Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837.

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure. TM38837 became the first peripherally restricted CB1 antagonist or inverse agonist to enter clinical trials supporting its lack of CNS effects and it is now believed that the non-CNS mediated efficacy is linked to high liver exposure. This opens opportunities to be explored in other indications such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Note that this is a first-time disclosure of the structure of TM38837 and other structures appearing in literature are not connected with this program.

Evaluating the Ecological Benefits of Management Actions to Complement Environmental Flows in River Systems.

Globally, many river systems are under stress due to overconsumption of water. Governments have responded with programmes to deliver environmental water to improve environmental outcomes. Although such programmes are essential, they may not be sufficient to achieve all desired environmental outcomes. The benefits of environmental water allocation may be improved using 'complementary measures', which are non-flow-based actions, such as infrastructure works, vegetation management and pest control. The value of complementary measures is recognised globally, but their ecological benefits are rarely well understood, either because there is limited experience with their application, or the importance of context- and location-specific factors make it difficult to generalise benefits. In this study, we developed an approach to evaluate complementary measures at different levels of detail as a mechanism to aid decision-making. For systems that require a rapid, high-level evaluation, we propose a score-based multi-criteria benefit assessment module. If more ecological detail is necessary, we outline a method based on conceptual models, expert elicitation and probability assessment. These results are used to populate a cumulative benefit assessment tool. The tool evaluates the benefits of proposed measures in the wider context by including variables such as flow, dependence on ongoing maintenance and additional ecological values. We illustrate our approach through application to the Murray-Darling Basin, Australia. As many water recovery programmes mature into their evaluation phases, there is an increasing need to evaluate the ecological benefits of including complementary measures in the toolkit available to policy makers.

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake.

The cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. The CB1R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitizing effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non-alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer.

Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists.

A series of fused bicyclic and urea derivatives of spirocyclic compounds were designed, synthesised and evaluated in vitro as potent CCR1 antagonists. In particular, 4 (7nM), 44 (1.3nM), 48 (0.89nM) and 50 (0.63nM) were the most potent hCCR1 antagonists in this series of compounds. Moreover, some of these substances demonstrated good rodent cross-over, especially 46 which exhibited very high rat CCR1 binding affinity with an IC50 value of 16nM.

Efficacy in diet-induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837.

BACKGROUND AND PURPOSE: The cannabinoid CB1 receptor has a well-established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet-induced obese (DIO) mice for 5 weeks at doses for which CNS-mediated effects were minimal. EXPERIMENTAL APPROACH: Compounds were tested in dose-response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study. KEY RESULTS: TM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake. CONCLUSION AND IMPLICATIONS: Weight loss and metabolic benefits of TM38837 are likely not CNS-mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co-morbidities.

Design, synthesis and structure activity relationships of spirocyclic compounds as potent CCR1 antagonists.

A series of CCR1 antagonists based upon spirocyclic compounds 1b and 2b were synthesised in which substituted aniline moiety was replaced with substituted benzamides. In vitro data revealed that CCR1 potency could be retained in such compounds.

Correction: Evaluation of a Mobile App to Enhance Relational Awareness and Change During Cognitive Analytic Therapy: Mixed Methods Case Series.

[This corrects the article DOI: 10.2196/19888.].

Blending Cognitive Analytic Therapy With a Digital Support Tool: Mixed Methods Study Involving a User-Centered Design of a Prototype App.

