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The objective of this study was to determine the effectiveness of lactated Ringer's (LR) solution, sodium hydroxyethyl starch (hetastarch), and dopamine (DA) on diaphragm shortening (DS), diaphragm blood flow (DBF), diaphragm hydrogen peroxide (H2O2), and diaphragm apoptosis following hemorrhagic shock (HS). Sprague-Dawley rats were assigned to the following groups: HS, LR, LR plus DA, hetastarch, and hetastarch plus DA. After removing 40% of the blood volume, with exception of the HS group, an equal volume of resuscitation fluid was administered. The diaphragm was excised so that DBF, H2O2, and apoptosis could be measured. LR did not increase DBF and DS, whereas the other fluids increased DBF and DS. H2O2 and apoptosis decreased with LR administration. H2O2 and apoptosis were decreased to a much greater extent with LR plus DA, hetastarch, and hetastarch plus DA infusions. In conclusion, LR plus DA, hetastarch, and hetastarch plus DA maintained DS and DBF, which may be attributed to the decreases in reactive oxygen species as reflected by H2O2 and apoptosis. [ABSTRACT FROM AUTHOR]

The aim of this article is to provide a review of the literature regarding oxygen administration and the use of oxygen in patients experiencing haemorrhagic shock (HS). Oxygen is administered to patients to assist them in maintaining oxygenation. The administration of oxygen is complex and varies significantly among patients. In order to optimize patient care, clinicians need to be aware of the potential effects, both beneficial and harmful, that oxygen can have on the body. Literature inclusion criteria for this article was any article (1995 to present) pertaining to oxygen administration and HS. Also included were articles related to tissue injury caused by an overabundance of free radicals with the administration of oxygen. Articles related to oxygen and wound healing, pollution, aerospace, food and industrial uses were excluded. This review of the literature provides an overview of the use of oxygen in clinical practice and HS. The harmful effects of oxygen are highlighted to alert the clinician to this potential when there is an overabundance of oxygen. Oxygen is one of the most common drugs used in the medical community; however, the effects of oxygen on the body are not well understood. The use of oxygen if not prescribed correctly can cause cellular damage and death. Clinicians need to be more aware of the effects of oxygen and the damage it may cause if not administered properly. [ABSTRACT FROM AUTHOR]

There are many organelles within a cell, each with individual responsibilities required for life. Of these organelles, the mitochondria are the hemi of the cell, producing the energy necessary for cell function. Reactive oxygen species can cause mitochondrial dysfunction and contribute to many diseases often seen in emergency departments. When reactive oxygen species are produced, the mitochondria undergo functional and structural changes causing the release of cytochrome c. Cytochrome c is responsible for activating apoptotic pathways leading to cell death. Apoptosis, or programmed cell death, is needed to maintain homeostasis in the body; however, when this occurs prematurely by an increase in reactive oxygen species production, many pathological conditions can occur. Clinicians in emergency departments caring for patients with different diseases should consider that the mitochondria may play an important role in patients' recovery. For instance, myocardial infarctions and burns are two examples of altered physiologic states that play a role in mitochondrial dysfunction. Awareness of the different treatments that target the mitochondria will prepare emergency department clinicians to better care for their patients. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock is a severe life-threatening emergency affecting all organ systems of the body by depriving tissue of sufficient oxygen and nutrients by decreasing cardiac output. This article is a short review of the different types of shock, followed by information specifically referring to hemorrhagic shock. The American College of Surgeons categorized shock into 4 classes: (1) distributive; (2) obstructive; (3) cardiogenic; and (4) hemorrhagic. Similarly, the classes of hemorrhagic shock are grouped by signs and symptoms, amount of blood loss, and the type of fluid replacement. This updated review is helpful to trauma nurses in understanding the various clinical aspects of shock and the current recommendations for fluid resuscitation therapy following hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Oral administration of single doses of bopindolol (1-4mg) caused significant reductions in the rises of systolic blood pressure and heart rate produced by exercise; only the reduction in the rise of heart rate was significantly dose-related. Resting heart rate was reduced by bopindolol. There were small effects on resting blood pressure. Bopindolol caused a significant attenuation of the rise in plasma renin activity produced by passive head-up tilting to 75-85 degrees. Bopindolol produced a dose-related attenuation of the increase in pulse rate evoked by passive tilting. All effects 1-4 were maintained for at least 24 h. There was no measurable effect on plasma potassium concentration, peak flow rate or forced expiratory volume (FEV1). [ABSTRACT FROM AUTHOR]

