Modelling the Nexus of municipal solid waste sector for climate resilience and adaptation to nature-based solutions: A case study of Pakistan.

Municipal solid waste management is a major concern in developing economies, requiring collective international efforts to achieve carbon neutrality by diverting waste from disposal facilities. This study aims to highlight the importance of the waste sector as it has the potential to significantly contribute to climate change and its toxicity impact on the local ecosystem. Out of the total municipal solid waste generated, only 78 % is collected, either open dumped or thrown in sanitary landfills. The waste sector's ecological impact value is calculated for the Earth's regions, and it is very high at >50 % in Africa, Asia, Latin America and the Caribbean. This sectoral impact value is mainly responsible for greenhouse gas emissions and degradation of the local ecosystem health. Current business‒as‒usual practices attribute 3.42 % of global emissions to the waste sector. Various scenarios are developed based on waste diversion and related emissions modelling, and it is found that scenarios 3 and 4 will support the policymakers of the regions in attaining zero carbon footprints in the waste sector. Our findings conclude that cost-effective nature-based solutions will help low‒income countries reduce emissions from disposal sites and significantly improve the local ecosystem's health. Developed economies have established robust waste‒handling policies and implementation frameworks, and there is a need for collaboration and knowledge sharing with developing economies at the regional level to sustain the sector globally.

Adolopment of clinical practice guidelines and creation of referral pathways for psychiatric conditions in Pakistan.

Psychiatric disorders are highly prevalent in Pakistan and burdens the scarce number of psychiatrists present in the country. The establishment of evidence-based clinical practice guidelines (EBCPGs) and primary-care referral pathways within the local context is imperative to make the process efficient. In this Health Policy, we aimed to develop EBCPGs and primary-care referral pathways that are specific to Pakistan's primary-care setting, with the aim of facilitating the management of psychiatric conditions. Ten EBCPGs were created through the GRADE-ADOLOPMENT process; two recommendations were adopted with minor changes, 43 were excluded, and all others were adopted without any changes. Ten primary-care referral pathways for managing ten psychiatric disorders were created and 23 recommendations were added which will help to bridge the gap in care provision. These psychiatric referral pathways and EBCPGs will bring Pakistan's healthcare system a step closer to achieving optimal health outcomes for patients.

Impact of Ebola and COVID-19 on maternal, neonatal, and child health care among populations affected by conflicts: a scoping review exploring demand and supply-side barriers and solutions.

INTRODUCTION: Armed conflicts have a severe impact on the health of women and children. Global health emergencies such as pandemics and disease outbreaks further exacerbate the challenges faced by vulnerable populations in accessing maternal, neonatal, and child healthcare (MNCH). There is a lack of evidence that summarizes the challenges faced by conflict-affected pregnant women, mothers, and children in accessing MNCH services during global health emergencies, mainly the Ebola and COVID-19 pandemics. This scoping review aimed to analyze studies evaluating and addressing barriers to accessing comprehensive MNCH services during Ebola and COVID-19 emergencies in populations affected by conflict. METHODS: The search was conducted on PubMed, Scopus, and Web of Science databases using terms related to Ebola and COVID-19, conflicts, and MNCH. Original studies published between 1990 and 2022 were retrieved. Articles addressing the challenges in accessing MNCH-related services during pandemics in conflict-affected settings were included. Thematic analysis was performed to categorize the findings and identify barriers and solutions. RESULTS: Twenty-nine studies met the inclusion criteria. Challenges were identified in various MNCH domains, including antenatal care, intrapartum care, postnatal care, vaccination, family planning, and the management of childhood illnesses. Ebola-related supply-side challenges mainly concerned accessibility issues, health workforce constraints, and the adoption of stringent protocols. COVID-19 has resulted in barriers related to access to care, challenges pertaining to the health workforce, and new service adoption. On the demand-side, Ebola- and COVID-19-related risks and apprehensions were the leading barriers in accessing MNCH care. Community constraints on utilizing services during Ebola were caused by a lack of trust and awareness. Demand-side challenges of COVID-19 included fear of disease, language barriers, and communication difficulties. Strategies such as partnerships, strengthening of health systems, service innovation, and community-based initiatives have been employed to overcome these barriers. CONCLUSION: Global health emergencies amplify the barriers to accessing MNCH services faced by conflict-affected populations. Cultural, linguistic, and supply-side factors are key challenges affecting various MNCH domains. Community-sensitive initiatives enhancing primary health care (PHC), mobile clinics, or outreach programs, and the integration of MNCH into PHC delivery should be implemented. Efforts should prioritize the well-being and empowerment of vulnerable populations. Addressing these barriers is crucial for achieving universal health coverage and the Sustainable Development Goals.

