (50%), wheezing (36%), and rhonchi (19%). Several had more than one feature; 23% presented with a normal examination. Radiologic findings in patients with SIPE most commonly revealed an interstitial pattern with perifissural thickening, larger average azygos vein diameter, larger average heart size, and normal lung height. ECG findings were not significantly different from baseline. Height and weight were not significantly different between the groups. Lower water temperatures were suggestive of increased SIPE incidence, but this was not a statistically significant trend., Interpretation: The burden of SIPE in NSW training was greater than anticipated. Clinical symptoms and physical examination assisted by imaging were able to differentiate SIPE from pneumonia. ECG was not a useful diagnostic or screening tool, and height and weight did not affect risk of SIPE., Trial Registry: Institutional Review Board registration at Naval Medical Center, San Diego, California; Registration No.: NMCSD.2017.0020., (Published by Elsevier Inc.)

Introduction: Lung cancer is the leading cause of cancer death among men and women, accounting for more fatalities than colon, breast, and prostate cancers combined. Smoking causes about 85% of all lung cancers in the United States and is the single greatest risk factor. In 2013, the US Preventive Services Task Force (USPSTF) published initial guidelines for low-dose computed tomography lung cancer screening (LCS) among patients 55-80 years old, with a 30-pack-year history, who are current smokers or who quit within the previous 15 years. Smoking prevalence is higher among military personnel compared to the civilian population, demonstrating a need for vigilant screening., Materials and Methods: A retrospective review of Naval Medical Center San Diego's (NMCSD) LCS data was conducted to examine screening numbers, lung cancer rates, and initial analysis of screening results. Patients were referred for screening if they met the USPSTF criteria. Between September 2013 and September 2018, 962 patients underwent LCS. A total of 1758 examinations were performed, including follow-up and annual surveillance examinations. The American College of Radiology's Lung CT Screening Reporting and Data System (Lung-RADS) was used to classify lung nodules' risk for malignancy., Results: On this initial analysis, 42 enrolled patients received the diagnosis of lung cancer detected by screening. The initial calculated lung cancer rate is 4.4% (42/962) over the 5-year reporting period. The lung cancer rate among those patients with a Lung-RADS score of 3 or 4 was 31% (42/135). Thirty-seven patients were classified as having non-small cell lung cancer (NSCLC), while five were classified as having small cell lung cancer. Of the 37 NSCLC patients, 76% (28/37) were diagnosed at stage I and II, 11% (4/37) were diagnosed at stage III, and 13% (5/37) were diagnosed at stage IV. The total number of years a person smoked was a significant risk factor (P = 0.004), but not pack-years a person smoked (P = 0.052)., Conclusions: These preliminary results demonstrate the success of a Military Treatment Facility (MTF)-based LCS Program in the detection of early stage lung cancer. Earlier stage detection may result in better health outcomes for affected patients. In the population studied, duration of smoking proved to be more significant than pack-years in predicting lung cancer risk. These results validate the newly dedicated resources and continued efforts to strengthen the LCS program at NMCSD and across MTFs., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Fungi have a well-established role in nutrient cycling and are widely used as agents in biological control and in the remediation of polluted landscapes. Competition for resources between different fungal communities is common in these contexts and its outcome impacts on the success of such biotechnological applications. In this investigation a mathematical model is constructed to represent competition between two fungal colonies that have access to different resources. It is shown that the model equations display a multitude of travelling wave solutions and that the outcome of competition between two fungal biomasses can be controlled through the simple manipulation of the nutrient resources available to each. The model equations are also numerically integrated to illustrate the range of outcomes arising from fungal competition and these results are placed in context of established experimental observations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) is a minimally invasive cardiac surgical procedure