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The world's understanding of the climate and ecological crises rests on science. However, scientists' conventional methods of engagement, such as producing ever more data and findings, writing papers and giving advice to governments, have not been sufficiently effective at persuading politicians to act on the climate and ecological emergency. To date, governments' decisions (such as continuing with vast subsidies for fossil fuels) clearly show that powerful vested interests have been much more influential than the amassed scientific knowledge and advice. We argue that in the face of this inaction, scientists can have the maximum amount of influence by lending their support to social movements pressing for action, joining as active participants and considering civil disobedience. Scientists seeking to halt continued environmental destruction also need to work through our institutions. Too many scientific organizations, from national academies of science to learned societies and universities, have not taken practical action on climate; for example, many still partner with fossil fuel and other compromised interests. We therefore also outline a vision for how scientists can reform our scientific institutions to become powerful agents for change., Competing Interests: The authors participate in and provide support to groups carrying out civil disobedience to press for a just and livable future., (© 2024 The Authors.)

Octanol/water partition coefficients guide drug design, but algorithms do not always accurately predict these values. For cationic triazine macrocycles that adopt a conserved folded shape in solution, common algorithms fall short. Here, the logD values for 12 macrocycles differing in amino acid choice were predicted and then measured experimentally. On average, AlogP, XlogP, and ChemAxon predictions deviate by 0.9, 2.8, and 3.9 log units, with XlogP overestimating lipophilicity and AlogP and ChemAxon underestimating lipophilicity. Importantly, however, a linear relationship ( R 2 > 0.98) exists between the values predicted by AlogP and the experimentally determined logD values, thus enabling more accurate predictions., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Our current economic and political structures have an increasingly devastating impact on the Earth's climate and ecosystems: we are facing a biospheric emergency, with catastrophic consequences for both humans and the natural world on which we depend. Life scientists - including biologists, medical scientists, psychologists and public health experts - have had a crucial role in documenting the impacts of this emergency, but they have failed to drive governments to take action in order to prevent the situation from getting worse. Here we, as members of the movement Scientist Rebellion, call on life scientists to re-embrace advocacy and activism - which were once hallmarks of academia - in order to highlight the urgency and necessity of systemic change across our societies. We particularly emphasise the need for scientists to engage in nonviolent civil resistance, a form of public engagement which has proven to be highly effective in social struggles throughout history., Competing Interests: FR, EV, GR, TS, AN, LA, MM, SH, FO, CG, JH No competing interests declared, (© 2022, Racimo et al.)

Tryptase is a serine protease that is released from mast cells during allergic responses. Tryptase inhibitors are being explored as treatments for allergic inflammation in the skin and respiratory system, most notably asthma. Here we report direct tryptase inhibition by natural product compounds. Candidate inhibitors were identified by computational screening of a large (98,000 compounds) virtual library of natural product compounds for tryptase enzymatic site binding. Biochemical assays were used to validate the predicted anti-tryptase activity in vitro, revealing a high (four out of six) success rate for predicting binding using the computational docking model. We further assess tryptase inhibition by a biflavonoid scaffold, whose structure-activity relationship is partially defined by assessing the potency of structurally similar analogs.

Intact forests provide diverse and irreplaceable ecosystem services that are critical to human well-being, such as carbon storage to mitigate climate change. However, the ecosystem functions that underpin these services are highly dependent on the woody vegetation-animal interactions occurring within forests. While vertebrate defaunation is of growing policy concern, the effects of vertebrate loss on natural forest regeneration have yet to be quantified globally. Here we conduct a meta-analysis to assess the direction and magnitude of defaunation impacts on forests. We demonstrate that real-world defaunation caused by hunting and habitat fragmentation leads to reduced forest regeneration, although manipulation experiments provide contrasting findings. The extirpation of primates and birds cause the greatest declines in forest regeneration, emphasising their key role in maintaining carbon stores, and the need for national and international climate change and conservation strategies to protect forests from defaunation fronts as well as deforestation fronts.