Empirical analysis of cost-effective and equitable solid waste management systems: Environmental and economic perspectives.

The solid waste management (SWM) system is in a transitional phase in developing economies, and local municipalities and waste management companies are stepping toward integrating a waste treatment approach in the scheme of waste handling. However, there is an urgent need to explore cost-effective techniques, models, and potential revenue streams to sustain the state-run waste sector self-sufficiently. The proposed SWM model aims to support the local waste sector in Islamabad, the capital city of Pakistan, with 100% service area coverage to attain environmental and economic sustainability by defining dedicated waste collection streams to ensure quality material recovery under a cost-effective approach and modality. The innovative approach is applied to allocate the tonnage to various streams as per the city's current land use plan. The estimated/cost of the cleanliness services will be USD13.1 million per annum with an estimated per ton cost of USD 23. The establishment of the proposed material recovery facility (MRF) will process about 500 t/d of waste to produce 45 t/d compost and recover 130 t/d of recyclables. The environmentally friendly model saves 2.4 million tons of CO2‒eq/month from composting and recycling. The average economic potential from MRF and debris-crushing plants, including environmental benefit value, is calculated as USD 3.97 million annually. Recovery of services fee (70%) for various collection streams based on city land use and socio-economic conditions will generate revenue of USD 7.33 million annually. The total revenue will be USD 11.31 million (86% of total annual expenditures) to track the sector's self-sufficiency. To successfully reach the Sustainable Development Goals (SDGs) and Nationally Determined Contributions (NDCs), engaging the private sector from environmentally advanced economies to collaborate in the waste sector to enhance local technical capabilities is recommended.

Exploration of the Tunability of BRD4 Degradation by DCAF16 Trans-labelling Covalent Glues.

Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand the number of proteins that can be manipulated pharmacologically. Current strategies for targeted protein degradation are mostly limited in their target scope to proteins with preexisting ligands. Alternate modalities such as molecular glues, as exemplified by the glutarimide class of ligands for the CUL4CRBN ligase, have been mostly discovered serendipitously. We recently reported a trans-labelling covalent glue mechanism which we named 'Template-assisted covalent modification', where an electrophile decorated small molecule binder of BRD4 was effectively delivered to a cysteine residue on an E3 ligase DCAF16 as a consequence of a BRD4-DCAF16 protein-protein interaction. Herein, we report our medicinal chemistry efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 trans-labeling and subsequent BRD4 degradation efficiency. We discovered a decent correlation between the ability of the electrophilic small molecule to induce ternary complex formation between BRD4 and DCAF16 with its ability to induce BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation is optimal for DCAF16 recruitment and subsequent BRD4 degradation. Unlike the sensitivity of CUL4CRBN glue degraders to chemical modifications, the diversity of covalent attachments in this class of BRD4 glue degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a potential new avenue for a rational design of covalent glue degraders by introducing covalent warheads to known binders.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry.

Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.

Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5 µM; MMH259, IC50 =2.3 µM) and adult S. mansoni (MMH258, IC50 =2.1 µM; MMH373, IC50 =3.4 µM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.

Managing rare fractures - a case report of an isolated avulsion fracture of the peroneus longus tendon.

Avulsion fractures of the peroneus longus tendon are seldom seen and potentially can go undiagnosed during an emergency visit. If not managed appropriately, it can lead to chronic pain and suffering. This case report presents a 55-year-old postman who was seen in the clinic complaining of persistent pain over the instep of his right foot with no history of trauma. His pain was localized to the first metatarsophalangeal joint with some radiation to the heel. Magnetic resonance imaging revealed an isolated avulsion fracture of the first metatarsal, which was initially missed on X-ray. In this case, the patient was successfully treated with a mixture of steroid and local anesthetic injections. Following our intervention, the Manchester Oxford Foot Questionnaire was reduced from 33 to 0. The goal of this article is to raise awareness of this rare finding for doctors who may face this in accident and emergency (A&E), Orthopedic clinics or at a general practice (GP) practice.

