#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Journals / Czech and Slovak Pharmacy / 2023 - 6

Stručný pohľad na vlastnosti in silico, vzťahy štruktúra– –aktivita a biotransformáciu fruquintinibu, protinádorovo účinkujúceho liečiva novej generácie obsahujúceho privilegované benzofuránové zoskupenie

Stiahnuť PDF English version

Autori: Dominika Nádaská 1;  Lucia Hudecova 2;  Gustáv Kováč 2;  Ivan Malík 1,2
Pôsobisko autorov: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic 1;  Institute of Chemistry, Clinical Biochemistry and Laboratory Medicine Faculty of Medicine, Slovak Medical University in Bratislava, Slovak Republic 2
Vyšlo v časopise: Čes. slov. Farm., 2023; 72, 267-276
Kategória: Review Articles
doi: https://doi.org/10.5817/CSF2023-6-267

Súhrn

Súčasné trendy projekcie liečiv významne reflektujú tzv. privilegované zoskupenia ako základné (tzv. jadrové) štruktúrne fragmenty s rozhodujúcim vplyvom na afinitu k vhodne zvoleným biologickým cieľom, účinok, selektivitu aj toxikologické charakteristiky týchto liečiv a perspektívnych kandidátov na liečivá. Fruquintinib (1) je nový syntetický selektívny inhibítor izoforiem receptora vaskulárneho endotelového rastového faktora (z angl. vascular endothelial growth factor receptor; VEGFR), t. j. VEGFR-1, VEGFR-2 a VEGFR-3. Terapeutikum (1) obsahuje planárne bicyklické heteroaromatické jadro, v ktorom sú vhodne inkorporované dva atómy dusíka, základný (jadrový) bicyklický heteroaromatický kruh – privilegované (substituované) benzofuránové zoskupenie a skupinu pôsobiacu ako donor a akceptor väzby vodíkovým mostíkom (VVM), t. j. amidové funkčné zoskupenie. Fruquintinib (1) bol prvýkrát schválený v Číne pre liečbu metastázujúceho kolorektálneho karcinómu, závažného nádorového ochorenia s vysokou mortalitou. Táto prehľadová publikácia ponúkla stručný pohľad na tému privilegovaných štruktúr, ich niekoľkých parametrov, ktorých rozsah približuje tzv. liečivu podobné (drug-like) vlastnosti, farmakodynamické charakteristiky fruquintinibu (1) a rôzne in silico-deskriptory definujúce štruktúrne a fyzikálno-chemické vlastnosti tohto liečiva (molekulová hmotnosť, počet ťažkých atómov, počet aromatických tažkých atómov, frakcia C-atómov v sp3-hybridizovanom stave, počet akceptorov VVM, počet donorov VVM, celkový polárny povrch, molekulová refrakcia, molekulový objem aj parametre lipofility a rozpustnosti). Niektoré z týchto deskriptorov súviseli s farmakokinetikou aj distribúciou fruquintinibu (1) a navyše by mohli pomôcť predikovať jeho schopnosť pasívne prechádzať hematoencefalickou bariérou (HEB). V publikácii sa hodnotila aj eventuálna súvislosť medzi indukčným potenciálom liečiva (1) voči izoenzýmom cytochrómu P450 (CYP1A2 a CYP3A4) a jeho pasívnym transportom do centrálneho nervového systému via HEB. Stručne boli takisto načrtnuté súčasné klinické skúsenosti s fruquintinibom (1) a budúce liečebné možnosti tohto terapeutika.

