Drug Strategy Research Articles

Marine bacterial exopolysaccharide EPS11 inhibits migration and invasion of liver cancer cells by directly targeting collagen I

Many natural polysaccharides have significant anticancer activity with low toxicity, but the complex chemical structures make in-depth studies of the involved mechanisms extremely difficult. The purpose of this study was to investigate the effect of the marine bacterial exopolysaccharide (exopolysaccharide 11 [EPS11]) on liver cancer metastasis to explore the underlying target protein and molecular mechanism. We found that EPS11 significantly suppressed cell adhesion, migration, and invasion in liver cancer cells. Proteomic analysis showed that EPS11 induced downregulation of proteins related to the extracellular matrix–receptor interaction signaling pathway. In addition, the direct pharmacological target of EPS11 was identified as collagen I using cellular thermal shift assays. Surface plasmon resonance and pull-down assays further confirmed the specific binding of EPS11 to collagen I. Moreover, EPS11 was shown to inhibit tumor metastasis by directly modulating collagen I activity via the β1-integrin–mediated signaling pathway. Collectively, our study demonstrated for the first time that collagen I could be a direct pharmacological target of polysaccharide drugs. Moreover, directly targeting collagen I may be a promising strategy for finding novel carbohydrate-based drugs.

Combined Neuroprotective Strategies Blocked Neurodegeneration and Improved Brain Function in Senescence-Accelerated Mice.

Increase in the quality of life, combined with drug strategies, has been studied as possibilities for improving memory and delaying the onset of neurodegenerative diseases. A previous study published by the group of the authors has shown that microdose lithium and enriched environment can improve memory in both mice and humans. To elucidate this relationship better, this study aimed to evaluate whether the chronic combination of these two strategies could increase healthy aging in Senescence Accelerated Mouse-Prone 8 (SAMP8). Animals were submitted to either one or both of these strategies until the age of 10 months when they were anesthetized and killed and their hippocampus was extracted. The untreated SAMP-8 group exhibited worse memory and reduced neuronal density with greater neurodegeneration and increased amyloid-β plaque density compared with the control group. Moreover, significant alterations in proteins related to long-term potentiation, such as, synaptophysin and brain-derived neurotrophic factor (BDNF), were observed in this group. The strategies used in the study maintained long-term memory, reduced anxiety, and increased neuroprotection. Both strategies were efficient in reducing neurodegeneration and increasing parameters related to memory maintenance. In many experiments, the combination of the two strategies was more effective in improving healthy aging. This study sheds light on the combination of strategies that choose to improve the quality of life and drugs with low side effects. Moreover, it opens perspectives for a new field of study for healthy aging.

Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival.

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.

Sequences of biological treatments for patients with moderate-to-severe rheumatoid arthritis in the era of treat-to-target in China: a cost-effectiveness analysis.

Biologic disease-modifying antirheumatic drugs (bDMARDs) are recommended to be added in sequentially in the treatment of moderate-to-severe rheumatoid arthritis (RA). All these drugs, however, are substantially more expensive than conventional synthetic DMARDs throughout the world, including in China. The objective of this study is to evaluate the cost-effectiveness of treatment sequences of bDMARDs for patients with moderate-to-severe rheumatoid arthritis from the Chinese healthcare system perspective. An individual patient simulation model was used to track the course of patients from first treatment through switches to further lines in a sequence. The comparator treatment sequence commenced with methotrexate, followed by non-biologic therapy. The intervention sequences were assumed to be the combinations of bDMARDs available, followed by non-biologic therapy. Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated. Univariable and probabilistic sensitivity analyses and scenario analyses were performed to evaluate the model uncertainty. Compared with the comparator treatment sequence, bDMARDs sequences were associated with more life years, QALYs, and cost. These produced ICERs ranged from $27,441.36/QALY to $40,149.2/QALY, above the willingness-to-pay threshold of $10,378 per QALY. The uncertainty analyses and the scenario analyses confirmed the result of the base case analysis. From the perspective of the Chinese healthcare system, bDMARDs sequences are estimated not to be cost-effective compared with conventional synthetic disease-modifying antirheumatic drug strategy for patients with moderate-to-severe RA at a WTP threshold of $10,378 per QALY. Price reductions are warranted to make bDMARDs cost-effective and affordable.