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is common among Veterans but overlapping symptoms with other prevalent psychiatric disorders (e.g., posttraumatic stress disorder [PTSD]) complicate diagnosis. This study aims to (1) assess the prevalence of ADHD, (2) evaluate the correspondence between ADHD self-report measures, and (3) examine the association between ADHD and PTSD in a sample of combat-deployed post-9/11 Veterans., Materials and Methods: A total of 332 combat-deployed post-9/11 Veterans from VA Boston Healthcare System completed the Clinician-Administered PTSD Rating Scale, 2 ADHD self-report questionnaires (Wender Utah Rating Scale-25 and the Adult ADHD Self-Report Scale v1.1), and report of the presence/absence of a historical ADHD diagnosis. Attention-deficit/hyperactivity disorder status via Wender Utah Rating Scale ([WURS-25] criterion standard) was compared to historical ADHD diagnosis and the ASRSv.1.1 screener. Log-binomial regression models assessed the relationship between ADHD and PTSD. This study was reviewed and approved by the VA Boston Institutional Review Board., Results: In all, 12.7% of the sample met criteria for ADHD per the WURS-25. The WURS-25 demonstrated poor sensitivity with historical ADHD diagnosis (27.7%) but adequate specificity (90.3%). Poor sensitivity (60.7%) and specificity (60.8%) were observed between the WURS-25 and the ASRS-v.1.1. The prevalence of ADHD was 2.5 times as high for Veterans with a history of PTSD (Prevalence Ratio [PR] = 2.53, 95% CI: 1.11, 7.28) and over twice as high for those with current PTSD (PR = 2.19, 95% CI: 1.17, 4.38)., Conclusions: Attention-deficit/hyperactivity disorder is prevalent in this sample of Veterans and is associated with an increased risk of current and lifetime PTSD. The low correspondence across self-report ADHD measures illustrates the complexity of assessing ADHD in this highly comorbid population. When evaluating ADHD in Veterans, clinicians should carefully consider alternative and contributory symptom etiologies, such as PTSD, to ensure accurate diagnosis and treatment., (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.)

Veterans deployed in the post-9/11 wars in Iraq and Afghanistan (Operations Enduring Freedom, Iraqi Freedom, and New Dawn) face a multitude of challenges reintegrating into civilian life after military service. There is a need for evidence-based support programs to address the wide-reaching cognitive, psychological, and physical symptoms that can impede civilian reintegration. The present study incorporates quantitative and qualitative methods to assess veterans' experiences with two reintegration treatments (Short-Term Executive Plus-Home [SH] and Present Centered Group Therapy for Reintegration [PCGT-R]) within the context of a larger randomized clinical trial. A total of 131 veterans ages 24-65 years, drawn from the SH ( n = 66) and PCGT-R ( n = 65) treatment arms, completed quantitative feedback forms and qualitative interviews. Quantitative surveys indicated SH was more highly rated than PCGT-R in terms of program satisfaction ( p < .01), helpfulness ( p = .03), and connection to other Veterans Affairs (VA) services ( p s < .05). Thematic qualitative analysis indicated that both interventions provided beneficial social support and that both groups appreciated online implementation. They also revealed that SH veterans acquired more emotion regulation and impulse control skills and reported greater willingness to engage in further VA treatments, than PCGT-R veterans. Dropout did not differ significantly between groups, and the most highly cited reasons for dropout among both groups were scheduling conflict and dislike of group formats. Findings emphasize the opportunity for group and skills-based interventions focused on reintegration to increase support and access to VA care among veterans. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: To reduce opioid consumption and decrease length of stay (LOS) in bariatric surgical patients by implementing an evidence-based, nonpharmacologic enhanced recovery after surgery (ERAS) intervention bundle., Design: Evidence-based practice project., Methods: We developed and implemented a nonpharmacologic ERAS bundle from existing American Society of PeriAnesthesia Nurses Standards and bariatric and subspecialty surgical ERAS protocols to standardize the postoperative nursing care of bariatric patients. The bundle consisted of early ambulation, immediate initiation and prolonged use of oxygenation, prevention of nausea and vomiting, frequent use of incentive spirometry, and application of ice packs to surgical sites. The two project outcomes were opioid consumption and patient LOS. We used descriptive statistics to summarize opioid consumption and LOS among surgical bariatric patients at baseline and post intervention and independent samples t tests to determine the statistical significance of pre- or post-LOS changes., Findings: After implementing the ERAS bundle in 31 bariatric surgical patients, we found that the percentage of patients given an opioid substantially decreased by 13.8%, with both fentanyl and hydromorphone (Dilaudid) consumption meaningfully decreasing by 11.0% and 25.6%, respectively. The average LOS significantly decreased (P = .015) by 23 minutes per patient following the intervention, from 1 hour and 58 minutes to 1 hour and 35 minutes, representing a 19.5% reduction in total patient time in the PACU., Conclusions: Use of a nonpharmacologic ERAS bundle and standardizing postoperative care decreased overall PACU bariatric surgical patient opioid consumption and significantly reduced PACU LOS. Optimizing pain management for bariatric patients in the PACU could lead to improved pain control and reduced reliance on opioids during their entire hospital stay, enhancing health care outcomes and improving patient safety. Perioperative leaders and educators can use our example to develop initiatives that decrease opioid use and LOS to improve care for the high-acuity bariatric patient population., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2024 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Metabolic syndrome has been associated with reduced brain white matter integrity in older individuals. However, less is known about how metabolic syndrome might impact white matter integrity in younger populations. This study examined metabolic syndrome-related global and regional white matter integrity differences in a sample of 537 post-9/11 Veterans. Metabolic syndrome was defined as ≥3 factors of: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. T1 and diffusion weighted 3 T MRI scans were processed using the FreeSurfer image analysis suite and FSL Diffusion Toolbox. Atlas-based regions of interest were determined from a combination of the Johns Hopkins University atlas and a Tract-Based Spatial Statistics-based FreeSurfer WMPARC white matter skeleton atlas. Analyses revealed individuals with metabolic syndrome (n = 132) had significantly lower global fractional anisotropy than those without metabolic syndrome (n = 405), and lower high-density lipoprotein cholesterol levels was the only metabolic syndrome factor significantly related to lower global fractional anisotropy levels. Lobe-specific analyses revealed individuals with metabolic syndrome had decreased fractional anisotropy in frontal white matter regions compared with those without metabolic syndrome. These findings indicate metabolic syndrome is prevalent in this sample of younger Veterans and is related to reduced frontal white matter integrity. Early intervention for metabolic syndrome may help alleviate adverse metabolic syndrome-related brain and cognitive effects with age., (Published by Oxford University Press 2024.)

