Associations among psychosis, mood, anxiety, and posttraumatic stress symptoms: A network analysis.

The associations among psychotic experiences (i.e., hallucinations and delusions), trauma exposure, and posttraumatic stress symptoms are complex and multidirectional. Using network analysis to understand how psychotic experiences and symptoms of posttraumatic stress disorder (PTSD) relate to one another may identify new interventional targets to treat comorbidity and its underlying pathological processes. This study aimed to use network analysis to examine the associations among psychotic experiences; negative symptoms of psychosis; and symptoms of PTSD, anxiety, and depression. In this population-based cohort study, 4,472 participants (36.7% male) were assessed for psychotic experiences, negative symptoms of psychosis, PTSD, anxiety, and depression at age 23 (M = 23.86 years, SD = 0.520) or 24 years (M = 24.03, SD = 0.848). Associations among symptoms were assessed via network analysis. Exploratory graph analysis identified three clusters of densely connected symptoms within the overall network: psychotic experiences; PTSD symptoms; and depressive and anxiety symptoms and negative symptoms of psychosis. Psychotic experiences had the strongest associations with other symptoms in the network, and symptoms of anxiety played a key role in bridging psychotic experiences, symptoms of PTSD, and depressive symptoms. Consistent with the stress reactivity and affective models for psychotic experiences, the results suggest that symptoms of anxiety and emotional distress (e.g., hyperarousal, panic) may have a key role in the development and maintenance of psychotic experiences and symptoms of PTSD. Targeting these symptoms may ameliorate symptom burden transdiagnostically.

Outside/inside: social determinants of mental health.

Individuals' mental health and wellbeing are dependent on many social factors including housing, employment, education and adequate nutrition among others. These factors can influence at personal, family and community levels. The interlinked and cumulative impact of these social determinants needs to be ascertained to aid appropriate patient management, as well as to establish prevention and health education programmes. Some of these determinants also have to be recognised at policy level. It is crucial for clinicians to understand the role social determinants play in the genesis and perpetuation of mental and physical illnesses, so that appropriate social interventions can be set in place. Clinicians have a role to play in their clinical practice, as well as advocates for their patients and policy leaders. In order to ensure that health is joined up with other sectors, such as education, employment, judiciary and housing, policy-makers must avoid silos. Every policy must have an impact assessment on physical health and mental health. Policy-makers need to understand scientific evidence and must work with researchers, clinicians, communities and patients to help develop and implement rights-based policies.

Incidence and Predictors of Gram-Negative Bacilli in Hospitalized People Who Inject Drugs with Injection Drug Use-Attributable Infections.

The objective of this study was to quantify incidence and determine predictors of Gram-negative bacilli (GNB) in people who inject drugs (PWID) with injection-drug use (IDU)-related infections. The investigation was a retrospective cohort of hospitalized PWID from January 2017 to December 2019. Inclusion criteria were age of ≥18 years, active IDU, treated IDU-attributable infection, and organism growth from microbiology cultures. Infection types included infective endocarditis (IE), acute bacterial skin/skin structure infection (ABSSSI), osteoarticular infection (OAI), and other bloodstream infections (BSI). Primary outcome was GNB identification from microbiologic culture; descriptive statistics were used to describe the cohort. Multivariable regression was used to identify variables associated with GNB infection. A total of 230 PWID were included, 65 (28%) with GNB infections and 165 (72%) with Gram-positive infections. The median (interquartile range [IQR]) population age was 38 (31 to 45) years. Most patients were women (56%); 37% had no insurance. Infection types were as follows: IE, 41%; ABSSSI, 37%; OAI, 20%; and other BSI, 2%. A total of 278 organisms were isolated from 230 patients. The most common organisms were methicillin-resistant Staphylococcus aureus (43%), Streptococcus spp. (19%), methicillin-susceptible S. aureus (17%), and Serratia marcescens (8%); 10% of infections were mixed GNB and Gram-positive infections. A total of 80% of patients received empirical Pseudomonas aeruginosa coverage; only 7% had P. aeruginosa infections. In multivariable regression, age of >50 years (adjusted odds ratio [adjOR], 2.9; 95% confidence interval [CI], 1.2 to 7.2), prior hospitalization within 90 days (adjOR, 2.2; 95% CI, 1.2 to 4.3), and OAI (adjOR, 3.2; 95% CI, 1.5 to 6.6) were associated with GNB infection. GNB in PWID with IDU-attributable infections were more frequently observed in recently hospitalized, older patients with OAI. The majority of patients received empirical antipseudomonal antibiotic coverage, but P. aeruginosa was infrequent. PWID are a potential population to target improved empirical antibiotic use.