The sector is ready, and the community needs Australian alcohol and other drug treatment services to ask about sexuality and gender identity.

Sexuality and gender diverse Australians are a priority population in federal and state-based alcohol and other drug (AOD) strategies. Research evidence shows higher prevalence of AOD use by lesbian, gay, bisexual, transgender and queer (LGBTQ) people, riskier use and a higher proportion have accessed AOD treatment. Despite these disparities, Australian AOD treatment services do not routinely collect data on sexuality or gender identity. As a result, the treatment needs, experiences and outcomes of LGBTQ people remain largely invisible. The Australian Bureau of Statistics' recently released standardised indicators for the recording of sex, gender, variations of sex characteristics and sexual orientation presents an opportunity for the AOD sector to implement inclusive data collection as a foundational step towards achieving policy priorities for LGBTQ people. This commentary includes an implementation case study from the New South Wales non-government AOD treatment sector, where sexuality and gender identity indicators have been collected since 2016.

Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice

Alcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking.

Who would try (or use more) cannabis if it were legal?

This study sought to determine: (i) whether decriminalisation of cannabis use would increase the proportion who would try the drug; and (ii) the proportion who would use more cannabis; and (iii) explore their characteristics. Australian National Drug Strategy Household surveys were used to address (i)-(iii). Significant independent predictors of (i) and (ii) were identified using logistic regression. An estimated 4.2% of the population aged 14 and over (n=882 708) who have never tried cannabis before would try it, if use of the drug were made legal, while 2.6% of the population aged 14 and over (537 000) would use more cannabis if its use were made legal. Respondents were more likely to say they would try cannabis if they were male, younger or suffered from a mild, moderate and/or severe level of psychological stress. Respondents were more likely to say they would use more cannabis if they were male, younger, psychologically stressed and not currently frequent users of the drug. Decriminalisation of cannabis use is likely to result in an increase in consumption of the drug among young people with mental health problems. If cannabis use is decriminalised, Australian State and Territory Governments should make provision for a possible increase in demand for drug treatment and for public education on the risks associated with frequent/prolonged cannabis use.

Advances and Limitations of Antibody Drug Conjugates for Cancer.

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

Age-related trends in cannabis use in Australia. Findings from a series of large nationally representative surveys

AimWe examine age-related trends in past-year cannabis use in a series of nationally representative surveys in Australia. MethodsWe analysed data from the largest nationally representative survey in Australia collected between 2001 and 2019 (National Drug Strategy Household Survey [NDSHS]; N = 157,151). Prevalence of past-year daily/occasional (non-daily)/non-use of cannabis use were estimated using weighted multinomial logistic regression and predicted marginal probabilities. Difference-in-difference analysis was used to examine if trends of cannabis use across age groups were different. ResultsThe youngest age group (14–17 s) witnessed the largest increase in past-year abstinence rate from 79% to 92% from 2001 to 2019 (p < .003); the increase in abstinent rate among the 18–24 and 25–39 were relatively moderate (from 68 to 76% and from 81% to 84% respectively; p < .003). The abstinent rate among the 40–54 s and 55–74 s decreased significantly from 93% to 90% and from 99% to 95% respectively (p < .003). There were similar diverging trends in occasional and daily cannabis use, with decreases in both patterns of use observed among the younger age group (14–17 s and 18–25 s) but increases among the older age group (40–54 s and 55–74 s). ConclusionThere is a diverging trend in cannabis use among younger and older age groups in Australia between 2001 and 2019. Cannabis use substantially decreased among the youngest age group (14–17 s) but modestly increased among older people (55–74 s).

