Basic & Clinical Pharmacology & Toxicology最新文献

{"title":"Small-molecule inhibitor HI-TOPK-032 improves NK-92MI cell infiltration into ovarian tumours","authors":"Mengqi Deng,&nbsp;Ruiye Yang,&nbsp;Qi Sun,&nbsp;Jiamin Zhang,&nbsp;Jinwei Miao","doi":"10.1111/bcpt.14002","DOIUrl":"10.1111/bcpt.14002","url":null,"abstract":"<p>The effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin-2 (IL-2). Genetically modified NK-92MI cells, which can release IL-2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL-2 administration. The role of PSD-95/discs large/ZO-1 (PDZ)-binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK-92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small-molecule inhibitor HI-TOPK-032, which inhibits PBK, enhances the cytotoxicity of NK-92MI cells toward OV cells. It increases the production of interferon-γ and tumour necrosis factor-α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI-TOPK-032 upregulates CD107a on NK-92 cells. In vivo studies demonstrated that HI-TOPK-032 improves the antitumour effects of NK-92MI cells in OVCAR3^Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI-TOPK-032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK-92MI cells with HI-TOPK-032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"629-642"},"PeriodicalIF":3.1,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157530","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}

{"title":"A review on the new age methodologies for early detection of Alzheimer's and Parkinson's disease","authors":"Nabanita Ghosh,&nbsp;Krishnendu Sinha,&nbsp;Parames C. Sil","doi":"10.1111/bcpt.14003","DOIUrl":"10.1111/bcpt.14003","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Backgrounds</h3>\u0000 \u0000 <p>Neurodegenerative diseases (NDDs) such as Alzheimer's (AD) and Parkinson's (PD) are often diagnosed late, impeding effective treatment; therefore, early detection is imperative. Modern methodologies can serve a pivotal role in fulfilling the crucial need for timely detection and intervention in this context.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Evaluate early detection's significance and summarize key technologies (biomarkers, neuroimaging, AI/ML, genetics, digital health) for enhanced diagnostic strategies in AD and PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study employs a focused descriptive review approach, encompassing analysis of peer-reviewed articles and clinical trials from existing literature, to provide a nuanced exploration of the subject matter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Findings</h3>\u0000 \u0000 <p>This review underscores the efficacy of non-invasive biomarkers, biosensors and emerging promising technologies for advancing early diagnosis of AD and PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The landscape of early NDD detection has been reshaped by technology, yet challenges persist, encompassing the domains of validation and ethics. A collaborative effort between medical professionals, researchers and technologists is imperative to effectively address and combat NDDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"602-613"},"PeriodicalIF":3.1,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118640","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}

{"title":"Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers","authors":"Elisabeth Kjær Jensen,&nbsp;Søren Bøgevig,&nbsp;Torben Balchen,&nbsp;Anders Holten Springborg,&nbsp;Mike Allan Royal,&nbsp;Ida Klitzing Storgaard,&nbsp;Trine Meldgaard Lund,&nbsp;Kirsten Møller,&nbsp;Mads Utke Werner","doi":"10.1111/bcpt.13998","DOIUrl":"10.1111/bcpt.13998","url":null,"abstract":"<p>A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (<i>n</i> = 16) or LIQ865B (<i>n</i> = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A <i>versus</i> diluent was 9.00 (1.81–52.23; <i>P</i> = 0.006) and for LIQ865B <i>versus</i> diluent 2.50 (0.69–9.94; <i>P</i> = 0.37). The RR for the development of hematomas (LIQ865A <i>versus</i> diluent) were 3.25 (1.52–8.16; <i>P</i> = 0.004) and 4.00 (0.72–24.89; <i>P</i> = 0.32) (LIQ865B <i>versus</i> diluent). Subcutaneous indurations persisting for 4–13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490–533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"657-675"},"PeriodicalIF":3.1,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.13998","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118641","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}