Consolidation/reconsolidation therapies for the prevention and treatment of PTSD and re-experiencing: a systematic review and meta-analysis.

Translational research highlights the potential of novel 'memory consolidation/reconsolidation therapies' to treat re-experiencing symptoms and post-traumatic stress disorder (PTSD). This systematic review and meta-analysis assessed the efficacy of so-called memory consolidation/reconsolidation therapies in randomised controlled trials (RCTs) for prevention and treatment of PTSD and symptoms of re-experiencing in children and adults (PROSPERO: CRD42020171167). RCTs were identified and rated for risk of bias. Available data was pooled to calculate risk ratios (RR) for PTSD prevalence and standardised mean differences (SMD) for PTSD/re-experiencing severity. Twenty-five RCTs met inclusion criteria (16 prevention and nine treatment trials). The methodology of most studies had a significant risk of bias. We found a large effect of reconsolidation interventions in the treatment of PTSD (11 studies, n = 372, SMD: -1.42 (-2.25 to -0.58), and a smaller positive effect of consolidation interventions in the prevention of PTSD (12 studies, n = 2821, RR: 0.67 (0.50 to 0.90). Only three protocols (hydrocortisone for PTSD prevention, Reconsolidation of Traumatic Memories (RTM) for treatment of PTSD symptoms and cognitive task memory interference procedure with memory reactivation (MR) for intrusive memories) were superior to control. There is some emerging evidence of consolidation and reconsolidation therapies in the prevention and treatment of PTSD and intrusive memories specifically. Translational research should strictly adhere to protocols/procedures describing precise reconsolidation conditions (e.g. MR) to both increase the likelihood of positive findings and more confidently interpret negative findings of putative reconsolidation agents.

The reconsolidation using rewind study (RETURN): trial protocol.

Background: An increasing body of research highlights reconsolidation-based therapies as emerging treatments for post-traumatic stress disorder (PTSD). The Rewind Technique is a non-pharmacological reconsolidation-based therapy with promising early results, which now requires evaluation through an RCT. Objectives: This is a preliminary efficacy RCT to determine if the Rewind Technique is likely to be a good candidate to test against usual care in a future pragmatic efficacy RCT. Methods: 40 participants will be randomised to receive either the Rewind Technique immediately, or after an 8 week wait. The primary outcome will be PTSD symptom severity as measured by the Clinician-Administered PTSD Scale for DSM5 (CAPS-5) at 8 and 16 weeks post-randomisation. Secondary outcome measures include the PTSD Checklist (PCL-5), International Trauma Questionnaire (ITQ), Patient Health Questionnaire (PHQ-9), the General Anxiety Disorder-7 (GAD-7), Insomnia Severity Index, the Euro-Qol-5D (EQ5D-5 L), the prominence of re-experiencing specific symptoms (CAPS-5) and an intervention acceptability questionnaire to measure tolerability of the intervention. Conclusions: This study will be the first RCT to assess the Rewind Technique. Using a cross-over methodology we hope to rigorously assess the efficacy and tolerability of Rewind using pragmatic inclusion criteria. Potential challenges include participant recruitment and retention. Trial registration: ISRCTN91345822.