Background to the Work: For centuries taxonomy has relied on dead animal specimens, a practice that persists today despite the emergence of innovative biodiversity assessment methods. Taxonomists and conservationists are engaged in vigorous discussions over the necessity of killing animals for specimen sampling, but quantitative data on taxonomic trends and specimen sampling over time, which could inform these debates, are lacking., Methods: We interrogated a long-term research database documenting 2,723 land vertebrate and 419 invertebrate taxa from Madagascar, and their associated specimens conserved in the major natural history museums. We further compared specimen collection and species description rates for the birds, mammals and scorpions over the last two centuries, to identify trends and links to taxon descriptions., Results: We located 15,364 specimens documenting endemic mammals and 11,666 specimens documenting endemic birds collected between 1820 and 2010. Most specimens were collected at the time of the Mission Zoologique Franco-Anglo-Américaine (MZFAA) in the 1930s and during the last two decades, with major differences according to the groups considered. The small mammal and bat collections date primarily from recent years, and are paralleled by the description of new species. Lemur specimens were collected during the MZFAA but the descriptions of new taxa are recent, with the type series limited to non-killed specimens. Bird specimens, particularly of non-passerines, are mainly from the time of the MZFAA. The passerines have also been intensely collected during the last two decades; the new material has been used to solve the phylogeny of the groups and only two new endemic taxa of passerine birds have been described over the last two decades., Conclusions: Our data show that specimen collection has been critical for advancing our understanding of the taxonomy of Madagascar's biodiversity at the onset of zoological work in Madagascar, but less so in recent decades. It is crucial to look for alternatives to avoid killing animals in the name of documenting life, and encourage all efforts to share the information attached to historical and recent collections held in natural history museums. In times of conservation crisis and the advancement in digital technologies and open source sharing, it seems obsolete to kill animals in well-known taxonomic groups for the sake of enriching natural history collections around the world.

Two kinds of humidity-induced, bendable smart clothing have been designed to reversibly adapt their thermal insulation functionality. The first design mimics the pores in human skin, in which pre-cut flaps open to produce pores in Nafion sheets when humidity increases, as might occur during human sweating thus permitting air flow and reducing both the humidity level and the apparent temperature. Like the smart human sweating pores, the flaps can close automatically after the perspiration to keep the wearer warm. The second design involves thickness adjustable clothes by inserting the bent polymer sheets between two fabrics. As the humidity increases, the sheets become thinner, thus reducing the gap between the two fabrics to reduce the thermal insulation. The insulation layer can recover its original thickness upon humidity reduction to restore its warmth-preservation function. Such humidity sensitive smart polymer materials can be utilized to adjust personal comfort, and be effective in reducing energy consumption for building heating or cooling with numerous smart design.

Despite an increasing recognition of the ecosystem services provided by mangroves, we know little about their role in maintaining terrestrial biodiversity, including primates. Madagascar's lemurs are a top global conservation priority, with 94 % of species threatened with extinction, but records of their occurrence in mangroves are scarce. I used a mixed-methods approach to collect published and unpublished observations of lemurs in mangroves: I carried out a systematic literature search and supplemented this with a targeted information request to 1243 researchers, conservation and tourism professionals, and others who may have visited mangroves in Madagascar. I found references to, or observations of, at least 23 species in 5 families using mangroves, representing >20% of lemur species and >50% of species whose distributions include mangrove areas. Lemurs used mangroves for foraging, sleeping, and traveling between terrestrial forest patches, and some were observed as much as 3 km from the nearest permanently dry land. However, most records were anecdotal and thus tell us little about lemur ecology in this habitat. Mangroves are more widely used by lemurs than has previously been recognized and merit greater attention from primate researchers and conservationists in Madagascar.

