Evaluating the Abuse Potential of Lenabasum, a Selective CB2 Cannabinoid Receptor Agonist.

Background: Endocannabinoids, which are present throughout the central nervous system (CNS), can activate CB1 and CB2 receptors. CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. Methods: This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n=56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120mg) were compared to placebo, and nabilone (3 and 6mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Results: Lenabasum was safe and well tolerated. Compared to placebo, a 20mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3mg and 6mg, which is a currently FDA-approved medication. Conclusions: At a target therapeutic dose (20mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120mg) did elicit subjective ratings of Drug Liking compared to placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared to 3mg and 6mg of nabilone, suggesting that lenabasum does have abuse potential and should be used cautiously in clinical settings. Significance Statement This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well-tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

Rights-based services for adolescents living with HIV: adolescent self-efficacy and implications for health systems in Zambia.

A rights-based approach in HIV service delivery for adults is increasingly taking root in sub-Saharan Africa in the context of greater availability of antiretroviral therapy. Yet there has been comparatively little progress in strengthening a rights-based approach to adolescent HIV services, which we learned during a qualitative study in 2010 among 111 adolescents living with HIV, 21 parents and 38 health providers in three districts in Zambia. Adolescents in the study expressed a range of information and support needs and wanted locally relevant interventions to meet those needs. They wanted greater access to HIV, sexual and reproductive health information, information on how to protect themselves, privacy and confidentiality in service sites, skills training so as to be able to earn money, and better control over disclosure of their HIV status to others. Both health workers and parents acknowledged that information and services needed to be improved to meet those needs far better. This paper provides examples of successful programmes in Zimbabwe, Uganda, Tanzania, Botswana and South Africa and calls for adolescent services to be linked to both paediatric and adult services, peer networks to be established to increase adolescents' ability to collectively voice their concerns and support each other, interventions supporting adolescents' control over self-disclosure, and lastly that adolescent health should become a training specialty in sub-Saharan Africa.

Community systems strengthening for HIV care: experiences from Uganda.

The growing HIV burden on families and health systems is exerting a shift toward community caregivers, and is increasing the demand for functional community systems. In Uganda, where the number of people with HIV is increasing against a background of weak health systems, the role of community systems is poorly understood. We investigated the role of community systems in palliative care and the system elements required for an effective community response in Uganda. Qualitative interviews and focus group discussions were conducted among providers and recipients of palliative care, their family members, and governmental and community stakeholders in Mbale and Jinja, Uganda. Results showed that community systems play an important role in many aspects of palliative care--including personal, livelihood, nutritional and bereavement support--and often strengthen care linkages and referrals. For community systems to fulfill these roles effectively, multiple system elements--including leadership, training, partnerships, and enabling policies--are essential. Strengthening community systems could be an effective strategy to alleviate HIV burden on families and health systems. A systems approach could be a potent mechanism for determining which community structures to strengthen in order to maximize the impact of palliative care programs, and for guiding investments in HIV and health.

Once-daily MMX(®) mesalamine for endoscopic maintenance of remission of ulcerative colitis.

OBJECTIVES: Treatment with mesalamine to maintain endoscopic remission (mucosal healing) of ulcerative colitis (UC) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy. To improve treatment adherence, a mesalamine formulation that can be administered once-daily, MMX(®) mesalamine (Lialda; Shire Pharmaceuticals LLC, Wayne, PA), was developed. This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine (Asacol; Warner Chilcott, Dublin, Ireland) for maintaining endoscopic remission in patients with UC. METHODS: A multicenter, randomized, double-blind, 6-month, active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission. The primary end point was maintenance of endoscopic remission at month 6 in the per-protocol (PP) population. RESULTS: Overall, 826 patients were randomized and dosed. The primary objective (non-inferiority) was met. At month 6, 83.7 and 77.8% of patients receiving MMX mesalamine in the PP and intent-to-treat (ITT) populations, respectively, had maintained endoscopic remission compared with 81.5% (PP) and 76.9% (ITT) of patients receiving delayed-release mesalamine (95% confidence interval for difference: -3.9%, 8.1% (PP); -5.0%, 6.9% (ITT)). Time to relapse was not significantly different between the two treatment groups (log-rank test, P=0.5116 (PP); P=0.5455 (ITT)). The proportion of patients with adverse events was 37.1 and 36.0% in patients receiving MMX mesalamine and delayed-release mesalamine, respectively. CONCLUSIONS: Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC.