Adverse surgical events cause negative patient health outcomes and harm that can often overshadow the safe and effective patient care provided daily by nurses as members of interprofessional healthcare teams. Near misses occur far more frequently than adverse events and are less visible to nurse leaders because patient harm is avoided due to chance, prevention, or mitigation. However, near misses have comparable root causes to adverse events and exhibit the same underlying patterns of failure. Reviewing near misses provides nurses with learning opportunities to identify patient care weaknesses and build appropriate solutions to enhance care. As the operating room is one of the most complex work settings in healthcare, identifying potential weaknesses or sources for errors is vital to reduce healthcare-associated risks for patients and staff. The purpose of this manuscript is to educate, inform, and stimulate critical thinking by discussing perioperative near miss case studies and the underlying factors that lead to errors. Our authors discuss 15 near miss case studies occurring across the perioperative patient experience of care and discuss barriers to near miss reporting. Nurse leaders can use our case studies to stimulate discussion among perioperative and perianesthesia nurses in their hospitals to inform comprehensive risk reduction programs., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2023. Published by Elsevier Inc.)

Adolescence represents a critical period of neural development during which binge drinking (BD) is prevalent. Though prior work has shown that white matter (WM) integrity is susceptible to damage from excessive alcohol intake in adults, the effect of early adolescent BD on WM health in adulthood remains unknown. Veterans with a history of BD onset before age 15 [n = 49; mean age = 31.8 years; early-onset adolescent binge drinkers (EBD)] and after age 15 [n = 290; mean age = 32.2 years; late-onset adolescent binge drinkers (LBD)] were studied with diffusion tensor imaging. Group differences in fractional anisotropy (FA; movement of water molecules along the WM) and mean diffusivity (MD; average movement of water molecules) were examined as indices of WM integrity using FreeSurfer and FMRIB Software Library (FSL) processing streams. Lower FA and higher MD are thought to represent degradations in WM integrity. A reference group (RG) of social drinkers with no history of BD (n = 31) was used to provide comparative normative data. We observed widespread decreased FA and increased MD in EBDs, compared to LBDs, as well as decreased FA in the pars triangularis, lateral orbitofrontal cortex, superior frontal cortex, isthmus cingulate, and genu and splenium of the corpus callosum EBDs also had lower WM integrity compared to the RG. Adults who initiated BD during early adolescence demonstrated decreased FA and increased MD throughout the frontostriatal circuits that mediate inhibitory control and thus may result in impulsive behavior and a predisposition for developing alcohol use disorder during adulthood., (© Published by Oxford University Press on behalf of Medical Council on Alcohol 2023.)

