Hroch M

References (12)

Title : UHPLC-HRMS study of pharmacokinetics of a novel hybrid cholinesterase inhibitor K1234: A comparison between in silico, in vitro and in vivo data - Mzik_2022_J.Pharm.Biomed.Anal_219_114898
Author(s) : Mzik M , Sestak V , Mezeiova E , Korabecny J , Hroch M , Pejchal J , Karasova-Zdarova J
Ref : J Pharm Biomed Anal , 219 :114898 , 2022
Abstract : Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching C(max) within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.
ESTHER : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedSearch : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedID: 35779353

Title : Tacrine and its 7-methoxy derivate\; time-change concentration in plasma and brain tissue and basic toxicological profile in rats - Karasova_2019_Drug.Chem.Toxicol__1
Author(s) : Karasova JZ , Soukup O , Korabecny J , Hroch M , Krejciova M , Hrabinova M , Misik J , Novotny L , Hepnarova V , Kuca K
Ref : Drug & Chemical Toxicology , :1 , 2019
Abstract :
ESTHER : Karasova_2019_Drug.Chem.Toxicol__1
PubMedSearch : Karasova_2019_Drug.Chem.Toxicol__1
PubMedID: 31257938

Title : The New Acetylcholinesterase Inhibitors PC-37 and PC-48 (7-Methoxytacrine-Donepezil-Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats - Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
Author(s) : Karasova JZ , Mzik M , Hroch M , Korabecny J , Nepovimova E , Vorisek V , Palicka V , Kuca K
Ref : Basic Clin Pharmacol Toxicol , 122 :373 , 2018
Abstract : The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUCtotal was 28179 +/- 4691 min.ng/mL for PC-37 and 23374 +/- 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.
ESTHER : Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
PubMedSearch : Zdarova Karasova_2018_Basic.Clin.Pharmacol.Toxicol_122_373
PubMedID: 29067789

Title : Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity - Karasova_2016_Neurotox.Res_29_267
Author(s) : Karasova JZ , Hroch M , Musilek K , Kuca K
Ref : Neurotox Res , 29 :267 , 2016
Abstract : Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 +/- 115.20 ng/ml) and 39 min (K524; 812.40 +/- 54.96 ng/ml) after i.m. APPLICATION: Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent pi-pi or pi-cationic interaction aside at the AChE catalytic site.
ESTHER : Karasova_2016_Neurotox.Res_29_267
PubMedSearch : Karasova_2016_Neurotox.Res_29_267
PubMedID: 26646154

Title : Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma - Karasova_2013_J.Appl.Toxicol_33_18
Author(s) : Karasova JZ , Chladek J , Hroch M , Josef F , Hnidkova D , Kuca K
Ref : J Appl Toxicol , 33 :18 , 2013
Abstract : K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-propane dibromide] is a promising new reactivator of organophosphate- or organophosphonate-inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 +/- 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg(-1)) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed-phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R(2) > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1-100 microg ml(-1). Near-identical plasma profiles were obtained for both compounds. No differences were found in the mean +/- SD values of C(max) (18.6 +/- 2.5 vs 20.0 +/- 6.3 microg ml(-1), P = 0.72) and AUC(0-180min) (2290 +/- 304 vs 2269 +/- 197 min microg ml(-1), P = 0.84). However, the percentage coefficient of variation of the first-order rate constant of absorption (k(a)) was 3-fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution.
ESTHER : Karasova_2013_J.Appl.Toxicol_33_18
PubMedSearch : Karasova_2013_J.Appl.Toxicol_33_18
PubMedID: 21717485

Title : [Induced cell fusion in the contact zone of cells with affected and unaffected surfaces. I] - Hroch_1990_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_33_699
Author(s) : Hroch M
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 33 :699 , 1990
Abstract : The change in capacity of the cell fusion stimulated with polyethylenglycol is applied as a criterion of accumulation of noxiously transformed properties of cell surfaces. Similar changes are induced with substances employed as follows: chinuclidyl benzilate, atropiniumsulphate, tetrahydroaminacridine. The dynamics of releasing these substances is also tracked by dynamics of fusions capacity. In the area of contact of cells both noxiously influenced and uninfluenced, the decrease in capacity of fusions is also observed. At least a part of toxical substance is so released outside the cells. The former is then linked to the surfaces of unfluenced cells. This is an example of transfer of substance linked with the cell surface which is concerned.
ESTHER : Hroch_1990_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_33_699
PubMedSearch : Hroch_1990_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_33_699
PubMedID: 2130504

Title : [Induced cell fusion after the accumulation of certain substances in the surface membrane. I] -
Author(s) : Hroch M , Kolarova J
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 31 :27 , 1988
PubMedID: 3212393

Title : [The effect of atropine, quinuclidinyl benzilate and their antidote tetrahydroaminoacridine on adhesion and spreading in cells cultured in vitro] -
Author(s) : Kolarova J , Hroch M
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 31 :459 , 1988
PubMedID: 3249932

Title : [The effect of tetrahydroaminoacridine on the toxic effects of atropine in cells cultured in vitro. II] -
Author(s) : Kolarova J , Hroch M
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 30 :437 , 1987
PubMedID: 3504604

Title : [Study of the toxic effects of atropine and the effect of tetrahydroaminoacrine on cells cultured in vitro. I] -
Author(s) : Kolarova J , Hroch M
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 28 :323 , 1985
PubMedID: 3879918

Title : [The toxic effects of quinuclidinyl benzilate and its antidote, tetrahydroaminocrine on cultured cells. II] -
Author(s) : Hroch M , Kolarova J
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 27 :379 , 1984
PubMedID: 6336286

Title : [The toxic effect of quinuclidinyl benzilate and its antidote tetrahydroaminoacrine on cell cultures. I] -
Author(s) : Hroch M , Kolarova J
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 26 :501 , 1983
PubMedID: 6336122