Miłosz Regulski - Academia.edu (original) (raw)
Papers by Miłosz Regulski
Journal of Medical Science, Mar 30, 2014
Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of h... more Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of hypertension and other cardiovascular system-related diseases. However, a wide range of their biological effects has turned the scientific interest towards other possible clinical applications of these drugs. The present review demonstrates the available data on the reported angiotensin-converting enzyme inhibitors-based therapies in the treatment of the following human disturbances: cancer, obesity, Barrett syndrome, erythrocytosis, a high-dose-chemotherapyinduced cardiotoxicity, Marfan syndrome, Duchenne muscular dystrophy, migraine, Raynaud's syndrome and Alzheimer disease.
Current Pharmaceutical Design, Mar 1, 2015
Iranian Journal of Pharmaceutical Research : IJPR, 2019
In this study a solid dispersion and a physical mixture of cilazapril (CIL) with a biopolymer - p... more In this study a solid dispersion and a physical mixture of cilazapril (CIL) with a biopolymer - polyvinylpyrrolidone (PVP) as a carrier were prepared so as to investigate the effect of PVP on the stability of CIL. CIL is unstable in solid state and decomposes rapidly under humid conditions. It requires stabilization to ensure safety of its use. The studied CIL/PVP formulations were prepared by milling and evaporation technique. Their identity was confirmed by FT-IR method. The stability of CIL in the CIL/PVP formulations was assessed by forced ageing test under isothermic conditions using RP-HPLC. The influence of temperature (experimental conditions: RH 76.4% and T = 70, 75, 80, 85, and 90 oC) and the effect of relative humidity (experimental conditions: RH 25.0%, 50.9%, 60.9%, 66.5%, 76.4%, T = 90 °C) on the rate of CIL degradation were examined. It was established that the process of CIL decay in the studied forms followed first-order kinetics with the formation of one degradatio...
Journal of Medical Science, 2014
Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of h... more Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of hypertension and other cardiovascular system-related diseases. However, a wide range of their biological effects has turned the scientific interest towards other possible clinical applications of these drugs. The present review demonstrates the available data on the reported angiotensin-converting enzyme inhibitors – based therapies in the treatment of the following human disturbances: cancer, obesity, Barrett syndrome, erythrocytosis, a high-dose-chemotherapy-induced cardiotoxicity, Marfan syndrome, Duchenne muscular dystrophy, migraine, Raynaud’s syndrome and Alzheimer disease.
European Journal of Pharmacology, 2017
Current Pharmaceutical Design, 2015
Farmacja Polska
Tom 75 • nr 4 • 2019 popularnej i najczęściej stosowanej grupy leków, a także omówione zostaną pe... more Tom 75 • nr 4 • 2019 popularnej i najczęściej stosowanej grupy leków, a także omówione zostaną perspektywy jej rozwoju. Odkrycie cyklooksygenazy i wyjaśnienie mechanizmu działania NLPZ Jak wspomniano w części I artykułu, działanie pierwszych leków z grupy NLPZ w fazie przedrejestracyjnej weryfikowane było jedynie w oparciu Wstęp Odkrycie i komercjalizację niesteroidowych leków przeciwzapalnych (NLPZ) można uznać za kamień milowy w rozwoju medycyny i przemysłu farmaceutycznego. Pierwszy syntetyczny lek z tej grupy-aspiryna (wprowadzona do obrotu w 1899 r.) udowodniła, że towarzyszący wielu chorobom ból można łatwo i skutecznie leczyć, istotnie podnosząc jakość życia wielu milionów ludzi na całym świecie. Kliniczny i marketingowy sukces aspiryny stał się impulsem do rozwoju chemii medycznej i farmacji przemysłowej na przełomie XIX i XX wieku, który spowodował przesunięcie ciężaru produkcji leków z aptek do fabryk. Taka tendencja istotnie zwiększyła możliwości dokonania kolejnych spektakularnych odkryć w dziedzinie farmakologii bólu. W poprzedniej części tego artykułu omówiono historię