Introduction: To reach the highest levels of health care quality, all nurses providing intraoperative care to surgical patients should have a firm grasp of the complex knowledge, skills, and guidelines undergirding the perioperative nursing profession. In military treatment facilities, either perioperative registered nurses or labor and delivery (L&D) nurses provide skilled intraoperative nursing care for cesarean deliveries. However, L&D and perioperative nurses occupy vastly different roles in the continuum of care and may possess widely differing levels of surgical training and experience., Materials and Methods: The purpose of this project was to improve surgical care quality by standardizing and strengthening L&D nurse perioperative training, knowledge, and competence. Our population, intervention, comparative, and outcome question was, "For labor and delivery nurses of a regional military medical center (P), does implementing an evidence-based training program (I), as compared to current institutional nursing practices (C), increase nursing knowledge and perioperative nursing competence (O)?" We implemented Periop 101: A Core Curriculum-Cesarean Section training for 17 L&D nurses, measured knowledge using product-provided testing, and assessed competence using the Perceived Perioperative Competence Scale-Revised., Results: We found that perioperative nursing knowledge and competence significantly improved and were less varied among the nurses after completing the training program. Nurses demonstrated the greatest knowledge area improvements in scrubbing, gowning, and gloving; wound healing; and sterilization and disinfection, for which median scores improved by more than 100%. Nurses reported significantly greater perceived competence across all six domains of the Perioperative Competence Scale-Revised, with the largest improvements realized in foundational skills and knowledge, leadership, and proficiency., Conclusions: We recommend that health care leaders develop policies to standardize perioperative education, training, and utilization for nurses providing intraoperative care to reduce clinician role ambiguity, decrease inefficiencies, and enhance care., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Nursing has a long and celebrated history of providing life-saving care during crises and periods of great need. Following the government collapse in Afghanistan and the withdrawal of US troops, a severe humanitarian and human rights crisis emerged. The US military participated in one of the largest and most complex humanitarian missions in history to aid Afghan relief efforts. US and coalition forces evacuated more than 130,000 people in the chaotic Allied airlift from the Kabul Airport. The overarching missions, Operation Allies Refuge and Operation Allies Welcome, provided humanitarian support to at-risk Afghan nationals who contributed to the Global War on Terrorism efforts, as well as US citizens living in Afghanistan. Landstuhl Regional Medical Center (LRMC), an overseas military treatment facility located in Germany, supported the healthcare needs of Afghan evacuees and injured US service members during the humanitarian crisis. LRMC clinicians provided emergent, urgent, and specialty care while advocating for evacuee health, wellness, and living conditions. Perioperative and perianesthesia nurses were essential to the humanitarian response, as many evacuees and injured US service members arrived in Germany requiring immediate surgical interventions. In this article, we describe the vital contributions of military perioperative and perianesthesia nurses to the Operation Allies Refuge and Operation Allies Welcome missions, and share our experiences providing humanitarian relief. Military and civilian healthcare planners can learn from our humanitarian relief contributions, experiences, and lessons to strategically prepare their health systems to respond to future crises., (Published by Elsevier Inc.)

