Women's experiences of using patient portals in healthcare settings: a rapid review.

BACKGROUND: The integration of patient portals into health systems has the potential to increase access for women. For example, within a mental health context, women are at a higher risk of developing anxiety and depression but may experience barriers in accessing care. Therefore, the aim of this rapid review was to understand what is currently known about patient portal use among women. The objectives were (1) To discover pertinent facilitators for women when using patient portals; (2) To discern if women face individual barriers to accessing patient portals; and (3) To explore the potential role of patient portals for women's mental health care. METHODS: A rapid review methodology was implemented using the Cochrane Rapid Reviews Methods Group, as well as a grey literature scan. Inclusion criteria included articles that focused on women's use of patient portals within healthcare settings. Four databases were searched, including Embase, MEDLINE (Ovid), CINAHL and PsycINFO in September 2023. Two independent reviewers performed screening, data extraction, and analysis. RESULTS: This search resulted in screening 1385 titles and abstracts, and 82 articles for full-text eligibility. 15 articles were included in the review. Data were extracted and analyzed, guided by the research objectives. Facilitators to patient portal use included processes that enhanced user engagement, the provision of portal tools, and management of health care features. Barriers included health equity factors and use of medical jargon. Applications to mental health care included how use of portals eased women's anxiety and increased their sense of internal control. CONCLUSIONS: The results of this review indicate that interrelated factors influence women's experiences with using patient portals. By understanding facilitators and barriers to portal use, and applications for mental health care, we can understand how to improve women's use of portals in the future.

Integrating trauma- and violence-informed care for adolescent mothers in Rwanda: a qualitative study with community health workers.

INTRODUCTION: In Rwanda, maternal community health workers play a critical role to improving maternal, newborn and child health, but little is known about their specific experiences with adolescent mothers, who face unique challenges, including trauma, ongoing violence, stigma, ostracism, mental health issues, barriers within the healthcare system, and lack of access to the social determinants of health. This study explored the experiences of maternal community health workers when caring for adolescent mothers in Rwanda to inform the delivery of trauma- and violence-informed care in community maternal services. METHODS: Interpretive Description methodology was used to understand the experiences of 12 community health workers purposively recruited for interviews due to their management roles. To gain additional insights about the context, seven key informants were also interviewed. FINDINGS: Maternal community health workers provided personalized support to adolescent mothers through the provision of continuity of care, acting as a liaison, engaging relationally and tailoring home visits. They reported feeling passionate about their work, supporting each other, and receiving support from their leaders as facilitators in caring for adolescent mothers. Challenges in their work included handling disclosures of violence, dealing with adolescent mothers' financial constraints, difficulties accessing these young mothers, and transportation issues. Adolescent mothers' circumstances are generally difficult, leading to self-reports of vicarious trauma among this sample of workers. CONCLUSION: Maternal community health workers play a key role in addressing the complex needs of adolescent mothers in Rwanda. However, they face individual and structural challenges highlighting the complexities of their work. To sustain and enhance their roles, it is imperative for government and other stakeholders to invest in resources, mentorship, and support. Additionally, training in equity-oriented approaches, particularly trauma- and violence-informed care, is essential to ensure safe and effective care for adolescent mothers and to mitigate vicarious trauma among maternal community health workers.

Intimate Partner Violence and Breastfeeding Outcomes Among Canadian Women: An Exploratory Correlational Study.

