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Metabolism of a new neuroprotector GZK-111 (N-phenylacetylglycyl-L-proline ethyl ester) in rat blood plasma was studied by HPLC-mass spectrometry. Four biotransformation products were identified. It is concluded that the main ways of GZK-111 biotransformation are hydrolysis of the ester bond by esterases followed by degradation of the resulting metabolite, as well as reactions leading to the formation of phenylacetic acid and cycloprolylglycine that exhibits neuropsychotropic activity., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

We studied the pharmacokinetics of GZK-111 (N-phenylacetyl-glycyl-L-proline ethyl ether), a compound with neuroprotective activity, and its metabolite CPG (cyclo-L-prolylglycine) in rat blood plasma after single intravenous and intragastric administration in a dose of 20 mg/kg. It was found that the parent drug undergoes intensive biotransformation; its metabolite CPG persists in the circulation more than twice as long as GZK-111 and its plasma concentrations were higher by 50-70 times than the concentrations of the parent compound., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The development of high-end targeted drugs and vaccines against modern pandemic infections, such as COVID-19, can take a too long time that lets the epidemic spin up and harms society. However, the countermeasures must be applied against the infection in this period until the targeted drugs became available. In this regard, the non-specific, broad-spectrum anti-viral means could be considered as a compromise allowing overcoming the period of trial. One way to enhance the ability to resist the infection is to activate the nonspecific immunity using a suitable driving-up agent, such as plant polysaccharides, particularly our drug Panavir isolated from the potato shoots. Earlier, we have shown the noticeable anti-viral and anti-bacterial activity of Panavir. Here we demonstrate the pro-inflammation activity of Panavir, which four-to-eight times intensified the ATP and MIF secretion by HL-60 cells. This effect was mediated by the active phagocytosis of the Panavir particles by the cells. We hypothesized the physiological basis of the Panavir proinflammatory activity is mediated by the indol-containing compounds (auxins) present in Panavir and acting as a plant analog of serotonin., (Copyright © 2021 Elsevier B.V. All rights reserved.)

One of the most promising areas of diagnosis and prognosis of diseases is radiomics, a science combining radiology, mathematical modeling, and deep machine learning. The main concept of radiomics is image biomarkers (IBMs), the parameters characterizing various pathological changes and calculated based on the analysis of digital image texture. IBMs are used for quantitative assessment of digital imaging results (CT, MRI, ultrasound, PET). The use of IBMs in the form of "virtual biopsy" is of particular relevance in oncology. The article provides the basic concepts of radiomics identifying the main stages of obtaining IBMs: data collection and preprocessing, tumor segmentation, data detection and extraction, modeling, statistical processing, and data validation. The authors have analyzed the possibilities of using IBMs in oncology, describing the currently known features and advantages of using radiomics and image texture analysis in the diagnosis and prognosis of cancer. The limitations and problems associated with the use of radiomics data are considered. Although the novel effective tool for performing virtual biopsy of human tissue is at the development stage, quite a few projects have already been implemented, and medical software packages for radiomics analysis of digital images have been created., Competing Interests: Conflict of interest. The authors have no conflicts of interest to declare.

This short report is dedicated to the description of the wide antiviral and antibacterial activity of the immune-modulating agent Panavir®. Panavir® is a high-molecular-weight fraction of the polysaccharides extracted from the shoots of the Solanum tuberosum. It demonstrates activity against many types of viruses, including animal coronavirus and also against bacterial infections. These properties look very promising considering the COVID-19 epidemy and allow propose that Panavir® would be effective in the therapy of the SARS-CoV-2 infection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pharmacokinetics and relative bioavailability of antidepressant GSB-106 (hexamethylendiamide bis-(N-monosuccinyl-L-seryl-L-lysine) were determined in rabbits after single oral administration of the pharmaceutical substance and tablet mass. GSB-106 concentrations in the blood plasma were determined by HPLC-mass spectrometry. Relative bioavailability of GSB-106 tablet form was 160.79±24.33%.