There are insufficient resources available to manage the world's existing protected area portfolio effectively, so the most important sites should be prioritised in investment decision-making. Sophisticated conservation planning and assessment tools developed to identify locations for new protected areas can provide an evidence base for such prioritisations, yet decision-makers in many countries lack the institutional support and necessary capacity to use the associated software. As such, simple heuristic approaches such as species richness or number of threatened species are generally adopted to inform prioritisation decisions. However, their performance has never been tested. Using the reptile fauna of Madagascar's dry forests as a case study, we evaluate the performance of four site prioritisation protocols used to rank the conservation value of 22 established and candidate protected areas. We compare the results to a benchmark produced by the widely-used systematic conservation planning software Zonation. The four indices scored sites on the basis of: i) species richness; ii) an index based on species' Red List status; iii) irreplaceability (a key metric in systematic conservation planning); and, iv) a novel Conservation Value Index (CVI), which incorporates species-level information on endemism, representation in the protected area system, tolerance of habitat degradation and hunting/collection pressure. Rankings produced by the four protocols were positively correlated to the results of Zonation, particularly amongst high-scoring sites, but CVI and Irreplaceability performed better than Species Richness and the Red List Index. Given the technological capacity constraints experienced by decision-makers in the developing world, our findings suggest that heuristic metrics can represent a useful alternative to more sophisticated analyses, especially when they integrate species-specific information related to extinction risk. However, this can require access to, and understanding of, more complex species data.

Objective: Prevalence of GH deficiency (GHD) caused by traumatic brain injury (TBI) is highly variable. Short-term studies show improvement in quality of life (QoL) during GH replacement (GHR), but long-term data are lacking. The aim of this study was to analyse the clinical characteristics of post-traumatic hypopituitarism and the QoL effects of long-term GHR., Design/methods: Pfizer International Metabolic Database patients with GHD caused by TBI and by non-functioning pituitary adenoma (NFPA) were compared regarding: clinical characteristics at baseline and 1-year of GHR, and QoL response up to 8-years of GHR (QoL-AGHDA total scores and dimensions) in relationship with country-specific norms., Results: TBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (P<0.0001), had a higher incidence of isolated GHD, higher GH peak, a more favourable metabolic profile and worse QoL, were shorter by 0.9 cm (1.8 cm when corrected for age and gender; P=0.004) and received higher GH dose (mean difference: 0.04 mg/day P=0.006). In TBI patients, 1-year improvement in QoL was greater than in NFPA (change in QoL-AGHDA score 5.0 vs 3.5, respectively, P=0.04) and was sustained over 8 years. In TBI patients, socialisation normalised after 1 year of GHR, self-confidence and tenseness after 6 years and no normalisation of tiredness and memory was observed., Conclusion: Compared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL., (© 2015 European Society of Endocrinology.)

The interactions between primates and their snake predators are of interest because snakes have influenced the evolution of primate visual systems and predation has driven the evolution of primate behaviour, including group living. However, there are few accounts of primate-snake interactions in the wild. We report an incident from Northwest Madagascar in which a large female Madagascar ground boa (Acrantophis madagascariensis) captured an adult female Coquerel's sifaka (Propithecus coquereli); upon capture, the prey's group members proceeded to bite and scratch the snake until it released the prey, which survived. However, a broken mandible suffered by the boa during the incident led to its death by starvation 2 months later. Our observations demonstrate that, in addition to improved predator detection and deterrence (i.e., mobbing), active defence against some predators may provide an additional benefit to group living in Coquerel's sifaka, and suggest that predation on group-living primates may be more costly for predators than attacking a solitary species of similar body size.

