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Methodist DeBakey Cardiovascular Journal 2023Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled... (Review)
Review
Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled vasodilation. Vasoplegia may occur due to various conditions, including cardiac failure, sepsis, and post-cardiac surgery. In the cardiac cohort, multiple risk factors for vasoplegia have been identified. Several factors contribute to the pathophysiology of this condition, and various mechanisms have been proposed, including nitric oxide, adenosine, prostanoids, endothelins, the renin-angiotensin-aldosterone system, and hydrogen sulfide. Early identification and prompt management of vasoplegia is crucial to prevent development of shock. This review expands upon the different vasopressors used in management of vasoplegia, including catecholamines such as norepinephrine, dopamine, epinephrine, phenylephrine, and other agents including vasopressin, methylene blue, angiotensin II, hydroxocobalamin, vitamin C, thiamine, and corticosteroids (ie, hydrocortisone). It also emphasizes the importance of conducting further research and making advancements in treatment regimens for vasoplegia.
Topics: Humans; Vasoplegia; Epinephrine; Norepinephrine; Phenylephrine; Sepsis
PubMed: 37547893
DOI: 10.14797/mdcvj.1245 -
Proceedings of the National Academy of... Aug 2022The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted...
The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8 T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.
Topics: Amino Alcohols; Animals; Antigens; CD8-Positive T-Lymphocytes; Cancer Vaccines; Decanoates; Immunologic Memory; Liposomes; Lymph Nodes; Mice; Nanoparticles; Neoplasm Metastasis; Neoplasms; Ovalbumin; mRNA Vaccines
PubMed: 35969778
DOI: 10.1073/pnas.2207841119 -
Journal of Critical Care Feb 2021Calculating equipotent doses between vasopressor agents is necessary in clinical practice and research pertaining to the management of shock. This scoping review... (Review)
Review
PURPOSE
Calculating equipotent doses between vasopressor agents is necessary in clinical practice and research pertaining to the management of shock. This scoping review summarizes conversion ratios between vasopressors and provides a formula to incorporate into study designs.
MATERIALS AND METHODS
Medline, Embase and Web of Science databases were searched from inception to 21st October 2020. Additional papers were obtained through bibliography searches of retrieved articles. Two investigators assessed articles for eligibility. Clinical trials comparing the potency of at least two intravenous vasopressors (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, metaraminol or angiotensin II), with regard to an outcome of blood pressure, were selected.
RESULTS
Of 16,315 articles, 21 were included for synthesis. The range of conversion ratios equivalent to one unit of norepinephrine were: epinephrine (0.7-1.4), dopamine (75.2-144.4), metaraminol (8.3), phenylephrine (1.1-16.3), vasopressin (0.3-0.4) and angiotensin II (0.07-0.13). The following formula may be considered for the calculation of norepinephrine equivalents (NE) (all in mcg/kg/min, except vasopressin in units/min): NE = norepinephrine + epinephrine + phenylephrine/10 + dopamine/100 + metaraminol/8 + vasopressin*2.5 + angiotensin II*10.
CONCLUSION
A summary of equipotent ratios for common vasopressors used in clinical practice has been provided. Our formula may be considered to calculate NE for studies in the intensive care unit.
Topics: Epinephrine; Humans; Norepinephrine; Phenylephrine; Shock; Vasoconstrictor Agents
PubMed: 33220576
DOI: 10.1016/j.jcrc.2020.11.002 -
The Enzymes 2020Choline oxidase catalyzes the four-electron, two-step, flavin-mediated oxidation of choline to glycine betaine. The enzyme is important both for medical and... (Review)
Review
Choline oxidase catalyzes the four-electron, two-step, flavin-mediated oxidation of choline to glycine betaine. The enzyme is important both for medical and biotechnological reasons, because glycine betaine is one among a limited number of compatible solutes used by cells to counteract osmotic pressure. From a fundamental standpoint, choline oxidase has emerged as one of the paradigm enzymes for the oxidation of alcohols catalyzed by flavoproteins. Mechanistic, structural, and computational studies have elucidated the mechanism of action of the enzyme from Arthrobacter globiformis at the molecular level. Both choline and oxygen access to the active site cavity are gated and tightly controlled. Amino acid residues involved in substrate binding, and their contribution, have been identified. The mechanism of choline oxidation, with a hydride transfer reaction, an asynchronous transition state, the formation and stabilization of an alkoxide transient species, and a quantum mechanical mode of reaction, has been elucidated. The importance of nonpolar side chains for oxygen localization and of the positive charge harbored on the substrate for activation of oxygen for reaction with the reduced flavin have been recognized. Interesting phenomena, like the formation of a metastable photoinduced flavin-protein adduct, the reversible formation of a bicovalent flavoprotein, and the trapping of the enzyme in inactive conformations, have been described. This review summarizes the current status of our understanding on the structure-function-dynamics of choline oxidase.
