17 research outputs found
Safety of Pharmacotherapy in COVID-19 Patients: A Literature Review
The safety of COVID-19 pharmacotherapy is a relevant issue, first of all, because of the current lack of experience with using particular medicinal products and with off-label prescribing. The aim of the study was to analyse information on potential adverse drug reactions (ADRs) and their predictors in etiology- and pathogenesis-oriented COVID-19 therapy. According to literature data, the main clinically significant risk factors for COVID-19 patients to develop an ADR are the duration of their hospital stay, combined use of antivirals, polypharmacy, and their history of drug allergies. The most common adverse reactions to antivirals, to virus-neutralising antibodies, and to human anti-COVID-19 immunoglobulin and convalescent plasma are, respectively, gastrointestinal and hepatobiliary disor ders; gastrointestinal disorders, neurological disorders, and allergic reactions; and transfusion reactions (fever, chills, etc.). For pathogenesis-oriented therapy with systemic glucocorticosteroids, the most characteristic ADR is hyperglycaemia. Janus kinase inhibitors and interleukin inhibitors are most often associated with gastrointestinal disorders and hypertransaminasemia; neutropenia is also characteristic of a number of interleukin inhibitors. Haemo static adverse reactions to anticoagulants depend on the patient’s dosing regimen and condition. Drug-drug interactions are a common problem in COVID-19 treatment, with the combination of nirmatrelvir and ritonavir showing the largest number of significant interactions attributed to their pharmacokinetics. Currently, there is data on the role of pharmacogenetic biomarkers in the safety and clinical outcomes of COVID-19 therapy. Thus, to improve the safety of COVID-19 therapy, an integrated approach is needed that will take into account both the clinical, demographic, and pharmacogenetic predictors of ADRs and the risk of drug-drug interactions
A Catalytic Mechanism for Cysteine N-Terminal Nucleophile Hydrolases, as Revealed by Free Energy Simulations
The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, the catalytic reactions of cysteine Ntn-hydrolases have never been investigated from a mechanistic point of view. In the present study, we used free energy simulations in the quantum mechanics/molecular mechanics framework to determine the reaction mechanism of amide hydrolysis catalyzed by the prototypical cysteine Ntn-hydrolase, conjugated bile acid hydrolase (CBAH). The computational analyses, which were confirmed in water and using different CBAH mutants, revealed the existence of a chair-like transition state, which might be one of the specific features of the catalytic cycle of Ntn-hydrolases. Our results offer new insights on Ntn-mediated hydrolysis and suggest possible strategies for the creation of therapeutically useful inhibitors
Interaction of Astramol Poly(propyleneimine) Dendrimers with DNA and Poly(methacrylate) Anion in Water and Water–Salt Solutions
Interaction
of polyÂ(propyleneimine) dendrimers DAB-<i>dendr-</i>(NH<sub>2</sub>)<sub><i>x</i></sub> of five generations
(<i>x</i> = 4, 8, 16, 32, and 64) with either calf thymus
DNA or tagged by pyrenyl groups polyÂ(methacrylate) anion (PMA*) as
well as destruction of formed polyelectrolyte complexes by the added
sodium chloride were studied by fluorescence quenching techniques.
DNA-containing complexes (dendriplexes) were investigated by ethidium
bromide assay, whereas formation of PMA* complexes was estimated by
fluorescence of the pyrenyl groups that remained free of contact with
the dendrimers-quenchers.
The ion pairing with DNA phosphate groups was pH-sensitive and accompanied
by inaccessibility of a part of the dendrimer amino groups even in
slightly acidic media. The growth of the generation number resulted
in successive stabilization of the dendriplexes against the added
salt. The dendriplexes of all dendrimers except DAB-<i>dendr-</i>(NH<sub>2</sub>)<sub>4</sub> were stable at physiological ionic strength.
In contrast to the highly charged cationic polymer polyÂ(<i>N</i>-ethyl-4-vinylpyridinium) bromide of different degrees of polymerization,
the dendrimers formed more stable complexes with flexible PMA* rather
than with DNA, proving the inaccessibility of a part of the amino
groups for the rigid double helix. The revealed regularities appear
to be a platform for design of dendriplexes with controllable stability,
in particular fulfilling the requirements imposed for gene delivery
vehicles
Ethidium Bromide as a Promising Probe for Studying DNA Interaction with Cationic Amphiphiles and Stability of the Resulting Complexes
Supercharged Polyplexes: Full-Atom Molecular Dynamics Simulations and Experimental Study
Quite recently, we reported the synthesis
of supercharged polycations
bearing pH-insensitive double-charged repeat units with either three
or five methylene groups in the space between charges. The developed
approach is based on the quaternization of the parent polyÂ(4-vinylpyridine)
with different alkylating agents, providing the possibility to perform
the modification as a one-step reaction, which occurs in mild conditions
with a controllable degree of conversion. In the present work, we
used the above approach for preparing and investigating supercharged
polyplexes (polyelectrolyte complexes of nucleic acids), in particular
to elucidate the reason for the key feature, i.e., the clearly defined
stability of the polyplexes formed by supercharged polyamines. The
main findings of the experimental study were confirmed by the results
of full atomic modeling, and the principal regularities responsible
for the structure, stability, and properties of the supercharged polyplexes
have been elucidated for the first time