Radial metallic nanopillar/nanowire structures can be created by a controlled radiofrequency (RF) plasma processing technique on the surface of certain alloy wires, including important biomedical alloys such as MP35N (Co-Ni-Cr-Mo alloy), platinum-iridium and stainless steel. In electrode applications such as pacemakers or neural stimulators, the increase in surface area in elongated MP35N nanopillars allows for decreased surface impedance and greater current density. However, the nanopillar height on MP35N alloy tends to be self-limiting at ∼1-3μm. The objective of this study was to further elongate the radial nanopillars so as to reduce electrode impedance for biomedical electrode applications. Intelligent experimental design allowed for efficient investigation of processing parameters, including plasma material, process duration, power, pressure and repetition. It was found that multi-step repeated processing in the parameter-controlled RF environment could increase nanopillar height to ∼10μm, a 400% improvement, while the RF plasma processing with identical total duration but in a single step did not lead to desired nanopillar elongation. Measurement of electrode impedance in phosphate-buffered saline solution showed an associated decrease to one-fifth of the surface impedance of unprocessed wire for signals below 100Hz. For the purposes of this study, MP35N and Pt-Ir wires were characterized and demonstrated augmented surface impedance properties which, in combination with superior cell integration, enhanced biomedical electrode performance., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: Hypopituitarism following subarachnoid haemorrhage (SAH) has been reported to be a frequent occurrence. However, there is considerable heterogeneity between studies with differing patient populations and treatment modalities and most importantly employing differing endocrine protocols and (normal) reference ranges of GH. We aimed to examine prospectively a cohort of SAH survivors for development of hypopituitarism post-SAH using rigorous endocrine testing and compare GH response to glucagon stimulation with a cohort of healthy controls of a similar BMI., Design and Methods: Sixty-four patients were investigated for evidence of hypopituitarism 3 months post-SAH with 50 patients tested again at 12 months. Glucagon stimulation testing (GST), with confirmation of deficiencies by GHRH/arginine testing for GH deficiency (GHD) and short synacthen testing for ACTH deficiency, was used. Basal testing of other hormonal axes was undertaken., Results: Mean age of patients was 53±11.7 years and mean BMI was 27.5±5.7 kg/m(2). After confirmatory testing, the prevalence of hypopituitarism was 12% (GHD 10%, asymptomatic hypocortisolaemia 2%). There was no association between hypopituitarism and post-SAH vasospasm, presence of cerebral infarction, Fisher grade, or clinical grading at presentation. There was a significant correlation between BMI and peak GH to glucagon stimulation in both patients and controls., Conclusions: Identification of 'true' GHD after SAH requires confirmatory testing with an alternative stimulation test and application of BMI-specific cut-offs. Using such stringent criteria, we found a prevalence of hypopituitarism of 12% in our population.

Objective: Non-alcoholic fatty liver disease (NAFLD) is reported to be more common in patients with GH deficiency (GHD) than in the general population. we aimed to determine: i) liver fat in patients with GHD compared with age and body mass index (BMI)-matched controls; and ii) effect of 6 months of GH replacement (GHR) on liver fat., Participants and Methods: The study included 28 GHD patients and 24 controls. 12 patients were studied before and after 6 months of GHR. Anthropometry, liver enzymes and lipid profiles were measured, and body composition and intrahepatocellular lipid (IHCL) were determined by magnetic resonance imaging and spectroscopy., Results: Age and BMI (median (inter-quartile range)) of patients and controls were 52.6 (14) vs 52.6 (12) years (P=0.9) and 27.8 (24.7, 34.7) vs 27.9 (25.1, 32.1) kg/m(2) (P=0.9). IGF1 was lower in the patients (11.5 vs 16.0 nmol/l, P=0.002). There was no difference in liver transaminases, lipids or IHCL between patients and controls (2.8 (1.3, 8.6) vs 5.0 (1.5, 12.7), P=0.72), despite significantly higher visceral fat in GHD patients. Thirty-two percent of patients and 50% of controls had NAFLD (defined as IHCL >5.6%), and the relationship between IHCL and BMI was the same in each group. GHR significantly reduced abdominal subcutaneous and visceral fat in all patients; however, GHR did not reduce liver fat., Conclusions: NAFLD is equally common in patients with GHD and matched controls. GHR is associated with a hierarchical reduction in fat deposition (fat loss: visceral > subcutaneous > liver). Further studies involving GHD patients with NAFLD are required to conclude the role of GHR in treating NAFLD.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Over the last decade subarachnoid haemorrhage (SAH) has increasingly been recognised as a cause of hypopituitarism. We report on the case of a patient with evidence of growth hormone deficiency manifesting after a period of time, with a favourable response to growth hormone replacement. This is followed by a review of the current literature.