Topics: Alcohol Oxidoreductases; Arthrobacter; Bacterial Proteins; Catalysis; Choline; Kinetics; Oxygen
PubMed: 32951822
DOI: 10.1016/bs.enz.2020.05.004 -
Molecular Pharmaceutics Jul 2022Ionizable cationic lipids are essential for efficient delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable...
Ionizable cationic lipids are essential for efficient delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines, while MC3 is used in siRNA therapy to knock down transthyretin in hepatocytes. Hepatocytes and hepatic stellate cells (HSCs) are particularly attractive targets for RNA therapy because they synthesize many plasma proteins, including those that influence blood coagulation. While LNPs preferentially accumulate in the liver, evaluating the ability of different ionizable cationic lipids to deliver RNA cargo into distinct cell populations is important for designing RNA-LNP therapies with minimal hepatotoxicity. Here, we directly compared LNPs containing either ALC-0315 or MC3 to knock-down coagulation factor VII (FVII) in hepatocytes and ADAMTS13 in HSCs. At a dose of 1 mg/kg siRNA in mice, LNPs with ALC-0315 achieved a 2- and 10-fold greater knockdown of FVII and ADAMTS13, respectively, compared to LNPs with MC3. At a high dose (5 mg/kg), ALC-0315 LNPs increased markers of liver toxicity (ALT and bile acids), while the same dose of MC3 LNPs did not. These results demonstrate that ALC-0315 LNPs achieves potent siRNA-mediated knockdown of target proteins in hepatocytes and HSCs, in mice, though markers of liver toxicity can be observed after a high dose. This study provides an initial comparison that may inform the development of ionizable cationic LNP therapeutics with maximal efficacy and limited toxicity.
Topics: Amino Alcohols; Animals; COVID-19; Caprylates; Cations; Decanoates; Hepatic Stellate Cells; Hepatocytes; Lipids; Liposomes; Mice; Nanoparticles; RNA, Small Interfering; SARS-CoV-2
PubMed: 35642083
DOI: 10.1021/acs.molpharmaceut.2c00033 -
Molecular Pharmaceutics Jun 2022Lipid nanoparticles (LNPs) are the leading technology for RNA delivery, given the success of the Pfizer/BioNTech and Moderna COVID-19 mRNA (mRNA) vaccines, and small...
Lipid nanoparticles (LNPs) are the leading technology for RNA delivery, given the success of the Pfizer/BioNTech and Moderna COVID-19 mRNA (mRNA) vaccines, and small interfering RNA (siRNA) therapies (patisiran). However, optimization of LNP process parameters and compositions for larger RNA payloads such as self-amplifying RNA (saRNA), which can have complex secondary structures, have not been carried out. Furthermore, the interactions between process parameters, critical quality attributes (CQAs), and function, such as protein expression and cellular activation, are not well understood. Here, we used two iterations of design of experiments (DoE) (definitive screening design and Box-Behnken design) to optimize saRNA formulations using the leading, FDA-approved ionizable lipids (MC3, ALC-0315, and SM-102). We observed that PEG is required to preserve the CQAs and that saRNA is more challenging to encapsulate and preserve than mRNA. We identified three formulations to minimize cellular activation, maximize cellular activation, or meet a CQA profile while maximizing protein expression. The significant parameters and design of the response surface modeling and multiple response optimization may be useful for designing formulations for a range of applications, such as vaccines or protein replacement therapies, for larger RNA cargoes.
Topics: Amino Alcohols; COVID-19; Caprylates; Decanoates; Humans; Liposomes; Nanoparticles; RNA, Messenger; RNA, Small Interfering
PubMed: 35604765
DOI: 10.1021/acs.molpharmaceut.2c00032 -
Chemical Biology & Drug Design May 2019Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of... (Review)
Review
Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential antimalarial drug. The major classes of approved antimalarial drugs that are governed as first-line treatment in tropical and subtropical areas include quinolines, naphthoquinones, antifolates, 8-aminoquinolines, and endoperoxides. However, the efficacy of antimalarial drugs has decreased due to ongoing multidrug resistance problem to current drugs. With increasing resistance to the current antimalarial artemisinin and its combination therapies, malaria prophylaxis has declined gradually. New-generation antimalarial and novel drug target are required to check the incidence of malaria resistance. This review summarizes the emergence of multidrug resistance to known antimalarial and the development of new antimalarial to resolve drug resistance condition. Few essential proteins are also discussed that can be considered as novel drug target against malaria in future.
