István Puskás - Academia.edu (original) (raw)

Papers by István Puskás

Periodica polytechnica. Chemical engineering, May 28, 2024

European Heart Journal

Background The management of acute pulmonary hypertension has recently been in the center of atte... more Background The management of acute pulmonary hypertension has recently been in the center of attention as Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction. Therefore inhalation therapy has been the object of several clinical trials. Purpose In this experimental study we aimed at investigating the hemodynamic effect of inhalative SIN-1a (3-morpholino-syndnonimine, the unstable active metabolite of molsidomine, stabilized by cyclodextrine) administration during physiological and pathological conditions in a large animal model. Methods Landrace pigs were randomized into the following experimental groups: iNO (inhaled nitric-oxide, n=3), SIN-1-5 (5 mg, n=3), SIN-1-10 (10 mg, n=3). Hemodynamic parameters were recorded after parallel insertion of PiCCO system and Swan-Ganz catheter. The effect of iNO and SIN-1 inhalation (30 min) was investigated under physiologic conditions and U46619, a throm...

Advances and applications in bioinformatics and chemistry, Mar 1, 2014

Research Square (Research Square), Mar 22, 2024

Stability assessment of drugs in space is particularly important for future missions., In space t... more Stability assessment of drugs in space is particularly important for future missions., In space there are multiple factors, such as the variability of the conditions (radiation, microgravity, vacuum etc.) that could affect the reliability and reproducibility of the data. Therefore, we investigated the stability of an anti-Covid drug formulation, Remdesivir (RDV) sulfobutyletherbeta-cyclodextrin (SBECD) complex, in two separate flight experiments on the International Space Station (ISS). While HPLC/MS studies revealed no degradation of the cyclodextrin excipient in any of the samples investigated in both missions, RDV purity analysis of the RDV/SBECD complex after the first mission revealed different stabilities and altered degradation in space and on Earth. This latter interesting finding was not supported by the second mission, where no differences in the drug stabilities were identified. This anomaly highlighted the importance of standardization together with increased control of the variable parameters during the entire space missions and the terrestrial control experiments.

Acta pharmaceutica Hungarica, Nov 15, 2021

Molecular Genetics and Metabolism, Feb 1, 2016

Aliivibrio fischeri is a heterotrophic marine bacterium capable of bioluminescence which is contr... more Aliivibrio fischeri is a heterotrophic marine bacterium capable of bioluminescence which is controlled by quorum sensing. Quorum sensing is a population density dependent communication method for the bacteria to coordinate their activities by producing and detecting low-molecular-weight signal molecules. The effective infectivity of the bacteria is based on various virulence factors controlled by quorum sensing. Cyclodextrins, a family of toroidal-shaped oligosaccharides, reversibly encapsulate in their hydrophobic interior the fatty acid acyl chain of the signal molecules, thus preventing their binding to the receptors and interrupting the bacterial communication consequently the expression of various properties including different virulence factors.Short-term tests were performed to examine the potential quorum quenching ability of newly prepared cyclodextrin derivatives: α- and β-cyclodextrins monosubstituted with alkylthio moieties. In these derivatives one of the modifiable hyd...

Molecular Genetics and Metabolism, 2016

Periodica Polytechnica Chemical Engineering

The number of the cyclodextrin-containing drug formulations on the market has been continuously g... more The number of the cyclodextrin-containing drug formulations on the market has been continuously growing since the first drug (prostaglandin E1 formulated with α-cyclodextrin) was launched in Japan in 1976. We have collected a list of drugs from various sources available on the internet to find 130 approved pharmaceutical ingredients formulated with either parent cyclodextrins or their hydroxypropyl, sulfobutyl, random methylated or sulfolipo derivatives. We have sorted the drug products according to the cavity size of the cyclodextrins, the administration route and dosage forms.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔGsolv = −9.98 kcal/mol), which has a minimal ΔGsolv of −67.01 kcal/mol. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco’s Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring ...

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔGsolv = −9.98 kcal/mol), which has a minimal ΔGsolv of −67.01 kcal/mol. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco’s Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring ...

International Journal of Pharmaceutics

As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospita... more As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospitalized patients due to intravenous administration, there is an urgent need of effective oral antiviral formulations to be used at early stage of infection in an outpatient setting. The present paper reports on the comparative pharmacokinetics of the electrospun nanofiber remdesivir/sulfobutyl ether beta-cyclodextrin formulation after intravenous and buccal administration. It was postulated that oral transmucosal administration avoids remdesivir from metabolic transformation and intact remdesivir can be detected in plasma, but only the active metabolite GS-441524 could be experimentally detected at a significantly lower plasma level, than that provided by the intravenous route. In buccally treated animals, the metabolite GS-441524 appeared only at 1hour after treatment, while in intravenously treated animals, GS-441524 was possible to quantify even at the first time-point of blood collection. Further optimization of formulation is required to improve pharmacokinetics of remdesivir-sulfobutyl ether beta-cyclodextrin formulation upon buccal administration.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-triO methyl)-βcyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (= −9.98 kcal•mol −1), which has a minimal of −67.01 kcal•mol −1. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding () value of −5.57 ± 0.02 kcal•mol −1 , an equilibrium binding constant () of 79.89 ± 2.706 μM, and a ligand efficiency index () of −0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase

Advances and Applications in Bioinformatics and Chemistry : AABC, 2014

The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its ... more The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure–activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q2 of 0.795 (0.687) and r2 of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r2 of 0.821 (CoMFA) and r2 of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) val...