Objective: Hurler Syndrome, (MPSIH) is an inborn error of glycosaminoglycan metabolism. Haematopoietic stem cell transplantation (HSCT) has transformed the prognosis for these children. Prior to transplant patients receive chemotherapy or chemo-radiotherapy. Regular screening for the development of endocrine sequelae is therefore essential. We present for the first time data on final adult height and endocrine complications in children with MPSIH post HSCT., Design: Retrospective case note study and a prospective programme of growth and endocrine assessment., Patients: 22 patients were included, mean age at last assessment 12.2 (Range 6.3-21.6) years. Mean age at HSCT was 1.3 (SD 0.6) years. Conditioning included mostly busulphan and cyclophosphamide, with 5 patients receiving total body irradiation prior to second transplant., Results: Height SDS decreased over time. Final height (FH) was attained in seven patients with male FH SDS -4.3 (Range -3.8, -5.1) and female FH SDS -3.4 (Range -2.9, -5.6). Eight of 13 patients tested had evidence of high growth hormone (GH) levels, while one had GH deficiency. Adrenal and thyroid function was normal in all. 11 patients were pubertal or post pubertal. Two females had pubertal failure requiring intervention. All male patients had spontaneous, complete puberty; however three patients have reduced testicular volumes. Five out of 13 patients tested had an abnormal oral glucose tolerance test., Conclusion: Growth is impaired, primarily related to skeletal dysplasia, but also associated with GH resistance. Pubertal development may be compromised and abnormalities of glucose metabolism are common. We recommend a structured endocrine surveillance programme for these patients.

A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Factors that may obscure the diagnosis of varicella zoster virus (VZV) vasculopathy include the absence of rash before TIAs or stroke as well as similar clinical features and imaging, angiographic, and CSF abnormalities to those of other vasculopathies. Diagnosis relies on virologic confirmation that detects VZV DNA, anti-VZV IgG antibody, or both in the CSF., Methods: We reviewed our current 14 cases of patients diagnosed with VZV vasculopathy based on combined clinical, imaging, angiographic, or CSF abnormalities. All CSFs must have been tested for VZV DNA by PCR and for anti-VZV IgG antibody by enzyme immunoassay and found to be positive for either or both. Of the 14 subjects, 8 had a history of recent zoster, whereas 6 had no history of zoster rash before developing vasculopathy., Results: All 14 subjects (100%) had anti-VZV IgG antibody in their CSF, whereas only 4 (28%) had VZV DNA. The detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001)., Conclusions: In varicella zoster virus (VZV) vasculopathy, the diagnostic value of detecting anti-VZV IgG antibody in CSF is greater than that of detecting VZV DNA. Although a positive PCR for VZV DNA in CSF is helpful, a negative PCR does not exclude the diagnosis of VZV vasculopathy. Only when the CSF is negative for both VZV DNA and anti-VZV IgG antibody can the diagnosis of VZV vasculopathy be excluded.