Dose-dependent protective effects of lanthanum nitrate solution and gel were shown on the model of experimental infection caused by a virulent strain of Shigella flexneri 2a or opportunistic bacteria Klebsiella pneumoniae in outbred and DBA mice.

Metabolism of a novel anxiolytic GML-1 (N-benzyl-N-methyl-1-phenylpyrrolo[1,2-a]pirazin-3-carboxamide) in rat blood plasma was studied by HPLC-mass spectrometry. Three biotransformation products with the corresponding molecular ions were detected. A conclusion was made that the main pathways of GML-1 metabolism are oxidative reactions yielding hydroxylated, methylated, and demethylated metabolites.

We have studied the pharmacokinetics of drug-marker of cytochrome P450 isoenzyme CYP2C9 (losartan) and its metabolite E-3174 after subchronic oral administration of afobazole in doses 5 and 25 mg/kg in rats. The metabolic ratio (MR) of E-3174/Losartan was calculated. The pharmacokinetic parameters of losartan and its metabolite on the background of 4-day afabazole administration 5 mg/kg dose were not significantly different from analogous values calculated for the control group of rats. Therefore, afobazole in the effective anxiolytic dose did not change the MR value of metabolized P450 isoform. A five-fold dose increase in the afobazole dose led to significant difference in pharmacokinetic parameters, including A UC0-t, Cmax, Kel, t1/2el, MRT, CL/F, and Vd/F of losartan and AUC0-T, Cmax, and Tmax of E-3174. These findings are indicative of the induction of CYP2C9 isoenzyme by afobazole.

The main pharmacokinetic parameters (AUC0-∞, Tmax, Cmax, Cl/F, t1/2 el, MRT, Cmax/AUC0-I, Vd/F) of afobazole base in a new pharmaceutical composition and afobazole dihydrochloride substance after single peroral administration have been determined in rats. The availability of afobazole base pharmaceutical composition relative to that of the substance amounted to 153.2%.

We studied pharmacokinetics of dilept after single cross-administration of tablets and substance of dilept in a dose of 40 mg to rabbits. The following pharmacokinetic parameters were calculated: maximum plasma concentration of dilept, time to maximum observed concentration, area under the pharmacokinetic curve, elimination half-life, and relative bioavailability. Dilept concentration in blood plasma was estimated using ultra-fast liquid chromatography with mass spectrometry detection. Relative bioavailability of dilept tablets was 93.46±28.91% of that for the substance.

Interspecies differences in pharmacokinetics of the original neuroleptic drug dilept have been studied in experimental animals (rabbits and rats) and volunteers after single oral administration of tablets and tablet mass of the drug. Parent drug in the rabbit blood plasma was detected for 4 h, in the rat plasma for about 2 h, and in the human blood plasma for about 1 h after drug administration. The degrees of dilept biotransformation into metabolites (defined as metabolism intensity, AUCM/AUCP) in rats were 21.3 (for M-1) and 1645 (for M-2), in human volunteers - 5.8 and 658.5, and in rabbits - 1.6 and 125.8, respectively. Thus, the intensity of drug metabolism in experimental animals and volunteers was different and decreased in the series rats humans rabbits.

Afobazole pharmacokinetics upon oral administration of tablets prepared according to various technologies was studied in rabbits. The main pharmacokinetic parameters were determined.

The pharmacokinetic study of a new original antipsychotic drug Dilept in healthy volunteers was performed. Volunteers received Dilept as single 20, 40 or 60 mg tablets. The parent drug in the human blood plasma was detected in low concentrations and short-term time due to intensive biotransformation with formation of two metabolites N-caproyl-L-prolyl-tyrosin (M-1) and N-caproyl-L-prolin (M-2). After 20 and 40 mg of Dilept parent drug was detected in certain time points and after 60 mg for 1 h. M-1 and M-2 metabolites were registered in the blood plasma for 4 - 8 h. Theirs concentrations were 10 - 100 times higher of unchanged drug ones. Metabolites pharmacokinetics in the studied dosage range was nonlinear.