Klíčová slova:

privilegované zoskupenie – fruquinti- nib – vlastnosti in silico – vzťahy štuktúra–aktivita – far- makokinetika

Zdroje

  1. Zhao H., Dietrich J. Privileged scaffolds in lead generation. Expert Opin. Drug. Discov. 2015; 10, 781–790. doi:10.1517/17460441.2015.1041496
  2. Evans B. E., Rittle K. E., Bock M. G., DiPardo R. M., Freidinger R. M., Whitter W. L., Lundell G. F., Veber D. F., Anderson P. S., Chang R. S. L., Lotti V. J., Cerino D. J., Chen T. B., Kling P. J., Kunkel K. A., Springer J. P., Hirshfield J. Methods for drug discovery: development of potent,selective, orally effective cholecystin antagonists. J. Med. Chem. 1988; 31, 2235–2246. doi: 10.1021/ jm00120a002
  3. Kourounakis A. P., Xanthopoulos D., Tzara A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev. 2020; 40, 709–752. doi: 10.1002/med.21634
  4. Datusalia A. K., Khatik G. L. Thiazole heterocycle: A privileged scaffold for drug design and discovery. Curr. Drug Discov. Technol.2018; 15, 162. doi: 10.2174/157016381503180620153423
  5. Gharat R., Prabhu A., Khambete M. P. Potential of triazines in Alzheimer’s disease: A versatile privileged scaffold. Arch. Pharm. (Weinheim) 2022; 355, art. no. e2100388 (12 pp.). doi: 10.1002/ardp.202100388
  6. Maclean D., Baldwin J. J., Ivanov V. T., Kato Y., Shaw A., Schenider P., Gordon E. M. Glossary of terms used in combinatorial chemistry (technical report). J. Comb. Chem. 2000; 2, 562–578. doi: 10.1021/cc000071u
  7. Horton D. A., Bourne G. T., Smythe M. L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures.Chem. Rev. 2003; 103, 893–930. doi: 10.1021/cr020033s
  8. Costantino L., Barlocco D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem. 2006; 13, 6585. doi: 10.2174/092986706775197999
  9. Rusinov V. L., Charushin V. N., Chupakhin O. N. Biologically active azolo-1,2,4-triazines and azolopyrimidines. Russ. Chem. Bull. 2018; 67, 573–599. doi: 10.1007/ s11172-018-2113-8
  10. Voinkov E. K., Drokin R. A., Fedotov V. V., Butorin I. I., Savateev K. V., Lyapustin D. N., Gazizov D. A., Gorbunov E. B., Slepukhin P. A., Gerasimova N. A., Evstigneeva N. P., Zilberberg N. V., Kungurov N. V., Ulomsky E. N., Rusinov V. L. Azolo[5,1-c][1,2,4]triazines and azoloazapurines: Synthesis, antimicrobial activity and in silico studies. ChemistrySelect 2022; 7, art. no. e202104253 (8 pp.). doi: 10.1002/slct.202104253
  11. Savateev K. V., Ulomsky E. N., Butorin I. I., Charushin V. N., Rusinov V. L., Chupakhin O. N. Azoloazines as A2a receptor antagonists.Structure–activity relationship. Russ. Chem. Rev. 2018; 87, 636–669. doi: 10.1070/RCR4792
  12. Han Ch., Zhang J., Zheng M., Xiao Y., Li Y., Liu G. An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties. Mol. Divers. 2011; 15, 857–876. doi: 10.1007/s11030-011-9317-2
  13. Hubatsch I., Ragnarsson E. G. E., Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2007; 2, 2111–2119. doi: 10.1038/nprot.2007.303
  14. Jakopin Ž. 2-Aminothiazoles in drug discovery: Privileged structures or toxicophores? Chem. Biol. Interact. 2020; 330, art. no. 109244 (8 pp.). doi: 10.1016/j. cbi.2020.109244
  15. Atmaram U. A., Roopan S. M. Biological activity of oxadiazole and thiadiazole derivatives. Appl. Microbiol. Biotechnol. 2022; 106, 3489–3505. doi: 10.1007/s00253-022-11969-0