Periodica polytechnica. Chemical engineering, May 28, 2024

European Heart Journal

Background The management of acute pulmonary hypertension has recently been in the center of atte... more Background The management of acute pulmonary hypertension has recently been in the center of attention as Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction. Therefore inhalation therapy has been the object of several clinical trials. Purpose In this experimental study we aimed at investigating the hemodynamic effect of inhalative SIN-1a (3-morpholino-syndnonimine, the unstable active metabolite of molsidomine, stabilized by cyclodextrine) administration during physiological and pathological conditions in a large animal model. Methods Landrace pigs were randomized into the following experimental groups: iNO (inhaled nitric-oxide, n=3), SIN-1-5 (5 mg, n=3), SIN-1-10 (10 mg, n=3). Hemodynamic parameters were recorded after parallel insertion of PiCCO system and Swan-Ganz catheter. The effect of iNO and SIN-1 inhalation (30 min) was investigated under physiologic conditions and U46619, a throm...

Advances and applications in bioinformatics and chemistry, Mar 1, 2014

Research Square (Research Square), Mar 22, 2024

Stability assessment of drugs in space is particularly important for future missions., In space t... more Stability assessment of drugs in space is particularly important for future missions., In space there are multiple factors, such as the variability of the conditions (radiation, microgravity, vacuum etc.) that could affect the reliability and reproducibility of the data. Therefore, we investigated the stability of an anti-Covid drug formulation, Remdesivir (RDV) sulfobutyletherbeta-cyclodextrin (SBECD) complex, in two separate flight experiments on the International Space Station (ISS). While HPLC/MS studies revealed no degradation of the cyclodextrin excipient in any of the samples investigated in both missions, RDV purity analysis of the RDV/SBECD complex after the first mission revealed different stabilities and altered degradation in space and on Earth. This latter interesting finding was not supported by the second mission, where no differences in the drug stabilities were identified. This anomaly highlighted the importance of standardization together with increased control of the variable parameters during the entire space missions and the terrestrial control experiments.

Acta pharmaceutica Hungarica, Nov 15, 2021

Molecular Genetics and Metabolism, Feb 1, 2016

Aliivibrio fischeri is a heterotrophic marine bacterium capable of bioluminescence which is contr... more Aliivibrio fischeri is a heterotrophic marine bacterium capable of bioluminescence which is controlled by quorum sensing. Quorum sensing is a population density dependent communication method for the bacteria to coordinate their activities by producing and detecting low-molecular-weight signal molecules. The effective infectivity of the bacteria is based on various virulence factors controlled by quorum sensing. Cyclodextrins, a family of toroidal-shaped oligosaccharides, reversibly encapsulate in their hydrophobic interior the fatty acid acyl chain of the signal molecules, thus preventing their binding to the receptors and interrupting the bacterial communication consequently the expression of various properties including different virulence factors.Short-term tests were performed to examine the potential quorum quenching ability of newly prepared cyclodextrin derivatives: α- and β-cyclodextrins monosubstituted with alkylthio moieties. In these derivatives one of the modifiable hyd...

Molecular Genetics and Metabolism, 2016

Periodica Polytechnica Chemical Engineering

The number of the cyclodextrin-containing drug formulations on the market has been continuously g... more The number of the cyclodextrin-containing drug formulations on the market has been continuously growing since the first drug (prostaglandin E1 formulated with α-cyclodextrin) was launched in Japan in 1976. We have collected a list of drugs from various sources available on the internet to find 130 approved pharmaceutical ingredients formulated with either parent cyclodextrins or their hydroxypropyl, sulfobutyl, random methylated or sulfolipo derivatives. We have sorted the drug products according to the cavity size of the cyclodextrins, the administration route and dosage forms.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔGsolv = −9.98 kcal/mol), which has a minimal ΔGsolv of −67.01 kcal/mol. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco’s Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring ...

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔGsolv = −9.98 kcal/mol), which has a minimal ΔGsolv of −67.01 kcal/mol. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco’s Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring ...

International Journal of Pharmaceutics

As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospita... more As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospitalized patients due to intravenous administration, there is an urgent need of effective oral antiviral formulations to be used at early stage of infection in an outpatient setting. The present paper reports on the comparative pharmacokinetics of the electrospun nanofiber remdesivir/sulfobutyl ether beta-cyclodextrin formulation after intravenous and buccal administration. It was postulated that oral transmucosal administration avoids remdesivir from metabolic transformation and intact remdesivir can be detected in plasma, but only the active metabolite GS-441524 could be experimentally detected at a significantly lower plasma level, than that provided by the intravenous route. In buccally treated animals, the metabolite GS-441524 appeared only at 1hour after treatment, while in intravenously treated animals, GS-441524 was possible to quantify even at the first time-point of blood collection. Further optimization of formulation is required to improve pharmacokinetics of remdesivir-sulfobutyl ether beta-cyclodextrin formulation upon buccal administration.

We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazola... more We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-triO methyl)-βcyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (= −9.98 kcal•mol −1), which has a minimal of −67.01 kcal•mol −1. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding () value of −5.57 ± 0.02 kcal•mol −1 , an equilibrium binding constant () of 79.89 ± 2.706 μM, and a ligand efficiency index () of −0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase

Advances and Applications in Bioinformatics and Chemistry : AABC, 2014

The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its ... more The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure–activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q2 of 0.795 (0.687) and r2 of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r2 of 0.821 (CoMFA) and r2 of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) val...