Pub Date : 2022-09-02DOI: 10.3390/futurepharmacol2030024
Karan Varshney, Prerana Ghosh, Akash J Patel
Multiple myeloma (MM) is one of the most common hematological malignancies. There is a clear need for research into new treatment options that can improve the life expectancy and quality of life for MM patients; this is particularly salient for those with relapsed/refractory disease. Cannabinoids (CB) have shown potential in treatment regimens for a number of cancers, but little is currently known about their effectiveness against MM. Hence, we conducted a scoping review regarding the usage of CB against MM cells. For our review, searches were conducted in PubMed, Web of Science, and OVID Medline. After screening, six articles were eligible for inclusion, all of which were laboratory studies. It was demonstrated that CB decrease MM cell viability, and this was consistently shown to occur alongside the activation of apoptotic pathways in MM cells. These effects were shown to continue to occur in dexamethasone-resistant MM cells. The effects of CB on MM cells were enhanced when used in combination with standard treatments for MM. Critically, these marked decreases in MM cell viability induced by CB did not occur in non-MM cells. Overall, these findings indicate a clear need for future clinical trials of the integration of CB into MM treatment regimens.
多发性骨髓瘤(MM)是最常见的血液系统恶性肿瘤之一。显然有必要研究新的治疗方案，以提高MM患者的预期寿命和生活质量;这对于那些复发/难治性疾病的患者尤其突出。大麻素(CB)在许多癌症的治疗方案中显示出潜力，但目前对其对MM的有效性知之甚少。因此，我们对CB对MM细胞的使用进行了范围审查。在我们的综述中，检索是在PubMed, Web of Science和OVID Medline进行的。筛选后，6篇文章符合纳入条件，均为实验室研究。结果表明，CB可降低MM细胞活力，并与MM细胞凋亡通路的激活同时发生。这些作用在地塞米松耐药的MM细胞中继续发生。当与MM标准治疗联合使用时，CB对MM细胞的作用增强。关键的是，CB诱导的MM细胞活力的显著下降并未发生在非MM细胞中。总的来说，这些发现表明，明确需要在未来的临床试验中将CB纳入MM治疗方案。
{"title":"The Influence of Cannabinoids on Multiple Myeloma Cells: A Scoping Review","authors":"Karan Varshney, Prerana Ghosh, Akash J Patel","doi":"10.3390/futurepharmacol2030024","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030024","url":null,"abstract":"Multiple myeloma (MM) is one of the most common hematological malignancies. There is a clear need for research into new treatment options that can improve the life expectancy and quality of life for MM patients; this is particularly salient for those with relapsed/refractory disease. Cannabinoids (CB) have shown potential in treatment regimens for a number of cancers, but little is currently known about their effectiveness against MM. Hence, we conducted a scoping review regarding the usage of CB against MM cells. For our review, searches were conducted in PubMed, Web of Science, and OVID Medline. After screening, six articles were eligible for inclusion, all of which were laboratory studies. It was demonstrated that CB decrease MM cell viability, and this was consistently shown to occur alongside the activation of apoptotic pathways in MM cells. These effects were shown to continue to occur in dexamethasone-resistant MM cells. The effects of CB on MM cells were enhanced when used in combination with standard treatments for MM. Critically, these marked decreases in MM cell viability induced by CB did not occur in non-MM cells. Overall, these findings indicate a clear need for future clinical trials of the integration of CB into MM treatment regimens.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"2022 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82912429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.3390/futurepharmacol2030023
I. Le-Deygen, Viktoria V. Rokosovina, A. Skuredina, I. Yakimov, E. Kudryashova
Liposomal complexes with mucoadhesive polymers, e.g., mannosylated chitosan, are considered as prospective antituberculosis drug delivery systems. The properties of such complexes can be critically affected by the charge and phase state of liposomes. The aim of our work was to study the interaction of mannosylated chitosan with liposomes of various compositions and to identify the key patterns of this process. We tracked the interaction by titrating the liposomes with an increasing base-molar excess using the DLS method and ATR-FTIR spectroscopy. Sorption isotherms were obtained using ATR-FTIR spectroscopy and linearized in the Scatchard coordinates to evaluate the dissociation constant (Kdis). The inclusion of cardiolipin (CL) in the lipid composition helps to reduce the Kdis of the complexes by an order of magnitude of 3.8 × 10−4 M and 6.4 × 10−5 M for dipalmitoylphosphatidylcholine (DPPC) and DPPC:CL 80:20 (weight ratio), respectively. Preheating at 37 °C of gel-like anionic liposomes helps to reduce the Kdis to 3.5 × 10−5 M. Anionic liposomes, both in liquid crystal and in the gel-like state, form multipoint non-covalent complexes with chitosan–mannose conjugates due to the partial neutralization of the charges on the surface of the vesicles. Meanwhile, neutral liposomes in both states form unstable heterogeneous complexes, probably due to the predominant sorption of the polymer on the vesicles. Complex formation provides preferable binding with the model mannose-binding receptor concanavalin A and sustained pH-sensitive release of the antituberculosis drug moxifloxacin.