{"title":"A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin-induced hepatotoxicity in mice","authors":"Lijuan Xiong,&nbsp;Kexin Lin,&nbsp;Tianmu He,&nbsp;Xingyan Liu,&nbsp;Rui Yuan,&nbsp;Xiaofei Li,&nbsp;Jianyong Zhang","doi":"10.1111/bcpt.13999","DOIUrl":"10.1111/bcpt.13999","url":null,"abstract":"<p>Cantharidin (CTD) is a widely used anticancer compound, but its clinical use is mainly limited due to hepatotoxicity. Ginsenoside Rb1 (GRb1) shows potential hepatoprotective effects. Nonetheless, the protective effect and underlying mechanism of GRb1 against CTD-induced hepatotoxicity in mice have not been investigated. This study aims to elucidate the effect and mechanism of GRb1 on CTD-induced hepatotoxicity using network pharmacology and in vivo experiments. Network pharmacology studies have shown that 263 targets were the main mechanisms by which GRb1 alleviates CTD-induced hepatotoxicity. KEGG enrichment analysis revealed that 75 hub genes were mainly enriched in TNF, IL-17 and apoptosis signalling pathways. Molecular docking analysis showed that GRb1 exhibited high affinity with Akt1, Tnf, Il6, Bcl2 and Caspase3. In addition, results from animal studies demonstrated that GRb1 could ameliorate CTD-induced hepatotoxicity by inhibiting protein expression of Caspase-3, Caspase-8, Bcl-2/Bax, GRP78, ATF6, ATF4, CHOP, IRE1α and PERK. This research revealed the mechanism of GRb1 against CTD-induced hepatotoxicity by inhibiting apoptosis and endoplasmic reticulum stress (ERS) and it may provide a scientific rationale for the potential use of GRb1 in the treatment of hepatotoxicity induced by CTD.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"737-749"},"PeriodicalIF":3.1,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140108990","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}

{"title":"Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders","authors":"Maria de Fátima dos Santos Sampaio,&nbsp;Yara Bezerra de Paiva,&nbsp;Tuane Bazanella Sampaio,&nbsp;Messias Gonzaga Pereira,&nbsp;Norberto Cysne Coimbra","doi":"10.1111/bcpt.13997","DOIUrl":"10.1111/bcpt.13997","url":null,"abstract":"<p>Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other <i>Cannabis sativa</i> L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT_1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT_1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT_1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"574-601"},"PeriodicalIF":3.1,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.13997","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140108991","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}

{"title":"Matrix metalloproteinases are associated with severity of disease among COVID-19 patients: A possible pharmacological target","authors":"Gisele Lopes Cavalcante,&nbsp;Lívia Pimenta Bonifacio,&nbsp;Jéssica Maria Sanches-lopes,&nbsp;Fernanda Guioti Puga,&nbsp;Felipe Santos de Carvalho,&nbsp;Fernando Bellissimo-Rodrigues,&nbsp;Jose Eduardo Tanus-Santos","doi":"10.1111/bcpt.14001","DOIUrl":"10.1111/bcpt.14001","url":null,"abstract":"<p>COVID-19 is a devastating disease and imbalanced matrix metalloproteinase (MMP) activity may contribute to its pathophysiology. This exploratory study examined whether increased circulating concentrations of MMP-2 and MMP-9, and their endogenous inhibitors, the tissue inhibitors of MMP (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4 are persistently found in patients 2 weeks after their recovery from severe or critical COVID-19 as compared with those in healthy controls. Subjects who had severe (<i>n</i> = 26) or critical (<i>n</i> = 25) PCR-confirmed COVID-19 and healthy controls (<i>n</i> = 21) had blood samples drawn 2 weeks after recovery and serum MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were determined using two Human Luminex® Discovery Assays. Circulating MMP activity was also determined by gel zymography. Patients who had severe or critical COVID-19 had increased circulating MMP-9 and MMP-2 concentrations, with increased MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios indicating increased MMP activity, confirmed by gel zymography (all <i>p</i> &lt; 0.05). Higher circulating MMP-9 (but not MMP-2) concentrations were found in critical <i>versus</i> severe COVID-19 (<i>p</i> &lt; 0.05). We found increased circulating MMP-9 and MMP-2 concentrations and activity many days after recovery from the acute disease, with MMP-9 levels associated with disease severity. These biochemical alterations suggest that MMP-2 and MMP-9 may be important pharmacological targets in COVID-19.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"727-736"},"PeriodicalIF":3.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100886","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}

{"title":"Dementia and depression: Biological connections with amyloid β protein","authors":"Helamã Moraes dos Santos,&nbsp;Amanda Gollo Bertollo,&nbsp;Maiqueli Eduarda Dama Mingoti,&nbsp;Roberta Eduarda Grolli,&nbsp;Kelli Maria Kreuz,&nbsp;Zuleide Maria Ignácio","doi":"10.1111/bcpt.13996","DOIUrl":"10.1111/bcpt.13996","url":null,"abstract":"<p>Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer's disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid β (Aβ) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aβ. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson's disease, with varying severity, and in 20 to 30% of cases of Alzheimer's disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aβ protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signalling pathways and neurotransmission.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"563-573"},"PeriodicalIF":3.1,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.13996","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140064707","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}