Antiretroviral Drugs in African Surface Waters: Prevalence, Analysis, and Potential Remediation.

The sources, ecotoxicological impact, and potential remediation strategies of antiretroviral drugs (ARVDs) as emerging contaminants in surface waters are reviewed based on recent literature. The occurrence of ARVDs in water bodies raises concern because many communities in Africa depend on rivers for water resources. Southern Africa is a potential hotspot regarding ARVD contamination due to relatively high therapeutic application and detection thereof in water bodies. Efavirenz and nevirapine are the most persistent in effluents and are prevalent in surface water based on environmental concentrations. Whereas the highest concentration of efavirenz reported in Kenya was 12.4 µg L-1 , concentrations as high as 119 and 140 µg L-1 have been reported in Zambia and South Africa, respectively. Concentrations of ARVDs ranging from 670 to 34 000 ng L-1 (influents) and 540 to 34 000 ng L-1 (effluents) were determined in wastewater treatment plants in South Africa, compared with Europe, where reported concentrations range from less than limit of detection (LOD) to 32 ng L-1 (influents) and less than LOD to 22 ng L-1 (effluents). The present African-based review suggests the need for comprehensive toxicological and risk assessment of these emerging pollutants in Africa, with the intent of averting environmental hazards and the development of sustainable remediation strategies. Environ Toxicol Chem 2022;41:247-262. © 2021 SETAC.

Development of Vancomycin Delivery Systems Based on Autologous 3D Platelet-Rich Fibrin Matrices for Bone Tissue Engineering.

Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues. Vancomycin hydrochloride (VANKA) is used to treat severe Staphylococcal infections but its absorption in the target tissue after oral administration is low; therefore, in this study, we have developed and analyzed two kinds of VANKA carriers—liposomes and microparticles in 3D PRF matrices. The adjustment, characterization, and analysis of VANKA carriers in 3D PRF scaffolds is carried out in terms of encapsulation efficiency, drug release kinetics and antibacterial activity; furthermore, we have studied the micro- and macrostructure of the scaffolds with microtomography.

Pathways to drug prevalence estimation: synthesizing three comments on triangulation.

Pathways to drug prevalence estimation: synthesizing three comments on triangulation.

Liposome Characterization, Applications and Regulatory landscape in US

Liposomes are lipid based drug carrier whose therapeutic performance depends on their structure. Liposomes offer several advantages over the conventional drug like target drug delivery, reduced toxicity, and extended pharmacokinetics. Characterization and Identification of critical attribute of liposomal formulation and suitable strategies for control during product development is important for quality of the liposomal drug product. This paper discusses the current status of the liposomal drug product and strategy used in regulating liposome product. Despite of lack of regulatory guidelines many liposome formulations get approved which shows the potential of liposome drug products.

Anti-thymocyte globulin with CsA and MMF as GVHD prophylaxis in nonmyeloablative HLA-mismatched allogeneic HCT.

Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting.

Patterns and Prevalence of Daily Tobacco Smoking in Australia by Industry and Occupation: 2007-2016.