farmakoterapii bólu i stanu zapalnego w kontekście odkrycia i rozwoju NLPZ w okresie od starożytności do lat 60. XX w. Jednakże oś czasu przedstawiająca ścieżkę ewolucji niesteroidowych leków przeciwzapalnych wskazuje wyraźnie, że do tamtego czasu, choć dysponowano już dosyć szeroką gamą leków przeciwbólowych, tak naprawdę niewiele wiedziano na temat patomechanizmu bólu i stanu zapalnego oraz związanych z tym farmakodynamicznych aspektów działania niesteroidowych leków przeciwzapalnych (rycina 1). W niniejszej części przedstawione zostaną wydarzenia ostatnich 60 lat w historii tej najbardziej From Salicis cortex to coxibs: historical background and innovative applications of non-steroidal anti-inflammatory drugs. Part II • The sequence of events associated with the discovery and development of non-steroidal anti-inflammatory drugs (NSAID) remains in complete opposition against the modern model of research and development program for new drug candidates. In this case, it was the drug that appeared first and then its mechanism of action was described. In the previous part of this article the history of discovery of non-steroidal anti-inflammatory drugs was described covering the period from ancient times until 1960s. In this part we will discuss the historical aspects of the last 60 years, related to the discovery of the pathomechanism of pain and pharmacodynamic properties of non-steroidal anti-inflammatory drugs, which contributed to the development of selective inhibitors of cyclooxygenase-2-coxibs. The story behind these compounds has been defined by great expectations and unexpected failure, which obviously has prompted the need for further development in the field of pharmacotherapy of pain and inflammatory conditions.
Bioorganic & Medicinal Chemistry
Journal of Medical Science, 2017
During pregnancy the demand for nutrients, energy, vitamins and minerals increases. The diet used... more During pregnancy the demand for nutrients, energy, vitamins and minerals increases. The diet used during pregnancy and before conception should provide the best conditions for the development of young, but often it is insufficient to cover the demands for both a pregnant woman and the fetus. Therefore pregnant woman, in the case of nutritional deficiencies and inability to cover them as the part of the daily diet, is often obliged to supplement the nutrition that she and the baby need. Moreover, the deficit of the nutritional elements during this period may increase the risk of various types of disorders complicating the pregnancy and affecting the development and the health of the baby. The working scheme of medicines may be changed due to nutritional supplements through the increase of their excretion, decrease in their absorption and/or disruption of metabolism. Many adverse events can occur due to the simultaneous application of both nutrition supplements and medicinal products....
Drug Discovery Today, 2015
Cyclooxygenase 2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogeno... more Cyclooxygenase 2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogenous actions that could be useful in the management of breast cancer. Here, we provide a complete understanding of the biochemistry of COX-2 and discuss the various molecular mechanisms behind its increased expression in breast cancer. We also analyze the possible mechanisms responsible for the anticancer effect of COX-2 inhibitors and provide an overview of the available preclinical and clinical data on the use of COX-2 inhibitors in breast cancer. Finally, we describe a mathematical model of the relation between the structure and biological potency of promising new COX-2 inhibitors (trans-stilbenes) using a 2D quantitative structure-activity relation (QSAR) technique.
Arabian Journal of Chemistry, 2015
Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznań and Polish Society of Radiation Oncology, 2014
The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impur... more The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the ...
