The Open Medicinal Chemistry Journal




ISSN: 1874-1045 ― Volume 13, 2019
RESEARCH ARTICLE

Dose-Dependent Tissue Distribution of K117, a Bis-pyridinium Aldoxime, in Rats



Huba Kalász1, *, Gellért Karvaly2, Kamil Musilek3, Kamil Kuca3, Jung Young-Sik4, Barbara Malawska5, Ernest A. Adeghate6, Syed M. Nurulain7, Judit Szepesy1, Tibor Zelles1, Kornélia Tekes8
1 Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Orczy út 2-4, Hungary
2 Department of Laboratory Medicine, Semmelweis University, 1089 Budapest, Orczy út 2-4, Hungary
3 Department of Chemistry, University of Hradec Kralove, 500 03 Hradec Kralove, Rokitanskeho 62, Czech Republic
4 Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
5 Department of Physicochemical Drug Analysis, Jagiellonian University, 30688 Krakow, ul. Mediczna 9, Poland
6 Department of Anatomy, College of Medicine, United Arab Emirates University, 17666, Al Ain, UAE
7 Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
8 Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Orczy út 2-4, Hungary

Abstract

Background:

Bis-pyridinium aldoximes are reactivators of the paraoxon-inhibited butyrylcholinesterase enzyme. Paraoxon is the active product of parathion, a widely used insecticide.

Objective:

The objective of this study is to examine the dose-dependent distribution of K117, a bis-pyridinium aldoxime in rat tissues.

Materials and Methods:

White male Wistar rats were intramuscularly injected with various doses of K117; the animals were sacrificed 30 minutes after injections. The dose-dependent body distribution of K117 was determined using reversed-phase HPLC.

Results:

Dose-dependent distribution of K117 in body tissues was linear in the serum and other body tissues throughout the whole range of the concentrations studied. However, the of distribution was not observed in the brain and cerebrospinal fluid, especially with high doses.

Conclusion:

The body distribution of K117 significantly depends on doses used, the p-value is: 500 nmol, i.m., when applied in the range of 100 to 10,000 nmol.

Keywords: K117, Dose-dependence, Pharmacokinetics, Wistar rats, Intramuscular injections, Linear Pattern.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 1
Last Page: 6
Publisher Id: TOMCJ-13-1
DOI: 10.2174/1874104501913010001

Article History:

Received Date: 02/11/2018
Revision Received Date: 27/01/2019
Acceptance Date: 06/02/2019
Electronic publication date: 28/02/2019
Collection year: 2019

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© 2019 Kalász et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Orczy út 2-4, Hungary; Tel: +36302747986; Fax: +3612104412; E-mail: drkalasz@gmail.com




1. INTRODUCTION

There are two types of cholinesterase enzymes in humans and animals. The acetylcholinesterase enzyme (AcChE, EC 3.1.1.7) is located in many tissues (red blood cell membranes, the central nervous system, peripheral organs, cholinergic and non-cholinergic fibers etc.) and functions postsynaptically with an extremely high catalytic activity at nerve synapses to terminate the effect of acetylcholine by its hydrolyzation.

The butyrylcholinesterase enzyme (BuChE, EC 3.1.1.8), also known as pseudocholinesterase or plasma esterase, serves as a backup for AcChE [1Nachon, F.; Brazzolotto, X.; Trovaslet, M.; Masson, P. Progress in the development of enzyme-based nerve agent bioscavengers. Chem. Biol. Interact., 2013, 206(3), 536-544.[http://dx.doi.org/10.1016/j.cbi.2013.06.012] [PMID: 23811386] ]. It is responsible for the quick inactivation through the hydrolysis of different endogenous and exogenous esters in the blood plasma. The potential poisons of AcChE are scavenged by BuChE, and the human body has BuChE (approximately 680 nanomoles) about tenfold as much as AcChE [2Masson, P.; Lockridge, O. Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior. Arch. Biochem. Biophys., 2010, 494(2), 107-120.[http://dx.doi.org/10.1016/j.abb.2009.12.005] [PMID: 20004171] ]. BuChE also plays en essential role in metabolizing cocaine, heroin, mivacurium, succinylcholine and procaine. BuChE-deficiency results in increased sensitivity to succinylcholine (a widely used depolarizing neuromuscular blocking agent in clinical practice). It is generally accepted that BuChE has an essential role in the inactivation of toxic compounds including organophosphorous esters. Measuring BuChE serves as a biomarker for organophosphate exposure [3Lockridge, O. Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol. Ther., 2015, 148, 34-46.[http://dx.doi.org/10.1016/j.pharmthera.2014.11.011] [PMID: 2544 8037] ]. Either AcChE- or BuChE-deficiency is an indicator of a special depression that is common in pesticide handlers [4Strelitz, J.; Engel, L.S.; Keifer, M.C. Blood acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among pesticide handlers. Occup. Environ. Med., 2014, 71(12), 842-847.[http://dx.doi.org/10.1136/oemed-2014-102315] [PMID: 25189163] ].