The influence of afobazole on isoenzyme CYP2C9 production in rats was studied using losartan as the marker drug. Single dose of losartan was administered orally without afobazole in a dose of 30 mg/kg and in the same single (30 mg/kg) on the background of 3- and 4-day administration of afobazole in a dose of 5, 25, 75, 100, and 125 mg/kg. At 5 mg/kg (effective dose for anxiolytic effect), afobazole did not cause any induction/inhibition effect on CYP2C9 isoenzyme. A multiple increase in afobazole dose was manifested by a moderate induction effect. The maximum induction effect of afobazole was achieved in a dose of 75 mg/kg. At doses above 75 mg/kg, the induction effect of afobazole was less pronounced.

The effect of aphobazole on CYP1A2 (drug-marker caffeine) was studied in rats. Aphobazole was administered orally at doses 5 and 25 mg/kg, caffeine 50 mg/kg. The metabolic ratios (MR) for the caffeine metabolites (theobromine and paraxanthine) were accounted. After aphobazole administration at the effective, anxiolytic dose (5 mg/kg) for 4 days (3 times per day every 3 hours) neither the inhibiting nor the inducing effects on NOD1A2 was revealed. Increasing the aphobazole dose up to 25 mg/kg after 2 days repeated administrations of the drug made it possible to reveal a moderate inducing effect. Longer aphobazole administration (4 days), the inducing effect is amplified. Since the MR values on theobromine and paraxanthine after 2-day administration aphobazole exceed similar values in the control of 2.5 and 3.3 times, respectively. MR values after the 4-days aphobazole administration in dose 25 mg/kg exceed similar values in the control of 4.2 times for theobromine and in 6.1 times for paraxanthine.

The excretion of compound M-11 and its metabolites with the urine and feces was studied in rats after intraperitoneal and oral administration in a dose of 25 mg/kg. Experiments showed that 1% metabolites were detected in excretions over 24 h irrespective of the route of administration, while the initial compound was not found even in trace amounts.

Human papilloma virus was detected by polymerase chain reaction in patients suffering from chronic cystitis with hyperplastic changes in urinary bladder mucosa. In most of the examinees (90%) it was HPV of highly oncogenic type 16. Panavir added to combined treatment of such patients produced a significant positive result in long-term period. Improvement was observed both in subjective assessment and the absence of dysuria episodes.

Purpose: To investigate if femoral venous pressure (FVP) measurement can be used as a surrogate measure for intra-abdominal pressure (IAP) via the bladder., Methods: This was a prospective, multicenter observational study. IAP and FVP were simultaneously measured in 149 patients. The effect of BMI on IAP was investigated., Results: The incidences of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) were 58 and 7% respectively. The mean APACHE II score was 22 ± 10, SAPS 2 score 42 ± 20, and SOFA score 9 ± 4. The mean IAP was 11.2 ± 4.5 mmHg versus 12.7 ± 4.7 mmHg for FVP. The bias and precision for all measurements were -1.5 and 3.6 mmHg respectively with the lower and upper limits of agreement being -8.6 and 5.7. When IAP was above 20 mmHg, the bias between IAP and FVP was 0.7 with a precision of 2.0 mmHg (lower and upper limits of agreement -3 and 4.6 respectively). Excluding those with ACS, according to the receiver operating curve analysis FVP = 11.5 mmHg predicted IAH with a sensitivity and specificity of 84.8 and 67.0% (AUC of 0.83 (95% CI 0.81-0.86) with P < 0.001). FVP = 14.5 mmHg predicted IAP above 20 mmHg with a sensitivity of 91.3% and specificity of 68.1% (AUC 0.85 (95% CI 0.79-0.91), P < 0.001). Finally, at study entry, the mean IAP in patients with a BMI less then 30 kg/m(2) was 10.6 ± 4.0 mmHg versus 13.8 ± 3.8 mmHg in patients with a BMI ≥ 30 kg/m(2) (P < 0.001)., Conclusions: FVP cannot be used as a surrogate measure of IAP unless IAP is above 20 mmHg.