Postępy Higieny i Medycyny Doświadczalnej, 2014
Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineo... more Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineoplastic drugs into clinical practice, which increased the efficiency of patient management. Also the prevalent use of combination treatment based on drug action synergy contributed to the improved clinical effect associated with cytotoxic drug administration. It seems, however, obvious that the multidirectional pharmacotherapy in oncology requires a thorough knowledge of drugs' pharmaceutical behavior in order to maximize their collective action and prevent the occurrence of unintended drug interactions that could potentially impair treatment effectiveness. In fact, drug interactions constitute a serious problem for current oncology primarily resulting from a narrow therapeutic index specific for the majority of anticancer drugs. This, in turn, indicates that even slight deviations of their pharmacokinetics could cause significant clinical consequences, manifested by alteration of the toxicological profile or reduction of therapeutic efficiency. Hence, the investigation of molecular aspects underlying the mechanisms of various drug interactions seems to be essential for proper and safe patient management. The present article is devoted to the extensive subject of drug interactions occurring in the therapy of colorectal cancer. It presents the Streszczenie Szybki postęp w dziedzinie chemioterapii nowotworów zaowocował wprowadzeniem do codziennej praktyki klinicznej wielu cennych leków o działaniu przeciwnowotworowym, umożliwiając skuteczniejsze leczenie chorych, również poprzez wykorzystanie terapii skojarzonych, których fundamentem jest synergizm działania substancji aktywnych. Prowadzenie wielokierunkowej farmakoterapii stwarza jednak kolejne wyzwania związane z koniecznością umiejętnego łączenia leków tak, aby zmaksymalizować ich skumulowany efekt oraz uniknąć niepożądanych interakcji, mogących negatywnie wpływać na przebieg procesu terapeutycznego. Interakcje w onkologii są poważnym problemem klinicznym, wynikającym przede wszystkim z wąskiego indeksu terapeutycznego leków przeciwnowotworowych, co oznacza, że nawet niewielka zmiana ich farmakokinetyki może spowodować bardzo istotne następstwa w postaci nadmiernego nasilenia toksyczności lub spadku skuteczności terapii. Z tego powodu analiza molekularnych mechanizmów leżących u podłoża rozlicznych interakcji jest niezwykle istotnym aspektem postępowania leczniczego w onkologii. W niniejszym artykule zaprezentowano przegląd odnotowanych w literaturze interakcji międzylekowych w terapii nowotworów jelita grubego, zarówno pozytywnych jak i negatywnych, omówiono ich molekularne mechanizmy oraz uwzględniono podział na interakcje zachodzące w fazie farmakokinetycznej oraz farmakodynamicznej. interakcje • chemioterapia • cytostatyki • nowotwory jelita grubego Molekularne podstawy interakcji międzylekowych w terapii nowotworów jelita grubego
Drug Discovery Today, 2014
Angiotensin-converting enzyme inhibitors (ACE-Is) are a valuable class of antihypertensive drugs ... more Angiotensin-converting enzyme inhibitors (ACE-Is) are a valuable class of antihypertensive drugs used in the treatment of cardiovascular system-related diseases. Hence, constant research into, and the development of, such compounds remain within the priorities of modern medical sciences. In this respect, a thorough understanding of their chemistry and biology is an important aspect of drug design; therefore, we present here available data on the pharmaceutical properties of ACE-Is. We also review the structural and biochemical features of the molecular target of ACE-Is and demonstrate several known enzyme-inhibitor complexes. Finally, we attempt to create a mathematical model describing the relation between the potency and/or stability of ACE-Is and their structural characteristics using quantitative structure-activity relation (QSAR), and quantitative structure-property relation (QSPR) techniques.
International Journal of Pharmaceutics, 2013
Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increa... more Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.
Postępy Higieny i Medycyny Doświadczalnej, 2012
inhibitors. This review presents a summary of their characteristics, analyzing their chemical str... more inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology.
Current Pharmaceutical Design, 2013
The role of the renin-angiotensin system (RAS) in the development of various malignancies has rec... more The role of the renin-angiotensin system (RAS) in the development of various malignancies has recently been extensively examined and, since it has been shown to significantly influence many aspect of cancer initiation and progression, the idea of RAS-targeted anticancer therapy has arisen. This article reviews the mechanisms underlying RAS-induced physiological and pathological responses related to cancer biology, including tumor growth, cell proliferation, apoptosis, angiogenesis, inflammation, and protein degradation, emphasizing the associated cellular transduction schemes activated by main RAS effectors. Also the dual nature of RAS-dependent effects, resulting from its complex physiology has been commented. Finally, based on the available data from clinical trials and experimental studies, the possibilities of the introduction of RAS-modulating drugs into standard clinical practice in oncology have been discussed with the focus on both, positive and negative effects associated with the administration of various classes of pharmaceuticals to cancer patients.
Journal of Pharmacokinetics and Pharmacodynamics, 2010
This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in... more This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V C = 27.7 l, V T = 801 l, and CL D = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to prop...