Fig. (1)
Chemical structure of K117 and that of K127.


Reactivation of AcChE- or BuChE-deficiency caused by insecticide poisoning is crucial to the survival of a poisoned patient. Karasova et al. [5Karasova, J.Z.; Kassa, J.; Jung, Y.S.; Musilek, K.; Pohanka, M.; Kuca, K. Effect of several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats. Int. J. Mol. Sci., 2008, 9(11), 2243-2252.[http://dx.doi.org/10.3390/ijms9112243] [PMID: 19330072] ] reported that both K117 and K127 were among the best reactivators of BuChE, when some currently available and several newly synthesized pyridinium aldoximes were studied on rats intoxicated by tabun. The reactivation efficiency of K117, and also that of HI-6, obidoxime, triedoxime, K127, K206, K250, K251, K269, K347, K628, were experimentally determined in plasma and the brain by Kovarik et al. [6Kovarik, Z.; Katalinić, M.; Sinko, G.; Binder, J.; Holas, O.; Jung, YS.; Musilova, L.; Jun, D.; Kuca, K. Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem. Biol. Interact., 2010, 187(1-3), 167-171.[http://dx.doi.org/10.1016/j. cbi. 2010.02.023] [PMID: 20206 154] ]. K117 showed similar effectivity as HI-6 in peripheral tissues. Jun et al. [7Jun, D.; Musilova, L.; Kuca, K.; Kassa, J.; Bajgar, J. Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro. Chem. Biol. Interact., 2008, 175(1-3), 421-424.[http://dx.doi.org/10.1016/j.cbi.2008.05.004] [PMID: 18617161] ] compared the reactivation potency of several pyridinium aldoximes in vitro on paraoxon-inhibited human AcChE and BuChE. Two of the reactivators (obidoxime and trimedoxime) worked well on inhibited AcChE, giving a reactivation rate over 75% when used in a concentration of 100 µM concentration. However, none of the classical pyridinium aldoximes (pralidoxime, methoxime, obidoxime, trimedoxime, HI-6) produced the reactivation rate of BuChE over 10%, even when they were used in a concentration of 100 µM. Kuca et al. [5Karasova, J.Z.; Kassa, J.; Jung, Y.S.; Musilek, K.; Pohanka, M.; Kuca, K. Effect of several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats. Int. J. Mol. Sci., 2008, 9(11), 2243-2252.[http://dx.doi.org/10.3390/ijms9112243] [PMID: 19330072] , 7Jun, D.; Musilova, L.; Kuca, K.; Kassa, J.; Bajgar, J. Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro. Chem. Biol. Interact., 2008, 175(1-3), 421-424.[http://dx.doi.org/10.1016/j.cbi.2008.05.004] [PMID: 18617161] , 8Kuca, K.; Jun, D.; Junova, L.; Musilek, K.; Hrabinova, M.; da Silva, J.A.V.; Ramalho, T.C.; Valko, M.; Wu, Q.; Nepovimova, E.; França, T.C.C. Synthesis, Biological evaluation, and docking studies of novel bisquaternary aldoxime reactivators on acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon. Molecules, 2018, 23(5), E1103.[http://dx.doi.org/10.3390/molecules23051103] [PMID: 29735900] ] found that K117 and atropine co-doses work efficiently in vitro on rats intoxicated by tabun.

