scholarly journals The next generation of RNA vaccines: self-amplifying RNA

2021 ◽  
Author(s):  
Anna Blakney
Keyword(s):  
Side Effects ◽  
Messenger Rna ◽  
Rapid Development ◽  
Next Generation ◽  
High Efficacy ◽  
Vaccine Platform ◽  
The Future ◽  
High Doses ◽  
The Stability

The global COVID-19 pandemic has brought tremendous momentum to the field of messenger RNA (mRNA) vaccines. The advantages of this vaccine platform, such as rapid development and high efficacy, resulted in mRNA vaccines being the first approved vaccines against COVID-19. Looking forward to the development of future vaccines, how can we make RNA vaccines even better? While improvements in the stability of the formulation and cost of the vaccine are inevitable, one of the main challenges is lowering the dose of RNA in order to avoid side effects associated with high doses of RNA. One way to do this is by using self-amplifying RNA (saRNA), a type of mRNA that encodes a replicase that copies the original strand of RNA once it’s in the cell. Here, we discuss the origins of saRNA, how it works in comparison to mRNA, current challenges in the field and the future of saRNA vaccines.

scholarly journals Formulation, Development and Assessment of Novel Phyto-Elastosomes Loaded with Devil’s Claw Extract

2021 ◽  
Author(s):  
Pascal Ntemi ◽  
Roderick B Walker ◽  
Sandile Khamanga
Keyword(s):  
Side Effects ◽  
Patient Adherence ◽  
Entrapment Efficiency ◽  
Cholesterol Content ◽  
Formulation Development ◽  
Charge Induction ◽  
Devil’S Claw ◽  
High Doses ◽  
The Stability ◽  
High Entrapment Efficiency

Abstract Background: Management of arthritis requires frequent administration of medications at high doses that may lead to unwanted side effects and diminished patient adherence to the therapy. Devil’s claw extract, a herbal medicine from the Kalahari sands possess similar therapeutic efficacy with less side effects as the commercialized NSAIDs. The objectives of this study were to formulate, develop and assess novel phyto-elastosomes loaded with Devil’s claw extract in order to combat the toxicity levels associated with Devil’s claw and enhance penetration of harpagoside to intended targeted site.Methods: Screening studies were undertaken to determine the ideal amount of Tween® 80, cholesterol, ethanol, diacetyl phosphate and the pH of the hydration medium necessary to produce stable Devil’s claw-loaded phyto-elastosomes. Parameters monitored were particle size, polydispersity index, zeta potential, entrapment efficiency and deformability index.Results: The use of 20 % v/v ethanol was sufficient to produce novel phyto-elastosomes capable of deforming with minimal size alterations. Hydration of thin films in acidic solution produced phyto-elastosomal dispersions with high entrapment efficiency. The presence of cholesterol impeded harpagoside entrapment and increased cholesterol content affected the stability of vesicles by causing agglomeration. Conversely, increasing Tween® 80 concentration promoted harpagoside entrapment. Diacetyl phosphate promoted the stability of vesicle through charge induction.Conclusions: Development of Devil’s claw loaded phyto-elastosomes is useful in ensuring harpagoside reach the target site of action in arthritis-affected patients. Incorporation of these elastic vesicles in transdermal dosage forms may significantly improve the management of arthritis in the near future.

scholarly journals High doses of immunoglobulin g in the therapy for severe forms of myasthenia gravis and Guillain-Barré syndrome

2006 ◽  
Vol 63 (1) ◽  
pp. 37-42
Author(s):  
Dragana Lavrnic ◽  
Marija Romic ◽  
Aleksandra Kacar ◽  
Vidosava Rakocevic-Stojanovic ◽  
Zorica Stevic ◽  
...  
Keyword(s):  
Side Effects ◽  
Myasthenia Gravis ◽  
Immunoglobulin G ◽  
Neurological Diseases ◽  
Ivig Therapy ◽  
Therapeutic Modality ◽  
Efficacy And Safety ◽  
High Efficacy ◽  
High Doses

Background/Aim. High doses of immunoglobulin G (IVIG) have been recognized as a very important therapeutic modality in the treatment of neurological diseases. The aim of this report was to present our experience in the treatment of severe forms of myasthenia gravis (MG) and Guillain-Barr? syndrome (GBS). Methods. We analyzed the efficacy and safety of immunoglobulin G therapy in 53 patients with severe forms of myasthenia gravis, and 27 patients with very severe forms of Guillain-Barr? syndrome. Results. At the end of the follow-up period, a significant improvement was noticed in 47 out of 53 patients with myasthenia gravis ( 88.7%). In the group of 27 patients with severe forms of Guillain-Barr? syndrome an improvement was registered in 19 patients (70.3%). The side effects of this therapy were mostly mild, manifested as headache, myalgia, skin rash, adynamia, and other clinically insignificant effects. No severe side effects were recognized. Conclusions. Our study clearly demonstrated the high efficacy of IVIG therapy in the treatment of severe forms of myastehnia gravis and Guillain-Barr? syndrome.