Journal of Medical Science, Mar 30, 2014
Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of h... more Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of hypertension and other cardiovascular system-related diseases. However, a wide range of their biological effects has turned the scientific interest towards other possible clinical applications of these drugs. The present review demonstrates the available data on the reported angiotensin-converting enzyme inhibitors-based therapies in the treatment of the following human disturbances: cancer, obesity, Barrett syndrome, erythrocytosis, a high-dose-chemotherapyinduced cardiotoxicity, Marfan syndrome, Duchenne muscular dystrophy, migraine, Raynaud's syndrome and Alzheimer disease.
Current Pharmaceutical Design, Mar 1, 2015
Iranian Journal of Pharmaceutical Research : IJPR, 2019
In this study a solid dispersion and a physical mixture of cilazapril (CIL) with a biopolymer - p... more In this study a solid dispersion and a physical mixture of cilazapril (CIL) with a biopolymer - polyvinylpyrrolidone (PVP) as a carrier were prepared so as to investigate the effect of PVP on the stability of CIL. CIL is unstable in solid state and decomposes rapidly under humid conditions. It requires stabilization to ensure safety of its use. The studied CIL/PVP formulations were prepared by milling and evaporation technique. Their identity was confirmed by FT-IR method. The stability of CIL in the CIL/PVP formulations was assessed by forced ageing test under isothermic conditions using RP-HPLC. The influence of temperature (experimental conditions: RH 76.4% and T = 70, 75, 80, 85, and 90 oC) and the effect of relative humidity (experimental conditions: RH 25.0%, 50.9%, 60.9%, 66.5%, 76.4%, T = 90 °C) on the rate of CIL degradation were examined. It was established that the process of CIL decay in the studied forms followed first-order kinetics with the formation of one degradatio...
Journal of Medical Science, 2014
Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of h... more Angiotensin converting enzyme inhibitors have emerged as a useful strategy in the management of hypertension and other cardiovascular system-related diseases. However, a wide range of their biological effects has turned the scientific interest towards other possible clinical applications of these drugs. The present review demonstrates the available data on the reported angiotensin-converting enzyme inhibitors – based therapies in the treatment of the following human disturbances: cancer, obesity, Barrett syndrome, erythrocytosis, a high-dose-chemotherapy-induced cardiotoxicity, Marfan syndrome, Duchenne muscular dystrophy, migraine, Raynaud’s syndrome and Alzheimer disease.
European Journal of Pharmacology, 2017
Current Pharmaceutical Design, 2015
Farmacja Polska
Tom 75 • nr 4 • 2019 popularnej i najczęściej stosowanej grupy leków, a także omówione zostaną pe... more Tom 75 • nr 4 • 2019 popularnej i najczęściej stosowanej grupy leków, a także omówione zostaną perspektywy jej rozwoju. Odkrycie cyklooksygenazy i wyjaśnienie mechanizmu działania NLPZ Jak wspomniano w części I artykułu, działanie pierwszych leków z grupy NLPZ w fazie przedrejestracyjnej weryfikowane było jedynie w oparciu Wstęp Odkrycie i komercjalizację niesteroidowych leków przeciwzapalnych (NLPZ) można uznać za kamień milowy w rozwoju medycyny i przemysłu farmaceutycznego. Pierwszy syntetyczny lek z tej grupy-aspiryna (wprowadzona do obrotu w 1899 r.) udowodniła, że towarzyszący wielu chorobom ból można łatwo i skutecznie leczyć, istotnie podnosząc jakość życia wielu milionów ludzi na całym świecie. Kliniczny i marketingowy sukces aspiryny stał się impulsem do rozwoju chemii medycznej i farmacji przemysłowej na przełomie XIX i XX wieku, który spowodował przesunięcie ciężaru produkcji leków z aptek do fabryk. Taka tendencja istotnie zwiększyła możliwości dokonania kolejnych spektakularnych odkryć w dziedzinie farmakologii bólu. W poprzedniej części tego artykułu omówiono historię farmakoterapii