Sakurada et al. [9Sakurada, K.; Matsubara, K.; Shimizu, K.; Shiono, H.; Seto, Y.; Tsuge, K.; Yoshino, M.; Sakai, I.; Mukoyama, H.; Takatori, T. Pralidoxime iodide (2-pAM) penetrates across the blood-brain barrier. Neurochem. Res., 2003, 28(9), 1401-1407.[http://dx.doi.org/10.1023/A:1024960819430] [PMID: 12938863] , 10Okuno, S.; Sakurada, K.; Ohta, H.; Ikegaya, H.; Kazui, Y.; Akutsu, T.; Takatori, T.; Iwadate, K. Blood-brain barrier penetration of novel pyridinealdoxime methiodide (PAM)-type oximes examined by brain microdialysis with LC-MS/MS. Toxicol. Appl. Pharmacol., 2008, 227(1), 8-15.[http://dx.doi.org/10.1016/j.taap.2007.09.021] [PMID: 17964625] ] were the first to detect and measure that pralidoxime penetrated through the blood-brain barrier. Similar determinations and statements were made by Kalász et al. [11Kalász, H.; Szöko, E.; Tábi, T.; Petroianu, G.A.; Lorke, D.E.; Omar, A.; Alafifi, S.; Jasem, A.; Tekes, K. Analysis of pralidoxime in serum, brain and CSF of rats. Med. Chem., 2009, 5(3), 237-241.[http://dx.doi.org/10.2174/157340609788185882] [PMID: 19442213] , 12Kalász, H.; Szegi, P.; Jánoki, G.; Balogh, L.; Pöstényi, Z.; Musilek, K.; Petroianu, G.A.; Siddiq, A.; Tekes, K. Study on medicinal chemistry of K203 in wistar rats and beagle dogs. Curr. Med. Chem., 2013, 20(16), 2137-2144.[http://dx.doi.org/10.2174/0929867311320160006] [PMID: 23531217] ], who expanded the analysis of pyridinium aldoximes on the cerebrospinal fluid.

This paper presents a dose-dependent tissue penetration of the K117 from the site of its intramuscular application to various target organs.

2. MATERIALS AND METHODS

2.1. Chemicals and Solvents

All solvents and chemicals were bought from commercial sources in the best possible quality. Pyridinium aldoximes (K117 and K127) were supplied by the Department of Chemistry, University of Hradec Kralove, Czech Republic. The chemical structures of these two compounds are given in Fig. (1).

2.2. Animals and Animal Treatment

White male Wistar rats weighing 180-199 grams were obtained from Toxicoop (Budapest, Hungary). Two animals were treated intramuscularly (i.m.) with an adequate dose of a freshly prepared aqueous solution of K117 (0.1, 0.3, 1.0, 3.0 and 10.0 µmol for each pair of rats). The rats were sacrificed 30 minutes after treatment, keeping the ethical regulation of Semmelweis University. Body fluids (serum, cerebrospinal fluid) were taken and certain organs/tissues (brain, eyes, lungs, testes, liver, kidneys and inner ear) were dissected and treated with perchloric acid, homogenized and centrifuged. HPLC determinations of K117 were done using K127 as an internal standard (Figs. 2 and 3), as detailed in our previous publication [13Tekes, K. Distribution of K117, a bispyridinium aldoxime with regenerating activity on diminished butyrylcholinesterase enzyme activity in preparation, ].

Fig. (2)
Calibration curve of K117 determination. R2 ˃ 0.99.


Fig. (3)
Representative chromatograms of K117 and the internal standard K127. (A) rat serum (340 ng/mL K117), (B) rat kidney homogenate (3430 ng/mL K117), (C) calibration sample (500 ng/mL K117), (D) blank serum.


Table 1
Dose-dependence of tissue and body fluid concentrations of K 117 injected intramuscularly to rats.


3. RESULTS

Dose-dependence of K117 levels in various body compartments of rats is given in Table 1.

Table 1 shows very high levels of K117 in the lungs, liver, kidney and Inner ear compared to those in serum. These relatively high levels continuously decrease with time in the lungs and inner ear, while they continue to increase in the liver and kidney.