PURPOSE: Human breastmilk is the optimal nutrition for infants; however, preliminary research suggests that women who experience intimate partner violence (IPV) are less likely to initiate and continue breastfeeding. Self-efficacy is a known facilitator to achieve positive breastfeeding outcomes. This study aimed to explore the relationship between experiencing IPV and breastfeeding duration, exclusivity, and self-efficacy for Canadian mothers, and to identify potential variables that influence breastfeeding decision-making among women with experiences of IPV. METHOD: This was a cross-sectional secondary analysis of surveys completed by 129 mothers with children under the age of 2 years from Ontario, Canada. Data were stratified according to those who had experienced IPV and those who had not. Breastfeeding outcomes assessed included breastfeeding self-efficacy and breastfeeding duration and exclusivity. Non-parametric tests and correlations were used to determine if relationships existed between IPV and breastfeeding outcomes. RESULTS: 72.3% (n = 94) of women in this sample breastfed their child(ren). Experiencing IPV was associated with lower breastfeeding self-efficacy scores (W = 768, p = 0.055) with a moderate effect size (r = 0.32 [95% 0.06,0.55]). This relationship was significant in the context of psychological abuse (W = 816.5, p = 0.015) with a small effect size (r = 0.22 [95% 0.03,0.41]). CONCLUSIONS: This study provides novel preliminary evidence suggesting that experiencing IPV of any type can negatively impact breastfeeding self-efficacy, with psychological abuse potentially being the most detrimental. Future research is required to build upon these findings.

" I carry their stories home ": experiences of nurses and midwives caring for perinatal adolescent mothers in primary health care settings in Rwanda.

INTRODUCTION: Adolescent mothers require trauma- and violence-informed care during the perinatal period due to trauma histories and ongoing violence as a result of pregnancy. Nurses and midwives play a critical role in caring for adolescent mothers in primary healthcare settings in Rwanda in the perinatal period. PURPOSE: To explore the experiences of nurses and midwives working with adolescent mothers in selected primary healthcare settings in Rwanda to inform the delivery of trauma- and violence- informed care. METHODS: This study utilized an interpretive description qualitative approach and was conducted in eight primary healthcare settings in Rwanda. Twelve nurses and midwives working in perinatal services and four heads of health centers participated in in-depth individual interviews. Data were analyzed thematically. RESULTS: The analysis revealed four main themes and 11 (sub-themes): (a) relational practice (being creative and flexible, "lending them our ears"); (b) individual challenges of providing care to adolescent mothers (lack of knowledge to provide care related to gender-based violence, and gendered experience); (c) factors contributing to workarounds (inflexible guidelines, lack of protocol and procedures, lack of nurses' and midwives' in service training, and the physical structure of the perinatal environment); and (d) vicarious trauma (living the feelings, "I carry their stories home," and hypervigilance in parenting). CONCLUSION: Nurses and midwives find caring for adolescent mothers challenging due to their unique needs. These needs require them to be creative, adaptable, and attentive listeners to better understand their challenges. These practitioners face difficulties such as insufficient specific knowledge related to, for example, gender-based violence, inflexible guidelines, and a lack of protocols and training. Additionally, in the perinatal environment attention to the needs of practitioners in those settings is often lacking, and many nurses and midwives report experiencing vicarious trauma. Consequently, there is a pressing need for guidelines and protocols specifically tailored for the care of adolescent mothers. Ongoing trauma- and violence- informed care training and professional education should be provided to enhance the ability of nurses and midwives to care for adolescent mothers and prevent re-traumatization and mitigate vicarious trauma effectively.

Barriers to the health and well-being of women with multiple sclerosis in Southwestern Ontario, Canada.

PURPOSE: This study explores the lived experiences of women living with multiple sclerosis (MS) and identifies barriers to their optimal health and well-being. METHODOLOGY: Using van Manen's interpretative phenomenologic analysis, the researchers conducted semistructured interviews with 23 women diagnosed with MS in Southwestern Ontario, Canada. Data were analyzed using NVivo 12 software, and themes were validated through member checking. RESULTS: The study revealed a key theme of "obstacles for women with MS" and subthemes related to barriers to physical, mental, and social well-being. Participants reported experiencing feelings of health despite their MS diagnosis but identified various constraints on their optimal health and well-being, including challenges with employment, financial support, and housing security. CONCLUSION: The findings highlight the need for healthcare professionals to advocate for equitable treatments, medication, and accessibility supports for women with MS, as well as for policies that address disability income support and affordable housing. Further research is recommended to explore power imbalances experienced by women with MS in precarious employment situations or living with episodic disabilities.

