Pub Date : 2024-04-08DOI: 10.1007/s40263-024-01084-1
Fernando L. Pagan, Paul E. Schulz, Yasar Torres-Yaghi, Gregory M. Pontone
Parkinson’s disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.
帕金森病(Parkinson's disease,PD)半数以上的患者会出现精神错乱(Psychosis,PDP),包括幻觉和妄想。因此,帕金森病的最佳治疗必须同时考虑运动症状和非运动症状。临床医生通常无法诊断出帕金森病患者是否患有精神病,即使发现了,治疗效果也不理想,尽管有多种干预措施可供选择。在本文中,我们总结了目前使用抗精神病药物治疗帕金森病的指南和临床证据。我们还提供了有关诊断和随访的建议。最后,我们利用专家的意见和经验,从有限的证据库中推断出一种最新的 PDP 治疗算法,其中包括使用匹马凡色林(美国 FDA 批准用于治疗 PDP 的唯一药物)。由于皮马凡色林只在美国获准用于治疗 PDP,因此在世界其他地区必须考虑其他建议和算法。
{"title":"On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson’s Disease Psychosis","authors":"Fernando L. Pagan, Paul E. Schulz, Yasar Torres-Yaghi, Gregory M. Pontone","doi":"10.1007/s40263-024-01084-1","DOIUrl":"https://doi.org/10.1007/s40263-024-01084-1","url":null,"abstract":"<p>Parkinson’s disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-07DOI: 10.1007/s40263-024-01086-z
Amira Salim, Elise Hennessy, Claire Sonneborn, Olivia Hogue, Sudipa Biswas, MaryAnn Mays, Aarushi Suneja, Zubair Ahmed, Ignacio F. Mata
Background
Many patients with chronic migraine do not achieve clinically meaningful improvement in their headache frequency with monotherapy. The burden associated with chronic migraine calls for a multifaceted treatment approach targeting multiple aspects of migraine pathophysiology.
Objective
The aim of this study was to evaluate the effect of concurrent anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) and onabotulinumtoxinA (onabot) treatment on median monthly migraine days (MMD) in patients with chronic migraine, through a retrospective study.
Methods
The electronic medical records of Cleveland Clinic patients either concurrently (dual therapy) or consecutively (monotherapy) treated with anti-CGRP mAbs and onabot between June 2018 and November 2021 were extracted. Only adult patients (≥ 18 years of age) were included in this study. MMDs for 194 concurrently treated (86.6% female and a median [interquartile range] age of 51 [41–61] years) and 229 consecutively treated (88.2% female and median age of 47 [IQR 39–57] years) patients were examined at baseline, after first therapy of either anti-CGRP mAb or onabot, and following dual therapy for 3 consecutive months. The reduction of MMDs for each treatment group were compared. The same approach was utilized to compare consecutive monotherapy at separate times (n = 229) and dual-therapy groups.
Results
The initial treatment of the dual-therapy group reduced the median (IQR) MMDs from 30 (30–30) to 15 (12–30) [p < 0.0001]. After initiation of dual therapy, the median MMDs was further decreased from 15 (12–30) to 8 (3–22) [p < 0.0001]. A majority [132/194 (68.0%)] of the dual-therapy patients reported a ≥ 50% reduction in MMD and 90/194 (46.4%) reported a ≥ 75% reduction. For the consecutive monotherapy group, median MMDs changed from a baseline of 30 (25–30) to 15 (8–25) from onabot monotherapy and decreased from 25 (15–30) to 12 (4–25) after anti-CGRP mAb monotherapy. Almost half (113/229 [49.3%] from onabot, and 104/229 [45.4%] from anti-CGRP mAb) of these patients achieved a ≥ 50% reduction in MMDs and a minority (38/229 [16.6%] from onabot, and 45/229 [19.7%] from anti-CGRP mAb) achieved a reduction of ≥ 75%. Additionally, dual therapy showed significant improvement in MMDs compared with monotherapy of either treatment (p < 0.0001).