{"title":"The Charge and Phase State of Liposomes Dramatically Affects the Binding of Mannosylated Chitosan","authors":"I. Le-Deygen, Viktoria V. Rokosovina, A. Skuredina, I. Yakimov, E. Kudryashova","doi":"10.3390/futurepharmacol2030023","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030023","url":null,"abstract":"Liposomal complexes with mucoadhesive polymers, e.g., mannosylated chitosan, are considered as prospective antituberculosis drug delivery systems. The properties of such complexes can be critically affected by the charge and phase state of liposomes. The aim of our work was to study the interaction of mannosylated chitosan with liposomes of various compositions and to identify the key patterns of this process. We tracked the interaction by titrating the liposomes with an increasing base-molar excess using the DLS method and ATR-FTIR spectroscopy. Sorption isotherms were obtained using ATR-FTIR spectroscopy and linearized in the Scatchard coordinates to evaluate the dissociation constant (Kdis). The inclusion of cardiolipin (CL) in the lipid composition helps to reduce the Kdis of the complexes by an order of magnitude of 3.8 × 10−4 M and 6.4 × 10−5 M for dipalmitoylphosphatidylcholine (DPPC) and DPPC:CL 80:20 (weight ratio), respectively. Preheating at 37 °C of gel-like anionic liposomes helps to reduce the Kdis to 3.5 × 10−5 M. Anionic liposomes, both in liquid crystal and in the gel-like state, form multipoint non-covalent complexes with chitosan–mannose conjugates due to the partial neutralization of the charges on the surface of the vesicles. Meanwhile, neutral liposomes in both states form unstable heterogeneous complexes, probably due to the predominant sorption of the polymer on the vesicles. Complex formation provides preferable binding with the model mannose-binding receptor concanavalin A and sustained pH-sensitive release of the antituberculosis drug moxifloxacin.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86482400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-31DOI: 10.3390/futurepharmacol2030022
Ana Rita Dias, R. Ferraz, J. Costa-Rodrigues, Andreia F. M. Santos, M. Jacinto, C. Prudêncio, J. Noronha, L. C. Branco, Ž. Petrovski
The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.
{"title":"Bioactivity of Ionic Liquids Based on Valproate in SH-SY5Y Human Neuroblastoma Cell Line","authors":"Ana Rita Dias, R. Ferraz, J. Costa-Rodrigues, Andreia F. M. Santos, M. Jacinto, C. Prudêncio, J. Noronha, L. C. Branco, Ž. Petrovski","doi":"10.3390/futurepharmacol2030022","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030022","url":null,"abstract":"The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73938546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-18DOI: 10.21203/rs.3.rs-1332649/v1
A. B. Jena, A. Duttaroy
SARS-CoV-2 vaccination is a life-saving strategy for the entire population living in this pandemic. Several vaccines were developed using different platforms such as nucleic acids, viral vectors recombinant proteins, live attenuated, and inactivated virus modalities, etc. Although immunogenicity and efficacy of these COVID vaccines were investigated, Covaxin (a vaccine code-named BBV152), an inactivated COVID-19 vaccine, has not been well studied yet. This study aimed to explore the interactions between biomolecules with vaccine adjuvants by analyzing molecular and protein–protein interactions of S protein, angiotensin-converting enzyme 2 (ACE2), and human serum albumin (HSA) with the ingredients of Covaxin (2-phenoxyethanol and imidazoquinolinone) by computational methods using Autodock Vina, Cluspro, and Swiss ADME. In addition, its drug-likeness property was investigated. The binding energies using Autodock Vina showed stronger interactions of 2-phenoxyethanol and imidazoquinolinone with viral surface protein, S protein, human cell membrane receptor ACE2, and drug carrier plasma HSA (−5.2, −5.3 and −5.3 kcal/mol; −8.5, −8.5 and −9.1 kcal/mol, respectively). The interaction between S protein with ACE2 in the presence of 2-phenoxyethanol and imidazoquinolinone hindered the S protein function by reducing the binding energy between these proteins. In addition, imidazoquinolinone may have the drug-likeness property based on pharmacokinetic and physicochemical parameters. These results suggest that the Covaxin vaccine, owing to these ingredients, may impart greater efficacy in averting the virus and thus it may be more effective in producing herd immunity. In conclusion, for the first time, this computational study predicts the possible useful effects of these two adjuvants of Covaxin in therapeutic and drug-likeness strategies against SARS-CoV-2.
