Pharmacology Research & Perspectives最新文献_第6页

Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief 扁桃体切除术后疼痛缓解双侧扁桃体窝局部给药后布比卡因的吸收和药代动力学

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-10 DOI: 10.1002/prp2.1196

Kristin Sandal Berg, Ellisiv Seines, Peter Gál, Lise Løberg‐Emanuelsen, Audun Stubhaug, Erik Waage Nielsen, Olav Spigset

{"title":"Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief","authors":"Kristin Sandal Berg, Ellisiv Seines, Peter Gál, Lise Løberg‐Emanuelsen, Audun Stubhaug, Erik Waage Nielsen, Olav Spigset","doi":"10.1002/prp2.1196","DOIUrl":"https://doi.org/10.1002/prp2.1196","url":null,"abstract":"No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra‐high‐performance liquid chromatography–tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500–4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"26 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140565236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel 通过 LC-HRMS 对健康人血浆中的磷左旋多巴/磷卡比多巴进行代谢物分析表明，与服用左旋多巴/卡比多巴肠道凝胶相比没有重大差异

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-10 DOI: 10.1002/prp2.1190

John P. Savaryn, Richard L. Smith, Matthew Rosebraugh, Melina Neenan, Richard Burton, Kennan Marsh, David Wagner

{"title":"Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel","authors":"John P. Savaryn, Richard L. Smith, Matthew Rosebraugh, Melina Neenan, Richard Burton, Kennan Marsh, David Wagner","doi":"10.1002/prp2.1190","DOIUrl":"https://doi.org/10.1002/prp2.1190","url":null,"abstract":"Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug‐related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open‐label, 2‐period crossover study in 20 healthy participants. Participants received either 24‐h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC–MSn was performed using high‐resolution mass spectrometry to identify drug‐related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3‐OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug‐related compounds with the exception of the administered foslevodopa. 3‐OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC–MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"14 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140565237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin‐converting enzyme 2 熊去氧胆酸可通过减少血管紧张素转换酶 2 保护人体免受严重急性呼吸系统综合征冠状病毒 2 Omicron 变体的感染

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-04 DOI: 10.1002/prp2.1194

Kyungmin Lee, Yujeong Na, Minjin Kim, Dongjin Lee, Jongseo Choi, Gwanyoung Kim, Min‐Soo Kim

{"title":"Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin‐converting enzyme 2","authors":"Kyungmin Lee, Yujeong Na, Minjin Kim, Dongjin Lee, Jongseo Choi, Gwanyoung Kim, Min‐Soo Kim","doi":"10.1002/prp2.1194","DOIUrl":"https://doi.org/10.1002/prp2.1194","url":null,"abstract":"The SARS‐CoV‐2 caused COVID‐19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS‐CoV‐2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS‐CoV‐2 Delta variant infection. UDCA is a well‐known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co‐housing with an Omicron variant‐infected hamster group resulted in spontaneous airborne transmission, the UDCA pre‐supplied group was protected from weight loss relative to the non‐treated group at 4 days post‐infection by more than 5%–10%. Furthermore, UDCA‐treated groups had a 3‐fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS‐CoV‐2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug‐repositioning of UDCA from liver health supplement to preventive drug of SARS‐CoV‐2 infection.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"118 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140565096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of histamine H₁ receptor in the anterior cingulate cortex on nociception level following acute restraint stress in male rats. 前扣带回皮层组胺 H1 受体对雄性大鼠急性束缚应激后痛觉水平的影响

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1188

Roxana Daniali, Fatemeh Zeraati, Mozhdeh Mohammadi, Rasool Haddadi

{"title":"The role of histamine H1 receptor in the anterior cingulate cortex on nociception level following acute restraint stress in male rats.","authors":"Roxana Daniali, Fatemeh Zeraati, Mozhdeh Mohammadi, Rasool Haddadi","doi":"10.1002/prp2.1188","DOIUrl":"10.1002/prp2.1188","url":null,"abstract":"Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and concurrently on acute pain induced by hot plate following restraint stress in male rats. 24-gauge, 10 mm stainless steel guide cannula was implanted over the ACC in the incised scalp of 4 groups. Restraint stress in healthy rats produced a significant increase (p < .05) in the pain threshold. The simultaneous microinjection of 4 μg/side histamine and 8 μg/side mepyramine as a histaminergic system inverse agonist in healthy nonrestraint animals did not affect the pain threshold. Although Histamine decreased the threshold of pain meaningfully, mepyramine elevated it in a significant manner (p < .05). In the restrained animals, intra-ACC microinjection of histamine produced no significant impact on the pain threshold. However, intra-ACC microinjection of mepyramine before histamine, significantly (p < .01) altered the result and enhanced the threshold of pain. The results of our study demonstrated that histaminergic neurons have an important role in the processing of pain in the ACC following restraint stress.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1188"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10938791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140120255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical metabolism and the disposition of vornorexant/TS-142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia. 用于治疗失眠症的新型双重奥曲肽 1/2受体拮抗剂 vornorexant/TS-142 的临床前代谢和处置。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1183