Antecedentes: Un creciente cuerpo de investigación destaca las terapias basadas en la reconsolidación como tratamientos emergentes para el trastorno de estrés postraumático (TEPT). La Técnica de Rebobinado es una terapia no farmacológica basada en la reconsolidación con resultados tempranos prometedores, que ahora requiere evaluación a través de un ECA.Objetivos: Este es un ECA preliminar de eficacia para determinar si es probable que la técnica de rebobinado sea una candidata adecuada para probar en comparación con el cuidado habitual en un futuro ECA de eficacia pragmática.Método: 40 participantes serán asignados al azar para recibir la técnica de rebobinado inmediatamente o después de una espera de 8 semanas. El resultado primario será la gravedad de los síntomas del TEPT según lo medido por la Escala de TEPT administrada por el médico para DSM5 (CAPS-5 en su sigla en inglés) a las 8 y 16 semanas posteriores a la aleatorización. Las medidas de resultados secundarios incluyen la Lista de Verificación de TEPT (PCL-5 en su sigla en inglés), el Cuestionario Internacional de Trauma (ITQ en su sigla en inglés), el Cuestionario de Salud del Paciente (PHQ-9 en su sigla en inglés), el Trastorno de Ansiedad General-7 (GAD-7 en su sigla en inglés), el Índice de Gravedad del Insomnio, el Euro-Qol- 5D (EQ5D-5L en su sigla en inglés), la prominencia de re-experimentar los síntomas específicos (CAPS-5) y un cuestionario de aceptabilidad de la intervención para medir la tolerabilidad de la intervención.Conclusiones: Este estudio será el primer ECA para evaluar la Técnica de Rebobinado. Utilizando una metodología cruzada, esperamos evaluar rigurosamente la eficacia y tolerabilidad del Rebobinado utilizando criterios de inclusión pragmáticos. Los desafíos potenciales incluyen el reclutamiento y la retención de los participantes.Registro de prueba: ISRCTN91345822.

High prevalence of somatisation in ICD-11 complex PTSD: A cross sectional cohort study.

BACKGROUND: While research demonstrates that somatisation is highly correlated with post-traumatic stress disorder (PTSD), the relationship between International Classification of Diseases 11th edition (ICD-11) PTSD, complex PTSD (CPTSD) and somatisation has not previously been determined. OBJECTIVE: To determine the relationship between frequency and severity of somatisation and ICD-11 PTSD/CPTSD. METHOD: This cross-sectional study included 222 individuals recruited to the National Centre for Mental Health (NCMH) PTSD cohort. We assessed rates of Patient Health Questionnaire 15 (PHQ-15) somatisation stratified by ICD-11 PTSD/CPTSD status. Path analysis was used to explore the relationship between PTSD/CPTSD and somatisation, including number of traumatic events, age, and gender as controls. RESULTS: 70% (58/83) of individuals with CPTSD had high PHQ-15 somatisation symptom severity compared with 48% (12/25) of those with PTSD (chi-square: 95.1, p value <0.001). Path analysis demonstrated that core PTSD symptoms and not disturbances in self organisation (DSO) symptoms were associated with somatisation (unstandardised coefficients: 0.616 (p-value 0.017) and - 0.012 (p-value 0.962) respectively. CONCLUSIONS: Individuals with CPTSD have higher somatisation than those with PTSD. The core features of PTSD, not the DSO, characteristic of CPTSD, were associated with somatisation.

Managing COVID-19 related distress in primary care: principles of assessment and management.

COVID-19 will cause normal feelings of worry and stress and many of those who experience higher levels of distress will experience resolution of their symptoms as society returns to pre-COVID-19 functioning. Only a minority are likely to develop a psychiatric disorder. Certain individuals may be vulnerable to experiencing persisting symptoms, such as those with pre-existing comorbidity. Management approaches could centre around using collaborative approaches to provide and build on already existing socioeconomic support structures, the avoidance of over-medicalisation, watchful waiting and finally treating those who do meet the criteria for psychiatric diagnosis. Primary care clinicians are likely be the first healthcare point of contact for most COVID-19 related distress and it is important that they are able to provide evidence based and evidence informed responses, which includes social, psychological and pharmacological approaches. This expert opinion paper serves to summarise some approaches, based primarily on indirect extrapolation of evidence concerning the general management of psychological distress, in the absence of COVID-19 specific evidence, to assist primary care clinicians in their assessment and management of COVID-19 related distress.

Preventing the onset of post traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a common mental health condition that requires exposure to a traumatic event. This provides unique opportunities for prevention that are not available for other disorders. The aim of this review was to undertake a systematic review and evaluation of randomized controlled trials (RCTs) of interventions designed to prevent PTSD in adults. Searches involving Cochrane, Embase, Medline, PsycINFO, PILOTS and Pubmed databases were undertaken to identify RCTs of pre-incident preparedness and post-incident interventions until May 2019. Six pre-incident and 69 post-incident trials were identified that could be included in meta-analyses. The overall quality of the evidence was low. There was emerging evidence that some interventions may be helpful but an absence of evidence for any intervention that can be strongly recommended for universal, selected or indicated prevention before or within the first three months of a traumatic event. The strongest results were found for cognitive-behavioural therapy with a trauma focus (CBT-T) in individuals with a diagnosis of acute stress disorder which supports calls to detect and treat individuals with significant symptoms rather than providing blanket preventative interventions. Further research is required to optimally configure existing interventions with some evidence of effect and to develop novel interventions to address this major public health issue.