{"title":"A Computational Approach for Molecular Characterization of Covaxin (BBV152) and Its Ingredients for Assessing Its Efficacy against COVID-19","authors":"A. B. Jena, A. Duttaroy","doi":"10.21203/rs.3.rs-1332649/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-1332649/v1","url":null,"abstract":"SARS-CoV-2 vaccination is a life-saving strategy for the entire population living in this pandemic. Several vaccines were developed using different platforms such as nucleic acids, viral vectors recombinant proteins, live attenuated, and inactivated virus modalities, etc. Although immunogenicity and efficacy of these COVID vaccines were investigated, Covaxin (a vaccine code-named BBV152), an inactivated COVID-19 vaccine, has not been well studied yet. This study aimed to explore the interactions between biomolecules with vaccine adjuvants by analyzing molecular and protein–protein interactions of S protein, angiotensin-converting enzyme 2 (ACE2), and human serum albumin (HSA) with the ingredients of Covaxin (2-phenoxyethanol and imidazoquinolinone) by computational methods using Autodock Vina, Cluspro, and Swiss ADME. In addition, its drug-likeness property was investigated. The binding energies using Autodock Vina showed stronger interactions of 2-phenoxyethanol and imidazoquinolinone with viral surface protein, S protein, human cell membrane receptor ACE2, and drug carrier plasma HSA (−5.2, −5.3 and −5.3 kcal/mol; −8.5, −8.5 and −9.1 kcal/mol, respectively). The interaction between S protein with ACE2 in the presence of 2-phenoxyethanol and imidazoquinolinone hindered the S protein function by reducing the binding energy between these proteins. In addition, imidazoquinolinone may have the drug-likeness property based on pharmacokinetic and physicochemical parameters. These results suggest that the Covaxin vaccine, owing to these ingredients, may impart greater efficacy in averting the virus and thus it may be more effective in producing herd immunity. In conclusion, for the first time, this computational study predicts the possible useful effects of these two adjuvants of Covaxin in therapeutic and drug-likeness strategies against SARS-CoV-2.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83316267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-11DOI: 10.3390/futurepharmacol2030020
Karima Tarchoun, Mo’ath Yousef, Z. Bánóczi
Peptides are highly potent biological active compounds with excellent selectivity and binding, but they have some drawbacks (e.g., low stability in vivo because of the enzymatic degradation, and fast elimination). To overcome their drawbacks, various peptidomimetics have been gaining ground. Different modifications have been examined, such as the modification of peptide backbone. One such seemingly simple modification is the replacement of the CHα group by an N atom. These amino acid derivatives are called azaamino acids, and peptides containing azaamino acid are called azapeptides. This exchange results in both steric and electronic differences from the original amino acids, thus affecting the structure and biological activity of the modified peptide. In this review, the synthesis possibilities of azapeptides and the impact of azaamino acid incorporation on the structure and biological activity are presented through examples. Different synthetic solutions for azaamino acid introduction and the various routes to build in the side chain are summarized to illustrate the improvement of the field of azaamino acid chemistry. The influence of the altered electronic and steric properties of N-atom on the structure is described, too. Finally, some examples are given with potent biological activity.