bólu i stanu zapalnego w kontekście odkrycia i rozwoju NLPZ w okresie od starożytności do lat 60. XX w. Jednakże oś czasu przedstawiająca ścieżkę ewolucji niesteroidowych leków przeciwzapalnych wskazuje wyraźnie, że do tamtego czasu, choć dysponowano już dosyć szeroką gamą leków przeciwbólowych, tak naprawdę niewiele wiedziano na temat patomechanizmu bólu i stanu zapalnego oraz związanych z tym farmakodynamicznych aspektów działania niesteroidowych leków przeciwzapalnych (rycina 1). W niniejszej części przedstawione zostaną wydarzenia ostatnich 60 lat w historii tej najbardziej From Salicis cortex to coxibs: historical background and innovative applications of non-steroidal anti-inflammatory drugs. Part II • The sequence of events associated with the discovery and development of non-steroidal anti-inflammatory drugs (NSAID) remains in complete opposition against the modern model of research and development program for new drug candidates. In this case, it was the drug that appeared first and then its mechanism of action was described. In the previous part of this article the history of discovery of non-steroidal anti-inflammatory drugs was described covering the period from ancient times until 1960s. In this part we will discuss the historical aspects of the last 60 years, related to the discovery of the pathomechanism of pain and pharmacodynamic properties of non-steroidal anti-inflammatory drugs, which contributed to the development of selective inhibitors of cyclooxygenase-2-coxibs. The story behind these compounds has been defined by great expectations and unexpected failure, which obviously has prompted the need for further development in the field of pharmacotherapy of pain and inflammatory conditions.
Bioorganic & Medicinal Chemistry
Journal of Medical Science, 2017
During pregnancy the demand for nutrients, energy, vitamins and minerals increases. The diet used... more During pregnancy the demand for nutrients, energy, vitamins and minerals increases. The diet used during pregnancy and before conception should provide the best conditions for the development of young, but often it is insufficient to cover the demands for both a pregnant woman and the fetus. Therefore pregnant woman, in the case of nutritional deficiencies and inability to cover them as the part of the daily diet, is often obliged to supplement the nutrition that she and the baby need. Moreover, the deficit of the nutritional elements during this period may increase the risk of various types of disorders complicating the pregnancy and affecting the development and the health of the baby. The working scheme of medicines may be changed due to nutritional supplements through the increase of their excretion, decrease in their absorption and/or disruption of metabolism. Many adverse events can occur due to the simultaneous application of both nutrition supplements and medicinal products....
Drug Discovery Today, 2015
Cyclooxygenase 2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogeno... more Cyclooxygenase 2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogenous actions that could be useful in the management of breast cancer. Here, we provide a complete understanding of the biochemistry of COX-2 and discuss the various molecular mechanisms behind its increased expression in breast cancer. We also analyze the possible mechanisms responsible for the anticancer effect of COX-2 inhibitors and provide an overview of the available preclinical and clinical data on the use of COX-2 inhibitors in breast cancer. Finally, we describe a mathematical model of the relation between the structure and biological potency of promising new COX-2 inhibitors (trans-stilbenes) using a 2D quantitative structure-activity relation (QSAR) technique.
Arabian Journal of Chemistry, 2015
Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznań and Polish Society of Radiation Oncology, 2014
The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impur... more The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the ...