that has revolutionized the treatment of aortic stenosis. This is the most common valvular heart condition in developed countries, affecting 3.4% of those ages 75 and above. Because there is no medical therapy that can arrest progression of the disease, valve replacement forms the cornerstone of therapy., Methods: Naval Medical Center San Diego and the VA San Diego Healthcare System have developed a unique collaborative TAVR program-a first in the Department of Defense-to offer this revolutionary procedure to their beneficiaries. Herein, we review development of the program and outcome for patients referred during the first 9 months., Findings: Development of the program was a multiyear process made successful because of administrative support, facility upgrades, and collaboration within the crossfacility and multispecialty heart valve team. In the first 9 months, 29 patients were referred for evaluation. Twenty-two (average age 80 years) underwent TAVR, whereas others were deemed nonoperable or were pending disposition at the time of this report. Patients who underwent TAVR had a predicted risk of procedural mortality from surgical aortic valve replacement of 7.7%, similar to other trials and registry studies. After mean follow-up of 5.6 months (range 30-355 days), zero deaths were recorded in the patients who underwent TAVR. Compared to other nonfederal local institutions, the program also realized a cost savings of approximately 17%, or nearly $10,000, per patient., Discussion: In the first 9 months, results were positive and consistent with expectations from national and international registries. Our hope is that this program may serve as an example for other federal facilities looking to start their own combined programs to improve health care quality and patient experience while simultaneously achieving considerable cost containment within a constrained national health care budget., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Objectives: To establish current radiation dose levels with contemporary scanners capable of prospectively triggered or high-pitch spiral scan modes to previous generation scanners among patients evaluated for coronary artery disease, pulmonary embolism, aortic disease, and "triple rule out" in a large population of patients at multiple centers., Background: Previous small-scale studies with carefully controlled scan protocols report that CT scanners that facilitate prospectively triggered scanning and provide high-pitch spiral CT scan modes drastically lower radiation doses. However, diagnostic reference levels should be selected by medical bodies on the basis of large surveys of representative sites and reviewed at appropriate time intervals., Methods: Scan data including dose and image quality parameters were collected retrospectively from 64 slice scanners (control) and prospectively after sites installed 128-slice dual-source scanners with high-pitch capability (study). Protocol selection was purposely not specified to survey "real world" results. Blinded quantitative image analysis was performed on every fifth scan., Results: From April 2011 to March 2012, 2085 patients at 9 sites completed the study: 1051 coronary artery disease (509 control, 542 study), 528 pulmonary embolism (267 control, 261 study), 419 aortic disease (268 control, 151 study), and 87 triple rule out (53 control, 34 study). There was a significant reduction in median dose-length product (DLP) from 669 mGy ∙ cm (interquartile range [IQR]: 419-1026 mGy ∙ cm) in the control group to 260 mGy ∙ cm (IQR: 159-441 mGy ∙ cm) in the study group, a reduction by 61% (P < .0001) and was lower in all categories. No significant differences were noted in image quality., Conclusion: Use of advanced scanners facilitating prospectively triggered or high-pitch spiral scan modes results in marked dose reduction across a variety of cardiovascular studies, with no compromise in image quality. These findings may contribute to new target dose recommendations in societal guidelines., (Copyright © 2014 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Carcinoid is a rare lung cancer that typically presents with a relatively indolent clinical behavior. We present the case of a 32-year-old male with progressive respiratory symptoms, which resulted in the diagnosis of typical bronchial carcinoid. This case shows a novel imaging technique for staging a bronchial carcinoid for determination of optimal management. This case also shows the multidisciplinary approach required for management of patients with carcinoid tumors., (Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.)

