scholarly journals Serotonergic Neurotransmission System Modulator, Vortioxetine, and Dopaminergic D2/D3 Receptor Agonist, Ropinirole, Attenuate Fibromyalgia-Like Symptoms in Mice

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2398
Author(s):  
Kinga Sałat ◽  
Anna Furgała-Wojas
Keyword(s):  
Pain Threshold ◽  
Intraperitoneal Administration ◽  
Unknown Etiology ◽  
Key Factors ◽  
Drug Candidates ◽  
Treatment And Prevention ◽  
Emotional Processes ◽  
Repurposed Drugs ◽  
Contemporary Medicine ◽  
Selection Of

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient’s key symptoms.

scholarly journals Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19

2021 ◽  
Author(s):  
Junzheng Wang ◽  
Jacob Levi ◽  
Leah Ellis ◽  
Andrew Hill
Keyword(s):  
Export Price ◽  
Equitable Access ◽  
Access To Treatment ◽  
Drug Candidates ◽  
Pharmaceutical Ingredients ◽  
Current Availability ◽  
Repurposed Drugs ◽  
Inhaled Budesonide ◽  
Selection Of ◽  
List Prices

Abstract Background Currently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programmes. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices. Methods We searched for repurposed drugs that have been approved by at least one of the WHO, FDA or NICE, or at least given emergency use authorisation or recommended for off-label prescription. Drug prices were searched for, for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab and imdevimab, and sarilumab using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. Results Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from $2.58 for IV dexamethasone (or $0.19 orally) and $4.34 for inhaled budesonide. No export price data was available for baricitinib, tocilizumab, casirivimab and imdevimab or sarilumab, but courses of these treatments are priced highly, ranging from $6.67 for baricitinib to $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries. Conclusions Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whilst monoclonal antibodies and IV treatment courses are more expensive.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Mitophagy Modulation, a New Player in the Race against ALS

2021 ◽  
Vol 22 (2) ◽  
pp. 740
Author(s):  
Enrique Madruga ◽  
Inés Maestro ◽  
Ana Martínez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Unknown Etiology ◽  
Drug Candidates ◽  
Relevant Evidence ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

scholarly journals A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

Sensors ◽  
2021 ◽  
Vol 21 (14) ◽  
pp. 4832
Author(s):  
Ann-Katrine Jakobsen ◽  
Josephine Geertsen Keller ◽  
María Gonzalez ◽  
Endika Martin-Encinas ◽  
Francisco Palacios ◽  
...  
Keyword(s):  
Dna Damage ◽  
In Vitro Selection ◽  
Main Function ◽  
Screening System ◽  
Drug Candidates ◽  
Topoisomerase 1 ◽  
High Throughput Drug Screening ◽  
Dual Sensor ◽  
Selection Of

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.

The overview of existing knowledge on medical cannabis plants growing  

2021 ◽  
Author(s):  
Matěj Malík ◽  
Jiří Velechovský ◽  
Pavel Tlustoš
Keyword(s):  
Plant Nutrition ◽  
Modern Medicine ◽  
Essential Elements ◽  
Pharmaceutical Sciences ◽  
Medical Cannabis ◽  
Key Factors ◽  
Factors Affecting ◽  
Cultivation Technology ◽  
Active Substances ◽  
Selection Of

The use of cannabis for medicinal purposes dates back well before the era of modern medicine, but in recent years research into the use of medical cannabis in the medical and pharmaceutical sciences has grown significantly. In European countries, most cannabis plants have been and still are grown for industrial purposes. For this reason, hemp cultivation technology is relatively well researched, while little is known about the key factors affecting cannabis cultivation for medical purposes. The active substances of cannabis plant targeted by this review are called phytocannabinoids. The biosynthesis of phytocannabinoids is relatively well understood, but the specific environmental factors that influence the type and number of phytocannabinoids have been much less studied. Indoor or greenhouse cultivation, which uses automated lighting, ventilation, irrigation systems and complex plant nutrition has become much more sophisticated and appears to be the most effective method for producing medical cannabis. There are many different cultivation systems for cannabis plants, but one of the essential elements of the process is an optimal plant nutrition and selection of fertilisers to achieve it. This review summarises the existing knowledge about phytocannabinoid biosynthesis and the conditions suitable for growing plants as sources of medical cannabis. This review also attempts to delineate how nutrient type and bioavailability influences the synthesis and accumulation of specific phytocannabinoids based on contemporary knowledge of the topic.  

Opportunity zones: Do tax benefits go to the most distressed communities?