BACKGROUND: Patients can struggle to make good use of psychotherapy owing to deficits in awareness, and digital technologies that support awareness are at a premium. Currently, when patients participate in cognitive analytic therapy (CAT), the technology supporting relational awareness work involves completion of paper-based worksheets as between-session tasks. OBJECTIVE: We aimed to design, with therapists and patients, a prototype digital mobile app. This was to help patients better engage in the "recognition" phase of the CAT treatment model by providing an unobtrusive means for practicing relational awareness with dynamic feedback on progress. METHODS: A national online survey was conducted with CAT therapists (n=50) to determine readiness for adoption of a mobile app in clinical practice and to identify core content, functionality, and potential barriers to adoption. A prototype mobile app based on data and existing paper-based worksheets was built. Initial face-to-face user testing of the prototype system was completed with three therapists and three CAT expatients. RESULTS: Among the therapists surveyed, 72% (36/50) reported not currently using any digital tools during CAT. However, the potential value of a mobile app to support patient awareness was widely endorsed. Areas of therapist concern were data security, data governance, and equality of access. These concerns were mirrored during subsequent user testing by CAT therapists. Expatients generated additional user specifications on the design, functionality, and usability of the app. Results from both streams were integrated to produce five key changes for the reiteration of the app. CONCLUSIONS: The user-centered design process has enabled a prototype CAT-App to be developed to enhance the relational awareness work of CAT. This means that patients can now practice relational awareness in a much more unobtrusive manner and with ongoing dynamic feedback of progress. Testing the acceptability and feasibility of this technological innovation in clinical practice is the next stage in the research process, which has since been conducted and has been submitted. The important challenges of data protection and governance must be navigated in order to ensure implementation and adoption if the CAT-App is found to be acceptable and clinically effective.

Exploring SAR features in diverse library of 4-cyanomethyl-pyrazole-3-carboxamides suitable for further elaborations as CB1 antagonists.

A chemically diverse library of secondary and tertiary 4-cyanomethyl-1,5-diphenyl-1H-pyrazole-3-carboxamides was synthesized to enable mapping of the SAR, in the eastern amide region, with regard to CB1 antagonist activity, This study was initiated as a prelude to the design and synthesis of possible CB1 antagonists that do not readily pass the blood-brain-barrier. In general a range of modifications were found to be tolerated in this part of the molecule, although polar and especially charged groups did to a degree reduce the CB1 antagonistic activity. Several compounds with single-digit or even sub-nanomolar potency, suitable for further elaboration of the nitrile moiety, were identified.

Conversion of 4-cyanomethyl-pyrazole-3-carboxamides into CB1 antagonists with lowered propensity to pass the blood-brain-barrier.

A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.

Ischemic conditioning shows a time-dependant influence on the fate of the gastric conduit after minimally invasive esophagectomy.

BACKGROUND: Minimally invasive esophagectomy (MIO) is now established as a valid alternative to open surgery for the management of esophagogastric cancers. However, a high incidence of ischemia-related gastric conduit failure (ICF) is observed, which is detrimental to any potential benefits of this approach. METHODS: Since April 2004, MIO has been the procedure of choice for esophagogastric resection in the authors' unit. Data relating to the surgical technique were collected, with a focus on ischemic conditioning by laparoscopic ligation of the left gastric artery (LIC) 2 weeks or 5 days before resection. RESULTS: A total of 97 patients underwent a planned MIO. Four in-patient deaths (4.1%) occurred, none of which were conduit related, and overall, 20 patients experienced ICF (20.6%). In four patients, ICF was recognized and dealt with at the initial surgery. The remaining 16 patients experienced this complication postoperatively, with 9 (9.3%) of them requiring further surgery. Of the 97 patients, 55 did not undergo ischemic conditioning, and conduit failure was observed in 11 (20%). Thirty-five patients had LIC at 2 weeks, and 2 (5.7%) experienced ICF. All seven patients (100%) who had LIC at 5 days experienced ICF. Timing of ischemic conditioning (p < 0.0001) had a definite impact on the conduit failure rate, and the benefit of ischemic conditioning at 2 weeks compared with no conditioning neared significance (p = 0.07). CONCLUSIONS: Ischemic failure of the gastric conduit significantly impairs recovery after MIO. Ischemic conditioning 2 weeks before surgery may reduce this complication and allow the benefits of this approach to be realized.

Fish migration, dams, and loss of ecosystem services in the Mekong basin.

The past decade has seen increased international recognition of the importance of the services provided by natural ecosystems. It is unclear however whether such international awareness will lead to improved environmental management in many regions. We explore this issue by examining the specific case of fish migration and dams on the Mekong river. We determine that dams on the Mekong mainstem and major tributaries will have a major impact on the basin's fisheries and the people who depend upon them for food and income. We find no evidence that current moves towards dam construction will stop, and consider two scenarios for the future of the fisheries and other ecosystems of the basin. We conclude that major investment is required in innovative technology to reduce the loss of ecosystem services, and alternative livelihood strategies to cope with the losses that do occur.