Sarcoidosis patients often have myocardial involvement, however, very few have clinically significant cardiac disease and ventricular tachycardia as the initial presentation is exceedingly rare. We report the case of a middle-aged male with symptomatic but clinically stable ventricular tachycardia. Chest radiograph, computed tomography, and positron emission tomography demonstrated pulmonary and mediastinal abnormalities but no definitive etiology for his arrhythmia. Transthoracic echocardiogram revealed the nonspecific cardiac abnormalities of right ventricular dilation and septal flattening. Cardiac magnetic resonance demonstrated delayed enhancement and akinesia of the right ventricular free and inferior walls--virtually diagnostic of an infiltrative myocardial disease. The diagnosis was then verified with transbronchial biopsy showing noncaseating granulomas consistent with sarcoidosis. In conclusion, this case illustrates an unusual presentation of sarcoidosis and demonstrates how the diagnosis can be made using cardiac magnetic resonance alongside transbronchial biopsy., (Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.)

Aortic insufficiency from iatrogenic valve perforation from nonaortic valve operations is rarely reported despite the prevalence of these procedures. Rapid diagnosis of these defects is essential to prevent deterioration of cardiac function. In this paper, we describe a young man who reported to our institution after two open cardiac surgeries with new aortic regurgitation found to be due to an iatrogenic perforation of his noncoronary aortic valve cusp. This defect was not appreciated by previous intraoperative transesophageal echocardiography and was inadequately visualized on follow-up transthoracic and transesophageal echocardiograms. In contrast, cardiac gated computed tomography clearly visualized the defect and its surrounding structures. This case highlights the utility of cardiac gated computed tomography for cases of suspected valvular perforation when echocardiography is not readily available or inadequate imaging is obtained.

The perioperative management of the patient with an anterior mediastinal mass (AMM) is viewed as one of the more challenging anesthetic endeavors. Diligent preoperative planning is essential and often involves imaging studies using multiple modalities, pulmonary function assessment, and minimally invasive biopsy for tissue diagnosis prior to arriving in the operating room. Anesthetic induction, often without major risks in most patients, can be catastrophic in AMM patients, with possible complications that include complete airway obstruction and cardiovascular collapse. The authors present the case of a biopsy via anterior mediastinotomy under monitored anesthesia care (MAC)/sedation in a 39-year-old man, who presented with a large AMM causing significant right heart compression without tracheobronchial involvement. This procedure was followed by definitive mass resection approximately 6 weeks later. This review will explore the following: (1) the use of MAC/sedation for AMM biopsy, (2) methods of safely securing the airway in patients undergoing definitive mass resection via median sternotomy, (3) current opinions regarding the need for preoperative pulmonary function testing in these patients, (4) current opinions regarding the need for and timing of cardiopulmonary bypass in these cases, (5) the use of intraoperative transesophageal echocardiography during resection, and (6) the characteristics of mediastinal germ-cell tumors with sarcomatous conversion. Though multiple anesthetic methods have been proposed for the management of patients undergoing tissue biopsy and resection of an AMM, this case report presents 2 successful anesthetic options for 2 distinct surgical procedures. In every instance, the anesthetic management options must be tailored to the unique physiological needs of the patient presenting for surgery.

Little data exist regarding the association of epicardial adipose tissue (EAT) and cardiovascular disease among HIV-infected persons. Among 213 HIV-infected men, there was a significant association between protease inhibitor use and increasing EAT volume. EAT was significantly associated with coronary artery calcium greater than 100. The elevated coronary artery disease risk in HIV-infected men may be partially explained by EAT associated with protease inhibitor use.

Background: Cardiovascular disease is an increasing concern among HIV-infected persons and their providers. We determined if fatty liver disease is a marker for underlying coronary atherosclerosis among HIV-infected persons., Methods: We performed a cross-sectional study in HIV-infected adults to evaluate the prevalence of and factors, including fatty liver disease, associated with subclinical coronary atherosclerosis. All participants underwent computed tomography for determination of coronary artery calcium (CAC; positive defined as a score >0) and fatty liver disease (defined as a liver-to-spleen ratio <1.0). Factors associated with CAC were determined using multivariate logistic regression models., Results: We included in the study 223 HIV-infected adults with a median age of 43 years [interquartile range (IQR) 36-50 years]; 96% were male and 49% were Caucasian. The median CD4 count was 586 cells/μL and 83% were receiving antiretroviral medications. Seventy-five (34%) had a positive CAC score and 29 (13%) subjects had fatty liver disease. Among those with CAC scores of 0, 1-100 and >100, the percentage with concurrent fatty liver disease was 8, 18 and 41%, respectively (P=0.001). In the multivariate model, CAC was associated with increasing age [odds ratio (OR) 4.3 per 10 years; P<0.01], hypertension (OR 2.6; P<0.01) and fatty liver disease (OR 3.8; P<0.01)., Conclusions: Coronary atherosclerosis as detected using CAC is prevalent among young HIV-infected persons. The detection of fatty liver disease among HIV-infected adults should prompt consideration of assessment for underlying cardiovascular disease and risk factor reduction., (© 2011 British HIV Association.)