Vaccine Hesitancy Among Canadian Mothers: Differences in Attitudes Towards a Pediatric COVID-19 Vaccine Among Women Who Experience Intimate Partner Violence.

OBJECTIVES: Vaccine hesitancy (VH) in maternal decision-making is important to understand to achieve community immunity targets and optimize pediatric COVID-19 vaccine adoption. COVID-19 is exacerbating the risk of intimate partner violence (IPV) for women in abusive relationships, a known risk factor for maternal VH. This project aimed to: (1) determine if IPV impacts maternal VH in Canada; and (2) understand maternal attitudes towards routine childhood vaccines and a pediatric COVID-19 vaccine in Canada. METHODS: As part of a cross-sectional, quantitative study, 129 women completed an online survey. IPV was assessed using the Abuse Assessment Screen and the revised, short-form Composite Abuse Scale. The Parent Attitudes about Childhood Vaccines scale evaluated maternal attitudes towards routine vaccinations and a COVID-19 vaccine. Questions informed by the World Health Organization's Increasing Vaccination Model (IVM) evaluated perceived barriers and facilitators to COVID-19 vaccination. RESULTS: In total, 14.5% of mothers were hesitant towards routine childhood vaccines, while 97.0% were hesitant towards a COVID-19 vaccine. Experiencing IPV was significantly associated with maternal COVID-19 VH (W = 683, p < 0.05). Social processes were identified as instrumental barriers and facilitators to COVID-19 vaccination, meaning that social norms and information sharing among social networks are critical in maternal vaccination decision-making. CONCLUSIONS FOR PRACTICE: This study provides novel evidence of maternal IPV significantly impacting VH and the presence of strong maternal VH specific to a COVID-19 vaccine in the Canadian context. Further research is required to fully understand the factors that build confidence and mitigate hesitancy in mothers, especially mothers who have experienced IPV.

A latent profile analysis of COVID-19 conspiracy beliefs: Associations with thinking styles, mistrust, socio-political control, need for closure and verbal intelligence.

Throughout the COVID-19 pandemic, attention has been drawn to conspiracy theories. To date, research has largely examined commonalities in conspiracy theory belief, however it is important to identify where there may be notable differences. The aim of the present research was first to distinguish between typologies of COVID-19 conspiracy belief and explore demographic, social cognitive factors associated with these beliefs. Secondly, we aimed to examine the effects of such beliefs on adherence to government health guidelines. Participants (N = 319) rated well known COVID-19 conspiracy theories, completing measures of thinking style, socio-political control, mistrust, verbal intelligence, need for closure and demographic information. Participants also rated the extent to which they followed government health guidelines. Latent profile analysis suggests three profiles of COVID-19 conspiracy beliefs with low, moderate, and high COVID conspiracy belief profiles and successively stronger endorsement on all but one of the COVID-19 conspiracy theories. Those holding stronger COVID-19 conspiracy theory beliefs are more likely to reason emotively, feel less socio-political control, mistrust others, have lower verbal ability and adhere less to COVID-19 guidelines. The social and health implications of these findings are discussed.

Population pharmacokinetic and exposure-efficacy analysis of ixekizumab in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).

AIMS: Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A used in the treatment of adult and paediatric patients with moderate-to-severe psoriasis. This analysis evaluated the pharmacokinetics (PK) of ixekizumab and the exposure-efficacy relationship in paediatric patients aged 6 to <18 years with psoriasis. METHODS: Population PK and exposure-efficacy models were developed. The models used data from paediatric patients with psoriasis participating in the Phase 3 IXORA-PEDS trial in which patients were dosed according to weight categories. The exposure-efficacy model is a Psoriasis Area and Severity Index (PASI) time course model using data up to Week 12, a co-primary efficacy endpoint. RESULTS: A 2-compartment population PK model describes the PK of ixekizumab in paediatric patients with the effect of body weight incorporated on clearance and volume terms using an allometric relationship. The weight category-based dosing ensured that ixekizumab mean trough serum concentrations in paediatric patients with psoriasis (3.20-3.33 µg/mL) were within the range of concentrations observed in adult patients with psoriasis (mean [standard deviation]: 3.48 [2.16] µg/mL) administered an efficacious dosing regimen. The observed PASI response rates at Week 12 in paediatric patients (91.9/81.8/52.5% for PASI75/90/100) are well predicted by the final exposure-efficacy model and response rates are similar or higher than those achieved in adults (86.2/66.6/35.0% for PASI75/90/100). CONCLUSION: This analysis is the first to describe the PK and exposure-efficacy relationship of ixekizumab in paediatric patients with psoriasis. The analyses support the selection of the weight category-based ixekizumab dosing regimens approved for use in paediatric patients with psoriasis.