Evaluation of a Mobile App to Enhance Relational Awareness and Change During Cognitive Analytic Therapy: Mixed Methods Case Series.

BACKGROUND: There has been a lack of technological innovation regarding improving the delivery of integrative psychotherapies. This project sought to evaluate an app designed to replace previous paper-based methods supporting relational awareness and change during cognitive analytic therapy (CAT). OBJECTIVE: We aimed to assess patients' and therapists' experience of using the technology (ie, the "CAT-App") and to evaluate the relationship between app usage and clinical outcome. METHODS: The design was a mixed methods case series. Patients completed the Clinical Outcomes in Routine Evaluation-Outcome Measure pre- and post-CAT. Mood data plus the frequency and effectiveness of relational awareness and change were collected via the app. Therapists and patients were interviewed about their experiences using the app. RESULTS: Ten patients (treated by 3 therapists) were enrolled; seven completed treatment and 4 had a reliable improvement in their mental health. App usage and mood change did not differ according to clinical outcome, but there was a statistically significant difference in app usage between completers and dropouts. The qualitative themes described by the therapists were (1) the challenge of incorporating the technology into their clinical practice and (2) the barriers and benefits of the technology. Clients' themes were (1) data protection, (2) motivation and engagement, and (3) restrictions versus flexibility. CONCLUSIONS: The CAT-App is capable of supporting relational awareness and change and is an upgrade on older, paper-based formats. Further clinical evaluation is required.

Identification and Optimization of Pyrrolidine Derivatives as Highly Potent Ghrelin Receptor Full Agonists.

Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects including the stimulation of growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and therefore has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of an indane based series of ghrelin receptor full agonists which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein we report on the identification of a series of pyrrolidine or piperidine based full agonists and attempted optimization to give compounds with profiles suitable for progression as clinical candidates.

Classification and early recognition of gastric conduit failure after minimally invasive esophagectomy.

BACKGROUND: Esophagectomy is a high-risk procedure, with significant morbidity resulting from gastric conduit failure. Early recognition and management of these complications is essential. This study aimed to investigate the clinical value of routine investigations after minimally invasive esophagectomy (MIO) and to propose a classification system for gastric conduit failure. METHODS: For esophagogastric resection, MIO is the procedure of choice in the authors' unit. Standard postoperative care similar to that for open esophagectomy is undertaken on a specialist ward. Routine investigations include daily assessment of C-reactive protein (CRP), white cell count (WCC), and a contrast swallow on postoperative day (POD) 5. The authors performed a retrospective analysis to assess the utility of these tests. RESULTS: Of a prospective cohort of 50 patients from April 2004 to July 2006, 26 (52%) had an uneventful recovery (U), 24 (48%) experienced complications (C) of varying nature and severity, and 1 died (2%). All the patients demonstrated a transient abnormal rise in CRP until POD 3. In group U, the levels then fell, but in group C, they remained elevated (POD 5: U = 96, C = 180; p < 0.01). This discrepancy trend was further exaggerated in the nine patients with gastric conduit failure (POD 5: GC = 254; p < 0.01), whereas contrast swallow failed to identify this complication in six patients. Simple anastomotic leaks (type 1, n = 4) were managed conservatively. Patients with conduit tip necrosis (type 2, n = 3) and complete conduit ischemia (type 2, n = 2) were managed by repeat thoracotomy and either refashioning of the conduit or take-down and cervical esophagostomy. None of the patients with conduit failure died. CONCLUSION: Postoperative CRP monitoring is a highly effective, simple method for the early recognition of gastric conduit failure. This new system of classification provides a successful guide to conservative management or revisional surgery.

Comparative experience of open and minimally invasive esophagogastric resection.