The management of patients with autoimmune rheumatic diseases such as rheumatoid arthritis (RA) remains a significant challenge. Often the rheumatologist is restricted to treating and relieving the symptoms and consequences and not the underlying cause of the disease. Oxidative stress occurs in many autoimmune diseases, along with the excess production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The sources of such reactive species include NADPH oxidases (NOXs), the mitochondrial electron transport chain, nitric oxide synthases, nitrite reductases, and the hydrogen sulfide producing enzymes cystathionine-β synthase and cystathionine-γ lyase. Superoxide undergoes a dismutation reaction to generate hydrogen peroxide which, in the presence of transition metal ions (e.g. ferrous ions), forms the hydroxyl radical. The enzyme myeloperoxidase, present in inflammatory cells, produces hypochlorous acid, and in healthy individuals ROS and RNS production by phagocytic cells is important in microbial killing. Both low molecular weight antioxidant molecules and antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and peroxiredoxin remove ROS. However, when ROS production exceeds the antioxidant protection, oxidative stress occurs. Oxidative post-translational modifications of proteins then occur. Sometimes protein modifications may give rise to neoepitopes that are recognized by the immune system as 'non-self' and result in the formation of autoantibodies. The detection of autoantibodies against specific antigens, might improve both early diagnosis and monitoring of disease activity. Promising diagnostic autoantibodies include anti-carbamylated proteins and anti-oxidized type II collagen antibodies. Some of the most promising future strategies for redox-based therapeutic compounds are the activation of endogenous cellular antioxidant systems (e.g. Nrf2-dependent pathways), inhibition of disease-relevant sources of ROS/RNS (e.g. isoform-specific NOX inhibitors), or perhaps specifically scavenging disease-related ROS/RNS via site-specific antioxidants., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The generation of 3-nitrotyrosine, within proteins, is a post-translational modification resulting from oxidative or nitrative stress. It has been suggested that this modification could be used as a biomarker for inflammatory diseases. Despite the superiority of mass spectrometry-based determinations of nitrotyrosine, in a high-throughput clinical setting the measurement of nitrotyrosine by an enzyme-linked immunosorbent assay (ELISA) is likely to be more cost-effective. ELISAs offer an alternative means to detect nitrotyrosine, but many commercially available ELISAs are insufficiently sensitive to detect nitrotyrosine in healthy human serum. Here, we report the development, validation and clinical application of a novel electrochemiluminescence-based ELISA for nitrotyrosine which provides superior sensitivity (e.g. a 50-fold increase in sensitivity compared with one of the tested commercial colorimetric ELISAs). This nitrotyrosine ELISA has the following characteristics: a lower limit of quantitation of 0.04 nM nitrated albumin equivalents; intra- and inter-assay coefficients of variation of 6.5% and 11.3%, respectively; a mean recovery of 106 ± 3% and a mean linearity of 0.998 ± 0.001. Far higher nitration levels were measured in normal human blood cell populations when compared to plasma. Mass spectrometry was used to validate the new ELISA method. The analysis of the same set of chemically modified albumin samples using the ELISA method and mass spectrometry showed good agreement for the relative levels of nitration present in each sample. The assay was applied to serum samples from patients undergoing elective surgery which induces the human inflammatory response. Matched samples were collected before and one day after surgery. An increase in nitration was detected following surgery (median (IQR): 0.59 (0.00-1.34) and 0.97 (0.00-1.70) nitrotyrosine (fmol of nitrated albumin equivalents/mg protein) for pre- and post-surgery respectively. The reported assay is suitable for nitrotyrosine determination in patient serum samples, and may also be applicable as a means to determine oxidative stress in primary and cultured cell populations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids., Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance., Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use., Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker.

Essential oils and their constituents have potential as ecologically acceptable pesticides that may also have novel modes of action. In this work hydroxy and ester derivatives of the naturally occurring monoterpenoids 1,8-cineole 3, the main component in most eucalyptus oils, and 1,4-cineole 4 were prepared and their pre-emergence herbicidal activity against annual ryegrass (Lolium rigidum) and radish (Raphanus sativus var. Long Scarlet) investigated in laboratory-based bioassays. 1,8-Cineole, eucalyptus oil and all derivatives showed a dose-dependent herbicidal activity against annual ryegrass and radish with many of the derivatives showing improved herbicidal activity relative to 1,8-cineole and high-cineole eucalyptus oil. Increased activity of cineole ester derivatives compared to their associated hydroxy-cineole and carboxylic acid was not observed. No relationship between lipophilicity of the carboxylic acid portion of cineole ester derivatives and herbicidal activity was observed. The results indicate that these cineole derivatives could be environmentally acceptable herbicides.

We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.

Ligand-based virtual screening with a 3D pharmacophore led to the discovery of 30 novel, diverse and drug-like ligands of the human cannabinoid receptor 1 (hCB(1)). The pharmacophore was validated with a hit rate of 16%, binding selectivity versus hCB(2), and expected functional profiles. The discovered compounds provide new tools for exploring cannabinoid pharmacology.

Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.

The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.

We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.

A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.

Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.

Database searching led to the identification of potent A(2A) antagonists which do not contain the privileged furan moiety and which show selectivity over A(1) receptors. Simple substructure searching on a proprietary database identified compounds with activities in the low nM range. A targeted approach to the identification of non-furan containing compounds resulted in the identification of two novel series, with potency, selectivity and directional SAR from screening 113 compounds.

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

In the present study we compared the affinity of various drugs for the high affinity "agonist-preferring" binding site of human recombinant 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors stably expressed in monoclonal mammalian cell lines. To ensure that the "agonist-preferring" conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([3H]-ketanserin for 5-HT(2A) receptor and [3H]-mesulergine for 5-HT(2B) and 5-HT(2C) receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([125I]-DOI for 5-HT(2A) receptor binding and [3H]-5-HT for 5-HT(2B) and 5-HT(2C) receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the "agonist-preferring" subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT2 receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors respectively). There remains, however, a lack of highly selective agonists. (-)DOI is potent and moderately selective for 5-HT(2A) receptors, BW723C86 has poor selectivity for human 5-HT(2B) receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT(2C) receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT2 receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT2 receptor pharmacology.

A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.