Site-specific PEGylation at histidine tags.

The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for the successful development of safe protein-based medicines. Protein PEGylation is a clinically proven strategy to increase the circulation half-life of protein-based medicines. One limitation of PEGylation is that there are few strategies that achieve site-specific conjugation of PEG to the protein. Here, we describe the covalent conjugation of PEG site-specifically to a polyhistidine tag (His-tag) on a protein. His-tag site-specific PEGylation was achieved with a domain antibody (dAb) that had a 6-histidine His-tag on the C-terminus (dAb-His(6)) and interferon α-2a (IFN) that had an 8-histidine His-tag on the N-terminus (His(8)-IFN). The site of PEGylation at the His-tag for both dAb-His(6)-PEG and PEG-His(8)-IFN was confirmed by digestion, chromatographic, and mass-spectral studies. A methionine was also inserted directly after the N-terminal His-tag in IFN to give His(8)Met-IFN. Cyanogen bromide digestion studies of PEG-His(8)Met-IFN were also consistent with PEGylation at the His-tag. By using increased stoichiometries of the PEGylation reagent, it was possible to conjugate two separate PEG molecules to the His-tag of both the dAb and IFN proteins. Stability studies followed by in vitro evaluation confirmed that these PEGylated proteins retained their biological activity. In vivo PK studies showed that all of the His-tag PEGylated samples displayed extended circulation half-lives. Together, our results indicate that site-specific, covalent PEG conjugation at a His-tag can be achieved and biological activity maintained with therapeutically relevant proteins.

Living as an adolescent with HIV in Zambia -- lived experiences, sexual health and reproductive needs.

HIV services in developing countries are often ill-equipped to address the specific needs of HIV-positive adolescents. Studies suggest a lack of consistent, age-appropriate support regarding sexuality, relationships and transitioning to adulthood. The aims of this study were to explore and document the informational, psychosocial, sexual and reproductive health (SRH) needs of adolescents (aged 10-19 years) living with HIV in Zambia, and identify gaps between these needs and existing services. This paper reports a qualitative explorative study. Semi-structured interviews and focus group discussions were conducted with 111 HIV-positive adolescents and 59 key informants, including health care workers (n=38) and parents/guardians (n=21). Participants were selected via a purposive sampling method. Three sites - Lusaka, Kitwe and Kalomo - were selected to ensure a broad representation of service-delivery settings in Zambia. Data were entered into NVIVO (QSR International) software, and analysed inductively to extract key themes, gather results and draw conclusions. Findings confirm that social networks have significant impact on treatment adherence and assist adolescents in coming to terms with an HIV diagnosis. The trauma of diagnosis, however, is exacerbated if poorly managed. Nevertheless, many adolescents are determined not to let HIV change their lives. They want to know SRH and HIV information, but service providers do not often adequately meet these informational needs. Where available, tailored and participatory events around HIV and SRH are greatly appreciated. Services that are welcoming, empowering and provide tailored information are highly valued. Adolescents living with HIV require effective, targeted and sustainable HIV services to navigate safely through adolescence.

Only connect--the role of PLHIV group networks in increasing the effectiveness of Ugandan HIV services.

In recent years, Uganda has experienced rapid growth in networked groups of people living with HIV (PLHIV) who provide support, engage in advocacy, treatment and care and raise the profile of HIV in the public domain. This qualitative study focused the benefits of joining a networked group, relationships between groups, impact of networked groups on the community and shaping private and public experience living with HIV. Data were collected from two Ugandan districts, using semi-structured interviews, focus group discussions (FGDs), observation and reviews of group records and archives. Respondents (n=46) were adults living with HIV, and members of rural and urban PLHIV groups. Narratives from PLHIV (n=27) were gathered, and records from PLHIV group service-registers (n=20) reviewed. Key Informants (n=15) were purposively selected for interview, based on participation in PLHIV groups, utilisation of network services and their positions as key stakeholders. FGDs were held with network support agents (NSAs), members of PLHIV groups, and their leaders. Following qualitative analysis, findings suggest that for respondents, PLHIV networks enhance the impact and effectiveness of individual groups: the whole is greater than the sum of the parts. For groups, being part of a wider network allows for diversity of service delivery, and well-defined roles for individuals to participate in community support and sensitisation, with a reduction in the experience of stigma. We conclude that networking PLHIV groups is an effective strategy for improving the quality and reach of community-based HIV services. Governments should be encouraged to support networks and include them in policy-making at the national level. Local and regional groups should explore further ways to collaborate and expand support to PLHIV in Uganda.