CLINICAL INVESTIGATIONS OF A LONG-ACTING OESTRIOL (POLYOESTRIOL PHOSPHATE)

1961 ◽  
Vol 38 (1) ◽  
pp. 73-87 ◽  
Author(s):  
Christian Lauritzen ◽  
Semih Velibese
Keyword(s):  
Side Effects ◽  
Phosphoric Acid ◽  
Quantitative Data ◽  
Water Soluble ◽  
Cholesterol Concentration ◽  
Experimental Investigations ◽  
Clinical Investigations ◽  
Prolonged Duration ◽  
High Doses ◽  
Long Acting

ABSTRACT A description is given of experimental investigations and preliminary clinical experience with the long-acting oestriol compound polyoestriol phosphate – a water-soluble polymere of oestriol and phosphoric acid. The compound seems to exert all the physiologically important effects of oestriol. Even with high doses the hormone causes no proliferation of the endometrium and no withdrawal bleeding. It has no untoward effect on metabolism. It decreases slightly the cholesterol concentration (to the extent of ⅓–⅕ of the effect produced by long-acting oestradiol esters). The compound has a wide therapeutic range. No side-effects have been observed. Doses of 10 mg or more have a prolonged duration. Additional prolongation of the effect is largely dependent on dosage. To ensure an effect lasting for 4 weeks 40 mg polyoestriol phosphate (corresponding with 30 mg oestriol) is required – an amount which roughly corresponds with physiological quantitative data. The compound, which involves an interesting new principle of prolongation, was most effectively used in the treatment of menopausal symptoms and genital organic disorders. For these indications it can be recommended without reservation.

Small Molecular Gemcitabine Prodrugs for Cancer Therapy

2020 ◽  
Vol 27 (33) ◽  
pp. 5562-5582 ◽  
Author(s):  
He Miao ◽  
Xuehong Chen ◽  
Yepeng Luan
Keyword(s):  
Drug Resistance ◽  
Side Effects ◽  
Anticancer Drug ◽  
Drug Stability ◽  
Effective Means ◽  
Active Form ◽  
Deoxycytidine Kinase ◽  
High Efficacy ◽  
Pyrimidine Nucleoside ◽  
Design And Synthesis

Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by sequential phosphorylation carried out by deoxycytidine kinase to mono-, di-, and triphosphate nucleotides with the last one as the active form. But the instability, drug resistance and toxicity severely limited its utilization in clinics. In the field of medicinal chemistry, prodrugs have proven to be a very effective means for elevating drug stability and decrease undesirable side effects including the nucleoside anticancer drug such as gemcitabine. Many works have been accomplished in design and synthesis of gemcitabine prodrugs, majority of which were summarized in this review.

The applications of next-generation sequencing (NGS) in drug development for cancer therapy

2020 ◽  
Vol 16 ◽  
Author(s):  
Pelin Telkoparan-Akillilar ◽  
Dilek Cevik
Keyword(s):  
Next Generation Sequencing ◽  
Drug Discovery ◽  
Cancer Therapy ◽  
Target Identification ◽  
Rapid Development ◽  
Next Generation ◽  
Biomedical Sciences ◽  
Dna And Rna ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background: Numerous sequencing techniques have been progressed since the 1960s with the rapid development of molecular biology studies focusing on DNA and RNA. Methods: a great number of articles, book chapters, websites are reviewed, and the studies covering NGS history, technology and applications to cancer therapy are included in the present article. Results: High throughput next-generation sequencing (NGS) technologies offer many advantages over classical Sanger sequencing with decreasing cost per base and increasing sequencing efficiency. NGS technologies are combined with bioinformatics software to sequence genomes to be used in diagnostics, transcriptomics, epidemiologic and clinical trials in biomedical sciences. The NGS technology has also been successfully used in drug discovery for the treatment of different cancer types. Conclusion: This review focuses on current and potential applications of NGS in various stages of drug discovery process, from target identification through to personalized medicine.

Dynamic Performance of High-Speed Electric Multiple Unit within Multi-Body System Simulation

2019 ◽  
Vol 12 (4) ◽  
pp. 339-349
Author(s):  
Junguo Wang ◽  
Daoping Gong ◽  
Rui Sun ◽  
Yongxiang Zhao
Keyword(s):  
High Speed ◽  
Rapid Development ◽  
Dynamic Performance ◽  
Body System ◽  
High Speed Railway ◽  
Evaluation Indexes ◽  
Actual Operation ◽  
Multiple Unit ◽  
The Stability ◽  
Multi Body

Background: With the rapid development of the high-speed railway, the dynamic performance such as running stability and safety of the high-speed train is increasingly important. This paper focuses on the dynamic performance of high-speed Electric Multiple Unit (EMU), especially the dynamic characteristics of the bogie frame and car body. Various patents have been discussed in this article. Objective: To develop the Multi-Body System (MBS) model of EMU, verify whether the dynamic performance meets the actual operation requirements, and provide some useful information for dynamics and structural design of the proposed EMU. Methods: According to the technical characteristics of a typical EMU, a MBS model is established via SIMPACK, and the measured data of China high-speed railway is taken as the excitation of track random irregularity. To test the dynamic performance of the EMU, including the stability and safety, some evaluation indexes such as wheel-axle lateral forces, wheel-axle lateral vertical forces, derailment coefficients and wheel unloading rates are also calculated and analyzed in detail. Results: The MBS model of EMU has better dynamic performance especially curving performance, and some evaluation indexes of the stability and safety have also reached China’s high-speed railway standards. Conclusion: The effectiveness of the proposed MBS model is verified, and the dynamic performance of the MBS model can meet the design requirements of high-speed EMU.