  16. He M., Fan M., Peng Z., Wang G. An overview of hydroxypyranone and hydroxypyridinone as privileged scaffolds for novel drug discovery. Eur. J. Med. Chem. 2021; 221, art. no. 113546 (29 pp.). doi: 10.1016/j.ejmech.2021.113546
  17. Rakesh K. P., Shantharam C. S., Sridhara M. B., Manukumar H. M., Qin H.-L. Benzisoxazole: a privileged scaffold for medicinal chemistry. Med. Chem. Commun. 2017; 8, 2023–2039. doi: 10.1039/c7md00449d
  18. Saroha B., Kumar G., Kumari M., Kaur R., Raghav N., Sharma P. K., Kumar N., Kumar S. A decennary update on diverse heterocycles and their intermediates as privileged scaffolds for cathepsin B inhibition. Int. J. Biol. Macromol. 2022; 222 (Part B),2270–2308. doi: 10.1016/j. ijbiomac.2022.10.017
  19. Avula S. K., Das B., Csuk R., Al-Harrasi A. Naturally occurring O-heterocycles as anticancer agents. Anticancer Agents Med.Chem. 2022; 22, 3208–3218. doi: 10.2174/1871520621666211108091444
  20. Pairas G. N., Perperopoulou F., Tsoungas P. G., Varvounis G. The isoxazole ring and its N-oxide: A privileged core structure in neuropsychiatric therapeutics. ChemMedChem. 2017; 12, 408–419. doi: 10.1002/ cmdc.201700023
  21. Wang Xi., Wang Xu., Zhao Y., Zhang X. Two previously undescribed benzofuran derivatives from the flowers of Callistephuschinensis. Phytochem. Lett. 2022; 51, 145–148. doi: 10.1016/j.phytol.2022.08.012
  22. Abu-Hashem A. A., Hussein H. A. R., Aly A. S., Gouda M. A. Reactivity of benzofuran derivatives. Synth. Commun. 2014; 44, 2899–2920. doi: 10.1080/00397911.2014.907425
  23. Abbas A. A., Dawood K. M. Anticancer therapeutic potential of benzofuran scaffolds. RSC Adv. 2023; 13, 11096–11120. doi: 10.1039/d3ra01383a
  24. Fuloria Sh., Sekar M., Khattulanuar F. S., Gan S. H., Rani N. N. I. M., Ravi S., Subramaniyan V., Jeyabalan S., Begum M. Y., Chidambaram K., Sathasivam K. V., Safi Sh. Z., Wu Y. S., Nordin R., Maziz M. N. H., Kumarasamy V., Lum P. T., Fuloria N. K.Chemistry, biosynthesis and pharmacology of viniferin: Potential resveratrol-derived molecules for new drug discovery, development and therapy. Molecules 2022; 27, art. no. 5072 (33 pp.). doi: 10.3390/molecules27165072
  25. Khanam H., Shamsuzzaman. Bioactive benzofuran derivatives: A review. Eur. J. Med. Chem. 2015; 97, 483–504. doi:10.1016/j.ejmech.2014.11.039
  26. Chiummiento L., D’Orsi R., Funicello M., Lupattelli P. Last decade of unconventional methodologies for the synthesis of substituted benzofurans. Molecules 2020; 25, art. no. 2327 (52 pp.). doi: 10.3390/molecules25102327
  27. Modell A. E., Blosser S. L., Arora P. S. Systematic targeting of protein–protein interactions. Trends Pharmacol. Sci. 2016; 37, 702–713. doi: 10.1016/j.tips.2016.05.008
  28. Farhat J., Alzyoud L., Alwahsh M., Al-Omari B. Structure–activity relationship of benzofuran derivatives with potential anticancer activity. Cancers (Basel) 2022; 14, art. no. 2196 (22 pp.). doi: 10.3390/cancers14092196
  29. Dawood K. M. Benzofuran derivatives: a patent review. Expert Opin. Ther. Pat. 2013; 23, 1133–1156. doi:10.1517/13543776.2013.801455
  30. Xu Zh., Zhao Sh., Lv Z., Feng L., Wang Y., Zhang F., Bai L., Deng J. Benzofuran derivatives and their anti-tubercular, antibacterial activities. Eur. J. Med. Chem. 2019; 162, 266–276. doi: 10.1016/j.ejmech.2018.11.025
  31. Nevagi R. J., Dighe S. N., Dighe S. N. Biological and medicinal significance of benzofuran. Eur. J. Med. Chem. 2015; 97, 561–581. doi: 10.1016/j.ejmech.2014.10.085