Right ventricular pseudoaneurysm is a rare complication following repair of Tetralogy of Fallot. Presented are two patients, both with history of Tetralogy of Fallot, successful repair and pseudoaneurysms discovered on symptomatic follow up. Because surgical intervention is often required, the location and characteristics of the pseudoaneurysm are critical determinants of successful outcomes. Cardiac gated CT provides physicians with an invaluable tool in evaluating pseudoaneurysms., (Published by Elsevier Inc.)

Those infected with the human immunodeficiency virus (HIV) have a greater risk of cardiovascular disease and might undergo computed tomographic (CT) scans for early detection. Incidental findings on cardiac CT imaging are important components of the benefits and costs of testing. We determined the prevalence and factors associated with incidental findings on CT scans performed to screen for coronary artery calcium (CAC) among HIV-infected men. A clinically significant finding was defined as requiring additional workup or a medical referral. A total of 215 HIV-infected men were evaluated. Their median age was 43 years; 17% were current tobacco users; the median CD4 count was 580 cells/mm(3); and 83% were receiving antiretroviral medications. Also, 34% had a positive CAC score of >0. An incidental finding was noted among 93 participants (43%), with 36 (17%) having ≥1 clinically significant finding. A total of 139 findings were noted, most commonly pulmonary nodules, followed by granulomas, scarring, and hilar adenopathy. Most of the incidental findings were stable on follow-up, and no malignancies were detected. The factors associated with the presence of an incidental finding in the multivariate model included increasing age (odds ratio 1.6 per 10 years, p <0.01), positive CAC score (odds ratio 2.3, p <0.01), and current tobacco use (odds ratio 2.5, p = 0.02). In conclusion, incidental findings were common among HIV-infected men undergoing screening CT imaging for CAC determination. The incidental findings were more common among older patients and those with detectable CAC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abdominal pain is a common presenting complaint in the Emergency Department. It extends to all populations regardless of age, sex, or socioeconomic status. After gathering a history and examining the patient, most Emergency Physicians form a differential diagnosis and initiate an appropriate work-up. However, in the postpartum woman, additional causes must be considered and treated accordingly, knowing that there are consequences for both mother and child. We present a case of a postpartum woman presenting with right-sided abdominal pain, the cause of which, although atypical, has potential for significant morbidity and mortality if it goes undiscovered.

Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry-based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure-activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability.

Motexafin gadolinium (Xcytrin) is an expanded porphyrin macrocyclic compound under development for the treatment of several types of cancer. Currently clinical trials and non-clinical pharmacology and toxicology studies are ongoing. The goals of this open label, four arm, non-crossover bioavailability study were to explore motexafin gadolinium pharmacokinetics, determine the i.p. bioavailability, and define a pharmacokinetic model suitable for descriptive and predictive use. Mice received one or seven daily i.v. or i.p. injections (40 mg/kg) then blood samples were collected and analyzed. Plasma concentration data were modelled using population pharmacokinetic methods and a two compartment model was the most appropriate model. The stability and predictive performance of the model were evaluated using bootstrap procedures. The accuracy of the predicted concentrations was 8.3%. Motexafin gadolinium was rapidly cleared from the plasma and although T(1/2beta) was 12.9 h there was no accumulation following seven doses. The i.p. bioavailability was 87.4% and higher plasma concentrations were sustainable for a longer period with i.p. dosing. V(c) was larger than the blood volume and the tissue compartment volume was 38% of V(c), suggesting motexafin gadolinium was not widely distributed into less well perfused tissues. The pharmacokinetic profile in this study was similar to that in oncology patients administered multiple doses of motexafin gadolinium. The unbiased model yields reliable parameter estimates and insight into the pharmacokinetics of motexafin gadolinium in mice, is suitable for both descriptive and predictive purposes, and is a valuable tool in the planning, analysis, and interpretation of pharmacology and toxicology studies in mice.

Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins. In the present study, the activity of sapphyrins as anticancer agents in hematopoietic-derived tumor cells was explored. It was found that a dihydroxylated water-soluble sapphyrin derivative (PCI-2000) is a potent inducer of apoptosis in a wide variety of tumor cell lines including lymphoma (Ramos, DHL-4, and HF-1), leukemia (Jurkat and HL-60), and myeloma (8226/S, 1-310, C2E3, and 1-414). PCI-2000 triggers an apoptotic pathway in these tumor cells as shown by release of cytochrome c from mitochondria; activation of caspases 9, 8, and 3; cleavage of the caspase substrate poly(ADP-ribose) polymerase; and Annexin V binding. Apoptosis can be partially inhibited by overexpression of the antiapoptotic protein Bcl-2 or treatment with benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone, a cell-permeable caspase inhibitor. Both PCI-2000 and PCI-2010, a tetrahydroxy bis-carbamate derivative of PCI-2000, result in increased levels of phosphorylated p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase phosphorylation resulted in a synergistic increase of PCI-2000 cytotoxicity. PCI-2010 showed less toxicity in mice than PCI-2000 and was active in slowing the growth of Ramos and HL-60 tumor xenografts in nude mice. These results provide preclinical rationale for the further study of sapphyrins for potential use in the treatment of hematopoietic-derived tumors.

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.

Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.

The synthesis of a novel series of 3-phenylprop-2-ynylamines as selective mammalian squalene epoxidase inhibitors is described. Structure activity relationship studies led to the discovery of compound 19, 1-[3-(3,5-dichlorophenyl)-prop-2-ynyl]-3- methylpiperidine hydrochloride with an IC50 of 2.8 +/- 0.6 microM against rat liver squalene epoxidase. Against 23 strains of fungal squalene epoxidase compound 19 was found to be inactive.

The causes of biological gigantism have received much attention, but only for individual organisms. What selection pressures might favour the evolution of gigantic societies? Here we consider the largest single-queen insect societies, those of the Old World army ant Dorylus, single colonies of which can have 20 million workers. We propose that colony gigantism in Dorylus arises as a result of an arms race and test this prediction by developing a size-structured mathematical model. We use this model for exploring and potentially explaining differences in colony size, colony aggression and colony propagation strategies in populations of New World army ants Eciton and Old World army ants Dorylus. The model shows that, by determining evolutionarily stable strategies (ESSs), differences in the trophic levels at which these army ants live feed forwards into differences in their densities and collision rates and, hence, into different strategies of growth, aggression and propagation. The model predicts large colony size and the occurrence of battles and a colony-propagation strategy involving highly asymmetrical divisions in Dorylus and that Eciton colonies should be smaller, non-combative and exhibit equitable binary fission. These ESSs are in excellent agreement with field observations and demonstrate that gargantuan societies can arise through arms races.

Tacrolimus (FK506, Prograf), marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation, is virtually completely metabolized. The major metabolic pathways are P450 3A4-mediated hydroxylation and demethylation. Since P450 hepatic drug-metabolizing enzymes may be impaired in hepatic dysfunction, a study was conducted to characterize oral and intravenous tacrolimus pharmacokinetics in 6 patients with mild hepatic dysfunction and compared with parameters to those from normal subjects obtained in a separate study. Patients received two treatments: a single 0.020 mg/kg ideal body weight (IBW) i.v. dose infused over 4 hours and approximately 0.12 mg/kg IBW orally; normal subjects were dosed at 0.02 mg/kg 4-hour i.v. and 5 mg (0.065 mg/kg) p.o. Mean blood pharmacokinetic parameters with mild hepatic dysfunction were as follows: clearance = 0.035 L/h/kg, terminal exponential volume of distribution = 2.59 L/kg, terminal exponential half-life = 60.6 hours (i.v.), p.o. maximum blood concentration = 48.2 ng/mL, time of p.o. maximum blood concentration = 1.5 hours, and absolute bioavailability = 22.3%. The respective parameters in normal subjects were as follows: 0.040 L/h/kg, 1.91 L/kg, 34.2 hours (i.v.), 29.7 ng/mL, 1.6 hours, and 17.8%. Inasmuch as clearance and bioavailability were not substantially different from that in normal subjects, patients with mild hepatic impairment may initially be treated with conventional tacrolimus doses, with subsequent dosage adjustments based on response, toxicity, and therapeutic drug monitoring.

Purpose: Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated., Methods: Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated., Results: Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] < or = 51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma: kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues., Conclusions: Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels >200 microg/ml and tissue levels >3000 microg/g.

