Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions:

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C

Tomography of the Darcy velocity from self-potential measurements

An algorithm is developed to interpret self-potential (SP) data in terms of distribution of Darcy velocity of the ground water. The model is based on the proportionality existing between the streaming current density and the Darcy velocity. Because the inverse problem of current density determination from SP data is underdetermined, we use Tikhonov regularization with a smoothness constraint based on the differential Laplacian operator and a prior model. The regularization parameter is determined by the L-shape method. The distribution of the Darcy velocity depends on the localization and number of non-polarizing electrodes and information relative to the distribution of the electrical resistivity of the ground. A priori hydraulic information can be introduced in the inverse problem. This approach is tested on two synthetic cases and on real SP data resulting from infiltration of water from a ditch

Preformulation characterization and identification of excipients for nevirapine loaded niosomes

Nevirapine (NVP) is used for the management of HIV/AIDS but must be dosed frequently, exhibits unpredictable bioavailability and a side effect profile that includes hepato- and dermo-toxicity. Niosomes are a colloidal drug delivery system that may be used to overcome the low bioavailability, side effect profile and frequent dosing needed when using conventional drug delivery systems. The compatibility of NVP with sorbitan esters, polysorbate, cholesterol and dihexadecyl phosphate (DCP) was investigated using Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Fourier Transform Infra-red Spectroscopy (FTIR) and X-ray Powder Diffraction (XRPD). Screening studies were undertaken to identify potential excipients that would produce niosomes with target critical quality attributes (CQA) viz, a particle size (PS) less than 1000 nm, a polydispersity index (PDI) less than 0.500 and an entrapment efficiency greater than 90%. The results revealed that sorbitan esters in combination with cholesterol and 5 μmol DCP produced niosomes with the best CQA and Zeta potential (ZP) less than -30 mV which suggests good stability of the niosomes on storage. Sorbitan esters produced the smallest niosomes of less than 400 nm diameter with a PDI less than 0.400 and an entrapment efficiency of more than 78% without cholesterol. The addition of cholesterol and DCP was essential to form niosomes with target CQA

A comparative study of the effect of different stabilizers on the critical quality attributes of self-assembling nano co-crystals

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) less than 1000 nm, polydispersity index (PDI) less than 0.500 and Zeta potential (ZP) less than −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process

Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal

Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA

Exploring Partnerships between Academia and Disabled Persons’ Organisations: Lessons Learned from Collaborative Research in Africa

In this article, we discuss how our academic research on disability and international development in five African countries has benefited hugely from active collaboration with advocates, practitioners, and policymakers, ultimately ensuring that research evidence is used to inform policy and practice. Whilst building such partnerships is seen as good practice, it is particularly important when working on disability issues, as the clarion call of the disability movement, ‘nothing about us without us’, attests. This is not just a slogan. Without the active and critical engagement of disabled people – as researchers, participants, advocates – the evidence gathered would not have the same impact. This article discusses experiences from research in Liberia, Kenya, Uganda, Sierra Leone, and Zambia. It highlights the challenges and opportunities such partnerships can bring in achieving the goals of leaving no one behind and doing nothing without the active engagement and inclusion of persons with disabilities.Department for International Development (DFID)Economic and Social Research Council (ESRC

A Qualitative Exploration of Community Ownership of a Maternity Waiting Home Model in Rural Zambia

Context Ownership is an important construct of sustainability for community-based health programming, though it is often not clearly defined or measured. We implemented and evaluated a community-driven maternity waiting home (MWH) model in rural Zambia. We engaged stakeholders at all levels and provided intensive mentorship to an MWH governance committee comprised of community-selected members. We then examined how different stakeholders perceive community ownership of the MWH. Methods We conducted 42 focus group discussions with community stakeholders (pregnant women, fathers, elders, and community health volunteers) and 161 in-depth interviews with MWH stakeholders (health facility staff, district health officials, and MWH governance committee and management unit members) at multiple time-points over 24 months. We conducted a content analysis and triangulated findings to understand community ownership of the MWH and observe changes in perceptions of ownership over time. Results Community members’ perceptions of ownership were related to their ability to use the MWH and a responsibility toward its success. Community and MWH stakeholders described increasingly more specific responsibilities over time. Governance committee and management unit members perceived their ability to represent the community as a crucial component of their role. Multiple respondent types saw collaboration between the governance committee and the health facility staff as key to allowing the MWH to meet its goal of serving the community. Conclusion The perceptions of community ownership evolved as the intervention became more established. Use of the MWH, and clear understanding of roles and responsibilities in management of the MWH, seemed to foster feelings of community ownership. To improve the sustainability of community-based maternal and child health programs, interventions should be accessible to target communities and clear roles should be established among stakeholders

Nano Co-Crystal Embedded Stimuli-Responsive Hydrogels: A Potential Approach to Treat HIV/AIDS

Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% w/w Pluronic® F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer–Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for n of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency

Creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding, observations from cross-sectional studies in Lesotho and Zambia

BACKGROUND: The health impact of the COVID-19 pandemic largely depends on the ability of the healthcare systems to develop effective and adaptable preparedness and mitigation strategies. A collaborative initiative (BRCCH-EDCTP COVID-19 Initiative) was set up between Lesotho and Zambia early on in the pandemic, to jointly conduct a project to investigate creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding. METHODS: Two different community case-finding strategies were deployed. In Lesotho, an approach was implemented whereby a community (village) health worker screened community members at their home or during community gatherings for COVID-19 signs and symptoms. All community members who screened positive were then offered SARS-CoV-2 testing. In Zambia, so-called community hubs, staffed by community health care workers, were set up at different locations in the community for people to walk in and get tested for SARS-CoV-2. Hubs changed location from week-to-week and targeted transmission hotspots. All persons visiting the hubs were offered testing for SARS-CoV-2 irrespective of self-reported signs and symptoms of COVID-19 though information was collected on occurrence of these. Testing in both approaches was done using SARS-CoV-2 rapid antigen tests. RESULTS: Setting up testing in the community setting was feasible in both countries. In Lesotho in the village health worker approach, over a period of 46 weeks, 7221 persons were screened, and 49 (11.4%) SARS-COV-2 cases identified among 428 COVID-19 screen positive participants. In the community hubs among 3150 people tested, 166 (5.3%) SARS-CoV-2 cases were identified in a period of 26 weeks. From the community hubs approach, where all seen were offered COVID-19 testing it was learned that people screening positive for COVID-19 signs and symptoms were more likely to test SARS-COV-2 positive, especially those reporting classic COVID-19 symptoms like loss of sense/smell for a short period of time (1-3 days). CONCLUSIONS: In conclusion, in this project we learned that implementing COVID-19 screening and testing by lay health workers in the community is possible. Characteristics of the population screened, tested, and identified to have SARS-CoV-2 are described to help guide development of future testing strategies