Yoshihiro Konno, Shunsuke Kamigaso, Hidetoh Toki, Shuichi Terasaka, Hirohiko Hikichi, Hiromi Endo, Jun-Ichi Yamaguchi, Akiko Mizuno-Yasuhira

{"title":"Preclinical metabolism and the disposition of vornorexant/TS-142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia.","authors":"Yoshihiro Konno, Shunsuke Kamigaso, Hidetoh Toki, Shuichi Terasaka, Hirohiko Hikichi, Hiromi Endo, Jun-Ichi Yamaguchi, Akiko Mizuno-Yasuhira","doi":"10.1002/prp2.1183","DOIUrl":"10.1002/prp2.1183","url":null,"abstract":"We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14 C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug-derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post-dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next-day residual effects in humans.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1183"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10943176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of OCT2-mediated drug-drug interactions between ulotaront and metformin in subjects with schizophrenia. 在精神分裂症患者中评估 OCT2 介导的乌洛他隆与二甲双胍之间的药物相互作用。

IF 2.6 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1191

Guangqing Xiao, Hironobu Tsukada, Yu-Luan Chen, Lei Shi, Seth C Hopkins, Gerald R Galluppi

{"title":"Evaluation of OCT2-mediated drug-drug interactions between ulotaront and metformin in subjects with schizophrenia.","authors":"Guangqing Xiao, Hironobu Tsukada, Yu-Luan Chen, Lei Shi, Seth C Hopkins, Gerald R Galluppi","doi":"10.1002/prp2.1191","DOIUrl":"10.1002/prp2.1191","url":null,"abstract":"Ulotaront (SEP-363856) is a TAAR1 agonist, with 5-HT1A agonist activity, currently in clinical development for the treatment of schizophrenia. In vitro studies indicate ulotaront is an OCT2-specific inhibitor with IC50 of 1.27 μM. The primary objective of this study is to determine if a single dose of ulotaront affects the PK of metformin, an index substrate of OCT2, in subjects with schizophrenia. In a randomized, single-blind, 2-period crossover study, 25 adults with schizophrenia received a single dose of metformin-HCl 850 mg (approximately 663 mg metformin) with and without coadministration of 100 mg ulotaront. The plasma samples were analyzed by fully validated LC-MS/MS methods. The primary PK endpoints for metformin were AUCinf, AUClast, Cmax, and tmax. The highest-anticipated clinical dose of ulotaront (100 mg) had no statistically significant effect on the PK of a single dose of metformin based on Cmax and AUCinf. Geometric least squares mean ratios were 89.98% and 110.63%, respectively, with the 90% confidential interval (CI) for each parameter contained within 80%-125%. Median tmax was comparable across the treatments. Ulotaront does not act as a perpetrator of OCT2-mediated DDI against metformin. Co-administration of ulotaront is not expected to require dose adjustment of metformin or other drugs cleared by OCT2.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1191"},"PeriodicalIF":2.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Progress in the treatment of diabetic cardiomyopathy, a systematic review. 糖尿病心肌病治疗进展，系统回顾。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1177

Yiyi Shou, Xingyu Li, Quan Fang, Aqiong Xie, Yinghong Zhang, Xinyan Fu, Mingwei Wang, Wenyan Gong, Xingwei Zhang, Dong Yang

{"title":"Progress in the treatment of diabetic cardiomyopathy, a systematic review.","authors":"Yiyi Shou, Xingyu Li, Quan Fang, Aqiong Xie, Yinghong Zhang, Xinyan Fu, Mingwei Wang, Wenyan Gong, Xingwei Zhang, Dong Yang","doi":"10.1002/prp2.1177","DOIUrl":"10.1002/prp2.1177","url":null,"abstract":"Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease, valve disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. It is considered a significant and consequential complication of diabetes in the field of cardiovascular medicine. The primary pathological manifestations include myocardial hypertrophy, myocardial fibrosis, and impaired ventricular function, which can lead to widespread myocardial necrosis. Ultimately, this can progress to the development of heart failure, arrhythmias, and cardiogenic shock, with severe cases even resulting in sudden cardiac death. Despite several decades of both fundamental and clinical research conducted globally, there are currently no specific targeted therapies available for DCM in clinical practice, and the incidence and mortality rates of heart failure remain persistently high. Thus, this article provides an overview of the current treatment modalities and novel techniques pertaining to DCM, aiming to offer valuable insights and support to researchers dedicated to investigating this complex condition.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1177"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10895687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor. 钙蛋白酶-2抑制剂NA-184的鉴定和神经保护特性