The new FDA Guidance for Industry BA and BE Studies for Orally Administered Drug Products--General Considerations and Average, Population, and Individual Approaches to Establishing Bioequivalence imply significant changes in the areas of enrollment, cost, ethics, time, entry, validation applications (EVAs), and statistical and pharmacokinetic methods. The changes from three-period to two-period design for food effect studies, the elimination of most steady state studies, and the analyses of only the active moiety or ingredient are welcome. However, if the current guidances are adopted, additional time will be needed for participants, and more participants will be needed, resulting in higher costs to drug developers. The PK parameters needed to assess BE and the need for replicate designs for drugs with long t1/2 are still unclear. Finally, the advantages of the aggregate property of the FDA metric versus the disaggregate criteria are challenged, and four bioequivalence criteria are proposed.

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long-term tacrolimus-based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12-hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12-hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra- and intergroup PK of T were variable. The mean AUC0-12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.

Purpose: Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses., Methods: Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1, 4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology., Results: Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable., Conclusions: AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18-94 microg/mL.

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl¿propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-¿2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy¿phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

AmBisome (NeXstarPharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid-complexed amphotericin B formulations, with greatly increased area under the plasma concentration-time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

AmBisome (ABLP) is a unilamellar liposomal preparation of amphotericin B that has demonstrated an improved safety profile compared to conventional amphotericin B. Single- and multiple-dose pharmacokinetics were determined by using noncompartmental methods for rats administered ABLP at 1, 3, 9, and 20 mg/kg/day. The toxicological profile was evaluated following 30 consecutive days of intravenous ABLP administration. Mean plasma amphotericin B concentrations reached 500 and 380 microg/ml (males and females, respectively) following 30 days of ABLP administration at 20 mg/kg. The overall apparent half-life was 11.2+/-4.5 h (males) or 8.7+/-2.2 h (females), and the overall clearance (CL) was 9.4+/-5.5 ml/h/kg (males) or 10.2+/-4.1 ml/h/kg (females). ABLP appears to undergo saturable disposition, resulting in a non-dose-proportional amphotericin B area under the curve and a lower CL at higher doses. Histopathological examination revealed dose-related transitional-cell hyperplasia in the transitional epithelium of the urinary tract (kidney, ureters, and urinary bladder) and moderate hepatocellular necrosis at the 20 mg/kg/day dose. Administration of ABLP in doses of up to 20 mg/kg/day resulted in 100-fold higher plasma amphotericin B concentrations, with significantly lower toxicity than that reported with conventional amphotericin B therapy.

The pharmacokinetics of tacrolimus following its administration as monotherapy or in combination with corticosteroids or methotrexate to 31 BMT patients are presented. All patients received i.v. tacrolimus initially and were subsequently switched to p.o. dosing. Patients received methotrexate by i.v. bolus on post-transplantation days 1, 3, 6 and 11. Patients were started on i.v. corticosteroids beginning on post-transplantation day 7. The noncompartmental pharmacokinetics of tacrolimus based on whole blood concentrations were determined following the i.v. and p.o. doses and were not different at steady-state compared to a single dose. The mean terminal elimination half-life of tacrolimus was 18.2 h following i.v. administration; the total body clearance was 71 ml/h/kg, the volume of distribution was 1.67 1/kg. Co-administration of methylprednisolone or methotrexate did not significantly alter tacrolimus pharmacokinetics. The p.o. bioavailability was 31-49%. Trough blood concentrations (Cmin) at 0 h (pre-dose) and 12 h (post-dose) correlated well to AUC(0-12)indicating that, as in solid organ transplantation, Cmin was a good index of drug exposure. Correlation at 0 h (r = 0.92) and at 12 h (r = 0.93) indicate that either time point can be used for therapeutic drug monitoring in patient management.

Racemic sodium warfarin, Coumadin, is widely used in the prevention of thromboembolic disease. The present study was undertaken to characterize three novel classes of warfarin analogs, and to compare them with the warfarin enantiomers. All three classes of compounds inhibit vitamin K epoxide reductase, the enzyme inhibited by racemic warfarin. The alcohol and the ester analogs have reduced protein binding compared with R-(+)-warfarin. The ester and the fluoro-derivatives have similar in vivo anticoagulant activity in the rat to that of S-(-)-warfarin. Thus, it is possible to synthesize novel warfarin analogs that differ from racemic warfarin or its enantiomers in certain selected properties.