Promoting Attachment Through Healing (PATH): Results of a retrospective feasibility study providing trauma-and-violence-informed care to pregnant women.

AIM: To evaluate the impact of a trauma and violence-informed cognitive behavioural therapy (TVICBT) intervention, compared with standard care on mental health, coping, bonding and maternal-infant attachment among pregnant women with a history of intimate partner violence and who displayed symptomatology consistent with anxiety, depression or post-traumatic stress disorder (PTSD). DESIGN: A mixed-methods case study design was employed, where women either received standard perinatal care or were referred to a specialized TVICBT program. METHODS: Data were collected through a retrospective obstetric medical chart audit in 2017 at an Ontario hospital in a large urban centre. Multiple choice and 'yes/no' questions were analysed using measures of central tendency and dispersion, in addition to frequency counts. Qualitative data from clinical notes were subjected to an inductive content analysis approach to identify key concepts. RESULTS: In total, 69 women participated (intervention group = 37, standard care group = 32). Prevalence of mental illness between groups was consistent, apart from the TVICBT group having a significant increase in PTSD. In the TVICBT group, 83.8% of women (n = 31) expressed perinatal concerns, compared with only 37.5% (n = 12) of the standard care group. More women in the intervention group (94.6%, n = 35) coped successfully in the intrapartum period than the standard care group (78.1%, n = 25). However, more women in the standard care group (97.0%, n = 31) exhibited appropriate bonding behaviours than the TVICBT group (88.6%, n = 31). CONCLUSION: The TVICBT intervention was effective in assisting women to identify triggers during their pregnancy journey, develop appropriate coping strategies and advocate for their needs to best cope. IMPACT: TVICBT offers an effective, individualized, trauma and violence-informed approach to optimize the health outcomes of perinatal women and their infants by promoting positive coping and maternal-infant bonding, thus filling an existing practice gap of a lack of individualized, trauma-informed care.

The Good, the Bad, and the Vision: Exploring the Mental Health Care Experiences of Transitional-Aged Youth Using the Photovoice Method.

Transitional-aged youth (TAY) between the ages of 16 and 24 experience higher rates of mental distress than any other age group. It has long been recognized that stability, consistency, and continuity in mental health care delivery are of paramount importance; however, the disjointed progression from paediatric to adult psychiatric services leaves many TAY vulnerable to deleterious health outcomes. In Spring 2019, eight TAY living with mental health challenges participated in a Photovoice study designed to: (1) illuminate their individual transition experiences; and, (2) support a collective vision for optimal mental health care at this nexus. Participants took photographs that reflected three weekly topics-the good, the bad, and the vision-and engaged in a series of three corresponding photo-elicitation focus group sessions. Twenty-four images with accompanying titles and captions were sorted into nine participant-selected themes. Findings contribute to an enhanced awareness of psychiatric service delivery gaps experienced by TAY, and advocate for seamless and supportive transitions that more effectively meet the mental health care needs of this population.

"I Fell through the Cracks": Navigating the Disjointed Transition from Paediatric to Adult Psychiatric Services.