Pharmacokinetics of compound M-11 (main metabolite of afobazole) after administration via different routes was studied in rats. After oral and intravenous administration, M-11 exhibited weakly pronounced bioconversion with the formation of a few metabolites that could be detected in plasma samples for about 3 hours. The absolute bioavailability of M-11 after oral administration was 68.3%. It was found that M-11 was completely absorbed from gastrointestinal tract of rats and characterized by "the first pass effect", after which approximately 70% of administered dose entered the circulation. The parent substance was determined neither in urine nor in feces.

Pharmacokinetics of magnesium ions after single peroral administration of Magnelis B6 and Magne B6 coated tablets (magnesium dose, 48 mg) was studied in rabbits. In the blood plasma, the level of magnesium ions was very low compared to the endogenous level, which did not allow the drug bioavailability to be reliable evaluated. At the same time, the level of magnesium ions was reliable determined in the daily urine of test animals. The relative bioavailability of magnesium for Magnelis B6 versus Magne B6 was estimated at 98.93 +/- 12.45% (average +/- SD).

Comparative analysis of pharmacokinetic parameters of afobazole and its main metabolite M-11 after single intraperitoneal injections of their solutions (25 mg/kg) to rats showed much more intense penetration of M-11 compared to afobazole into rat tissues and organs, judging from the area under the pharmacokinetic curve (AUC) and maximum concentrations (C(max)). The half-life periods (T(l/2e)l) of afobazole and M-11 were similar.

Afobazole and M-11, its major metabolite were detected in placental and embryonic rat tissues after single peroral administration to pregnant female rats at a dose of 100 mg/kg. The anxiolytic drug and its metabolite are also detected in rat milk and body of the breast-fed infant rat pups after 4 days of daily administration (200 mg/kg, per os) to lactating female rats.

The pharmacokinetics of dihydroquercetin (DHQ) in the forms of parent substance and a new liposomal formulation (Flamena D) have been studied in rats upon single peroral administration in a dose of 50 mg/kg. DHQ concentration after enzymatic hydrolysis in the blood plasma was determined by HPLC with UV detection. The elimination half-life of DHQ introduced in the form of Flamena D was about T(1/2) = 1.3 h. The relative bioavailability of DHQ after the administration of Flamena D amounted to 159% in comparison to that of the parent substance of DHQ.

The antiviral activity of Panavir was studied on a model of mice infected with the strain Sofjin of tick-borne encephalitis (TBE) virus. The efficacy of Panavir was studied in the treatment of the chronic (monotherapy; 30 patients) and acute febrile and meningeal (combined therapy; n = 113) forms of TBE. Panavir was found to have a positive effect on the clinical course of TBE and the immune mechanisms of the body's protection.

Clinical investigation of a transdermal phenazepam preparation (phenapercuten) in patients diagnosed with different anxiety disorders revealed an original therapeutic action of the new drug, which included both a selective anxiolytic effect and an activating (antiasthenic) component in the absence of undesired sedative and miorelaxant properties. It is shown that the specific action of phenapercuten is related to features of the pharmacokinetic profile of this transdermal drug that is characterized by a low levels of active compound in the blood plasma and by the absence of peak concentrations. TTS Phenapercuten was most effective in patients with anxiety disorders of simple structure.

Antiviral activity of Panavir was studied in a model of experimental infection due to Morbillivirus in subcultures of cells Vero and B-16. It was shown that at multiplicity of the infection (0.001-0.0001 TCD50/cell) Panavir inhibited reproduction of the virus in concentrations of 12-100 mcg/0.2 ml.

The effect of Panavir on the synthesis of ultraearly (alpha), early (beta) and late (gamma) proteins of Herpes simplex virus types 1 and 2 in the culture of Vero cells was studied. It was shown that the level of the proteins suppression depended on the infection multiplicity and the time of the Panavir addition to the culture.