Comparison of linezolid step-down therapy to standard parenteral therapy in methicillin-resistant Staphylococcus aureus bloodstream infections.

Data supporting oral step-down therapy in methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are sparse; linezolid offers potential in this setting. This study aimed to determine the effectiveness and safety of oral step-down linezolid compared with standard parenteral therapy (SPT) in MRSA-BSI. This was a retrospective cohort performed in adults receiving step-down/outpatient linezolid or SPT (vancomycin, daptomycin) for MRSA-BSI from 2011-2019. Primary outcome was 90-day infection-related re-admission (IRR) from clinical worsening/relapse or infection recurrence. 215 patients included (54 linezolid, 161 SPT). Infection sources were skin (34%), bone/joint (15%), endocarditis (13%), other (32%), multiple (6%). Patients receiving SPT more commonly had complicated bacteraemia (72% vs. 41%; P < 0.0001) and metastatic foci (45% vs. 20%; P = 0.001). 90-day IRR occurred in 17% and 26% of linezolid and SPT groups, respectively (P = 0.159). When accounting for disease severity, linezolid use was not independently associated with 90-day IRR (adjOR, 1.0, 95% CI 0.24-4.3; P = 0.986). There were no differences in all-cause 90-day mortality (4% vs. 6%, P = 0.487) or overall incidence of drug-related adverse events (AEs) (17% vs. 16%; P = 0.843) between the groups. More patients in the SPT group developed an AE requiring re-hospitalisation (12% vs. 2%; P = 0.024), most commonly line-related complications. Oral step-down linezolid demonstrated similar clinical and safety outcomes compared with SPT for MRSA-BSI, except linezolid was associated with fewer AEs requiring re-hospitalisation. Additional research is needed exploring step-down linezolid in MRSA-BSI, particularly in patients requiring shorter durations of outpatient therapy.

Complex PTSD symptoms mediate the association between childhood trauma and physical health problems.

The ICD-11 reconceptualized Posttraumatic Stress Disorder (PTSD) as a narrowly defined fear-based disorder, and introduced Complex PTSD (CPTSD) as a new diagnosis comprised of PTSD symptoms and symptoms of 'Disturbances in Self-Organization' (DSO) that are more reflective of general dysphoria. Previous research suggests that PTSD symptoms mediate the association between childhood trauma and physical health problems, including cardiovascular disease. No study has yet assessed how posttraumatic stress symptoms, as outlined in the ICD-11, influence the association between childhood trauma and somatic problems in adulthood. OBJECTIVE: This cross-sectional descriptive study examined whether PTSD and DSO symptoms mediated the associations between childhood physical and sexual abuse and childhood emotional abuse and neglect and somatic problems and cardiovascular diseases (CVD) load in adulthood. METHODS: General adult population samples from Ireland (N = 1020) and the United Kingdom (N = 1051) completed self-report questionnaires online. RESULTS: Structural equation modelling results indicated that PTSD and DSO symptoms fully mediated the association between both forms of childhood trauma and somatic problems, and that PTSD symptoms but not DSO symptoms fully mediated the association between childhood trauma and CVD load. CONCLUSION: Psychological interventions that effectively treat CPTSD symptoms may have the added benefit of reducing risk of physical health problems.

Disturbed Sleep Connects Symptoms of Posttraumatic Stress Disorder and Somatization: A Network Analysis Approach.

Posttraumatic stress disorder (PTSD) and physical health problems, particularly somatic symptom disorder, are highly comorbid. Studies have only examined this co-occurrence at the disorder level rather than assessing the associations between specific symptoms. Using network analysis to identify symptoms that act as bridges between these disorders may allow for the development of interventions to specifically target this comorbidity. We examined the association between somatization and PTSD symptoms via network analysis. This included 349 trauma-exposed individuals recruited through the National Centre for Mental Health PTSD cohort who completed the Clinician-Administered PTSD Scale for DSM-5 and the Patient Health Questionnaire-15. A total of 215 (61.6%) individuals met the DSM-5 diagnostic criteria for PTSD. An exploratory graph analysis identified four clusters of densely connected symptoms within the overall network: PTSD, chronic pain, gastrointestinal issues, and more general somatic complaints. Sleep difficulties played a key role in bridging PTSD and somatic symptoms. Our network analysis demonstrates the distinct nature of PTSD and somatization symptoms, with this association connected by disturbed sleep.