The transition from adolescence to adulthood is a tumultuous time riddled with stress, confusion, and uncertainty. An abrupt shift in biobehavioural development between the ages of 16 and 24 corresponds with an increase in mental health challenges; thereby necessitating comprehensive and coordinated psychiatric services that bridge pediatric and adult care realms. Unfortunately, this transition is often unsupportive and disjointed, leaving many transitional-aged youth (TAY) overwhelmed and ill-equipped to cope with the increased demands of adulthood independently. Eight TAY with mental health challenges were invited to participate in a PhotoVoice study that explored the strengths and shortcomings of this transition process, through a combination of photography and photo-elicitation focus group discussions. A descriptive qualitative approach was used to analyze all participant dialogue. Four themes emerged from the data: accessibility, coordination, independence, and support. Participant insights illuminated critical gaps in mental health care delivery, but also revealed novel solutions and opportunities for transformational change.

Evaluation of the Arabic version of the Chronic Pain Grade scale: Psychometric properties.

To increase our understanding of chronic pain in clinical and research contexts, an assessment of its dimensions using reliable and valid self-reported pain measures is imperative. However, well-validated Arabic chronic pain assessment scales are lacking. The Chronic Pain Grade (CPG) scale has been used worldwide, yet an Arabic version of the CPG scale has not yet been validated. Thus, we conducted this study to demonstrate the psychometric properties, including reliability, convergent validity, and construct validity of the Arabic CPG scale. A cross-sectional study was conducted in two hospitals in Saudi Arabia. Data were collected from a convenience sample of 233 chronic pain patients. The confirmatory factor analysis showed an excellent fit with the factor structure of the CPG scale and, thus, supported construct validity. The two identified subscales were pain intensity and pain disability. Convergent validity was supported by having significant correlations between the short-form McGill Pain Questionnaire and CPG subscales. Internal consistency reliability was demonstrated, as Cronbach's α was 0.916 for pain intensity and 0.815 for pain disability. This study provides evidence that the Arabic CPG scale is a reliable and valid measure of chronic pain dimensions, including pain intensity, and pain-related disability. This Arabic version of the CPG scale has the potential to expand research and clinical assessment in the Arab world. Future studies are required for further validation.

An Exploration of How Persons Receiving In-Center Hemodialysis Describe How Access to Transportation for Treatment Influences Their Overall Health.

Individuals having in-center hemodialysis treatment re quire transportation services on average six trips a week (three roundtrips for three treatment days), making access to transportation an important component for sustaining the health and well-being of these individuals. This qualitative study aimed to explore how persons receiving in-center hemodialysis treatment explain ways in which access to transportation for such treatment influences their overall health using the World Health Organization's definition of health. Purposive sampling was used to recruit eight participants from a community hemodialysis center in a suburban region of Southwestern Ontario, Canada. Data were obtained using semi-structured individual interviews and analyzed using inductive analysis. Three interrelated themes revealed each patient's experience: reliability, choice, and personal safety.

Exploring the Characteristics and Behaviors of Nurses Who Have Attained Microcelebrity Status on Instagram: Content Analysis.

BACKGROUND: Instagram is a social media platform that enables users to share images and videos worldwide. Some nurses have used Instagram to document their experiences as a nurse and have subsequently gained microcelebrity status-that is, a user who purposefully seeks to amass a substantive Web-based following and has become recognized as a niche area of interest. OBJECTIVE: This study aimed to identify the characteristics and behaviors of microcelebrity nurses who act as influencers on Instagram and use their nursing profile to gain attention and presence on the Web. METHODS: A qualitative, exploratory, nonparticipatory content analysis of media and text generated by a purposeful sample of 10 registered nurses who use Instagram and sustain a definable microcelebrity status was conducted. In this study, manifest and latent data were examined to gain an understanding of the characteristics and behaviors of nurses who have attained microcelebrity status on Instagram. RESULTS: Data analysis revealed 5 themes of Instagram posts: (1) engaging Instagram users, (2) educational opportunities and insights, (3) nursing-related humor, (4) emotions experienced by nurses, and (5) media and narratives including patient details or work context. Messages were primarily positive in nature; however, multiple potential privacy, ethical, and professional issues were noted throughout the posted content. CONCLUSIONS: The findings of this study help to expand the current knowledge related to the use of social media platforms such as Instagram, especially in regard to the emergence of nurses who use this form of technology to achieve or maintain a microcelebrity status. This study calls for additional research on nurses' attainment of microcelebrity status on social media as well as further policy development to adequately prepare nurses to navigate social media.