During a program to investigate the biochemical basis of side effects associated with the antimalarial drug mefloquine, the authors made the unexpected discovery that the (-)-(R,S)-enantiomer of the drug is a potent adenosine A2A receptor antagonist. Although the compound was ineffective in in vivo animal models of central adenosine receptor function, it provided a unique nonxanthine adenosine A2A receptor antagonist lead structure and encouraged the initiation of a medicinal chemistry program to develop novel adenosine A2A antagonists for the management of Parkinson's disease (PD). The authors have synthesized and screened more than 2,000 chemically diverse and novel adenosine A(2A antagonists. Early examples from two distinct chemical series are the thieno[3,2-dy]pyrimidine VER-6623 and the purine compounds VER-6947 and VER-7835, which have high affinity at adenosine A2A receptors (K(i) values 1.4, 1.1, and 1.7 nmol/L, respectively) and act as competitive antagonists. In particular, VER-6947 and VER-7835 demonstrate potent in vivo activity reversing the locomotor deficit caused by the D2 receptor antagonist haloperidol, with minimum effective doses comparable with that of KW6002 (0.3 to 1 mg/kg). In conclusion, the authors have discovered potent, selective, and in vivo active nonxanthine adenosine A2A antagonists that have considerable promise as a new therapy for PD.

In the present study, we have sought to solubilise adenosine A(2A) receptors from rat striatal membranes using a variety of different detergents. Of the detergents tested, 1% CHAPS (3-[(3-deoxycholic acid (cholamidopropyl) dimethylammonio]-1-propanesulfonate) yielded optimal conditions for solubilisation (in the presence of 3 mg/ml protein, 44% of receptor was solubilised, 50% of total protein was solubilised). An antipeptide antibody was raised against a 15 amino-acid sequence within the predicted third intracellular loop region of the human and rat adenosine A(2A) receptor. The antibody was coupled to protein A immobilised on sepharose CL-4B and used to immunoprecipitate adenosine A(2A) receptors from solubilised rat striatal preparations. Radioligand-binding studies were performed using the selective adenosine A(2) antagonist [(3)H]ZM 241385 (4-(2-[7-amino-2-(2-fury1)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol). Using [(3)H]ZM 241385, the pharmacology of immunoprecipitated adenosine A(2A) receptors was composed to striatal membrane bound adenosine A(2A) receptors and detergent solubilised adenosine A(2A) receptors. [(3)H]ZM 241385 labelled a single saturable binding site with high affinity in all three preparations (membrane bound K(d) 2.7 nM+/-1.0; solubilised K(d) 1.9 nM+/-0.3; immunoprecipitated K(d) 2.2 nM+/-0.7). Additionally, all three assays confirmed a rank order of potency for displacers consistent with adenosine A(2A) receptor pharmacology: ZM 241385>KW 6002 ((E)-8-[2-(3,4-dimethoxyphenyl)ethynyl]-1-3-diethyl-3,7-dihydro-7-methyl-1-purine 2,6 dione)>CGS 21680, (2-(4-(2 carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosine)>DPCPX (8-cyclopentyl-1,3-dipropylxanthine). We conclude that we have solubilised and immunoprecipitated adenosine A(2A) receptors from rat striatum and that their pharmacology is consistent with native striatal adenosine A(2A) receptors.

The 5-HT2C receptor is expressed in different isoforms as a result of mRNA editing. Both INI (unedited) and VSV (a fully edited version) isoforms are abundant in rat brain. The VSV isoform lacks the high affinity recognition site for 5-HT, which may be caused by low efficiency coupling to G-proteins. In this study we have investigated the pharmacology of the agonist binding site of these two isoforms of the 5-HT2C receptor. The VSV isoform was expressed in Chinese hamster ovary cells (CHO) and the INI isoform in both Chinese hamster ovary cells and human embryonic kidney cells (HEK-293). Saturation analysis using [3H]5-HT revealed high and low affinity recognition sites on the INI isoform in both cell types whilst the VSV isoform did not have the high affinity binding site for [3H]5-HT. Displacement studies were undertaken using [3H]5-HT to label the receptors. In these studies the affinity of agonists (5-HT, Ro600175 ((S)-2-(6-Chloro-5-fluoroindol-1-yl)-1-methylethylamine), MK212 (6-Chloro-2-(piperazinyl) pyrazine), mCPP (1-(m-chlorophenyl)-piperazine), TfMPP (N-(m-trifluoromethylphenyl)piperazine), DOI (1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane), DOB (1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane) and 8OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin) was higher at the INI isoform, whilst antagonist affinity (ketanserin and mesulergine) did not change between the two receptor isoforms. There were no differences between the INI isoform expressed in the CHO and HEK-293. This suggests that the INI isoform of the 5-HT2C receptor is pharmacologically similar to the VSV form of the 5-HT2C receptor but that it couples more efficiently to G-proteins.