The Mae On Project: using acupuncture for symptom relief and improved quality of life for people living with HIV and AIDS in rural Thailand.

Acupuncture in combination with antiretroviral therapies is a potentially useful treatment for HIV-related symptom relief in resource-poor settings. Traditional Chinese medicine has a long history of being used to enhance immune function. In the setting of HIV, Chinese traditional medicine allows for symptom treatment without adding extra medications to a complex drug regime. This paper provides details of a project at Mae On Hospital in rural northern Thailand where allopathic/conventional treatments are used in tandem with acupuncture. A preliminary evaluation of the project suggests that an integrated approach to symptom relief is viewed positively by respondents receiving acupuncture, though further studies are required to confirm the association between acupuncture and symptom relief. The project also demonstrates the feasibility of developing a cost-effective acupuncture programme using local healthcare staff.

"An unspoken world of unspoken things": a study identifying and exploring core beliefs underlying self-stigma among people living with HIV and AIDS in Ireland.

PRINCIPLES: Human immunodeficiency virus (HIV) related self-stigma--negative self-judgements resulting in shame, worthlessness and self-blame - negatively influences access to care and treatment, and overall quality of life for people living with HIV (PLHIV). Despite evidence that high levels of self-stigma exist among PLHIV, and is experienced to a far greater extent than stigma received from the broader community, there is a paucity of research aimed at understanding causes and functions of self-stigma, and an absence of interventions to mitigate its harmful effects. Understanding the core beliefs underlying self-stigma is therefore essential. METHODS: This pilot study used a qualitative approach to analyse interviews and written statements to uncover core beliefs underlying self-stigma, the functions thereof, and strategies used to overcome it, among a heterogeneous group of PLHIV in Ireland. RESULTS: Core beliefs underlying HIV-related self-stigma were uncovered and grouped into four categories: disclosure; sexuality and sexual pleasure; self-perception; and body, illness and death. Reported functions of self-stigma included contributing to maintaining a "victim" status; providing protection against stigma received from others; and justifying non-disclosure of HIV status. To cope with self-stigma, participants highlighted: community involvement and professional development; personal development; and connection to others and sense of belonging. Findings were also used to create a conceptual framework. CONCLUSIONS: This study helps fill identified gaps in knowledge about self-stigma as experienced by PLHIV. By understanding the core beliefs driving self-stigma, it will be possible to create targeted interventions to challenge and overcome such beliefs, supporting PLHIV to achieve improved wellbeing and lead productive lives free of self-limitation and self-judgement.

Adolescent HIV disclosure in Zambia: barriers, facilitators and outcomes.