Epidural administration of clonidine, a partial alpha 2-adrenergic agonist, provides effective relief for patients with intractable cancer pain. However, clonidine's long plasma elimination half-life suggests a potential for plasma accumulation following repeated doses or constant infusion. Adult male and female cancer patients experiencing severe, intractable pain were administered a continuous epidural infusion (30 micrograms/h) of clonidine hydrochloride for 14 days. Plasma clonidine concentrations were determined for 31 patients using a radioimmunoassay with a limit of quantitation of 0.062 ng/mL. Mean (+/- SD) plasma clonidine concentration and calculated total body clearance after 7 days of infusion (respectively, 2.19 +/- 1.17 ng/mL, n = 24; 279 +/- 184 mL/min, n = 27) were comparable to those following 14 days of infusion (2.50 +/- 1.51 ng/mL, n = 19; 272 +/- 163 mL/min, n = 21). Clonidine does not appear to accumulate in the plasma compartment during prolonged (14-day) continuous epidural infusion in cancer patients.

Novel 4,4-bis(trifluoromethyl)imidazolines have been found to be the potent acyl-CoA cholesterol acyltransferase (ACAT) inhibitors. ACAT is responsible for cholesterol esterification in the intestine, liver, and the arterial wall. These novel imidazolines also inhibit cholesterol ester formation in the macrophage. Several compounds have shown potent serum cholesterol-lowering activity in several animal models. Para-substitution of the 2-phenyl is critical for in vitro and in vivo activity. The 4,4-bis(trifluoromethyl)imidazolines with a para-cyano group on 2-phenyl and a 4-alkylcyclohexyl amide as the side-chain at the 5-position possess the most potent inhibitory activity in this series. Based on biochemical studies, this series acts as a competitive inhibitor with respect to cholesterol binding at the enzyme, which distinguishes it from most of the ACAT inhibitors discovered to date. Preliminary biological studies supported by X-ray crystal structures, molecular modeling, and structure-activity relationship (SAR) studies suggest that this series may be a cholesterol mimic.

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.

A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine-induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 microM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3-alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 microM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 microM.

Pretreatment with the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has previously been shown to reduce polymorphonuclear leukocyte (PMN) infiltration into the airways of ozone-exposed rats. The present study further examined the effects of 1 and 2 days EDU pretreatment on rat lung inflammatory responses by determining PMN infiltration in response to intratracheal instillation with the chemoattractant formyl-norleucine-leucine-phenylalanine (fNLP). Maximal recovery of PMNs by bronchoalveolar lavage was observed 4 hr after fNLP instillation with no alteration in the numbers of recoverable macrophages and lymphocytes. Although 1-day pretreatment with EDU did not affect PMN recovery from fNLP-instilled rat lungs, 2 days of EDU pretreatment prevented PMN infiltration as indicated by PMN recoveries that were similar to those obtained from saline-instilled lungs. Measurements of lung-marginated and interstitial pools of inflammatory cells using collagenase tissue digestion demonstrated no effect of 2 days EDU pretreatment. Although 2 days EDU pretreatment alone did not alter blood PMN content, lung permeability, and the lavage recoveries of inflammatory cells, blood PMN responses to chemotactic stimuli in vitro were impaired. In addition, EDU was shown to directly inhibit PMN chemotaxis and superoxide anion generation in vitro. These data demonstrated that EDU acts by interfering with PMN activation and migration rather than by decreasing PMN availability. EDU, by modulating the inflammatory response, represents a useful compound for preventing PMN-associated amplification of acute lung injuries.

The ability of the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)-ethyl]-N'-phenylurea) to affect polymorphonuclear leukocyte (PMNL) activation was examined by measuring superoxide anion, hydrogen peroxide and hydroxyl radical release from human PMNLs stimulated by phorbol ester. Results demonstrated that EDU effectively interferes with PMNLs reactive oxygen intermediate production, making it a potentially useful compound to be used to modulate PMNL-associated oxidant damage of inflamed tissues.