Australian workers' daily tobacco smoking over time was examined by industry and occupation, to identify factors associated with high and/or low prevalence. Secondary analyses of 2007, 2010, 2013, and 2016 National Drug Strategy Household Surveys were undertaken (pooled n = 49 395). Frequency analyses informed subsequent modeling of select industries and occupations. Four logistic regression models estimated adjusted effects of demographics on daily smoking in industries with high (≥20%) and low (≤15%) daily smoking prevalence and occupations with high (≥20%) and low-moderate (<20%) daily smoking prevalence. The sample comprised 55.7% men, 34.1% 25-39-year-olds, 31.4% New South Wales residents, 70.1% metropolitan residents, 66.9% high socioeconomic status workers, and 70.6% with low psychological distress. Daily smoking prevalence differed by industry and occupation in 2007, generally decreasing between 2007 and 2016. In high prevalence industries, daily smoking was associated with male gender and age (25-39-year-olds) and in low prevalence industries with males and nonmetropolitan workers. In high prevalence occupations, daily smoking was associated with males, female nonmetropolitan workers, and age 25-39 years and in low-moderate prevalence occupations with nonmetropolitan workers and negatively associated with females aged 14-24 years. In all models, increased odds of daily smoking were associated with low socioeconomic status and very high psychological distress. Low socioeconomic status and very high psychological distress were risk factors for daily smoking regardless of industry, occupation, or high preexisting smoking prevalence. Targeted, as well as universal, interventions are required for workplaces and workers with greatest smoking vulnerability and least smoking cessation progress. Specific strategies are warranted for identified industries, occupations, and subgroups with increased odds of daily tobacco smoking. Industries and occupations with low-moderate smoking prevalence may confer workers some protection but are not without risk; some subgroups in these settings (eg, nonmetropolitan areas) had elevated daily smoking risk. Hence, the following are supported: (1) universal interventions directed at low socioeconomic workers and workers with very high psychological distress regardless of workplace; (2) interventions targeted at high prevalence industries; (3) cessation efforts targeted for young workers in high prevalence industries and occupations; and (4) focused interventions addressing specific needs of nonmetropolitan at-risk workers in low prevalence industries.

Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach.

Simple SummaryHigh levels of Heat shock proteins (Hsps) in specific cancers are usually linked to a poor prognosis, tumor progression, invasiveness, and resistance to treatment. Chaperone inhibition could therefore be toxic for cancer cells due to their high dependence on chaperone activity to survive. This study shows the potential to repurpose the small chemical compound pinaverium bromide, currently used to treat functional gastrointestinal disorders, as a possible antitumor drug since it displays a marked toxicity against two melanoma cell lines without affecting the viability of fibroblast and primary melanocytes. This compound interacts with structural regions shared by representatives of the Hsp70 and Hsp110 families, inhibiting the substrate remodeling ability of the Hsp70 system in vitro and in a cellular context.Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.

Label-Free Multiphoton Microscopy for the Detection and Monitoring of Calcific Aortic Valve Disease.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease. CAVD results in a considerable socio-economic burden, especially considering the aging population in Europe and North America. The only treatment standard is surgical valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. Novel diagnostic techniques and biomarkers for early detection and monitoring of CAVD progression are thus a pressing need. Additionally, non-destructive tools are required for longitudinal in vitro and in vivo assessment of CAVD initiation and progression that can be translated into clinical practice in the future. Multiphoton microscopy (MPM) facilitates label-free and non-destructive imaging to obtain quantitative, optical biomarkers that have been shown to correlate with key events during CAVD progression. MPM can also be used to obtain spatiotemporal readouts of metabolic changes that occur in the cells. While cellular metabolism has been extensively explored for various cardiovascular disorders like atherosclerosis, hypertension, and heart failure, and has shown potential in elucidating key pathophysiological processes in heart valve diseases, it has yet to gain traction in the study of CAVD. Furthermore, MPM also provides structural, functional, and metabolic readouts that have the potential to correlate with key pathophysiological events in CAVD progression. This review outlines the applicability of MPM and its derived quantitative metrics for the detection and monitoring of early CAVD progression. The review will further focus on the MPM-detectable metabolic biomarkers that correlate with key biological events during valve pathogenesis and their potential role in assessing CAVD pathophysiology.