scholarly journals InsP7is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics

2020 ◽  
Vol 117 (32) ◽  
pp. 19245-19253 ◽  
Author(s):  
Soumyadip Sahu ◽  
Zhenzhen Wang ◽  
Xinfu Jiao ◽  
Chunfang Gu ◽  
Nikolaus Jork ◽  
...  
Keyword(s):  
Stress Responses ◽  
Messenger Rna ◽  
Control Process ◽  
Stem Cell Differentiation ◽  
Wild Type ◽  
Inositol Pyrophosphate ◽  
Body Dynamics ◽  
Processing Body ◽  
The Stability

Regulation of enzymatic 5′ decapping of messenger RNA (mRNA), which normally commits transcripts to their destruction, has the capacity to dynamically reshape the transcriptome. For example, protection from 5′ decapping promotes accumulation of mRNAs into processing (P) bodies—membraneless, biomolecular condensates. Such compartmentalization of mRNAs temporarily removes them from the translatable pool; these repressed transcripts are stabilized and stored until P-body dissolution permits transcript reentry into the cytosol. Here, we describe regulation of mRNA stability and P-body dynamics by the inositol pyrophosphate signaling molecule 5-InsP7(5-diphosphoinositol pentakisphosphate). First, we demonstrate 5-InsP7inhibits decapping by recombinant NUDT3 (Nudix [nucleoside diphosphate linked moiety X]-type hydrolase 3) in vitro. Next, in intact HEK293 and HCT116 cells, we monitored the stability of a cadre of NUDT3 mRNA substrates following CRISPR-Cas9 knockout ofPPIP5Ks(diphosphoinositol pentakisphosphate 5-kinases type 1 and 2, i.e.,PPIP5KKO), which elevates cellular 5-InsP7levels by two- to threefold (i.e., within the physiological rheostatic range). ThePPIP5KKO cells exhibited elevated levels of NUDT3 mRNA substrates and increased P-body abundance. Pharmacological and genetic attenuation of 5-InsP7synthesis in the KO background reverted both NUDT3 mRNA substrate levels and P-body counts to those of wild-type cells. Furthermore, liposomal delivery of a metabolically resistant 5-InsP7analog into wild-type cells elevated levels of NUDT3 mRNA substrates and raised P-body abundance. In the context that cellular 5-InsP7levels normally fluctuate in response to changes in the bioenergetic environment, regulation of mRNA structure by this inositol pyrophosphate represents an epitranscriptomic control process. The associated impact on P-body dynamics has relevance to regulation of stem cell differentiation, stress responses, and, potentially, amelioration of neurodegenerative diseases and aging.

scholarly journals STUDIES ON THE FUNCTION OF INTRACELLULAR RIBONUCLEASES

1966 ◽  
Vol 29 (3) ◽  
pp. 395-403 ◽  
Author(s):  
Takeshi Utsunomiya ◽  
Jay S. Roth
Keyword(s):  
Natural Products ◽  
Sodium Chloride ◽  
Rat Liver ◽  
Messenger Rna ◽  
Rnase Activity ◽  
Optimum Ph ◽  
Normal Rat ◽  
Pancreatic Rnase ◽  
The Stability ◽  
Normal Constituent

The RNase activity and properties of ribosome and polysome preparations from normal rat liver and some hepatomas have been examined. Polysome and ribosome preparations from the Novikoff, McCoy MDAB, and Dunning hepatomas had considerably higher specific RNase activity than corresponding preparations from normal rat liver, Novikoff ascites, or Morris 5123 hepatomas. The optimum pH of the RNase was approximately 8.5 for all samples tested, and the samples showed no evidence of latent RNase activity when treated with 3 M sodium chloride, EDTA, urea, or p-chloromercuribenzenesulfonic acid. The RNase activity appeared to be associated principally with breakdown products and/or subunits smaller than 80S. In the presence of Mg++ ions, subunits could reaggregate to form monomer ribosomes indistinguishable from the natural products, but some of the reassociated ribosomes could contain RNase activity which had been bound to the smaller particles. Similar results were obtained with spermine. In the hepatomas, evidence was obtained for the preexistence of considerable amounts of the smaller, RNase-containing subunits in the cell. When a small amount of crystalline bovine pancreatic RNase was added to partly dissociated ribosomes, the RNase was found only in association with the smaller subunits, and little or no enzyme was taken up by ribosomes or polysomes. The results have led to the conclusion that RNase is not a normal constituent of the ribosome or polysome, but that RNase may become associated with these particulates if dissociation and reassociation take place. Some implications of these findings for the stability of messenger RNA and for the mechanism of its breakdown are discussed.

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