Critical discourse analysis of policies impacting the intersection of health and experiences of intimate partner violence for rural women in Ontario, Canada.

INTRODUCTION: Intimate partner violence (IPV) impacts approximately one quarter of Canadian women, and services provided to support women are heavily influenced by policy. Policy sets the stage and tone for action in all sectors. To date, there have been no critical discourse analyses examining how provincial, hospital, and women's shelter policies intersect and impact women in rural communities. METHODS: A critical discourse analysis using a case study of one rural community in south-western Ontario was undertaken by a multisectoral team of researchers using a critical, feminist, intersectional lens. The selected policies were (1) Domestic Violence Action Plan for Ontario (ODVAP), (2) the rural women's shelter policy, and (3) the hospital policy. RESULTS: The internal analysis of the policies revealed that ODVAP focused on societal solutions to violence requiring cross-sectoral cooperation with a focus on marginalized populations, whereas the rural shelter policy focused on creating a philosophical orientation to underpin their work with clients. There was no formal hospital policy related to the provision of services for women who have experienced violence. The policies revealed a disconnect between the stated goals and the specifics concerning how the policies would come together to achieve these goals. Obstacles such as having no clear link for how ODVAP and the shelter policy would work together, idealization of training but a lack of specificity on what training would be useful, and the requirement of affirmative action on the part of women to engage with services functioned as a means to maintain the status quo, that is, working in a siloed approach to care. CONCLUSIONS: Integrative systems are important for women who have experienced IPV given the wide range of health, social, and economic consequences of violence. Policy alignment is important for women who have experienced or are experiencing IPV, particularly in rural contexts where services are fraught with additional barriers.

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects.

AIMS: The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of single and multiple doses of a novel mGlu2 agonist were assessed in healthy males. METHODS: In two, Phase 1 investigator- and subject-blind, placebo-controlled studies, oral doses of prodrug LY2979165 were evaluated: single doses (20-150 mg, N = 30) and multiple once-daily (QD) doses (20-400 mg; N = 84), using a titration regimen. The plasma and urine PK of LY2979165 and active moiety, 2812223, were measured. Cerebrospinal fluid (CSF) was collected to determine PK and neurotransmitter levels. Safety parameters were assessed throughout. RESULTS: Nausea and vomiting were dose limiting following single doses; dose titration allowed higher doses to be tested over 14 days. The most common adverse events related to LY2979165 were dizziness, vomiting, nausea, somnolence and headache. The plasma PK of 2812223 were approximately linear with minimal accumulation with QD dosing. Conversion of LY2979165 to 2812223 was extensive, with minimal LY2979165 measurable in plasma. There was no effect of food on the PK of LY2979165 and 2812223. After 60 mg LY2979165 single-dose, 2812223 exposure in CSF was approximately 2-6% and plasma exposure and peak concentrations were approximately four-fold higher than the mGlu2 agonist in vitro EC50 value. No consistent effects were observed on CSF neurotransmitter levels. CONCLUSIONS: Oral doses of LY2979165 up to 60 mg as a single dose and up to 400 mg given as multiple QD doses, using a titration regimen, were well tolerated with linear PK. Overall, these data support further clinical evaluation of LY2979165.

Lanolin for the treatment of nipple pain in breastfeeding women: a randomized controlled trial.