Conclusion
Dual therapy of anti-CGRP mAbs and onabot may be more efficacious than monotherapy, possibly due to their synergistic mechanisms of action.
{"title":"Synergism of Anti-CGRP Monoclonal Antibodies and OnabotulinumtoxinA in the Treatment of Chronic Migraine: A Real-World Retrospective Chart Review","authors":"Amira Salim, Elise Hennessy, Claire Sonneborn, Olivia Hogue, Sudipa Biswas, MaryAnn Mays, Aarushi Suneja, Zubair Ahmed, Ignacio F. Mata","doi":"10.1007/s40263-024-01086-z","DOIUrl":"https://doi.org/10.1007/s40263-024-01086-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Many patients with chronic migraine do not achieve clinically meaningful improvement in their headache frequency with monotherapy. The burden associated with chronic migraine calls for a multifaceted treatment approach targeting multiple aspects of migraine pathophysiology.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>The aim of this study was to evaluate the effect of concurrent anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) and onabotulinumtoxinA (onabot) treatment on median monthly migraine days (MMD) in patients with chronic migraine, through a retrospective study.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The electronic medical records of Cleveland Clinic patients either concurrently (dual therapy) or consecutively (monotherapy) treated with anti-CGRP mAbs and onabot between June 2018 and November 2021 were extracted. Only adult patients (≥ 18 years of age) were included in this study. MMDs for 194 concurrently treated (86.6% female and a median [interquartile range] age of 51 [41–61] years) and 229 consecutively treated (88.2% female and median age of 47 [IQR 39–57] years) patients were examined at baseline, after first therapy of either anti-CGRP mAb or onabot, and following dual therapy for 3 consecutive months. The reduction of MMDs for each treatment group were compared. The same approach was utilized to compare consecutive monotherapy at separate times (<i>n</i> = 229) and dual-therapy groups.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The initial treatment of the dual-therapy group reduced the median (IQR) MMDs from 30 (30–30) to 15 (12–30) [<i>p</i> < 0.0001]. After initiation of dual therapy, the median MMDs was further decreased from 15 (12–30) to 8 (3–22) [<i>p</i> < 0.0001]. A majority [132/194 (68.0%)] of the dual-therapy patients reported a ≥ 50% reduction in MMD and 90/194 (46.4%) reported a ≥ 75% reduction. For the consecutive monotherapy group, median MMDs changed from a baseline of 30 (25–30) to 15 (8–25) from onabot monotherapy and decreased from 25 (15–30) to 12 (4–25) after anti-CGRP mAb monotherapy. Almost half (113/229 [49.3%] from onabot, and 104/229 [45.4%] from anti-CGRP mAb) of these patients achieved a ≥ 50% reduction in MMDs and a minority (38/229 [16.6%] from onabot, and 45/229 [19.7%] from anti-CGRP mAb) achieved a reduction of ≥ 75%. Additionally, dual therapy showed significant improvement in MMDs compared with monotherapy of either treatment (<i>p</i> < 0.0001).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Dual therapy of anti-CGRP mAbs and onabot may be more efficacious than monotherapy, possibly due to their synergistic mechanisms of action.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"48 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.1007/s40263-024-01082-3
Ming Sun, Martijn L. Manson, Tingjie Guo, Elizabeth C. M. de Lange
Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood–brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.