INTRODUCTION: As adolescents living with HIV gain autonomy over their self-care and begin to engage in sexual relationships, their experiences of being informed about their HIV status and of telling others about their HIV status may affect their ability to cope with having the disease. METHODS: In 2010, we conducted a qualitative study among adolescents aged 10-19 living with HIV in Zambia, and with their parents and health care providers. Through interviews and focus group discussions, we explored the disclosure of HIV status to adolescents living with HIV; adolescents' disclosure of their status to others; and the impact of both forms of disclosure on adolescents. RESULTS: Our study identified three main barriers to disclosure of HIV status: local norms that deter parents from communicating with their children about sexuality; fear of HIV stigma; and an underlying presumption that adolescents would not understand the consequences of a HIV diagnosis on their lives and relationships. With regard to adolescents' disclosure of their HIV status to their sexual partners, our study identified fear of rejection as a common barrier. In rare cases, open family conversations about HIV helped adolescents come to terms with a HIV diagnosis. Findings indicated that disclosure had various outcomes at the individual and interpersonal levels. At the individual level, some adolescents described being anxious, depressed and blaming themselves after being told they had HIV. At the interpersonal level, disclosure created opportunities for adolescents to access adherence support and other forms of psychosocial support from family members and peers. At the same time, it occasionally strained adolescents' sexual relationships, although it did not always lead to rejection. CONCLUSIONS: There is a need for public health interventions that guide adolescents living with HIV, their parents and families through the disclosure process. Such interventions should help parents to assess and understand the evolving cognitive capacity and maturity of their adolescents in order to determine the appropriate time to inform them of their HIV-positive status. Such interventions should also mitigate the risk of HIV stigma, as well as local norms that may prevent discussions of sexuality within families. Adolescents who have been informed of their HIV status should be provided with on-going support to prevent disclosure from negatively affecting their psychological and sexual wellbeing. Further research is needed to explore the potential role of trusted family members in contributing to the disclosure process.

A systematic review of individual and contextual factors affecting ART initiation, adherence, and retention for HIV-infected pregnant and postpartum women.

BACKGROUND: Despite progress reducing maternal mortality, HIV-related maternal deaths remain high, accounting, for example, for up to 24 percent of all pregnancy-related deaths in sub-Saharan Africa. Antiretroviral therapy (ART) is effective in improving outcomes among HIV-infected pregnant and postpartum women, yet rates of initiation, adherence, and retention remain low. This systematic literature review synthesized evidence about individual and contextual factors affecting ART use among HIV-infected pregnant and postpartum women. METHODS: Searches were conducted for studies addressing the population (HIV-infected pregnant and postpartum women), intervention (ART), and outcomes of interest (initiation, adherence, and retention). Quantitative and qualitative studies published in English since January 2008 were included. Individual and contextual enablers and barriers to ART use were extracted and organized thematically within a framework of individual, interpersonal, community, and structural categories. RESULTS: Thirty-four studies were included in the review. Individual-level factors included both those within and outside a woman's awareness and control (e.g., commitment to child's health or age). Individual-level barriers included poor understanding of HIV, ART, and prevention of mother-to-child transmission, and difficulty managing practical demands of ART. At an interpersonal level, disclosure to a spouse and spousal involvement in treatment were associated with improved initiation, adherence, and retention. Fear of negative consequences was a barrier to disclosure. At a community level, stigma was a major barrier. Key structural barriers and enablers were related to health system use and engagement, including access to services and health worker attitudes. CONCLUSIONS: To be successful, programs seeking to expand access to and continued use of ART by integrating maternal health and HIV services must identify and address the relevant barriers and enablers in their own context that are described in this review. Further research on this population, including those who drop out of or never access health services, is needed to inform effective implementation.

Open-label, dose-titration and continuation study to assess efficacy, safety, and pharmacokinetics of anagrelide in treatment-naïve Japanese patients with essential thrombocythemia.

Although anagrelide is widely used for the treatment of essential thrombocythemia (ET) in the USA and Europe, it is not licensed in Japan. Existing literature has reported differences in polymorphism and activity of CYP1A2 in Japanese and non-Japanese ethnic groups, which may alter anagrelide metabolism. We intended to identify the optimum dosage of anagrelide in treatment-naïve Japanese patients with ET and assess its long-term safety and efficacy. Twelve patients with ET and a platelet count of ≥ 80 × 10(4)/µL were enrolled. Anagrelide was administered at an initial dose of 0.5 mg/day (weeks 1-4), then increased to 1.0 mg/day (weeks 5-8). During the following maintenance (weeks 9-52) and continuation periods (weeks 53-104), the dose was adjusted according to patient safety data and to maintain target platelet counts (<60 × 10(4)/µL). Increasing the dose led to a decrease in mean platelet count, and target platelet counts were maintained in 11 patients. Adverse events were mild or moderate, and none led to discontinuation. This cohort of Japanese patients exhibited higher pharmacokinetic exposures of anagrelide and its active metabolite than those previously documented in non-Japanese patients. These differences were modest, suggesting specific dosing regimens for Japanese patients are not required.

