Impurity study of tecovirimat.

This article delineates the systematic identification, synthesis, and impurity control methods used during the manufacturing process development of tecovirimat, an antiviral drug that treats monkeypox. Critical impurities were synthesized, and their chemical structure was confirmed through NMR analysis, GC, and HPLC mass spectrometry. The results established a thorough approach to identify, address, and control impurities to produce high-quality tecovirimat drug substance in accordance with International Conference on Harmonization (ICH)-compliant standards. This study is the first of its kind to evaluate both process and genotoxic impurities in tecovirimat, demonstrating effective control measures during commercial sample investigations and scaling up to a 60-kg batch size. The findings highlight the importance of critical impurity characterization and control in pharmaceutical development and production to ensure the safety and efficacy of the final product.

Improved and ligand-free copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles.

We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from o-bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods. By eliminating the use of harsh reagents and high temperatures associated with traditional synthesis approaches, this method proves to be more efficient and robust. Notably, we successfully applied this synthetic approach to the synthesis of bendazol and thiabendazole, yielding 82% and 78%, respectively, on a 100 gram scale.

Advance Care Planning and palliative care for patients with advanced cancer in Uganda.

The study sought to identify the extent to which Advance Care Planning (ACP) is practised by palliative care health professionals providing care to patients with advanced cancer and their families in Uganda. A mixed methods study design using qualitative and quantitative methods was used for the assessment. In-depth interviews with a group of nine highly experienced health professionals were conducted using a semi-structured interview guide. Quantitative data were retrieved and analysed from a survey administered to 124 health professionals of whom only 57 (45.9%) responded. The qualitative data were analysed using inductive thematic analysis and descriptive analysis was used for the quantitative data. Of the 57 health professionals who participated in the survey, 87% were aware of ACP and 55% reported regular practice. Fifty-five (55%) percent reported regular provision of ACP for their patients and 46% reported engaging in informal ACP practices. However, 58.5% resp. 37.5% reported that they routinely provide ACP to more than 50% resp. 75% of their patients. A group of nine highly experienced palliative care professionals had a pooled ACP prevalence of only 1.2%. There was a generally good attitude towards ACP with 98.2% acknowledging that patients should be able to determine their future care. However, 32% reported being uncomfortable withholding or withdrawing life sustaining treatment. There are a number of socio-cultural beliefs and barriers, for instance that discussing death and dying is a "taboo", as well as witchcraft, family influence in decision-making, religious beliefs that do not agree with palliative care practices and a preference to use aggressive treatment like chemotherapy for terminally ill, etc. Institutional barriers like lack of a legal framework for ACP, limited time for health professionals to engage in ACP and other patient factors such as denial of diagnosis and collusion to withhold information from patients were reported by 78.2% resp. 84% of the respondents. Despite the good awareness and attitude to ACP, there is a range of barriers that are affecting the implementation of ACP in Uganda. There is need for development of a legal framework for ACP, more research to understand the contextual barriers and develop appropriate education and public sensitisation programs.

Insights into Advance Care Planning in Africa.

Advance Care Planning is an important element of palliative care whose relevance has over the years shifted from focusing on patients at end of life to being applicable at any stage of an individual's health. It is said to be beneficial not only to the patient but also to the general health care system. It may facilitate a peaceful death in addition to minimizing unnecessary costs and the use of resources yet its use among health care workers in Africa is not well researched. This study therefore aimed to explore the use of Advance Care Planning among health care providers in sub-Saharan Africa. It was a survey that targeted health care professionals across Sub-Saharan Africa who were either current staff or alumni of Hospice Africa Uganda (HAU) between 2012 and 2023. These were conveniently sampled from HAU data base. An electronic survey was sent out, data was collected into an excel sheet and it was analysed descriptively. Responses to the survey came from nine out of 37 countries with PC services across Africa and there was a 14% response rate. 83% of the respondents had insight into Advance Care Planning and a surprise finding was that 40% had cared for patients with ACP. The majority (96%) would respect Advance Care Plans of their patients. These findings gave some insights into the use of ACP although the results cannot be generalised to a wider demography of healthcare providers.

Towards person-centred quality care for children with life-limiting and life-threatening illness: Self-reported symptoms, concerns and priority outcomes from a multi-country qualitative study.

BACKGROUND: Paediatric life-limiting and life-threatening conditions (life-limiting conditions) place significant strain on children, families and health systems. Given high service use among this population, it is essential that care addresses their main symptoms and concerns. AIM: This study aimed to identify the symptoms, concerns and other outcomes that matter to children with life-limiting conditions and their families in sub-Saharan Africa. SETTING AND PARTICIPANTS: Cross-sectional qualitative study in Kenya, Namibia, South Africa and Uganda. Children/caregivers of children aged 0-17 years with life-limiting conditions were purposively sampled by age, sex and diagnosis. Children aged 7 and above self-reported; caregiver proxies reported for children below 7 and those aged 7 and above unable to self-report. RESULTS: A total of 120 interviews were conducted with children with life-limiting conditions (n = 61; age range: 7-17 years), and where self-report was not possible, caregivers (n = 59) of children (age range: 0-17) were included. Conditions included advanced HIV (22%), cancer (19%), heart disease (16%) endocrine, blood and immune disorders (13%), neurological conditions (12%), sickle cell anaemia (10%) and renal disease (8%). Outcomes identified included physical concerns - pain and symptom distress; psycho-social concerns - family and social relationships, ability to engage with age-appropriate activities (e.g. play, school attendance); existential concerns - worry about death, and loss of ambitions; health care quality - child- and adolescent-friendly services. Priority psycho-social concerns and health service factors varied by age. CONCLUSION: This study bridges an important knowledge gap regarding symptoms, concerns and outcomes that matter to children living with life-limiting conditions and their families and informs service development and evaluation.

Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery.

Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound 21a exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC50 = 2.44 nM; L100I, EC50 = 4.24 nM; Y181C, EC50 = 4.80 nM; F227L + V106A, EC50 = 17.8 nM) and 4-5-fold (K103N, EC50 = 1.03 nM; Y188L, EC50 = 7.16 nM; E138K, EC50 = 3.95 nM) more potent than the reference drug ETV. Furthermore, molecular simulation was conducted to understand the binding mode of interactions of these novel NNRTIs and to provide insights for the next optimization studies.

Two-year virologic outcomes of an alternative AIDS care model: evaluation of a peer health worker and nurse-staffed community-based program in Uganda.

BACKGROUND: There is growing concern about the human resources needed to care for increasing numbers of patients receiving antiretroviral therapy in resource-limited settings. We evaluated an alternative model, community-based, comprehensive antiretroviral program staffed primarily by peer health workers and nurses. METHODS: We conducted a retrospective cohort study of patients receiving antiretroviral therapy during the first 10 months of program enrollment beginning in late 2003. Virologic, immunologic, clinical, and adherence data were collected. RESULTS: Of 360 patients started on treatment, 258 (72%) were active and on therapy approximately 2 years later. Viral load testing demonstrated that 86% of active patients (211/246 tested) had a viral load <400 copies per milliliter. The median CD4 increase for active patients was 197 cells per cubic millimeter (interquartile range, 108-346). Patients with either a history of antiretroviral use or lack of CD4 response were more likely to experience virologic failure. Survival was 84% at 1 year and 82% at 2 years. World Health Organization stage 4 was predictive of both not sustaining therapy and increased mortality. CONCLUSIONS: A community-based antiretroviral treatment program in a resource-limited setting can provide excellent AIDS care over at least a 2-year period. A comprehensive program based upon peer health workers and nurses provides an effective alternative model for AIDS care.