{"title":"Azapeptides as an Efficient Tool to Improve the Activity of Biologically Effective Peptides","authors":"Karima Tarchoun, Mo’ath Yousef, Z. Bánóczi","doi":"10.3390/futurepharmacol2030020","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030020","url":null,"abstract":"Peptides are highly potent biological active compounds with excellent selectivity and binding, but they have some drawbacks (e.g., low stability in vivo because of the enzymatic degradation, and fast elimination). To overcome their drawbacks, various peptidomimetics have been gaining ground. Different modifications have been examined, such as the modification of peptide backbone. One such seemingly simple modification is the replacement of the CHα group by an N atom. These amino acid derivatives are called azaamino acids, and peptides containing azaamino acid are called azapeptides. This exchange results in both steric and electronic differences from the original amino acids, thus affecting the structure and biological activity of the modified peptide. In this review, the synthesis possibilities of azapeptides and the impact of azaamino acid incorporation on the structure and biological activity are presented through examples. Different synthetic solutions for azaamino acid introduction and the various routes to build in the side chain are summarized to illustrate the improvement of the field of azaamino acid chemistry. The influence of the altered electronic and steric properties of N-atom on the structure is described, too. Finally, some examples are given with potent biological activity.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83776379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-01DOI: 10.3390/futurepharmacol2030019
P. Kiani, J. Balikji, J. Garssen, J. Verster
Vaccination against SARS-CoV-2 is an important and essential strategy to combat the 2019 coronavirus disease (COVID-19) pandemic. Vaccination has shown to be effective in reducing the spread of SARS-CoV-2, reducing the chances of becoming infected and developing severe COVID-19, and reducing hospitalization and mortality rates. However, the vaccinations against SARS-CoV-2 are accompanied by undesirable side effects which may be in part responsible for a reduction in the willingness to become vaccinated. At this moment (June 2022), 24.3% of the US adult population (18+ years old) is not fully vaccinated against SARS-CoV-2, and 49.5% did not receive their follow-up booster vaccination. The most important motives for refusing vaccination are the unknown long-term side effects and the known acute side effects of vaccination. Here, we discuss the importance of recognizing the impact of this reactogenicity on individuals’ willingness to vaccinate and how the development of effective and safe medicines that prevent or mitigate the unwanted side effects of the vaccination may help to increase the willingness to vaccinate.
{"title":"Pandemic Preparedness: The Potential Advantage of Medicines That Prevent Acute Side Effects of Vaccination, SARS-CoV-2 as an Example","authors":"P. Kiani, J. Balikji, J. Garssen, J. Verster","doi":"10.3390/futurepharmacol2030019","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030019","url":null,"abstract":"Vaccination against SARS-CoV-2 is an important and essential strategy to combat the 2019 coronavirus disease (COVID-19) pandemic. Vaccination has shown to be effective in reducing the spread of SARS-CoV-2, reducing the chances of becoming infected and developing severe COVID-19, and reducing hospitalization and mortality rates. However, the vaccinations against SARS-CoV-2 are accompanied by undesirable side effects which may be in part responsible for a reduction in the willingness to become vaccinated. At this moment (June 2022), 24.3% of the US adult population (18+ years old) is not fully vaccinated against SARS-CoV-2, and 49.5% did not receive their follow-up booster vaccination. The most important motives for refusing vaccination are the unknown long-term side effects and the known acute side effects of vaccination. Here, we discuss the importance of recognizing the impact of this reactogenicity on individuals’ willingness to vaccinate and how the development of effective and safe medicines that prevent or mitigate the unwanted side effects of the vaccination may help to increase the willingness to vaccinate.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87060622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-24DOI: 10.3390/futurepharmacol2030018
María Ortega-Ruiz, Paula Soria-Chacartegui, Gonzalo Villapalos-García, F. Abad‐Santos, P. Zubiaur
Quetiapine is a second-generation antipsychotic used for the treatment of schizophrenia, depression and bipolar disorder. The aim of this traditional review was to summarize the available pharmacogenetic information on this drug and to conclude about its clinical relevance. For this purpose, bibliographic research was performed in the Pharmacogenomics Knowledge Base (PharmGKB) database. A total of 23 articles were initially retrieved, of which 15 were finally included. A total of 19 associations were observed between 15 genes, such as CYP3A4, CYP3A5, COMT or MC4R, and 29 clinical events. No associations were consistently replicated between pharmacogenetic biomarkers and clinical events, except for that between the CYP3A4 phenotype and quetiapine exposure, which was the only one considered clinically relevant. Consistently, the DPWG published a clinical guideline on this association, where dose adjustments for CYP3A4 poor metabolizers (PMs) are indicated to prevent the occurrence of adverse drug reactions (ADRs).