Resisting and challenging stigma in Uganda: the role of support groups of people living with HIV.

INTRODUCTION: Global scale up of antiretroviral therapy is changing the context of HIV-related stigma. However, stigma remains an ongoing concern in many countries. Groups of people living with HIV can contribute to the reduction of stigma. However, the pathways through which they do so are not well understood. METHODS: This paper utilizes data from a qualitative study exploring the impact of networked groups of people living with HIV in Jinja and Mbale districts of Uganda. Participants were people living with HIV (n=40), members of their households (n=10) and their health service providers (n=15). Data were collected via interviews and focus group discussions in 2010, and analyzed inductively to extract key themes related to the approaches and outcomes of the groups' anti-stigma activities. RESULTS: Study participants reported that HIV stigma in their communities had declined as a result of the collective activities of groups of people living with HIV. However, they believed that stigma remained an ongoing challenge. Gender, family relationships, social and economic factors emerged as important drivers of stigma. Challenging stigma collectively transcended individual experiences and united people living with HIV in a process of social renegotiation to achieve change. Groups of people living with HIV provided peer support and improved the confidence of their members, which ultimately reduced self-stigma and improved their ability to deal with external stigma when it was encountered. CONCLUSIONS: Antiretroviral therapy and group-based approaches in the delivery of HIV services are opening up new avenues for the collective participation of people living with HIV to challenge HIV stigma and act as agents of social change. Interventions for reducing HIV stigma should be expanded beyond those that aim to increase the resilience and coping mechanisms of individuals, to those that build the capacity of groups to collectively cope with and challenge HIV stigma. Such interventions should be gender sensitive and should respond to contextual social, economic and structural factors that drive stigma.

Exploring the delivery of antiretroviral therapy for symptomatic HIV in Swaziland: threats to the successful treatment and safety of outpatients attending regional and district clinics.

AIM: To examine the safety and acceptability of providing antiretroviral therapy (ART) in a resource poor setting. DESIGN: Two-stage observational and qualitative study. SETTING: Rural hospital in Southern Africa. METHODS: Structured observation using failure modes and effects analysis (FMEA) of the drug supply, dispensing, prescribing and administration processes. The findings from the FMEA were explored further in qualitative interviews with eight health professionals involved in the delivery of ART. To obtain a patient perspective, a stratified sample of 14 patients receiving ART was also interviewed. RESULTS: Key vulnerabilities in the process of ART provision include supply problems, poor packaging and labelling, inadequate knowledge among staff and lack of staff. Key barriers to successful patient adherence include transport inconsistency in supply and personal financial difficulties. There is, however, strong evidence of patient commitment and adherence. IMPLICATIONS AND CONCLUSION: Medication safety is relatively unexplored in the developing world. This study reveals an encouraging resilience in the health system and adherence among patients in the delivery of complex ART. The vulnerabilities identified, however, undermine patient safety and effectiveness of ART. There are implications for drug manufacturers; international aid agencies funding and supplying ART; and local practitioners. FMEA can help identify potential vulnerabilities and inform safety improvement interventions.

Empathy, inclusion and enclaves: the culture of care of people with HIV/AIDS and nursing implications.

AIM: This paper reports an empirical research study investigating specific features of the culture of care on a specialized unit supporting people living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). BACKGROUND: The anxiety felt by healthcare workers coming into contact with people living with HIV and AIDS (PLWHA) has been recognized in numerous studies. There is often an amplified notion of threat and a worldview fuelled by stereotypes, which inevitably leads to negative attitudes and stigmatization. METHODS: An ethnographic approach was used, including a 14-month period of observation and 31 semistructured interviews. The data were collected during 2000 and 2001 in a large teaching hospital in the United Kingdom. FINDINGS: Carers working on this unit who regularly contributed to the care of this client group had a broad range of experience and in many cases had chosen to work in the field. They worked within a social context that had a high level of egalitarianism, a view of PLWHA that appeared more positive and less pejorative than others, and a strongly empathetic approach accompanied by close engagement with the client group. CONCLUSION: Using nursing staff specially prepared for the care of PLWHA could be the most effective way to minimize stigma and discrimination against this client group in the healthcare sector.