{"title":"The glucocorticoid dexamethasone alleviates allergic inflammation through a mitogen-activated protein kinase phosphatase-1-dependent mechanism in mice","authors":"Tiina Lehtola,&nbsp;Elina Nummenmaa,&nbsp;Riina Nieminen,&nbsp;Mari Hämäläinen,&nbsp;Katriina Vuolteenaho,&nbsp;Eeva Moilanen","doi":"10.1111/bcpt.13995","DOIUrl":"10.1111/bcpt.13995","url":null,"abstract":"<p>Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti-allergic activity of glucocorticoids. Mitogen-activated protein kinase phosphatase-1 (MKP-1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP-1 is one of the anti-inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP-1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild-type and MKP-1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT-PCR). Dexamethasone reduced the ovalbumin-induced paw edema at 1.5, 3 and 6 h time points in wild-type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP-1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin-induced inflammatory factors cyclooxygenase-2 (COX-2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1β, 6 and 13; C-C motif chemokine 11 (CCL-11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild-type mice by more than 40%. In contrast, in MKP-1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP-1-dependent mechanism. The results also demonstrate MKP-1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin-induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP-1 enhancing compounds as potential novel anti-inflammatory and anti-allergic drugs.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"686-694"},"PeriodicalIF":3.1,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.13995","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027310","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}

{"title":"Perineuronal nets as regulators of parvalbumin interneuron function: Factors implicated in their formation and degradation","authors":"Thamyris Santos-Silva,&nbsp;Debora A. E. Colodete,&nbsp;João Roberto Fernandes Lisboa,&nbsp;Ícaro Silva Freitas,&nbsp;Caio Fábio Baeta Lopes,&nbsp;Victor Hadera,&nbsp;Thaís Santos Almeida Lima,&nbsp;Adriana Jesus Souza,&nbsp;Felipe V. Gomes","doi":"10.1111/bcpt.13994","DOIUrl":"10.1111/bcpt.13994","url":null,"abstract":"<p>The brain extracellular matrix (ECM) has garnered increasing attention as a fundamental component of brain function in a predominantly “neuron-centric” paradigm. Particularly, the perineuronal nets (PNNs), a specialized net-like structure formed by ECM aggregates, play significant roles in brain development and physiology. PNNs enwrap synaptic junctions in various brain regions, precisely balancing new synaptic formation and long-term stabilization, and are highly dynamic entities that change in response to environmental stimuli, especially during the neurodevelopmental period. They are found mainly surrounding parvalbumin (PV)-expressing GABAergic interneurons, being proposed to promote PV interneuron maturation and protect them against oxidative stress and neurotoxic agents. This structural and functional proximity underscores the crucial role of PNNs in modulating PV interneuron function, which is critical for the excitatory/inhibitory balance and, consequently, higher-level behaviours. This review delves into the molecular underpinnings governing PNNs formation and degradation, elucidating their functional interactions with PV interneurons. In the broader physiological context and brain-related disorders, we also explore their intricate relationship with other molecules, such as reactive oxygen species and metalloproteinases, as well as glial cells. Additionally, we discuss potential therapeutic strategies for modulating PNNs in brain disorders.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"614-628"},"PeriodicalIF":3.1,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995448","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}

{"title":"Characteristics of α1-adrenoceptor antagonists-induced ejaculatory dysfunction on spontaneous seminal emission in rats","authors":"Masaru Yoshizumi,&nbsp;Shin-nosuke Ise,&nbsp;Akihiko Yonezawa,&nbsp;Chizuko Watanabe,&nbsp;Shinobu Sakurada,&nbsp;Hirokazu Mizoguchi","doi":"10.1111/bcpt.13993","DOIUrl":"10.1111/bcpt.13993","url":null,"abstract":"<p>Although α₁-adrenoceptor (α₁-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α₁-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin &gt; terazosin &gt; prazosin &gt; naftopidil. The selective α_1D-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α₁-AR antagonists against SSE was due to the involvement of α_1A-AR subtypes. Our results further suggested that α₁-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"134 5","pages":"704-711"},"PeriodicalIF":3.1,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970775","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}