Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. O... more Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. Our previous preclinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl). An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability. These effects can be detrimental for muscle function leading to druginduced myopathy. Our goal is to study the causes of statin-induced muscle side effects in patients at the aim to identify biological markers useful to prevent and counteract statin-induced muscle damage. We examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs. Western Blot (WB) analysis showed a 40% reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type. Real-time PCR analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting posttranscriptional modification. The mRNA expression of a series of genes was also evaluated. MuRF-1 was increased in accord with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit. Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation. In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration. Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggests mitochondrial biogenesis. Thus, the reduction of ClC-1 protein and consequent sarcolemma hyperexcitability together with energy deficiency appear to be among the most important alterations to be associated with statin-related risk of myopathy in
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Pflügers Archiv - European Journal of Physiology, 2014
In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, co... more In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, controls the sarcolemma electrical stability. Indeed, loss-of-function mutations in ClC-1 gene are responsible of myotonia congenita. The ClC-1 channel can be phosphorylated and inactivated by protein kinases C (PKC), but the relative contribution of each PKC isoforms is unknown. Here, we investigated on the role of PKCθ in the regulation of ClC-1 channel expression and activity in fast-and slow-twitch muscles of mouse models lacking PKCθ. Electrophysiological studies showed an increase of gCl in the PKCθ-null mice with respect to wild type. Muscle excitability was reduced accordingly. However, the expression of the ClC-1 channel, evaluated by qRT-PCR, was not modified in PKCθ-null muscles suggesting that PKCθ affects the ClC-1 activity. Pharmacological studies demonstrated that although PKCθ appreciably modulates gCl, other isoforms are still active and concur to this role. The modification of gCl in PKCθ-null muscles has caused adaptation of the expression of phenotypespecific genes, such as calcineurin and myocyte enhancer factor-2, supporting the role of PKCθ also in the settings of muscle phenotype. Importantly, the lack of PKCθ has prevented the aging-related reduction of gCl, suggesting that its modulation may represent a new strategy to contrast the aging process.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. O... more Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. Our previous preclinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl). An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability. These effects can be detrimental for muscle function leading to druginduced myopathy. Our goal is to study the causes of statin-induced muscle side effects in patients at the aim to identify biological markers useful to prevent and counteract statin-induced muscle damage. We examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs. Western Blot (WB) analysis showed a 40% reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type. Real-time PCR analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting posttranscriptional modification. The mRNA expression of a series of genes was also evaluated. MuRF-1 was increased in accord with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit. Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation. In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration. Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggests mitochondrial biogenesis. Thus, the reduction of ClC-1 protein and consequent sarcolemma hyperexcitability together with energy deficiency appear to be among the most important alterations to be associated with statin-related risk of myopathy in
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Pflügers Archiv - European Journal of Physiology, 2014
In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, co... more In skeletal muscle, the resting chloride conductance (gCl), due to the ClC-1 chloride channel, controls the sarcolemma electrical stability. Indeed, loss-of-function mutations in ClC-1 gene are responsible of myotonia congenita. The ClC-1 channel can be phosphorylated and inactivated by protein kinases C (PKC), but the relative contribution of each PKC isoforms is unknown. Here, we investigated on the role of PKCθ in the regulation of ClC-1 channel expression and activity in fast-and slow-twitch muscles of mouse models lacking PKCθ. Electrophysiological studies showed an increase of gCl in the PKCθ-null mice with respect to wild type. Muscle excitability was reduced accordingly. However, the expression of the ClC-1 channel, evaluated by qRT-PCR, was not modified in PKCθ-null muscles suggesting that PKCθ affects the ClC-1 activity. Pharmacological studies demonstrated that although PKCθ appreciably modulates gCl, other isoforms are still active and concur to this role. The modification of gCl in PKCθ-null muscles has caused adaptation of the expression of phenotypespecific genes, such as calcineurin and myocyte enhancer factor-2, supporting the role of PKCθ also in the settings of muscle phenotype. Importantly, the lack of PKCθ has prevented the aging-related reduction of gCl, suggesting that its modulation may represent a new strategy to contrast the aging process.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduc... more Background: As it is illustrated in the 2007 European Medicines Agency (EMA) 'Guideline on conduct of pharmacovigilance for medicines used by the paediatric population', it is not possible to compare the paediatric population with the adult one because physiological growth changes may influence the pharmacologic aspects of medicines used in children in terms of efficacy, safety and dosing regimens. Consequently, safety data in children cannot necessarily be extrapolated from data in adults. So the ability to assess the safety profile in children is particularly limited and the evaluation and detection of Adverse Drug Reactions (ADRs) in this population require specific expertise. The aim of our study is to identify the already available tools for the assessment of severity and causality of Adverse Events (AEs) and ADRs in the paediatric population. Methods: We conducted a systematic review of published paediatric studies from 1966 to 2017 using the MEDLINE database. Keywords included 'paediatric, 'adverse events', 'causality tool' and 'severity tool'. Results: A total of 718 paediatric studies have been reviewed and only 151 reported the causality assessment tool used. The most used tools are: Naranjo (25.16 percent), WHO-UMC (5.16 percent), others (25.16 percent (Karch&Lasagna, Liverpool's tool, Barkley's etc.)). About severity assessment tool no scales were mentioned. Further research using two keywords 'Adverse drug event' and 'Severity' showed that the most available tool used for determining the severity are 'Hartwig and Seigel' and 'Karch and Lasagna'. Conclusions: Our bibliographic research highlighted the lack of use of tools for the assessment of AEs' and ADRs' causality in paediatric studies. Only few studies employed specific tools that however are algorithms developed for adults and need adaptation to the paediatric population and possibly also stratification to each of its subsets. As for the severity assessment, no relevant results have been reached because no tool has been used or identified.
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