Positive selection as a key player for SARS-CoV-2 pathogenicity: Insights into ORF1ab, S and E genes

The human β-coronavirus SARS-CoV-2 epidemic started in late December 2019 in Wuhan, China. It causes Covid-19 disease which has become pandemic. Each of the five-known human β-coronaviruses has four major structural proteins (E, M, N and S) and 16 non-structural proteins encoded by ORF1a and ORF1b together (ORF1ab) that are involved in virus pathogenicity and infectivity. Here, we performed detailed positive selection analyses for those six genes among the four previously known human β-coronaviruses and within 38 SARS-CoV-2 genomes to assess signatures of adaptive evolution using maximum likelihood approaches. Our results suggest that three genes (E, S and ORF1ab genes) are under strong signatures of positive selection among human β-coronavirus, influencing codons that are located in functional important protein domains. The E protein-coding gene showed signatures of positive selection in two sites, Asp 66 and Ser 68, located inside a putative transmembrane α-helical domain C-terminal part, which is preferentially composed by hydrophilic residues. Such Asp and Ser sites substitutions (hydrophilic residues) increase the stability of the transmembrane domain in SARS-CoV-2. Moreover, substitutions in the spike (S) protein S1 N-terminal domain have been found, all of them were located on the S protein surface, suggesting their importance in viral transmissibility and survival. Furthermore, evidence of strong positive selection was detected in three of the SARS-CoV-2 nonstructural proteins (NSP1, NSP3, NSP16), which are encoded by ORF1ab and play vital roles in suppressing host translation machinery, viral replication and transcription and inhibiting the host immune response. These results are insightful to assess the role of positive selection in the SARS-CoV-2 encoded proteins, which will allow to better understand the virulent pathogenicity of the virus and potentially identifying targets for drug or vaccine strategy design

Modern Approaches to the Elimination of Visceral Pain

In modern medicine, one of the most common situations requiring emergency care is biliary or renal colic as a manifestation of abdominal pain syndrome. In both cases, smooth muscle spasm plays an important role in the pathogenesis of visceral pain syndrome. Taking into account the fact that, regardless of the chosen treatment tactics, at the first stage it is necessary to stop pain, the question arises about the choice of a drug strategy for the relief of these conditions. It used to be thought that the more intense the pain, the more indications for the prescription of narcotic drugs, which were considered reference analgesics. In recent years, the world has become embroiled in an «opioid crisis». This prompted clinicians to consider the use of drugs from other groups, namely, non-steroidal anti-inflammatory drugs and antispasmodics alone or in combination, which turned out to be no less effective and, often, safer in comparison with narcotic analgesics.&#x0D; New opportunities for effective treatment of visceral pain are opened by the drug Neospastil® (PJSC «Pharmaceutical Company «Darnitsa»), which combines the benefits of nonsteroidal anti-inflammatory drugs (ketorolac tromethamine) with antispasmodic effect of cholinolytics, ganglioblockers and phenytoin phenytoin. The drug increases the effectiveness of analgesia, as well as the control of muscle spasm.

Changing patterns and prevalence of daily tobacco smoking among Australian workers: 2007–2016

ObjectiveTo map patterns and prevalence of daily smoking among employed Australians over time. MethodsData from four waves of the triennial National Drug Strategy Household Survey (2007, 2010, 2013 and 2016) were used to assess daily smoking. Frequency analyses and significance testing examined smoking prevalence by sex, age, state, remoteness, Indigeneity, socioeconomic status (SES) and psychological distress. Logistic regression models estimated adjusted effects of demographics on smoking prevalence. ResultsWorkers’ daily smoking prevalence reduced by 32% between 2007 and 2016. The adjusted model showed the lowest smoking reductions among men and non‐metropolitan workers. Other interaction effects showed the highest daily smoking rates for: male workers aged 14–39 years; low SES non‐metropolitan workers; and low SES workers aged 40–59 years. ConclusionsSpecific workplace policies, prevention and intervention strategies are warranted for male workers, especially those aged 14–39; non‐metropolitan workers, especially low SES rural workers; and low SES workers especially 40–59‐year‐olds. Implications for public healthIn spite of significant smoking reductions among workers over time, reductions were unevenly distributed. Tailored, innovative workplace prevention and intervention strategies that apply principles of proportionate universalism and address individual, workplace settings and cultural factors are warranted to reduce smoking disparities among male, rural and low SES workers.