BACKGROUND: A minimally invasive approach to esophagogastric cancer resection offers an attractive alternative to traditional open surgery; however, concerns regarding feasibility, safety, cost, and outcomes have restricted widespread acceptance of these procedures. This study outlines our comparative experiences of both open and minimally invasive esophagectomy over a 4-year period. METHODS: Surgical outcomes were analyzed and compared between 30 consecutive patients who underwent open (Ivor Lewis) transthoracic esophagectomy (TTO) between January 2002 and December 2003 and 50 consecutive patients who underwent minimally invasive esophagectomy (MIO) from January 2004 to July 2006. RESULTS: Inpatient mortality and overall surgical morbidity were identical for each cohort (TTO versus MIO: mortality 3% versus 2%; morbidity 50% versus 48%). Pulmonary-related complications were higher in the open series (23% versus 8%; p = 0.05). The incidence of gastric-conduit-related complications was similar between the two cohorts (13% versus 18%; p = 0.52). Survival at 1 and 2 years was 86% and 58% in the TTO group and 94% and 74% in the MIO group. No significant difference in calculated cost was observed (7,017 pounds sterling versus 7,885 pounds sterling). CONCLUSIONS: Transition from open to minimally invasive techniques of esophagogastric resection for cancer is possible without compromising patient safety or incurring excessive financial expenses, and the minimally invasive procedure results in similar or potentially better outcomes.

On Singleton Arc Consistency for CSPs Defined by Monotone Patterns.

Singleton arc consistency is an important type of local consistency which has been recently shown to solve all constraint satisfaction problems (CSPs) over constraint languages of bounded width. We aim to characterise all classes of CSPs defined by a forbidden pattern that are solved by singleton arc consistency and closed under removing constraints. We identify five new patterns whose absence ensures solvability by singleton arc consistency, four of which are provably maximal and three of which generalise 2-SAT. Combined with simple counter-examples for other patterns, we make significant progress towards a complete classification.

A rich discrete labeling scheme for line drawings of curved objects.

We present a discrete labeling scheme for line drawings of curved objects which can be seen as an information-rich extension of the classic line-labeling scheme in which lines are classified as convex, concave, occluding or extremal. New labels are introduced to distinguish between curved and planar surface-patches, to identify orthogonal edges and to indicate gradient directions of planar surface-patches.

The significance of the Van Nuys prognostic index in the management of ductal carcinoma in situ.

BACKGROUND: Debate regarding the benefit of radiotherapy after local excision of ductal carcinoma in situ (DCIS) continues. The Van Nuys Prognostic Index (VNPI) is thought to be a useful aid in deciding which patients are at increased risk of local recurrence and who may benefit from adjuvant radiotherapy (RT). Recently published interim data from the Sloane project has showed that the VNPI score did significantly affect the chances of getting planned radiotherapy in the UK, suggesting that British clinicians may already be using this scoring system to assist in decision making. This paper independently assesses the prognostic validity of the VNPI in a British population. PATIENTS AND METHODS: A retrospective review was conducted of all patients (n = 215) who underwent breast conserving surgery for DCIS at a single institution between 1997-2006. No patients included in the study received additional radiotherapy or hormonal treatment. Kaplan Meier survival curves were calculated, to determine disease free survival, for the total sample and a series of univariate analyses were performed to examine the value of various prognostic factors including the VNPI. The log-rank test was used to determine statistical significance of differential survival rates. Multivariate Cox regression analysis was performed to analyze the significance of the individual components of the VNPI. All analyses were conducted using SPSS software, version 14.5. RESULTS: The mean follow-up period was 53 months (range 12-97, SD19.9). Ninety five tumours were high grade (44%) and 84 tumours exhibited comedo necrosis (39%). The closest mean initial excision margin was 2.4 mm (range 0-22 mm, standard deviation 2.8) and a total of 72 tumours (33%) underwent further re-excision. The observed and the actuarial 8 year disease-free survival rates in this study were 91% and 83% respectively. The VNPI score and the presence of comedo necrosis were the only statistically significant prognostic indicators (P < 0.05). CONCLUSION: This follow-up study of 215 patients with DCIS treated with local excision and observation alone is one of the largest series in which rates of recurrence are unaffected by radiation therapy, hormone manipulation or chemotherapy. It has afforded us the opportunity to assess the prognostic impact of patient and tumour characteristics free of any potentially confounding treatment related influences. The results suggest that the VNPI can be used to identify a subset of patients who are at risk of local recurrence and who may potentially benefit from RT.

Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties.

We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.