Significant and reliable activity of panavir was shown in experiments on mice intramuscularly infected with the rabies virus. The animal protection depended on the dose of panavir and the treatment scheme. The reliable protection (30-45% of the mice, p<0.05-0.01) was observed only after the panavir intramuscular injection to the site of the virus inoculation (the infection atrium), but not after the systemic (intraperitoneal) administration. High titers of the virus-neutralizing antibodies (7.92-10.45 IU/ml), comparable to the antibody titers in the combined suspensions of the brain tissues (6.01-10.45% IU/ml), were detected in the combined sera of the survived animals treated with panavir. For the first time a quantitative method for determination of the virus-neutralizing antibody levels in IU/ml was used (the FAVN test, the gold standard for comparative evaluation of the level of the vaccinal and infective antirabies immunity).

The amount of afobazole and identified metabolites was measured in the urine and feces of rats after intraperitoneal and peroral administration of the drug in a dose of 25 mg/kg. Over 1 day after intraperitoneal or peroral treatment with afobazole, urine and feces contained 0.1% initial compound (from administered dose) and 42.1% metabolites.

Metabolism of afobazole in rats has been studied using mass-spectrometry and HPLC, which revealed 17 products of afobazole biotransformation along with the parent compound. The structures of six afobazole metabolites were established and confirmed by comparison of HPLC retention times with the synthetic reference compounds and HPLC/mass spectrometry. Other metabolites were characterized by the masses of molecular ions. A significant fraction of the drug dose is biotransformed with the formation of hydroxylated benzimidazole moiety and oxidated morpholine.

Protective action of Panavir was studied in the treatment of experimental herpes virus infection on albino mice. It was shown, that intravenous and rectal Panavir formulations were able to increase survival of the experimental animals (decreased lethality) infected by HSV-1.

Intraperitoneally injected afobazole and its major metabolites are intensively distributed in highly vascularized tissues of rats, including the liver, spleen, and kidneys; the content of these compounds in moderately and poorly vascularized tissues (muscles and mesentery) is much lower. Afobazole and its metabolites possess intermediate ability to penetrate into the brain.

Afobazole pharmacokinetics was studied after the administration via different ways in rats. After oral administration, afobazole is subject to intensive biotransformation with the formation of several metabolites (M-6, M-7, and M-11). The drug and its metabolites were detected in the blood plasma for 3 h and characterized by a high elimination rate after both oral and intravenous administration. Afobazole and its main metabolite (M-11) had a medium rate of permeability into brain (the target organ): the tissue availability was 0.584 for afobazole and 0.793 for M-11. The absolute bioavailability of afobazole upon oral administration was 43.6% for. Afobazole was completely absorbed from the gastrointestinal tract of rats and characterized by the first-pass effect, after which more than 40% of administered dose entered the circulation. The parent compound was determined in extremely low amounts in urine and feces: its content in 24-h urine on the average did not exceed 0.07% of the administered dose; in 24-h feces, it did not exceed 0.05 % after intravenous administration and 0.01% after oral administration).

Mitogenic properties of panavir, as well as its effect on the grippe virus reproduction in cell systems in vitro and the effect on the survival of mice with the experimental grippe infection were studied. It was shown that panavir had no cytotoxic action whereas it was characterized by pronounced mitogenic activity and subsequently could be considered as a perspective immunomodulator. Under in vitro conditions with the use of relatively high doses for the cell contamination with the grippe virus, panavir lowered the virus production in the cell systems. When the contaminating doses were low, panavir inhibited the virus production detected at the early stages of the infection. In the in vivo studies on mice with the experimental grippe infection panavir showed antigrippe activity against both the romantadine resistant and the remantadine nonresistant populations of the grippe A virus.

The effect of panavir on Parkinson's syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was studied in C57Bl/6 mice and outbred albino rats. Two injections of panavir significantly reduced the severity of oligokinesia and autonomic manifestations of experimentally induced Parkinson's syndrome.

The pharmacokinetics of fenazepam upon application of the transdermal therapeutic system (TTS) fenapercuten in various forms and under different conditions was studied in rabbits. The rate of the transdermal transfer of fenazepam from TTS to blood varied from 0.76 to 2.89 mg/(ml cm2). It was found that the drug transfer rate remains constant for 2-3 days. After removal of the TTS, fenazepam is eliminated within 3 days.