Objective: Because the analgesic effects of ketorolac are equivalent to those of narcotic analgesics, we investigated the possibility that this non-steroidal antiinflammatory drug might also exhibit anesthetic-sparing properties similar to those described for narcotic agents., Design: A nonrandomized, double-blind convenience sample. The treatment group received a preoperative dose of ketorolac 60 mg im 45 minutes prior to the induction of anesthesia. All other preoperative medications were identical., Setting: Brooke Army Medical Center, a primary care setting., Participants: Six women requiring vaginal hysterectomies from American Society of Anesthesiologists class I/II, all of similar age, weight, and body surface area., Outcome Measures: End-tidal concentrations of the anesthetic gas were measured at five-minute intervals using a gas analyzer. A mean percent end-tidal concentration versus time curve was generated for each group., Results: The area under the concentration curves for the anesthetic gas in the ketorolac and control group were 15.9 +/- 5.1 and 52.3 +/- 13.4, respectively (p = 0.006)., Conclusions: Ketorolac exhibits an anesthetic-sparing quality similar to that observed with narcotic analgesics.

Activated neutrophils and possibly xanthine oxidase-derived free radicals are believed to be mediators of ischemia and reperfusion-induced myocardial damage. We studied the cardioprotective effect of the neutrophil stabilizer and xanthine oxidase inhibitor azapropazone in dogs subjected to thrombotic occlusion of the left anterior descending coronary artery (LAD), induced by intracoronary introduction of a copper coil, followed 60 min later by thrombolytic treatment with intracoronary streptokinase and 4-day reperfusion; we then determined infarct size by triphenyltetrazolium stain. Azapropazone [100 mg/kg intravenously (i.v.) followed by a 24-h i.v. infusion of 10 mg/kg/h, n = 8] or vehicle (n = 10) treatments were started immediately before the streptokinase infusion. Steady-state plasma levels of azapropazone ranged from 97 to 163 micrograms/ml during the infusion. Myocardial blood flow and underperfused area at risk were determined using radiolabeled microspheres. Results were as follows (mean +/- SEM): area at risk (percentage of left ventricle) azapropazone 22.7 +/- 3.16 and vehicle 21.8 +/- 4.13; infarct size (percentage of area at risk), azapropazone 45.1 +/- 11.8 and vehicle 75.7 +/- 10.6, p less than 0.03; collateral blood flow (ml/min/g), azapropazone 0.27 +/- 0.02 and vehicle 0.23 +/- 0.02; total ischemic period (min), azapropazone 106 +/- 5.9 and vehicle 91.5 +/- 4.9. Azapropazone had no effects on heart rate (HR), blood pressure (BP), or rate/pressure product (RPP). These dta show that azapropazone limits infarct size in a canine model of coronary thrombosis and long-term reperfusion and that this cardioprotection is independent of cardiovascular parameters.

The biological fate of 14C-labeled dimercaptosuccinic acid (DMSA) in monkeys and rabbits was determined by measuring the 14C activity in their urine, feces, and expired air (14CO2). Monkeys absorbed less than 20% DMSA from three oral dose levels (0.082, 0.16, and 0.5 mmol/kg) of 14C-DMSA, and the rabbits absorbed 32% DMSA or less from an oral dose of 14C-DMSA (0.5 mmol/kg). Although the bioavailability of DMSA was limited in either species, DMSA was detected in the blood of both species within minutes after oral dosing. In either species, most of the radiolabel from the absorbed 14C-DMSA was detected in the urine within 12 hours. We also developed a sensitive assay for directly measuring levels of DMSA (as free thiols) in blood. Intact DMSA was not detected in the blood of the monkeys or the rabbits more than 200 minutes after oral or intravenous dosing at 0.5 mmol DMSA/kg body weight. However, 14C activity in blood and urine of the monkeys was measurable 72 hours after this dose. Differences between measured 14C concentrations and intact DMSA concentrations in the blood suggest the presence of DMSA metabolites that have longer half-lives than DMSA. Consequently, until the biological activities of these compounds are identified, the pharmacokinetic analysis of DMSA may be incomplete.