The positive impact of GIRFT (getting it right first time) on arthroplasty services in times of COVID-19.

Background: This observational study evaluates the trends in arthroplasty services across National Health Services (NHS) following the COVID-19 pandemic about GIRFT (Getting it Right First Time) guidelines concerning National joint registry data (NJR data). Introduction: Since the advent of the COVID-19 crisis sustainability of elective arthroplasty services have become a burning question in NHS. Capacity crisis, unknown COVID-19 infection status, lack of ring-fenced beds, winter crisis, and unprecedented trauma have aggravated the situation further leading to severe impairment in quality of life and service provision. GIRFT guidelines have suggested a few solutions to this crisis and one of them is dividing the hospitals into Hot (trauma) and cold (elective) sites. Objectives: To review NJR data for pre and post COVID era along with the service structure of the hospital and test the hypothesis that whether redistribution of services into hot and cold sites is a possible solution for sustainable arthroplasty service across NHS. Methodology: A search was made into the NJR data from 2019, 2020, and 2021. The First 7 months were taken from each year I.e. From Ist January to 31st of July. A review of entries for arthroplasty was considered for all hospitals across England and Wales. Hospitals in Scotland, Ireland, and Isles of Man and major trauma centers were excluded.Any hospital that was recording at least 15 arthroplasty cases for 4 out of 7 months in 2021 was considered for review. A brief evaluation of their service structure was made, and hospitals were divided into Elective Centres (EC), Urgent Care Centres (UCC), and District General Hospitals (DGH) with in-house emergency services based on the information provided on their official website. In NJR data "completed operations by submission date" column was considered as a reference for data collection. A total of 1807, 1800, and 1810 were identified for 2019, 2020, and 2021 respectively.However, after applying inclusion criteria total number of entries was reduced to 120 hospitals. Data analysis and selection of hospitals were reviewed twice by two authors (MMK and AP) at different times to avoid any bias and reduce the chances of human error that can affect the outcome. A sub-analysis of data for the last 3 months (May, June, and July) was also performed for the respective years to get a better picture of arthroplasty trends and reduce the flaws of data interpretation. Ethical approval and data consideration: A formal approval was taken from the NJR team in the UK before the data processing was initiated. The data source being used was available for public review on the NJR website. The team was happy for us to process and evaluate the data as per needs of our study. However, they requested a disclaimer and appreciation note for the members of the NJR team and hospital personnel across the UK that have made the provision of data and subsequent analysis leading to this study feasible. Results: 18 EC were included. The mean number of cases recorded per center was 427, 68, 348 for 2019, 2020, and 2021 respectively.20 UCC were identified. The mean number of cases performed were 213, 24, and 195 in 2019, 2020, and 2021 respectively.Similarly, 60 DGH with emergency services were included and the average number of cases recorded were 194, 27, and 166 for 2019, 2020, and 2021 respectively. Compared to 2019 out of 148 DGH in 2019 only 60 can provide a sustainable arthroplasty service signifying a drop of 40% in 2021 in the number of DGH which are contributing to elective services. Conclusions: The overall productivity of theatres in terms of arthroplasty services has decreased since the reinitialization of services in 2021. There is a need of hour to divide the services into hot and cold sites in terms of A/E and elective centers to provide safe and uninterrupted provision of arthroplasty services and address long waiting times for patients. Provisional of ring-fenced beds and arthroplasty wards is more technically feasible in centers that are not providing in-house emergency admission pathways or are specialist, dedicated elective centers.

Discovery of HDAC6-Selective Inhibitor NN-390 with in Vitro Efficacy in Group 3 Medulloblastoma.

Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role in oncogenic transformation and metastasis. Through a second-generation structure-activity relationship (SAR) study, the design, and biological evaluation of the selective HDAC6 inhibitor NN-390 is reported. With nanomolar HDAC6 potency, >200-550-fold selectivity for HDAC6 in analogous HDAC isoform functional assays, potent intracellular target engagement, and robust cellular efficacy in cancer cell lines, NN-390 is the first HDAC6-selective inhibitor to show therapeutic potential in metastatic Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor often associated with leptomeningeal metastases and therapy resistance. MB stem cells contribute to these patients' poor clinical outcomes. NN-390 selectively targets this cell population with a 44.3-fold therapeutic margin between patient-derived Group 3 MB cells in comparison to healthy neural stem cells. NN-390 demonstrated a 45-fold increased potency over HDAC6-selective clinical candidate citarinostat. In summary, HDAC6-selective molecules demonstrated in vitro therapeutic potential against Group 3 MB.