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1181

Michel Baudry, Yubin Wang, Xiaoning Bi, Yun Lyna Luo, Zhijun Wang, Zeechan Kamal, Alexander Shirokov, Ed Sullivan, Dennis Lagasca, Hany Khalil, Gary Lee, Kathy Fosnaugh, Philippe Bey, Shujaath Mehdi, Greg Coulter

{"title":"Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor.","authors":"Michel Baudry, Yubin Wang, Xiaoning Bi, Yun Lyna Luo, Zhijun Wang, Zeechan Kamal, Alexander Shirokov, Ed Sullivan, Dennis Lagasca, Hany Khalil, Gary Lee, Kathy Fosnaugh, Philippe Bey, Shujaath Mehdi, Greg Coulter","doi":"10.1002/prp2.1181","DOIUrl":"10.1002/prp2.1181","url":null,"abstract":"Our laboratory has shown that calpain-2 activation in the brain following acute injury is directly related to neuronal damage and the long-term functional consequences of the injury, while calpain-1 activation is generally neuroprotective and calpain-1 deletion exacerbates neuronal injury. We have also shown that a relatively selective calpain-2 inhibitor, referred to as C2I, enhanced long-term potentiation and learning and memory, and provided neuroprotection in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in mice. Using molecular dynamic simulation and Site Identification by Ligand Competitive Saturation (SILCS) software, we generated about 130 analogs of C2I and tested them in a number of in vitro and in vivo assays. These led to the identification of two interesting compounds, NA-112 and NA-184. Further analyses indicated that NA-184, (S)-2-(3-benzylureido)-N-((R,S)-1-((3-chloro-2-methoxybenzyl)amino)-1,2-dioxopentan-3-yl)-4-methylpentanamide, selectively and dose-dependent inhibited calpain-2 activity without evident inhibition of calpain-1 at the tested concentrations in mouse brain tissues and human cell lines. Like NA-112, NA-184 inhibited TBI-induced calpain-2 activation and cell death in mice and rats, both male and females. Pharmacokinetic and pharmacodynamic analyses indicated that NA-184 exhibited properties, including stability in plasma and liver and blood-brain barrier permeability, that make it a good clinical candidate for the treatment of TBI.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1181"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats. 血管活性物质对雌雄达尔盐敏感大鼠阻力小动脉生物力学的影响

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1180

Eric A Mensah, Noriko Daneshtalab, Reza Tabrizchi

{"title":"Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats.","authors":"Eric A Mensah, Noriko Daneshtalab, Reza Tabrizchi","doi":"10.1002/prp2.1180","DOIUrl":"10.1002/prp2.1180","url":null,"abstract":"Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex-specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt-sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third-order mesenteric arteries (n = 6). Animals on high-salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle-treated time-control studies. The presence of verapamil (0.3 μM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 μM). BaCl2 (100 μM), ouabain (100 μM), and L-NAME (0.3 μM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 μM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1180"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10902908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phenotype versus genotype to optimize cancer dosing in the clinical setting-focus on 5-fluorouracil and tyrosine kinase inhibitors. 表型与基因型在临床中优化癌症用药--聚焦 5-氟尿嘧啶和酪氨酸激酶抑制剂。

IF 2.9 4区医学

Pharmacology Research & Perspectives Pub Date : 2024-04-01 DOI: 10.1002/prp2.1182

Jennifer H Martin, Peter Galettis, Alex Flynn, Jennifer Schneider

{"title":"Phenotype versus genotype to optimize cancer dosing in the clinical setting-focus on 5-fluorouracil and tyrosine kinase inhibitors.","authors":"Jennifer H Martin, Peter Galettis, Alex Flynn, Jennifer Schneider","doi":"10.1002/prp2.1182","DOIUrl":"10.1002/prp2.1182","url":null,"abstract":"Cancer medicines often have narrow therapeutic windows; toxicity can be severe and sometimes fatal, but inadequate dose intensity reduces efficacy and survival. Determining the optimal dose for each patient is difficult, with body-surface area used most commonly for chemotherapy and flat dosing for tyrosine kinase inhibitors, despite accumulating evidence of a wide range of exposures in individual patients with many receiving a suboptimal dose with these strategies. Therapeutic drug monitoring (measuring the drug concentration in a biological fluid, usually plasma) (TDM) is an accepted and well validated method to guide dose adjustments for individual patients to improve this. However, implementing TDM in routine care has been difficult outside a research context. The development of genotyping of various proteins involved in drug elimination and activity has gained prominence, with several but not all Guideline groups recommending dose reductions for particular variant genotypes. However, there is increasing concern that dosing recommendations are based on limited data sets and may lead to unnecessary underdosing and increased cancer mortality. This Review discusses the evidence surrounding genotyping and TDM to guide decisions around best practice.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"12 2","pages":"e1182"},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0