Comparison of dalbavancin to standard-of-care for outpatient treatment of invasive Gram-positive infections.

OBJECTIVE: To assess the efficacy and safety of dalbavancin compared to standard-of-care (SOC) or vancomycin and daptomycin in invasive infections due to suspected or confirmed Gram-positive organisms. METHODS: Retrospective cohort of adults who received dalbavancin or SOC on discharge or as an outpatient from 12/2016 to 11/2019. Indications were osteoarticular infection (OAI), infective endocarditis (IE), or other bloodstream infection (BSI). Primary endpoint was 90-day infection-related readmission (IRR); secondary endpoints included time-to-IRR, frequency of adverse drug events (ADEs), and all-cause readmission and mortality. RESULTS: 215 patients were included: 70 (33%) receiving dalbavancin, and 145 (67%) receiving SOC. Indications were OAI (47%), IE (27%), and other BSI (26%). OAI was more common in patients on dalbavancin compared with those receiving SOC (70% vs. 37%, P<0.001). Dalbavancin patients had shorter median (interquartile range [IQR]) length of stay (LOS) prior to drug initiation compared with those receiving SOC (10 [7-17] vs. 13 [9-19], P=0.021). IRR incidence was 17% for dalbavancin patients and 28% for SOC patients. Dalbavancin use was independently associated with lower IRR (adjusted odds ratio [adjOR], 0.10; 95% confidence interval [CI], 0.04-0.31). There was longer median (IQR) time-to-IRR in the dalbavancin group (43 [30-87] vs. 23 [11-63] days, P=0.039), but no differences in all-cause readmission or mortality. Treatment-related ADE incidence was 3% and 14% for the dalbavancin and SOC groups, respectively (P=0.013). Infusion reactions (1/2) and catheter-related complications (1/2) were the most common dalbavancin ADEs; catheter-related complications (14/21), nephrotoxicity (3/21), rhabdomyolysis (2/21), and rash (2/21) were the most common SOC ADEs. CONCLUSIONS: Dalbavancin use was associated with lower 90-day IRR, a shorter hospital LOS prior to therapy, and longer time-to-IRR compared with SOC.

Pharmacological prevention and early treatment of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis.

Post-traumatic stress disorder (PTSD) is a common mental disorder associated with significant distress and reduced functioning. Its occurrence after a severe traumatic event and association with characteristic neurobiological changes make PTSD a good candidate for pharmacological prevention and early treatment. The primary aim for this systematic review and meta-analysis was to assess whether pharmacological interventions when compared to placebo, or other pharmacological/psychosocial interventions resulted in a clinically significant reduction or prevention of symptoms, improved functioning or quality of life, presence of disorder, or adverse effects. A systematic search was undertaken to identify RCTs, which used early pharmacotherapy (within three months of a traumatic event) to prevent and treat PTSD and acute stress disorder (ASD) in children and adults. Using Cochrane Collaboration methodology, RCTs were identified and rated for risk of bias. Available data was pooled to calculate risk ratios (RR) for PTSD prevalence and standardised mean differences (SMD) for PTSD severity. 19 RCTs met the inclusion criteria; 16 studies with adult participants and three with children. The methodological quality of most trials was low. Only hydrocortisone in adults was found to be superior to placebo (3 studies, n = 88, RR: 0.21 (CI 0.05 to 0.89)) although this was in populations with severe physical illness, raising concerns about generalisability. No significant effects were found for the other pharmacotherapies investigated (propranolol, oxytocin, gabapentin, fish oil (1470 mg DHA/147 mg EPA), fish oil (224 mg DHA/22.4 mg EPA), dexamethasone, escitalopram, imipramine and chloral hydrate). Hydrocortisone shows the most promise, of pharmacotherapies subjected to RCTs, as an emerging intervention in the prevention of PTSD within three months after trauma and should be a target for further investigation. The limited evidence for hydrocortisone and its adverse effects mean it cannot be recommended for routine use, but, it could be considered as a preventative intervention for people with severe physical illness or injury, shortly after a traumatic event, as long as there are no contraindications. More research is needed using larger, high quality RCTs to establish the most efficacious use of hydrocortisone in different populations and optimal dosing, dosing window and route. There is currently a lack of evidence to suggest that other pharmacological agents are likely to be effective.