Unnecessary magnetic resonance imaging of the knee: How much is it really costing the NHS?

AIMS AND OBJECTIVES: The aim of this study was to evaluate the indications for patients undergoing magnetic resonance imaging (MRI) of the knee prior to referral to an orthopaedic specialist and to ascertain whether these scans altered initial management. MATERIALS AND METHOD: A retrospective review of all referrals received by a single specialist knee surgeon over a 1-year period was performed. Patient demographics, relevant history, examination findings and past surgical procedures were documented. Patients having undergone Magnetic resonance imaging (MRI) prior to referral were identified and indications for the scans recorded. These were reviewed against The National health services (NHS) guidelines for Primary Care Physicians to identify if the imaging performed was appropriate in each case. RESULTS: A total of two sixty-one (261) patients were referred between 1st July 2018 and 30th June 2019. Eight seven out of two hundred and sixty-one patients (87/261) patients underwent knee MRI prior to referral. The average patient age was 53 years with male predominance (52 verses 35 females). Twenty-one out of eight seven patients under review (24%) underwent appropriate imaging prior to referral as per guidelines. However, only thirteen percent of patients underwent plain radiograph of knee before their scan. In cases where magnetic resonance imaging was not indicated, patients waited an average of twelve weeks between their scan and for a referral to be sent to a knee surgeon. CONCLUSION: Seventy six percent of patients referred to orthopaedics had inappropriate Magnetic resonance imaging arranged by their primary care physician. For a single consultant's referrals over 1 year these unnecessary MRI (magnetic resonance imaging) of knee cost National Health Services (NHS) £13,200. Closer adherence to the guidelines by primary care physicians will result in a financial saving, better patient experience and a more effective use of resources.

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia.

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.

Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype.

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (Ki = 0.7 nM) and inhibits the enzyme function (IC50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.

Barriers to diabetic foot care in a disadvantaged population: A qualitative assessment.

OBJECTIVE: We explored barriers to proper foot care in this population using a qualitative approach with focus group discussions (FGD). METHODS: Participants were recruited from clinics at a safety-net hospital in Atlanta, Georgia and stratified into two groups: diabetic foot ulcer (DFU) and minor amputation (below ankle). The FGDs addressed patient experience in receiving care with a goal of understanding: foot care knowledge, barriers to care, and preferred educational methods. Surveys were performed to supplement FGDs. RESULTS: Forty participants (90% Black) were enrolled. Dominant themes emerging from FGDs were: 1-Patients reported adequate understanding of recommended foot care practices; 2-Personal barriers to self-care included lack of motivation, high cost, poor insurance coverage of supplies, and difficulty limiting activity for proper offloading; 3-Hospital system barriers included difficulty making timely appointments and reaching a provider to arrange care; 4-Access to footcare-related information and services improved with greater disease severity. Participants stressed that improved access often came too late to alter their course. They expressed interest in developing peer support groups to facilitate learning and sharing information relating to DFU. CONCLUSION: We found that patients with DFU or minor amputations have adequate footcare-related knowledge, but personal and systemic barriers limited appropriate foot care.

Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting.

Histone deacetylases (HDACs) are an attractive therapeutic target for a variety of human diseases. Currently, all four FDA-approved HDAC-targeting drugs are nonselective, pan-HDAC inhibitors, exhibiting adverse side effects at therapeutic doses. Although selective HDAC inhibition has been proposed to mitigate toxicity, the targeted catalytic domains are highly conserved. Herein, we describe a series of rationally designed, conformationally constrained, benzanilide foldamers which selectively bind the catalytic tunnel of HDAC8. The series includes benzanilides, MMH371, MMH409, and MMH410, which exhibit potent in vitro HDAC8 activity (IC50 = 66, 23, and 66 nM, respectively) and up to 410-fold selectivity for HDAC8 over the next targeted HDAC. Experimental and computational analyses of the benzanilide structure docked with human HDAC8 enzyme showed the adoption of a low-energy L-shaped conformer that favors HDAC8 selectivity. The conformationally constrained HDAC8 inhibitors present an alternative biological probe for further determining the clinical utility and safety of pharmacological knockdown of HDAC8 in diseased cells.