4. DISCUSSION

During their in vitro experiments, Jun et al. [7Jun, D.; Musilova, L.; Kuca, K.; Kassa, J.; Bajgar, J. Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro. Chem. Biol. Interact., 2008, 175(1-3), 421-424.[http://dx.doi.org/10.1016/j.cbi.2008.05.004] [PMID: 18617161] ] compared AcChE and BuChE reactivating process of several K-compounds against paraoxon-inhibition, using a concentration as high as 100 µM, as the overall (in vivo) toxicity does not limit the dose used. However, studying the dose-dependence in in vivo experiments injections up to 100 µM could be applied, as higher doses of K117 were toxic [6Kovarik, Z.; Katalinić, M.; Sinko, G.; Binder, J.; Holas, O.; Jung, YS.; Musilova, L.; Jun, D.; Kuca, K. Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem. Biol. Interact., 2010, 187(1-3), 167-171.[http://dx.doi.org/10.1016/j. cbi. 2010.02.023] [PMID: 20206 154] ]. Horn et al. [14Horn, G.; Wille, T.; Musilek, K.; Kuca, K.; Thiermann, H.; Worek, F. Reactivation kinetics of 31 structurally different bispyridinium oximes with organophosphate-inhibited human butyrylcholinesterase. Arch. Toxicol., 2015, 89(3), 405-414.[http://dx.doi.org/10.1007/s00204-014-1288-5] [PMID: 24912784] ] experimentally proved that K117 fulfils one of the basic requirements of an adequate antidote, it does not even influence the enzyme activity of BuChE in excess (1,000 µM). Thereby, K117 belongs to the group of pyridinium aldoximes that can be potentially used (K27, K48, K74, K75, K99, K127, K203, etc.) in medical practice. The BuChE reactivation power of K117 is preferable in paraoxon-inhibited BuChE, while its (in vitro) activity on tabun-inhibited enzyme is not significant.

It is the circulating blood that supplies K117 from the site of i.m. injection to each organ, tisssue and cell of rats. However, special barriers of the organism (e.g. blood-brain barrier, blood-testis barrier etc.) can either totally or partially hinder the transfer of K117 to special organs such as the central nervous system and the organs of reproduction. Each biological barrier has its own characteristics. When brain concentrations are compared to the serum levels of K117 no proportionality can be observed. About 50% of K117 could penetrate into the brain when a dose of 0.1 µmol was given. However, this ratio decreased to 9% when 1 µmol and to 7% when 10 µmol K117 were applied, respectively. This dynamic function of the blood-brain-barrier was even more expressed for CSF; at a dose of 0.1 µmol. The relative concentration of K117 in the CSF compared to that in the serum, was 45%, however, this ratio decreased to 5% and 1.6% using doses of 1 µmol and 10 µmol, respectively. Lorke et al. [15Lorke, D.E.; Kalász, H.; Petroianu, G.A.; Tekes, K. Entry of oximes into the brain: A review. Curr. Med. Chem., 2008, 15(8), 743-753.[http://dx.doi.org/10.2174/092986708783955563] [PMID: 18393843] ] also demonstrated dynamic changes in blood-brain barrier and blood-CSF barrier functions. The relatively high proportion of K-117 in the kidneys, 30 minutes following intramuscular administration, compared to serum and the liver versus serum, indicates the essential role of the kidneys in the removal of K117 from the organism. It also indicates that K117 is hydrophilic and, therefore, is excreted from the body via the kidney.

The inner ear has a multi-compartmental structure (peri-, endolymph) with several different barrier systems (e.g. blood-endolymph, blood-perilymph, CSF-perilymph) [16Juhn, S.K. Barrier systems in the inner ear. Acta Otolaryngol. Suppl., 1988, 458, 79-83.[http://dx.doi.org/10.3109/00016488809125107] [PMID: 3245438] , 17Sun, W.; Wang, W. Advances in research on labyrinth membranous barriers. J. Otol., 2015, 10(3), 99-104.[http://dx.doi.org/10.1016/j.joto.2015.11.003] [PMID: 29937790] ], which makes the explanation of the relatively high K117 concentrations in the inner ear difficult. Experimental data suggest that a much slower elimination from the perilymph [18Tran Ba Huy, P.; Bernard, P.; Schacht, J. Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J. Clin. Invest., 1986, 77(5), 1492-1500.[http://dx.doi.org/10.1172/JCI112463] [PMID: 3700652] , 19Chen, Z.; Duan, M.; Lee, H.; Ruan, R.; Ulfendahl, M. Pharmacokinetics of caroverine in the inner ear and its effects on cochlear function after systemic and local administrations in Guinea pigs. Audiol. Neurotol., 2003, 8(1), 49-56.[http://dx.doi.org/10.1159/000067893] [PMID: 12566692] ] is presumably a major factor in the development of substance accumulation in the inner ear.