  32. Ahmad A., Nawaz M. I. Molecular mechanism of VEGF and its role in pathological angiogenesis. J. Cell. Biochem. 2022; 123, 1938–1965. doi: 10.1002/jcb.30344
  33. Malekan M., Ebrahimzadeh M. A. Vascular endothelial growth factor receptors [VEGFR] as target in breast cancer treatment: Current status in preclinical and clinical studies and future directions. Curr. Top. Med. Chem. 2022; 22, 891–920. doi: 10.2174/1568026622666220308161710
  34. Olsson A.-K., Dimberg A., Kreuger J., Claesson-Welsh L. VEGF receptor signalling – in control of vascular function. Nat. Rev. Mol. Cell Biol. 2006; 7, 359–371. doi: 10.1038/nrm1911
  35. Mabeta P., Steenkamp V. The VEGF/VEGFR axis revisited: Implications for cancer therapy. Int. J. Mol. Sci. 2022; 23, art. no. 15585 (14 pp.). doi: 10.3390/ijms232415585
  36. Zhang Y., Zou J.-Y., Wang Zh., Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag. Res. 2019; 11, 7787–7803. doi: 10.2147/CMAR.S215533
  37. Li X., Zhou J., Wang X., Li Ch., Ma Z., Wan Q., Peng F. New advances in the research of clinical treatment and novel anticanceragents in tumor angiogenesis. Biomed. Pharmacother. 2023; 163, art. no. 114806 (16 pp.). doi: 10.1016/j.biopha.2023.114806
  38. Sun Q., Zhou J., Zhang Zh., Guo M., Liang J., Zhou F., Long J., Zhang W., Yin F., Cai H., Yang H., Zhang W., Gu Y., Ni L., Sai Y., Cui Y., Zhang M., Hong M., Sun J., Yang Zh., Qing W., Su W., Ren Y. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol. Ther. 2014; 15, 1635–1645. doi:10.4161/15384047.2014.964087
  39. Chen Zh., Jiang L. The clinical application of fruquintinib on colorectal cancer. Expert Rev. Clin. Pharmacol. 2019; 12, 713–721. doi:10.1080/17512433.2019.1630272
  40. Shirley M. Fruquintinib: First global approval. Drugs 2018; 78, 1757–1761. doi: 10.1007/s40265-018-0998-z
  41. Lavacchi D., Roviello G., Guidolin A., Romano S., Venturini J., Caliman E., Vannini A., Giommoni E., Pellegrini E., Brugia M., Pillozzi S., Antonuzzo L. Evaluation of fruquintinib in the continuum of care of patients with colorectal cancer. Int. J. Mol. Sci. 2023; 24, art. no. 5840 (12 pp.). doi: 10.3390/ijms24065840
  42. Modi S. J., Kulkarni V. K. Exploration of structural requirements for the inhibition of VEGFR-2 tyrosine kinase: Binding site analysis of type II, ’DFG-out’ inhibitors. J. Biomol. Struct. Dyn. 2022; 40, 5712–5727. doi: 10.1080/07391102.2021.1872417
  43. Daina A., Michielin O., Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7, art. no. 42717 (13 pp.). doi: 10.1038/ srep42717
  44. Moriguchi I., Hirono Sh., Liu Q., Nakagome I., Matsushita Y. Simple method of calculating octanol / water partition coefficient.Chem. Pharm. Bull. 1992; 40, 127–130. doi: 10.1248/cpb.40.127
  45. Moriguchi I., Hirono Sh., Nakagome I., Hirano H. Comparison of reliability of log P values for drugs calculated by several methods. Chem. Pharm. Bull. 1994; 42, 976–978. doi: 10.1248/cpb.42.976
  46. Lipinski Ch. A., Lombardo F., Dominy D. W., Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001; 46, 3–26. doi: 10.1016/s0169-409x(00)00129-0
  47. PerkinElmer. https://www.perkinelmer.com/analytical-and-enterprise-solutions.html (accessed on: September 24, 2023)
  48. Molinspiration Cheminformatics. https://www.molinspiration.com/cgi-bin/properties (accessed on: September 24, 2023)