Hypertensive encephalopathy is one of the manifestations of a hypertensive crisis. It is not the absolute value of the blood pressure that causes the encephalopathy, rather the presence of an abrupt rise in pressure. In terms of clinical and radiographic findings, there are many similarities among a group of entities, including hypertensive encephalopathy, eclampsia, and immunosuppressant neurotoxicity. Hyperperfusion syndromes may represent these clinical disease states that may share the same pathophysiology. Magnetic resonance imaging fluid attenuated inversion recovery sequences have recognized the prominent cortical involvement of the disease that had been previously missed on computed tomography. Studies have found cortical involvement in 94% of their patients, particularly in mild cases. Animal models demonstrate endothelial damage and enhanced pinocytosis in the cortex as reasons why edema may begin in that region of the brain. Patients diagnosed with hypertensive encephalopathy should be diagnosed and treated promptly in order to avoid further neurological complications. The mean arterial pressure should be lowered by 20% to 25% within the first hour of patient presentation, followed by further gradual reduction in blood pressure over the following 24 hours. Hypertensive emergency in acute ischemic stroke should be managed with more caution. According to the 2003 American Stroke Association treatment guidelines, for patients with ischemic stroke not eligible for thrombolytic therapy, target blood pressures are a diastolic blood pressure <120 mmHg and systolic blood pressure <220 mmHg. The systolic pressure must be <185 mmHg and diastolic pressure <110 mmHg at all times if eligible for thrombolytic therapy.

Livestock grazing is a major driver of ecosystem change and has been associated with significant declines in various bird species in Britain and worldwide. However, there is little experimental evidence to show how grazing affects bird populations. We manipulated livestock densities in a replicated field experiment and found that mixed sheep and cattle grazing, at low intensity, improved the breeding abundance of a common upland passerine, the meadow pipit Anthus pratensis, after two years. Plots stocked with sheep alone (at high or low density) or not stocked at all held fewer pipit territories. Despite a year-on-year decline in pairs of meadow pipits in intensively grazed plots, we found no effect of sheep number on breeding abundance. Our results support the hypothesis that mixed species of herbivores generate greater heterogeneity in vegetation structure, which modifies prey availability, resulting in a greater abundance of birds. The results of our study should inform the management of grassland areas and enhance the abundance of some bird species, particularly in areas that have seen significant shifts from mixed livestock grazing to grazing dominated by single species of animals.

Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS.

A systematic modification of the C(3) side-chain of the beta-aminoester class of factor Xa inhibitors and a survey of P(4) variations is described. These changes have resulted in the identification of sub-nanomolar inhibitors with improved selectivity versus related proteases. Coagulation parameters (i.e., APTT doubling concentrations) are also improved.

Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials.

The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.

1. The effects of GR203040, a tachykinin neurokinin1 receptor antagonist, on tissue damage induced by X-irradiation (Rad) or cisplatin (Cisp) were investigated in ferrets. 2. GR203040 (0.3 mg/kg SC) reduced the Rad-induced plasma protein extravasation (PPE) in the duodenum and kidney by 25% in each tissue. 3. GR203040 (3 mg/kg SC, 5-min pretreatment and every 8 hr for 48 hr after Cisp) reduced the Cisp-induced PPE in the duodenum, jejunum and lung by 59, 52 and 60%, respectively. 4. Histological examination showed that GR203040 also ameliorated the Rad- and Cisp-induced tissue damage.

The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet. Animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0(-15 min)), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg(-1)), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg(-1)) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n = 8), 0.3 (n = 16) or 1.0 (n = 13) mg kg(-1). In eight additional piglets, GR205171 (1 mg kg(-1)) was administered 15 min before the onset of the delayed phase (T16(-15 min)). A further five piglets received GR205171 (1 mg kg(-1)) every 6 h throughout the experiment. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0(-15 min), and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0(-15 min) with GR205171 1 mg kg(-1), eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg(-1)) at T16(-15 min) exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.

The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitution at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

The introduction of 5-HT3 antagonists, such as ondansetron, as antiemetic agents has transformed the management of patients receiving chemotherapy or radiation therapy. Studies in animal models with NK1 antagonists suggest that these represent a new class of antiemetic agents having a broader spectrum of activity than 5-HT3 antagonists. Compounds of this class may prove to be more effective in man against delayed emesis induced by cisplatin, post-operative nausea and vomiting and motion sickness. Thus, they have the potential to complement 5-HT3 antagonists and so provide a further advance in the management of nausea and vomiting.