Recent Advances in Chemical Biology Using Benzophenones and Diazirines as Radical Precursors.

The use of light-activated chemical probes to study biological interactions was first discovered in the 1960s, and has since found many applications in studying diseases and gaining deeper insight into various cellular mechanisms involving protein-protein, protein-nucleic acid, protein-ligand (drug, probe), and protein-co-factor interactions, among others. This technique, often referred to as photoaffinity labelling, uses radical precursors that react almost instantaneously to yield spatial and temporal information about the nature of the interaction and the interacting partner(s). This review focuses on the recent advances in chemical biology in the use of benzophenones and diazirines, two of the most commonly known light-activatable radical precursors, with a focus on the last three years, and is intended to provide a solid understanding of their chemical and biological principles and their applications.

Crystal structures of the synthetic inter-mediate 3-[(6-chloro-7H-purin-7-yl)meth-yl]cyclo-butan-1-one, and of two oxetanocin derivatives: 3-[(6-chloro-8,9-di-hydro-7H-purin-7-yl)meth-yl]cyclo-butan-1-ol and 3-[(6-chloro-9H-purin-9-yl)meth-yl]cyclo-butan-1-ol.

The crystal structures of an inter-mediate, C10H9ClN4O, 3-[(6-chloro-7H-purin-7-yl)meth-yl]cyclo-butan-1-one (I), and two N-7 and N-9 regioisomeric oxetanocin nucleoside analogs, C10H13ClN4O, 3-[(6-chloro-8,9-di-hydro-7H-purin-7-yl)meth-yl]cyclo-butan-1-ol (II) and C10H11ClN4O, 3-[(6-chloro-9H-purin-9-yl)meth-yl]cyclo-butan-1-ol (IV), are reported. The crystal structures of the nucleoside analogs confirmed the reduction of the N-7- and N-9-substituted cyclo-butano-nes with LiAl(OtBu)3 to occur with facial selectivity, yielding cis-nucleosides analogs similar to those found in nature. Reduction of the purine ring of the N-7 cyclo-butanone to a di-hydro-purine was observed for compound (II) but not for the purine ring of the N-9 cyclo-butanone on formation of compound (IV). In the crystal of (I), mol-ecules are linked by a weak Cl⋯O inter-action, forming a 21 helix along [010]. The helices are linked by offset π-π inter-actions [inter-centroid distance = 3.498 (1) Å], forming layers parallel to (101). In the crystal of (II), mol-ecules are linked by pairs of O-H⋯N hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked by O-H⋯N hydrogen bonds, forming chains along [001], which in turn are linked by C-H⋯π and offset π-π inter-actions [inter-centroid distance = 3.509 (1) Å], forming slabs parallel to the ac plane. In the crystal of (IV), mol-ecules are linked by O-H⋯N hydrogen bonds, forming chains along [101]. The chains are linked by C-H⋯N and C-H⋯O hydrogen bonds and C-H⋯π and offset π-π inter-actions [inter-centroid distance = 3.364 (1) Å], forming a supra-molecular framework.

Formulation, characterization and in vivo evaluation of Hedera helix L., topical dosage forms.

The purpose of this study was to prepare topical formulations of micro emulsion, gel and ointment containing the Hedera helix L. extracts against asthma and to evaluate the physicochemical characteristics. A validated HPLC method was used for the analysis of blood plasma. In-vivo studies of the drugs were compared in rabbit plasma with oral dosing. Stability studies were performed for 3 months. The results showed that formulations were stable. No Skin irritation observed on rabbits. The optimized micro emulsion and gel showed fast absorption. Maximal plasma concentration (cmax) and the maximal time to reach cmax (tmax) were 70.226µg/mL, 75.26µg/mL and 2 hours for the micro emulsion and gel, 90.11µg/mL and 1 hour for the oral drug syrup respectively. Pharmacokinetic parameters such as tmax, cmax and AUC of the selected formulations and oral dosing were significantly different (P < 0.01).