Topics: Amino Alcohols; Antimalarials; Apicoplasts; Computational Biology; Drug Resistance; Folic Acid Antagonists; Naphthoquinones; Peroxides; Plasmodium falciparum; Primaquine
PubMed: 30663249
DOI: 10.1111/cbdd.13484 -
Molecules (Basel, Switzerland) Mar 2022Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity...
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.
Topics: Acrylonitrile; Amino Alcohols; Anti-Bacterial Agents; Antifungal Agents; Escherichia coli; Klebsiella pneumoniae; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Piperazine; Pseudomonas aeruginosa; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 35408448
DOI: 10.3390/molecules27072050 -
Organic Letters Nov 2014The first synthesis of 1,2-trans-homoiminosugars devised as mimics of β-D-GlcNAc and α-D-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic...
The first synthesis of 1,2-trans-homoiminosugars devised as mimics of β-D-GlcNAc and α-D-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic sulfite and a β-amino alcohol skeletal rearrangement applied to a polyhydroxylated azepane. The β-D-GlcNAc derivative has been coupled to serine to deliver an iminosugar C-amino acid. The two homoiminosugars demonstrate moderate glycosidase inhibition.
Topics: Amino Alcohols; Enzyme Inhibitors; Galactosamine; Glucosamine; Glycoside Hydrolases; Heterocyclic Compounds; Magnetic Resonance Spectroscopy; Molecular Structure
PubMed: 25330462
DOI: 10.1021/ol502929h -
American Journal of Kidney Diseases :... May 2021Beta-blockers are recommended for patients with heart failure (HF) but their benefit in the dialysis population is uncertain. Beta-blockers are heterogeneous, including... (Observational Study)
Observational Study
RATIONAL & OBJECTIVE
Beta-blockers are recommended for patients with heart failure (HF) but their benefit in the dialysis population is uncertain. Beta-blockers are heterogeneous, including with respect to their removal by hemodialysis. We sought to evaluate whether β-blocker use and their dialyzability characteristics were associated with early mortality among patients with chronic kidney disease with HF who transitioned to dialysis.
STUDY DESIGN
Retrospective cohort study.
SETTING & PARTICIPANTS
Adults patients with chronic kidney disease (aged≥18 years) and HF who initiated either hemodialysis or peritoneal dialysis during January 1, 2007, to June 30, 2016, within an integrated health system were included.
EXPOSURES
Patients were considered treated with β-blockers if they had a quantity of drug dispensed covering the dialysis transition date.
OUTCOMES
All-cause mortality within 6 months and 1 year or hospitalization within 6 months after transition to maintenance dialysis.
ANALYTICAL APPROACH
Inverse probability of treatment weights using propensity scores was used to balance covariates between treatment groups. Cox proportional hazard analysis and logistic regression were used to investigate the association between β-blocker use and study outcomes.
RESULTS
3,503 patients were included in the study. There were 2,115 (60.4%) patients using β-blockers at transition. Compared with nonusers, the HR for all-cause mortality within 6 months was 0.79 (95% CI, 0.65-0.94) among users of any β-blocker and 0.68 (95% CI, 0.53-0.88) among users of metoprolol at transition. There were no observed differences in all-cause or cardiovascular-related hospitalization.
LIMITATIONS
The observational nature of our study could not fully account for residual confounding.
CONCLUSIONS
Beta-blockers were associated with a lower rate of mortality among incident hemodialysis patients with HF. Similar associations were not observed for hospitalizations within the first 6 months following transition to dialysis.
Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Atenolol; Bisoprolol; Carvedilol; Cause of Death; Cohort Studies; Female; Heart Failure; Hospitalization; Humans; Kidney Failure, Chronic; Labetalol; Logistic Models; Male; Metoprolol; Middle Aged; Mortality; Nadolol; Proportional Hazards Models; Propranolol; Protective Factors; Renal Dialysis; Retrospective Studies; Risk; Risk Factors
PubMed: 33010357
DOI: 10.1053/j.ajkd.2020.07.023