喹硫平是第二代抗精神病药物，用于治疗精神分裂症、抑郁症和双相情感障碍。这篇传统综述的目的是总结有关该药物的现有药理学信息，并总结其临床相关性。为此，在Pharmacogenomics Knowledge Base (PharmGKB)数据库中进行了文献研究。最初共检索到23篇文章，其中15篇最终被纳入。共观察到CYP3A4、CYP3A5、COMT或MC4R等15个基因与29个临床事件之间的19种关联。药物遗传生物标志物与临床事件之间没有一致的关联，除了CYP3A4表型与喹硫平暴露之间的关联，这是唯一被认为与临床相关的关联。与此一致，DPWG发布了一份关于这种关联的临床指南，其中指出CYP3A4代谢不良药物(PMs)的剂量调整是为了防止药物不良反应(adr)的发生。
{"title":"The Pharmacogenetics of Treatment with Quetiapine","authors":"María Ortega-Ruiz, Paula Soria-Chacartegui, Gonzalo Villapalos-García, F. Abad‐Santos, P. Zubiaur","doi":"10.3390/futurepharmacol2030018","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030018","url":null,"abstract":"Quetiapine is a second-generation antipsychotic used for the treatment of schizophrenia, depression and bipolar disorder. The aim of this traditional review was to summarize the available pharmacogenetic information on this drug and to conclude about its clinical relevance. For this purpose, bibliographic research was performed in the Pharmacogenomics Knowledge Base (PharmGKB) database. A total of 23 articles were initially retrieved, of which 15 were finally included. A total of 19 associations were observed between 15 genes, such as CYP3A4, CYP3A5, COMT or MC4R, and 29 clinical events. No associations were consistently replicated between pharmacogenetic biomarkers and clinical events, except for that between the CYP3A4 phenotype and quetiapine exposure, which was the only one considered clinically relevant. Consistently, the DPWG published a clinical guideline on this association, where dose adjustments for CYP3A4 poor metabolizers (PMs) are indicated to prevent the occurrence of adverse drug reactions (ADRs).","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76490413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-22DOI: 10.3390/futurepharmacol2030017
A. Jiménez-Uribe, J. Pedraza-Chaverri
Kidney function highly depends on mitochondria, organelles that regulate different metabolic pathways. Mitochondria-altered function and structure are present during acute kidney injury (AKI) and chronic kidney disease (CKD). Targeting mitochondria using several strategies has been shown to improve kidney function. Here, we review some experimental mitochondria targeting strategies with clinical potential in kidney diseases encompassing cationic/lipophilic small molecules, peptides, nanocarriers, and even the entire organelle.
{"title":"Promising Therapeutic Strategies Targeting Mitochondria in Kidney Diseases: From Small Molecules to Whole Mitochondria","authors":"A. Jiménez-Uribe, J. Pedraza-Chaverri","doi":"10.3390/futurepharmacol2030017","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030017","url":null,"abstract":"Kidney function highly depends on mitochondria, organelles that regulate different metabolic pathways. Mitochondria-altered function and structure are present during acute kidney injury (AKI) and chronic kidney disease (CKD). Targeting mitochondria using several strategies has been shown to improve kidney function. Here, we review some experimental mitochondria targeting strategies with clinical potential in kidney diseases encompassing cationic/lipophilic small molecules, peptides, nanocarriers, and even the entire organelle.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89404422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-30DOI: 10.3390/futurepharmacol2030015
Aadil Javed, Gianluca Malagraba, M. Yarmohammadi, Catalina M. Perelló-Reus, C. Barceló, Teresa Rubio-Tomás
Mitosis entails mechanistic changes required for maintaining the genomic integrity in all dividing cells. The process is intricate and temporally and spatially regulated by the ordered series of activation and de-activation of protein kinases. The mitotic kinases ensure the stepwise progression of entry into mitosis after the G2 phase of the cell cycle, followed by prophase, pro-metaphase, metaphase, anaphase, telophase, and subsequently cytokinesis and birth of two daughter cells with equal segregation and distribution of the genome. The major mitotic kinases include cyclin-dependent kinase 1 (CDK1), Aurora A and B Kinases, and Polo-Like-Kinase 1 (PLK1), among others. Overexpression of some of these kinases has been reported in many cancers as the mitotic fidelity and genome integrity are interlinked and dependent on these regulators, the native irregularities in these factors can be targeted as therapeutic strategies for various cancers. Here, we report and summarize the recent updates on the literature describing the various mitotic inhibitors targeting kinases, which can be used as potential therapeutic interventions for gastrointestinal cancers including gastric cancer, liver cancer, pancreatic cancer and colorectal cancer.