CONCLUSION

The analysis of tissue concentrations of K117 levels relative to serum concentrations is a useful method to determine the special characteristics of the penetration of this compound into critically important organs and tissues. The validated reversed-phase HPLC bioanalytical method developed was sensitive and selective enough for detailed pharmacokinetic measurements.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All animal experiments were carried out according to the ethical requirements of Semmelweis University (permission number of Governmental Office of Pest County, Hungary, PE/EA/385-5/2018.)

HUMAN AND ANIMAL RIGHTS

No human were used in the study. Al the procedures followed were in accordance with the standards set forth in the eighth edition of “Guide for the Care and Use of Laboratory Animals” (grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals_prepub.pdf published by the National Academy of Sciences, The National Academies Press, Washington, D.C.).

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

This project is based on a Corsorcium Agreement between Korea Research Institute (Daejeon, Korea), Jagiellonian University (Krakow, Poland), University of Hradec Kralove (Hradec Kralove, Czech Republic) and Semmelweis University (Budapest, Hungary).

The authors express their thanks to Mr. János Horváth and Ms. Bogi Szalacsi for their advice. Technical assistance was provided by Ms. Györgyike Guth, Ms. Krisztina Kecskés, Mr. Zoltán Szimrók and Mr. András Keglevich.

This project was financially supported by the grant NN126968 of National Research, Development and Innovation Office (NRDIO, Budapest, Hungary) this research was supported by Ministry of Education, Youth and Sports of the Czech Republic (No. 8F17004) via V4-Korea Joint Research Program and also by Kalász Teaching and Research Co. (Budapest, Hungary). Grant No. K128875 of NRDIO served as partial source of salary to JSz.