Nipple pain and damage are commonly experienced by breastfeeding women and are associated with negative breastfeeding outcomes. Health care providers often recommend the application of lanolin to treat painful/damaged nipples, yet no randomized controlled trial has evaluated the effectiveness of lanolin on nipple pain and breastfeeding outcomes. The purpose of this study was to evaluate the effect of lanolin on nipple pain among breastfeeding women with damaged nipples. A randomized, single-blind, controlled trial was conducted at a tertiary care hospital in Hamilton, Ontario, Canada. Breastfeeding women (N = 186) identified as having nipple pain/damage were randomized to apply lanolin (intervention group; n = 93) or to receive usual postpartum care (control group; n = 93). The primary outcome was nipple pain at 4 days post-randomization measured by the Numeric Rating Scale. Additional outcomes included nipple pain measured by the Short Form McGill Pain Questionnaire, breastfeeding duration/exclusivity, breastfeeding self-efficacy, and maternal satisfaction with lanolin treatment versus usual care. The results revealed no significant group differences in mean pain scores at 4 days post-randomization. Women in both groups experienced clinically relevant decreases in nipple pain by 7 days post-randomization. Significantly, more women in the lanolin group reported that they were satisfied with treatment compared with those receiving usual care. No significant group differences were found for other secondary outcomes. While more women were satisfied using lanolin, its application to sore/damaged nipples was ineffective for reducing nipple pain or improving breastfeeding outcomes.

Proof-of-Concept Study to Assess the Nociceptin Receptor Antagonist LY2940094 as a New Treatment for Alcohol Dependence.

BACKGROUND: This was a proof-of-concept study to evaluate the efficacy of LY2940094, a nociceptin/orphanin FQ peptide receptor antagonist, in reducing alcohol consumption in actively alcohol-drinking patients with alcohol dependence. METHODS: Eighty-eight patients, 21 to 66 years of age, diagnosed with alcohol dependence, reporting 3 to 6 heavy drinking days per week, were randomized (1:1) to 8 weeks of treatment with once-daily oral placebo (N = 44) or 40 mg/d of LY2940094 (N = 44). The primary efficacy analysis was the change from baseline in number of drinks per day (NDD) utilizing mixed-model repeated measures comparing LY2940094 and placebo in Month 2 of the 8-week double-blind treatment period. The probability that the difference relative to placebo in NDD was ≤0 at endpoint was calculated, and a probability ≥80% was considered to be evidence that LY2940094 was associated with the reduction in NDD. RESULTS: After 8 weeks of treatment, reduction in mean NDD did not differ between LY2940094 versus placebo (-1.4 vs. -1.5, respectively, 44% probability of greater reduction relative to placebo), but there was a greater reduction in the mean percentage of heavy drinking days in a month with LY2940094 versus placebo (-24.5 vs. -15.7%, respectively, 93% probability of a greater reduction relative to placebo), and an increase in the mean percentage of abstinent days in a month compared to placebo (9.1 vs. 1.9%, respectively, 91% probability of a greater increase relative to placebo). Patients who were treated with LY2940094 showed decreased plasma levels of gamma-glutamyl transferase with probabilities ≥98% for greater reduction compared with placebo at Weeks 1, 4, 6, and 8. Treatment-emergent adverse events in ≥5% of patients treated with LY2940094 included insomnia, vomiting, and anxiety. There were no serious adverse events or significant changes in laboratory assessments or vital signs with LY2940094. CONCLUSIONS: Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence.

A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin.

PURPOSE: LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. RESULTS: MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥ 40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. CONCLUSIONS: The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.

A population PK model for citalopram and its major metabolite, N-desmethyl citalopram, in rats.

A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague-Dawley (SD) rats at doses: 0.3, 1, 3, and 10 mg/kg IV and 10 mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60 mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quantification limit (BLQ < 0.1 ng/mL) were included in the analyses and treated as censored information. The disposition of citalopram was best described by a 3-compartment model and its desmethyl metabolite by a 2-compartment model. Several models for the absorption rate were explored (e.g. first, zero order and combined first and zero order absorption, Michaelis-Menten, lag time) in combination with dose and/or time dependent covariate effects. Dose dependent oral bioavailability properties were also identified in this analysis. Citalopram IV clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was adequately described using a Michaelis-Menten clearance with different parameters depending on the strain. This analysis demonstrates a very complex absorption/metabolism process explaining the highly non-linear pharmacokinetics observed across all the doses. This is the first combined parent/metabolite population PK analysis in both SD and Wistar rats over a wide range of IV and PO dosages for citalopram, a compound that exhibits highly nonlinear oral pharmacokinetics in rats.