Postępy Higieny i Medycyny Doświadczalnej, 2014
Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineo... more Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineoplastic drugs into clinical practice, which increased the efficiency of patient management. Also the prevalent use of combination treatment based on drug action synergy contributed to the improved clinical effect associated with cytotoxic drug administration. It seems, however, obvious that the multidirectional pharmacotherapy in oncology requires a thorough knowledge of drugs' pharmaceutical behavior in order to maximize their collective action and prevent the occurrence of unintended drug interactions that could potentially impair treatment effectiveness. In fact, drug interactions constitute a serious problem for current oncology primarily resulting from a narrow therapeutic index specific for the majority of anticancer drugs. This, in turn, indicates that even slight deviations of their pharmacokinetics could cause significant clinical consequences, manifested by alteration of the toxicological profile or reduction of therapeutic efficiency. Hence, the investigation of molecular aspects underlying the mechanisms of various drug interactions seems to be essential for proper and safe patient management. The present article is devoted to the extensive subject of drug interactions occurring in the therapy of colorectal cancer. It presents the Streszczenie Szybki postęp w dziedzinie chemioterapii nowotworów zaowocował wprowadzeniem do codziennej praktyki klinicznej wielu cennych leków o działaniu przeciwnowotworowym, umożliwiając skuteczniejsze leczenie chorych, również poprzez wykorzystanie terapii skojarzonych, których fundamentem jest synergizm działania substancji aktywnych. Prowadzenie wielokierunkowej farmakoterapii stwarza jednak kolejne wyzwania związane z koniecznością umiejętnego łączenia leków tak, aby zmaksymalizować ich skumulowany efekt oraz uniknąć niepożądanych interakcji, mogących negatywnie wpływać na przebieg procesu terapeutycznego. Interakcje w onkologii są poważnym problemem klinicznym, wynikającym przede wszystkim z wąskiego indeksu terapeutycznego leków przeciwnowotworowych, co oznacza, że nawet niewielka zmiana ich farmakokinetyki może spowodować bardzo istotne następstwa w postaci nadmiernego nasilenia toksyczności lub spadku skuteczności terapii. Z tego powodu analiza molekularnych mechanizmów leżących u podłoża rozlicznych interakcji jest niezwykle istotnym aspektem postępowania leczniczego w onkologii. W niniejszym artykule zaprezentowano przegląd odnotowanych w literaturze interakcji międzylekowych w terapii nowotworów jelita grubego, zarówno pozytywnych jak i negatywnych, omówiono ich molekularne mechanizmy oraz uwzględniono podział na interakcje zachodzące w fazie farmakokinetycznej oraz farmakodynamicznej. interakcje • chemioterapia • cytostatyki • nowotwory jelita grubego Molekularne podstawy interakcji międzylekowych w terapii nowotworów jelita grubego
Drug Discovery Today, 2014
Angiotensin-converting enzyme inhibitors (ACE-Is) are a valuable class of antihypertensive drugs ... more Angiotensin-converting enzyme inhibitors (ACE-Is) are a valuable class of antihypertensive drugs used in the treatment of cardiovascular system-related diseases. Hence, constant research into, and the development of, such compounds remain within the priorities of modern medical sciences. In this respect, a thorough understanding of their chemistry and biology is an important aspect of drug design; therefore, we present here available data on the pharmaceutical properties of ACE-Is. We also review the structural and biochemical features of the molecular target of ACE-Is and demonstrate several known enzyme-inhibitor complexes. Finally, we attempt to create a mathematical model describing the relation between the potency and/or stability of ACE-Is and their structural characteristics using quantitative structure-activity relation (QSAR), and quantitative structure-property relation (QSPR) techniques.
International Journal of Pharmaceutics, 2013
Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increa... more Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.
Postępy Higieny i Medycyny Doświadczalnej, 2012
inhibitors. This review presents a summary of their characteristics, analyzing their chemical str... more inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology.
Current Pharmaceutical Design, 2013
The role of the renin-angiotensin system (RAS) in the development of various malignancies has rec... more The role of the renin-angiotensin system (RAS) in the development of various malignancies has recently been extensively examined and, since it has been shown to significantly influence many aspect of cancer initiation and progression, the idea of RAS-targeted anticancer therapy has arisen. This article reviews the mechanisms underlying RAS-induced physiological and pathological responses related to cancer biology, including tumor growth, cell proliferation, apoptosis, angiogenesis, inflammation, and protein degradation, emphasizing the associated cellular transduction schemes activated by main RAS effectors. Also the dual nature of RAS-dependent effects, resulting from its complex physiology has been commented. Finally, based on the available data from clinical trials and experimental studies, the possibilities of the introduction of RAS-modulating drugs into standard clinical practice in oncology have been discussed with the focus on both, positive and negative effects associated with the administration of various classes of pharmaceuticals to cancer patients.
Journal of Pharmacokinetics and Pharmacodynamics, 2010
This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in... more This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V C = 27.7 l, V T = 801 l, and CL D = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to prop...