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Pub Date : 2022-06-30DOI: 10.3390/futurepharmacol2030016
Jacinthe Frangieh, Claire Legendre, D. Bréard, P. Richomme, D. Henrion, Z. Fajloun, C. Mattei, A. Le Ray, C. Legros
The isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltage-gated Ca2+ channels (LTCC). In this study, we aimed to search for new blockers of LTCC, which are therapeutic targets in neurological and cardiovascular diseases. We set up a screening assay using the rat pituitary GH3b6 cell line, which expresses two LTCC isoforms, Cav1.2 and Cav1.3. Both LTCC subtypes can be indirectly activated by KCl concentration elevation or directly by the dihydropyridine (DHP), BAY K8644, leading to an increase in the intracellular Ca2+ concentration ([Ca2+]i). These Ca2+ responses were completely blocked by the selective LTCC DHP inhibitor, nifedipine. Thereby, 16 selected IAs were tested for their ability to inhibit KCl and BAY K8644-induced Ca2+ responses. We then identified three new potent LTCC blockers, namely, oxostephanine, thaliphyline, and thalmiculine. They inhibited LTCC with IC50 values in the micromolar range through interaction to a binding site different to that of dihydropyridines. The two subfamilies of IAs, oxoaporphine with oxostephanine, and BBIQs with both thalyphilline and thalmiculine, constitute interesting pharmacophores for the development of future therapeutic leads for neurological and cardiovascular diseases.
异喹啉生物碱(IAs)在结构和药理活性方面代表了一个庞大而多样的植物化学亚家族，包括离子通道抑制。liriodenine(一种oxoaporphine)和curine(一种bisbenzylisoquinoline (BBIQ))等几种IAs可抑制l型电压门控Ca2+通道(LTCC)。在这项研究中，我们旨在寻找新的LTCC阻滞剂，作为神经和心血管疾病的治疗靶点。我们使用大鼠垂体GH3b6细胞系建立了筛选实验，该细胞系表达两种LTCC亚型Cav1.2和Cav1.3。两种LTCC亚型均可被KCl浓度升高间接激活或直接被二氢吡啶(DHP) BAY K8644激活，导致细胞内Ca2+浓度升高([Ca2+]i)。这些Ca2+反应被选择性LTCC DHP抑制剂硝苯地平完全阻断。因此，我们测试了16个选定的IAs对KCl和BAY k8644诱导的Ca2+反应的抑制能力。然后，我们确定了三种新的有效的LTCC阻滞剂，即氧stephine, thaliphyline和thalmiculine。它们通过与不同于二氢吡啶的结合位点相互作用抑制LTCC, IC50值在微摩尔范围内。IAs的两个亚家族，oxoaporphine与oxostephine，以及bbiq与thalyphiline和thalmiculine，构成了未来神经和心血管疾病治疗线索开发的有趣药效团。
{"title":"Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca2+ Channels","authors":"Jacinthe Frangieh, Claire Legendre, D. Bréard, P. Richomme, D. Henrion, Z. Fajloun, C. Mattei, A. Le Ray, C. Legros","doi":"10.3390/futurepharmacol2030016","DOIUrl":"https://doi.org/10.3390/futurepharmacol2030016","url":null,"abstract":"The isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltage-gated Ca2+ channels (LTCC). In this study, we aimed to search for new blockers of LTCC, which are therapeutic targets in neurological and cardiovascular diseases. We set up a screening assay using the rat pituitary GH3b6 cell line, which expresses two LTCC isoforms, Cav1.2 and Cav1.3. Both LTCC subtypes can be indirectly activated by KCl concentration elevation or directly by the dihydropyridine (DHP), BAY K8644, leading to an increase in the intracellular Ca2+ concentration ([Ca2+]i). These Ca2+ responses were completely blocked by the selective LTCC DHP inhibitor, nifedipine. Thereby, 16 selected IAs were tested for their ability to inhibit KCl and BAY K8644-induced Ca2+ responses. We then identified three new potent LTCC blockers, namely, oxostephanine, thaliphyline, and thalmiculine. They inhibited LTCC with IC50 values in the micromolar range through interaction to a binding site different to that of dihydropyridines. The two subfamilies of IAs, oxoaporphine with oxostephanine, and BBIQs with both thalyphilline and thalmiculine, constitute interesting pharmacophores for the development of future therapeutic leads for neurological and cardiovascular diseases.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"124 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87881289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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