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
James R. Barth ◽  
Yanfei Sun ◽  
Shen Zhang
Keyword(s):  
African American ◽  
Family Income ◽  
Tax Incentives ◽  
Poverty Rate ◽  
Key Factors ◽  
Median Family Income ◽  
Content Type ◽  
Explanatory Factors ◽  
Tax Benefits ◽  
Selection Of

Purpose The exact criteria used by state governors for choosing opportunity zones (OZs) are not publicly available. This paper aims to examine whether state governors selected the most distressed communities, or those with the highest proportions of minorities, as OZs. Design/methodology/approach This paper compares the distressed communities chosen as OZs in states throughout the country to an equal number of those eligible distressed communities but not selected. Moreover, this paper uses regression analysis to determine whether the poverty rate, median family income, population, percentage of population that is minority and the percentage of population that is African American are significant explanatory factors in the choice of OZs. Findings After describing the tax incentives for investing in OZs, this paper documents that governors did not select many of the most distressed communities, or those with high proportions of minorities, in their individual states. Originality/value This paper describes in some detail the way in which investors may generate tax benefits by investing in eligible property or businesses in OZs. It also examines the extent to which the degree of poverty and the percentage of the population that is minority (and African American) were key factors in the selection of OZs. It arises an issue that the chosen communities are not necessarily those most in need of more investment or those heavily populated by minorities, particularly African Americans.

scholarly journals Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

2021 ◽  
Author(s):  
Julianne Tieu ◽  
Siddhee Sahasrabudhe ◽  
Paul Orchard ◽  
James Cloyd ◽  
Reena Kartha
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Candidates ◽  
Target Patient Population ◽  
Site Of Action ◽  
Repurposed Drugs ◽  
Gait Disturbances ◽  
Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

scholarly journals Why We Go Where We Go: Profiling User Decisions on Choosing POIs

2020 ◽  
Author(s):  
Renjun Hu ◽  
Xinjiang Lu ◽  
Chuanren Liu ◽  
Yanyan Li ◽  
Hao Liu ◽  
...  
Keyword(s):  
Key Factors ◽  
Real World Data ◽  
Decision Factors ◽  
Point Of Interest ◽  
Learning Factor ◽  
Poi Recommendation ◽  
Key Factor ◽  
Selection Of ◽  
Decision Structures

While Point-of-Interest (POI) recommendation has been a popular topic of study for some time, little progress has been made for understanding why and how people make their decisions for the selection of POIs. To this end, in this paper, we propose a user decision profiling framework, named PROUD, which can identify the key factors in people's decisions on choosing POIs. Specifically, we treat each user decision as a set of factors and provide a method for learning factor embeddings. A unique perspective of our approach is to identify key factors, while preserving decision structures seamlessly, via a novel scalar projection maximization objective. Exactly solving the objective is non-trivial due to a sparsity constraint. To address this, our PROUD adopts a self projection attention and an L2 regularized sparse activation to directly estimate the likelihood of each factor to be a key factor. Finally, extensive experiments on real-world data validate the advantage of PROUD in preserving user decision structures. Also, our case study indicates that the identified key decision factors can help us to provide more interpretable recommendations and analyses.

scholarly journals Screening Strategies and Methods for Better Off-Target Liability Prediction and Identification of Small-Molecule Pharmaceuticals

2018 ◽  
Vol 24 (1) ◽  
pp. 1-24 ◽  
Author(s):  
Terry R. Van Vleet ◽  
Michael J. Liguori ◽  
James J. Lynch ◽  
Mohan Rao ◽  
Scott Warder
Keyword(s):  
Data Sets ◽  
Multiple Sources ◽  
Drug Candidates ◽  
Critical Gap ◽  
Screening Strategies ◽  
Feasible Option ◽  
Stage Development ◽  
Integrated Screening ◽  
Expensive Process ◽  
Selection Of

Pharmaceutical discovery and development is a long and expensive process that, unfortunately, still results in a low success rate, with drug safety continuing to be a major impedance. Improved safety screening strategies and methods are needed to more effectively fill this critical gap. Recent advances in informatics are now making it possible to manage bigger data sets and integrate multiple sources of screening data in a manner that can potentially improve the selection of higher-quality drug candidates. Integrated screening paradigms have become the norm in Pharma, both in discovery screening and in the identification of off-target toxicity mechanisms during later-stage development. Furthermore, advances in computational methods are making in silico screens more relevant and suggest that they may represent a feasible option for augmenting the current screening paradigm. This paper outlines several fundamental methods of the current drug screening processes across Pharma and emerging techniques/technologies that promise to improve molecule selection. In addition, the authors discuss integrated screening strategies and provide examples of advanced screening paradigms.

scholarly journals Unified theory of beam bending within flexoelectricity with including piezoelectricity

2020 ◽  
Vol 310 ◽  
pp. 00063
Author(s):  
Vladimir Sladek ◽  
Jan Sladek
Keyword(s):  
Shear Deformation ◽  
Deformation Theory ◽  
Shear Deformation Theory ◽  
Electric Polarization ◽  
Unified Theory ◽  
Key Factors ◽  
Governing Equations ◽  
Proper Selection ◽  
Beam Bending ◽  
Selection Of

The behaviour of small size dielectric elastic beams is described within higher-grade theory with including electric polarization. The coupling between strain gradients and polarization is incorporated into the constitutive laws in the form of flexoelectricity, while piezoelectricity is involve in the classical form. Both the governing equations and boundary conditions are derived using variational formulation for electro-elastic continuous media and deformation assumptions employed in three various beam bending theories such as the classical theory (Euler-Bernoulli theory), the 1st order shear deformation theory (Timoshenko theory) and 3rd order shear deformation theory. The unified formulation allows switching between theories with various bending assumptions by a proper selection of two key factors.

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