REFERENCES

[1] Nachon, F.; Brazzolotto, X.; Trovaslet, M.; Masson, P. Progress in the development of enzyme-based nerve agent bioscavengers. Chem. Biol. Interact., 2013, 206(3), 536-544.[http://dx.doi.org/10.1016/j.cbi.2013.06.012] [PMID: 23811386]
[2] Masson, P.; Lockridge, O. Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior. Arch. Biochem. Biophys., 2010, 494(2), 107-120.[http://dx.doi.org/10.1016/j.abb.2009.12.005] [PMID: 20004171]
[3] Lockridge, O. Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol. Ther., 2015, 148, 34-46.[http://dx.doi.org/10.1016/j.pharmthera.2014.11.011] [PMID: 2544 8037]
[4] Strelitz, J.; Engel, L.S.; Keifer, M.C. Blood acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among pesticide handlers. Occup. Environ. Med., 2014, 71(12), 842-847.[http://dx.doi.org/10.1136/oemed-2014-102315] [PMID: 25189163]
[5] Karasova, J.Z.; Kassa, J.; Jung, Y.S.; Musilek, K.; Pohanka, M.; Kuca, K. Effect of several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats. Int. J. Mol. Sci., 2008, 9(11), 2243-2252.[http://dx.doi.org/10.3390/ijms9112243] [PMID: 19330072]
[6] Kovarik, Z.; Katalinić, M.; Sinko, G.; Binder, J.; Holas, O.; Jung, YS.; Musilova, L.; Jun, D.; Kuca, K. Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem. Biol. Interact., 2010, 187(1-3), 167-171.[http://dx.doi.org/10.1016/j. cbi. 2010.02.023] [PMID: 20206 154]
[7] Jun, D.; Musilova, L.; Kuca, K.; Kassa, J.; Bajgar, J. Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro. Chem. Biol. Interact., 2008, 175(1-3), 421-424.[http://dx.doi.org/10.1016/j.cbi.2008.05.004] [PMID: 18617161]
[8] Kuca, K.; Jun, D.; Junova, L.; Musilek, K.; Hrabinova, M.; da Silva, J.A.V.; Ramalho, T.C.; Valko, M.; Wu, Q.; Nepovimova, E.; França, T.C.C. Synthesis, Biological evaluation, and docking studies of novel bisquaternary aldoxime reactivators on acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon. Molecules, 2018, 23(5), E1103.[http://dx.doi.org/10.3390/molecules23051103] [PMID: 29735900]
[9] Sakurada, K.; Matsubara, K.; Shimizu, K.; Shiono, H.; Seto, Y.; Tsuge, K.; Yoshino, M.; Sakai, I.; Mukoyama, H.; Takatori, T. Pralidoxime iodide (2-pAM) penetrates across the blood-brain barrier. Neurochem. Res., 2003, 28(9), 1401-1407.[http://dx.doi.org/10.1023/A:1024960819430] [PMID: 12938863]
[10] Okuno, S.; Sakurada, K.; Ohta, H.; Ikegaya, H.; Kazui, Y.; Akutsu, T.; Takatori, T.; Iwadate, K. Blood-brain barrier penetration of novel pyridinealdoxime methiodide (PAM)-type oximes examined by brain microdialysis with LC-MS/MS. Toxicol. Appl. Pharmacol., 2008, 227(1), 8-15.[http://dx.doi.org/10.1016/j.taap.2007.09.021] [PMID: 17964625]
[11] Kalász, H.; Szöko, E.; Tábi, T.; Petroianu, G.A.; Lorke, D.E.; Omar, A.; Alafifi, S.; Jasem, A.; Tekes, K. Analysis of pralidoxime in serum, brain and CSF of rats. Med. Chem., 2009, 5(3), 237-241.[http://dx.doi.org/10.2174/157340609788185882] [PMID: 19442213]
[12] Kalász, H.; Szegi, P.; Jánoki, G.; Balogh, L.; Pöstényi, Z.; Musilek, K.; Petroianu, G.A.; Siddiq, A.; Tekes, K. Study on medicinal chemistry of K203 in wistar rats and beagle dogs. Curr. Med. Chem., 2013, 20(16), 2137-2144.[http://dx.doi.org/10.2174/0929867311320160006] [PMID: 23531217]
[13] Tekes, K. Distribution of K117, a bispyridinium aldoxime with regenerating activity on diminished butyrylcholinesterase enzyme activity in preparation,
[14] Horn, G.; Wille, T.; Musilek, K.; Kuca, K.; Thiermann, H.; Worek, F. Reactivation kinetics of 31 structurally different bispyridinium oximes with organophosphate-inhibited human butyrylcholinesterase. Arch. Toxicol., 2015, 89(3), 405-414.[http://dx.doi.org/10.1007/s00204-014-1288-5] [PMID: 24912784]
[15] Lorke, D.E.; Kalász, H.; Petroianu, G.A.; Tekes, K. Entry of oximes into the brain: A review. Curr. Med. Chem., 2008, 15(8), 743-753.[http://dx.doi.org/10.2174/092986708783955563] [PMID: 18393843]
[16] Juhn, S.K. Barrier systems in the inner ear. Acta Otolaryngol. Suppl., 1988, 458, 79-83.[http://dx.doi.org/10.3109/00016488809125107] [PMID: 3245438]
[17] Sun, W.; Wang, W. Advances in research on labyrinth membranous barriers. J. Otol., 2015, 10(3), 99-104.[http://dx.doi.org/10.1016/j.joto.2015.11.003] [PMID: 29937790]
[18] Tran Ba Huy, P.; Bernard, P.; Schacht, J. Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J. Clin. Invest., 1986, 77(5), 1492-1500.[http://dx.doi.org/10.1172/JCI112463] [PMID: 3700652]
[19] Chen, Z.; Duan, M.; Lee, H.; Ruan, R.; Ulfendahl, M. Pharmacokinetics of caroverine in the inner ear and its effects on cochlear function after systemic and local administrations in Guinea pigs. Audiol. Neurotol., 2003, 8(1), 49-56.[http://dx.doi.org/10.1159/000067893] [PMID: 12566692]

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Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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