GABA(A) receptors composed of alpha1beta3 gamma2 and alpha1beta3 subunits were expressed in insect Sf9 cells and solubilized in 1% Triton X100. In sucrose density gradients, [3H]-Ro15-1788 binding activity, in the case of alpha1beta3 gamma2, and [3H]-muscimol binding activity, in the case of alpha1beta3 containing receptors sedimented as a single sharp peak suggesting the formation of receptors containing a defined number of subunits. When alpha1beta3gamma2 -containing receptors were incubated with an alpha-subunit specific antibody (bd24), a single class of antibody receptor complex was formed irrespective of the receptor-antibody ratio. This is consistent with two alpha subunits cross-linked within the receptor by the antibody. Similar results were obtained using a beta-subunit specific antibody (bd17). Several classes of antibody-receptor complex were formed when receptors were pre-incubated with a gamma specific antibody (anti gamma(2) 1-15 Cys). This profile is consistent with the presence of a single gamma subunit in each complex. Experiments with alpha1beta3 subunit containing receptors and antibody bd24 produced a profile similar to that seen with alpha1beta3 gamma2 receptors, consistent with two alpha subunits per receptor complex. In this case, the anti-beta subunit antibody, bd17, produced a unique and complex profile consistent with three beta subunits per receptor. This method permits the rapid determination of subunit stoichiometries of homogeneous receptor populations

The present study examines the physical properties of recombinant human GABAA receptors. The baculovirus/Sf9 cell system was used to express combinations of human GABAA receptor subunits: alpha 1 alone, alpha 1 with beta 1, and alpha 1 with beta 1 and gamma 2. Receptors were solubilized using 1% Triton X-100. In sucrose density gradients containing 150mM NaCl, alpha 1 beta 1 receptor-detergent complexes sedimented more slowly than alpha 1 beta 1 gamma 2 constructs (sedimentation coefficient = 7.00 +/- 0.32 and 8.63 +/- 0.48 S, respectively). Stokes' radii for the two receptor-detergent complexes were determined by gel filtration in Sephacryl S-300. These experiments were performed in the presence of 1 M sodium chloride to prevent aggregation. The Stokes' radii for alpha 1 beta 1 and alpha 1 beta 1 gamma 2 receptor-detergent complexes were 9.06 +/- 0.23 and 7.91 +/- 0.19 nm, respectively. Sedimentation experiments in 1 M NaCl revealed similar sedimentation coefficients for alpha 1 beta 1 and alpha 1 beta 1 gamma 2 receptor-detergent complexes (8.79 +/- 0.59 and 8.46 +/- 0.72 S, respectively). The molecular weight of the alpha 1 beta 1 receptor excluding detergent was estimated to be 281 +/- 19 kDa, that of the alpha 1 beta 1 gamma 2 receptor, 247 +/- 21 kDa. This difference is not statistically significant. Given subunit molecular weights which are close to 50 kDa, this suggested a pentameric structure for the majority of alpha 1 beta 1 gamma 2 receptors, and that alpha 1 beta 1 receptors are not"assembly intermediates" with fewer subunits.

GABAB receptor activation inhibits forskolin-stimulated adenylyl cyclase activity but augments noradrenaline-stimulated adenylyl cyclase activity. The present study investigated the pharmacology of these two GABAB receptor mediated responses. In a cross-chopped rat cortical slice preparation, it was confirmed that (-)baclofen inhibited forskolin-stimulated adenylyl cyclase activity and augmented noradrenaline-stimulated adenylyl cyclase activity. The potency of five further agonists was investigated (SKF97541, CGP47656, CGP44533, 3-APA and CGP44532). Of these agonists two compounds were significantly more potent as inhibitors of forskolin-stimulated adenylyl cyclase than as augmenters of noradrenaline-stimulated adenylyl cyclase activity, these were (-)baclofen (pEC50 = 6.07 +/- 0.29 and 5.04 +/- 0.17, respectively (p < 0.05)), and CGP47656 (pEC50 = 6.44 +/- 0.05 and 4.48 +/- 0.26, respectively (p < 0.05)). It is possible to explain this difference in potency by proposing that these compounds have low intrinsic efficacy, and the augmentation of noradrenaline-stimulated adenylyl cyclase has a low receptor reserve. In addition six antagonists (CGP49311A, CGP46381, CGP45024, CGP45397, CGP36742) were also tested for their ability to antagonize 10 microM (-)baclofen in these two assays. These antagonists ranged in potency as inhibitors of forskolin-stimulated adenylyl cyclase activity from CGP49311A (pEC50 = 5.45 +/- 0.30) to CGP36742 (pEC50 = 3.87 +/- 0.16). Each antagonist had similar potency in the two assays, suggesting that these two responses are mediated by pharmacologically similar receptors.