Problems encountered in the testing for bioequivalence of reproduced drugs (generics) are discussed in the parts incompletely resolved in domestic methodological recommendations. There are special cases when such drugs significantly vary in concentration and dosage, contain endogenous substances, exhibit intensive metabolism with a genetically polymorphous component, belong to "long-lived" compounds, and are intended for local administration. Also mentioned are problems related to insufficient sensitivity of analytical methods and some ethical aspects of investigations.

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.

The new drug Bradizol (SM-345), a 2-mercaptobenzimidazole derivative producing a specific bradycardic effect, is quite rapidly eliminated upon intravenous bolus in anaesthetiezed cats. After a combined injection (bolus followed by a 60-min infusion), a constant bradizol concentration in the blood plasma is observed over a time period of 90 min. The bradizol-induced bradycardic effect and the drug concentration in the blood plasma are tightly correlated. Upon per os administration of bradizol to the experimental animals, neither the drug is detected in the blood plasma, nor the bradycardic effect is observed. It is suggested that bradizol, possessing antiarrhythmic, antifibrillator, and antiischemic properties, can be used (by intravenous injections) for the therapy of patients with diverse tachyarrhythmia geneses, including those with the ischemic heart disease.

Experimental study of pharmacokinetics of transdermal system with cytisin in rabbits showed a possibility of controlled intake of the drug over a 4-day period. The two stages of attaining the stationary levels of cytisin concentrations are revealed. The first stage lasted during first 24h and the second stage during succeeding 3 days. Using the data on intravenous cytisin injection we found that the stationary concentrations and the rate of cytisin intake in the first stage is twice as large as in the second stage. Thus cytisin can be classed as a short-living drug.

Using HPLC with fluorescence detector we studied elimination kinetics of the antioxidant drug mexidol and its glucuronoconjugated metabolite in 16 patients suffering from neurosis and traumatic CNS injury after receiving mexadol (in a dose of 500 mg, in tablets). It is found that mexidol undergoes rapid glucuronoconjugation and is excreted with urine (0.31% and 49.6% of the received dose in the form of mexidol and its glucuronoconjugate, respectively) within 11.5-h period of examination. A substantial variability in the rate and degree of mexidol and glucuronoconjugate elimination with urine is observed. A trend to intensive glucuronoconjugation is observed in patients aged up to 40.

A mathematical model for the development of the SOS signal in nucleotide-excision repair deficient Escherichia coli cells subjected to ultraviolet light irradiation is proposed, in which regions of single-stranded DNA (gaps) are created during replication of a damaged chromosome when the strand elongation stops at pyrimidine dimers. The concentration of single-stranded DNA of gaps as a function of time is obtained. The model for the interaction of the LexA and RecA proteins, a well-established key event in SOS regulation, is presented, resulting in a system of differential equations for the concentrations of LexA, RecA and activated RecA proteins. The simulated LexA protein kinetic curves agree with the experimental data for two excision repair deficient mutants: uvrA6 and dnaC28 uvrB(del), which is also a temperature-sensitive DNA replication initiation mutant. It is shown that the model can be used to quantitatively describe the kinetics of SOS response through the amount of the SOS signal (concentration of single-stranded DNA) in a cell as a function of time.

The pharmacokinetics of baclofen was studied in the rat blood plasma and brain. The concentrations of the agent were found to be considerably lower in the brain than in the plasma. This is associated with the weakly pronounced lipophilicity of the agent in question and with the protective properties of the blood-brain barrier. Baclofen penetrates into the brain middle regions to a greater extent than into cerebral hemispheres.

When gidazepam was administered to rats in combination with 4% solutions of Tween 80 or polyvinylpyrrolidone, its bioavailability was higher than its combination with 4% polyethylene glycol 400 solution, as shown by high performance liquid chromatography. Increasing the quantities of these high-molecular compounds in gidazepam solutions was demonstrated to enhance gidazepam dealkylation in the animals after oral administration.