Understanding public opinion to the introduction of minimum unit pricing in Scotland: a qualitative study using Twitter.

OBJECTIVES: On 1 May 2018 minimum unit pricing (MUP) of alcohol was introduced in Scotland. This study used Twitter posts to quantify sentiment expressed online during the introduction of MUP, conducted a thematic analysis of these perceptions and analysed which Twitter users were associated with which particular sentiments. DESIGN AND SETTING: This qualitative social media analysis captured all tweets relating to MUP during the 2 weeks after the introduction of the policy. These tweets were assessed using a mixture of human and machine coding for relevance, sentiment and source. A thematic analysis was conducted. PARTICIPANTS: 74 639 tweets were collected over 14 days. Of these 53 574 were relevant to MUP. RESULTS: Study findings demonstrate that opinion on the introduction of MUP in Scotland was somewhat divided, as far as is discernible on Twitter, with a slightly higher proportion of positive posts (35%) than negative posts (28%), with positive sentiment stronger in Scotland itself. Furthermore, 55% of positive tweets/retweets were originally made by health or alcohol policy-related individuals or organisations. Thematic analysis of tweets showed some evidence of misunderstanding around policy issues. CONCLUSIONS: It is possible to appreciate the divided nature of public opinion on the introduction of MUP in Scotland using Twitter, the nature of the sentiment around it and the key actors involved. It will be possible to later study how this changes when the policy becomes more established.

Safety and effectiveness of direct oral anticoagulants following ultrasound-assisted catheter directed thrombolysis for venous thromboembolism.

Ultrasound-assisted catheter-directed thrombolysis (USAT) is a novel approach for the treatment of venous thromboembolism (VTE) that is thought to be associated with a decreased risk of bleeding. Direct oral anticoagulants (DOACs) are approved for the treatment of VTE but have not been studied in a post-fibrinolysis setting. The intention of this retrospective observational study was to determine the safety and effectiveness of DOACs compared to the vitamin-K-antagonist (VKA) warfarin following USAT in patients with documented VTE. Included patients were aged 18 years or older who had documented VTE and received oral anticoagulation with either a DOAC or VKA following USAT. The primary outcome of this study was to compare the 90-day composite incidence of major and minor bleeding and recurrent VTE between patients receiving DOACs after USAT to those receiving VKA after USAT. Similar rates of bleeding and recurrent VTE were observed (4/42; 9.5% in the DOAC group versus 2/34; 5.9% in the VKA group). The use of DOAC therapy post-USAT for VTE was not associated with higher rates of 90-day major or minor bleeding or 90-day recurrent VTE.

An analysis of variable dissolution rates of sacrificial zinc anodes: a case study of the Hamble estuary, UK.

Sacrificial anodes are intrinsic to the protection of boats and marine structures by preventing the corrosion of metals higher up the galvanic scale through their preferential breakdown. The dissolution of anodes directly inputs component metals into local receiving waters, with variable rates of dissolution evident in coastal and estuarine environments. With recent changes to the Environmental Quality Standard (EQS), the load for zinc in estuaries such as the Hamble, UK, which has a large amount of recreational craft, now exceeds the zinc standard of 7.9 µg/l. A survey of boat owners determined corrosion rates and estimated zinc loading at between 6.95 and 7.11 t/year. The research confirms the variable anode corrosion within the Hamble and highlighted a lack of awareness of anode technology among boat owners. Monitoring and investigation discounted metal structures and subterranean power cables as being responsible for these variations but instead linked accelerated dissolution to marina power supplies and estuarine salinity variations.

Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.

Scaffold hopping with molecular field points: identification of a cholecystokinin-2 (CCK2) receptor pharmacophore and its use in the design of a prototypical series of pyrrole- and imidazole-based CCK2 antagonists.

A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK(2)) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK(1). In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.

Optimization of the in vitro and in vivo properties of a novel series of 2,4,5-trisubstituted imidazoles as potent cholecystokinin-2 (CCK2) antagonists.

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.