We have used the technique of autoradiography to study the binding of [3H]-GABA to GABAA and GABAB receptors in brains taken from rats that are genetically predisposed to petit mal type seizures. A range of concentrations of [3H]-GABA were employed to test the hypothesis that this predisposition was due to regional changes in either the number of GABAA or GABAB receptors, or affinity of GABA for these receptors. We found no statistical difference in the levels of radioligand binding to GABAA and GABAB receptors in animals susceptible to seizures compared to control animals in any of the brain regions studied over the concentration range 25 nM to 400 nM. This indicated that there was no change in either the Kd (affinity) or Bmax (receptor number) in these animals and that the pharmacological basis for the efficacy of GABAB antagonists in this seizure condition probably lies elsewhere.

1,3-di(2-[5-3H]tolyl)Guanidine ([3H]DTG) was found to bind to a single saturable population of binding sites in human cerebral cortex and NCB20 cells, a second low-affinity site was apparent in guinea pig brain. Displacement studies were performed to determine the pharmacology of the [3H]DTG binding site in these 3 membrane preparations. In human cortical tissue and NCB20 cell membranes the (+)-stereoisomers of benzomorphans displaced binding with Hill coefficients close to one, displayed similar affinity and did not give the biphasic displacement curve characteristic of guinea pig membranes. The pIC50 of the low-affinity component of the sigma binding site in guinea pig brain correlates best with the affinity of drugs for the binding site in human cortex.

The effect of dosing guinea pigs with spironolactone (100 mg/kg twice daily for 3 days) upon the sigma recognition site labelled with [3H]-DTG was investigated. Animals were dosed with 100 mg/kg spironolactone twice a day for 3 days. Spironolactone treatment caused a decrease in sigma radioligand binding in membranes prepared from liver and brain but not in adrenals or testes. Saturation analysis of [3H]-DTG radioligand binding in the brain indicated that the decrease in specifically bound [3H]-DTG binding was due to a reduction in receptor number with no change in affinity. This method for the selective depletion of brain and liver sigma recognition sites will provide a useful tool for exploring the functional significance of this site.

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.

Several hydrogenated derivatives of the potent NMDA antagonist 1 have been prepared and evaluated as competitive inhibitors of [3H]-1 binding. These compounds were also tested for their ability to act as noncompetitive antagonists of NMDA in vitro. These studies indicate that two aromatic rings are not strictly required for high-affinity binding or NMDA antagonism.

1. Eight patients with essential hypertension were challenged with an infusion of 32 mmol of potassium chloride in saline before and after control of their blood pressure by the angiotensin converting-enzyme (ACE) inhibitor enalapril. 2. The potassium infusion was associated with similar increases in plasma aldosterone before and during enalapril treatment, although absolute aldosterone levels were lower after enalapril treatment despite higher plasma potassium levels. 3. The handling of the potassium load was altered by ACE inhibition. The area under the curve of a plot of the increase in plasma potassium above baseline against time was greater during enalapril treatment than during treatment with placebo. 4. These observations contrast with data obtained in the dog and demonstrate that in patients with essential hypertension stimulation of aldosterone secretion by potassium is not abolished by chronic suppression of plasma angiotensin II; and although plasma aldosterone remains at a lower level, the homoeostasis of plasma potassium is only mildly impaired.

A review of the American Cancer Society's statistics for colorectal cancer indicates that there has been little improvements in the survival rate for this disease in the past 25 years. Although there have been advances in surgical techniques, radiation therapy, and chemotherapy, the key to improved survival rates is earlier diagnosis. A significant percentage of patients continues to present with regional or distal metastasis at the time of their initial diagnosis. Both proctosigmoidoscopy and guaiac impregnated filter slide paper methods have been productive in diagnosing this disease at an earlier stage. The "Hemoccult" test, however, is inexpensive, can be used on a routine basis, is easier for patients to perform themselves, and is aesthetically pleasing. It represents a significant cost savings compared to proctosigmoidoscopy and should be advocated for routine use in all patients over 40 years of age. Although there continues to be a role for local and regional mass screening programs, significant improvements in colorectal survival rates cannot be expected until routine application of this type of screening is practiced.

The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist [3H]MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of [3H]MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. [3H]MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated [3H]MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by [3H]TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-[3H]SKF 10,047. [3H]MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that [3H]MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.