  49. Ali J., Camilleri P., Brown M. B., Hutt A. J., Kirton S. B. In silico prediction of aqueous solubility using simple QSPR models: theimportance of phenol and phenol-like moieties. J. Chem. Inf. Model. 2012; 52, 2950–2957. doi: 10.1021/ci300447c
  50. Silicos-IT. https://www.silicos-it.be/ (accessed on: September 24, 2023)
  51. Wang X., Bove A. M., Simone G., Ma B. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front. Cell Dev. Biol. 2020; 8, art. no. 599281 (12 pp.). doi: 10.3389/fcell.2020.599281
  52. Peng F.-W., Liu D.-K., Zhang Q.-W., Xu Y.-G., Shi L. VE-GFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012–2016). Expert Opin. Ther. Pat. 2017; 27, 987–1004. doi: 10.1080/13543776.2017.1344215
  53. Lipinski Ch. A. Leadand drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 2004; 1, 337–341. doi: 10.1016/j.ddtec.2004.11.007
  54. Veber D. F., Johnson S. R., Cheng H.-Y., Smith B. R., Ward K. W., Kopple K. D. Molecular properties that influence the oralbioavailability of drug candidates. J. Med. Chem. 2002; 45, 2615–2623. doi: 10.1021/jm020017n
  55. Gu Y., Wang J., Li K., Zhang L., Ren H., Guo L., Sai Y., Zhang W., Su W. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemother.Pharmacol. 2014; 74, 95–115. doi: 10.1007/s00280-014-2471-3
  56. Kelder J., Grootenhuis P. D. J., Bayada D. M., Delbressine L. P. C., Ploemen J.-P. Polar molecular surface as a dominatingdeterminant for oral absorption and brain penetration of drugs. Pharm. Res. 1999; 16, 1514–1519. doi: 10.1023/A:1015040217741
  57. van de Waterbeemd H., Camenish G., Folkers G., Chretien J. R., Raevsky O. A. Estimation of blood–brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target. 1998; 6, 151–156. doi: 10.3109/10611869808997889
  58. Levin V. A. Relationship of octanol / water partition coefficient and molecular weight to rat brain capillary permeability. J. Med. Chem.1980; 23, 682–684. doi: 10.1021/ jm00180a022
  59. Hansch C., Leo A. J. Substituent constant for correlation analysis in chemistry and biology. New York: Wiley 1979. doi:10.1002/jps.2600690938
  60. Ghose A. K., Herbertz T., Hudkins R. L., Dorsey B. D., Mallamo J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012; 3, 50–68. doi: 10.1021/cn200100h
  61. Pajouhesh H., Lenz G. R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2005; 2, 541–553. doi: 10.1602/neurorx.2.4.541
  62. de Klerk D. J., Honeywell R. J., Jansen G., Peters G. J. Transporter and lysosomal mediated (multi)drug resistance to tyrosine kinase inhibitors and potential strategies to overcome resistance. Cancers (Basel) 2018; 10, art. no. 503 (27 pp.). doi: 10.3390/cancers10120503
  63. Fischer H., Gottschlich R., Seelig A. Blood–brain barrier permeation: Molecular parameters governing passive diffusion. J. Membr. Biol. 1998; 165, 201–211. doi: 10.1007/ s002329900434
  64. Raub T. J., Lutzke B. S., Andrus P. K., Sawada G. A., Staton B. A. Early preclinical evaluation of brain exposure in support of hitidentification and lead optimization. In: Borchardt R. T., Kerns E. H., Hageman M. J., Thakker D. R., Stevens J. L. (eds.) Optimizing the"Drug-Like" Properties of Leads in Drug Discovery. Biotechnology: Pharmaceutical Aspects, Vol. IV. New York: Springer 2006; 355–410. doi: 10.1007/978-0-387-44961-6_16
  65. Wang R., Cong D., Bai Y., Zhang W. Case report: long-term sustained remission in a case of metastatic colon cancer with high microsatellite instability and KRAS exon 2 p.G12D mutation treated with fruquintinib after local radiotherapy: a case report and literature review. Front. Pharmacol. 2023; 14, art. no. 1207369 (8 pp.). doi: 10.3389/fphar.2023.1207369
  66. Hoy S. M. Sintilimab: First global approval. Drugs 2019; 79, 341–346. doi: 10.1007/s40265-019-1066-z
  67. Guo Y., Zhang W., Ying J., Zhang Y., Pan Y., Qiu W., Fan Q., Xu Q., Ma Y., Wang G., Guo J., Su W., Fan S., Tan P., Wang Y., Luo Y., Zhou H., Li J. Phase 1b/2 trial of fruquintinib plus sintilimab in treating advanced solid tumours: The dose-escalation and metastatic colorectal cancer cohort in the dose-expansion phases. Eur. J. Cancer 2023; 181, 26–37. doi: 10.1016/j.ejca.2022.12.004
  68. Ma Sh., Chen R., Duan L., Li Ch., Yang T., Wang J., Zhao D. Efficacy and safety of toripalimab with fruquintinib in the third-line treatment of refractory advanced metastatic colorectal cancer: results of a single-arm, single-center, prospective, phase II clinical study. J. Gastrointest. Oncol. 2023; 14, 1052–1063. doi: 10.21037/jgo-23-108
  69. Keam S. J. Toripalimab: First global approval. Drugs 2019; 79, 573–578. doi: 10.1007/s40265-019-01076-2
  70. Ding X., Liu Y., Zhang Y., Liang J., Li Q., Hu H., Zhou Y. Efficacy and safety of fruquintinib as thirdor further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study. Anticancer Drugs 2023; 34, 877–882. doi: 10.1097/ CAD.0000000000001482
  71. Zhang P., Yang Y., Gou H., Li Q. Phase II study of fruquintinib as secondor further-line therapy for patients with advanced biliary tract cancer. J. Clin. Oncol. 2023; 41(Suppl), art. no. e16161 (1 pp.). doi: 10.1200/ JCO.2023.41.16_suppl.e16161
  72. Deng Y.-Y., Chen Y.-W., Wang M.-X., Zhu P.-F., Pan Sh.-Y., Jiang D.-Y., Chen Zh.-L., Yang L. Acute aortic dissection caused by fruquintinib for metastatic colorectal cancer–a case report and literature review. Transl. Cancer Res. 2023; 12, 177–185. doi: 10.21037/tcr-22-1872
  73. Zhang N., Xin X., Feng N., Wu D., Zhang J., Yu T., Jiang Q., Gao M., Yang H., Zhao S., Tian Q., Zhang Zh. Combiningfruquintinib and doxorubicin in size-converted nano-drug carriers for tumor therapy. ACS Biomater. Sci. Eng. 2022; 8, 1907–1920. doi:10.1021/acsbiomaterials.1c01606
Štítky
Pharmacy Clinical pharmacology
Článek Ethical aspects of conducting clinical trials of human medicinal products
Článek Potential impact on mental health in patients with treatment-resistant schizophrenia – clozapine augmentation with long-acting parenteral antipsychotics: a case series
Článek Prospects of сomplex pharmaceutical composition application for pharmacological correction of metabolic syndrome
Článek Increasing the efficiency of hypolipidemic therapy with the combined use of quercetin in patients with non-alcoholic fatty liver disease on the background of the metabolic syndrome
Článek Analysis of medication administration in relation to food and beverages in inpatients
Článek On the history and development of some changes in pharmacy practice – work safety in pharmacies
Článek Beauty in books: pharmaceutical bookplates in the territory of the present Czech Republic
Článek Úvodník
Článok vyšiel v časopise

Czech and Slovak Pharmacy

Číslo 6
2023 Číslo 6
Najčítanejšie v tomto čísle
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#