{"title":"CNS Viral Infections—What to Consider for Improving Drug Treatment: A Plea for Using Mathematical Modeling Approaches","authors":"Ming Sun, Martijn L. Manson, Tingjie Guo, Elizabeth C. M. de Lange","doi":"10.1007/s40263-024-01082-3","DOIUrl":"https://doi.org/10.1007/s40263-024-01082-3","url":null,"abstract":"<p>Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood–brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"28 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1007/s40263-024-01083-2
Jian-Shun Zhou, Zhen Chen, Ying-Ying Liu, Mao-Lin Zhong, Qiong Zhong, Jun Wei, Qian Hu, Jia-Sheng Wang, Li-Feng Wang
<h3 data-test="abstract-sub-heading">Background</h3><p>Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems.</p><h3 data-test="abstract-sub-heading">Objectives</h3><p>The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions.</p><h3 data-test="abstract-sub-heading">Methods</h3><p>One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg<sup>−1</sup> esketamine + dexmedetomidine), and an E2 group (0.2 mg kg<sup>−1</sup> esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO<sub>2</sub>) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded.</p><h3 data-test="abstract-sub-heading">Results</h3><p>Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at <i>T</i><sub>6</sub>, <i>T</i><sub>7</sub>, and <i>T</i><sub>9</sub> (<i>P</i> < 0.05). From <i>T</i><sub>4</sub> to <i>T</i><sub>10</sub>, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (<i>P</i> < 0.05), and at the <i>T</i><sub>4</sub>–<i>T</i><sub>6</sub> time points, the OAA/S score of the E2 group was lower than that of group E1 (<i>P</i> < 0.05). At <i>T</i><sub>4</sub> and <i>T</i><sub>5</sub>, the HR and BP of patients in groups E1 and E2 were greater than those in group C (<i>P</i> < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (<i>P</i> < 0.01). There was no significant difference in patient RR, SpO<sub>2</sub>, or postoperative satisfaction with anesthesia among the three groups (<i>P</i> > 0.05).</p><h3 data-test="abstract-sub-heading">Conclusion</h3><p>The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients’ compliance with surgical instructions from medical staff. Patient sati
{"title":"Observation on the Analgesic Effect of Different Doses of a Combination of Esketamine and Dexmedetomidine Administered for Percutaneous Endoscopic Transforaminal Discectomy: A Randomized, Double-Blind Controlled Trial","authors":"Jian-Shun Zhou, Zhen Chen, Ying-Ying Liu, Mao-Lin Zhong, Qiong Zhong, Jun Wei, Qian Hu, Jia-Sheng Wang, Li-Feng Wang","doi":"10.1007/s40263-024-01083-2","DOIUrl":"https://doi.org/10.1007/s40263-024-01083-2","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems.</p><h3 data-test=\"abstract-sub-heading\">Objectives</h3><p>The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg<sup>−1</sup> esketamine + dexmedetomidine), and an E2 group (0.2 mg kg<sup>−1</sup> esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO<sub>2</sub>) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at <i>T</i><sub>6</sub>, <i>T</i><sub>7</sub>, and <i>T</i><sub>9</sub> (<i>P</i> < 0.05). From <i>T</i><sub>4</sub> to <i>T</i><sub>10</sub>, the OAA/S scores of the E1 and E2 groups were both lower than those of group C (<i>P</i> < 0.05), and at the <i>T</i><sub>4</sub>–<i>T</i><sub>6</sub> time points, the OAA/S score of the E2 group was lower than that of group E1 (<i>P</i> < 0.05). At <i>T</i><sub>4</sub> and <i>T</i><sub>5</sub>, the HR and BP of patients in groups E1 and E2 were greater than those in group C (<i>P</i> < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (<i>P</i> < 0.01). There was no significant difference in patient RR, SpO<sub>2</sub>, or postoperative satisfaction with anesthesia among the three groups (<i>P</i> > 0.05).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients’ compliance with surgical instructions from medical staff. Patient sati","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"48 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s40263-024-01073-4
Abstract
The concept of a ‘microbiota-gut-brain axis’ has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.
This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.
{"title":"The Gut Microbiota in Parkinson Disease: Interactions with Drugs and Potential for Therapeutic Applications","authors":"","doi":"10.1007/s40263-024-01073-4","DOIUrl":"https://doi.org/10.1007/s40263-024-01073-4","url":null,"abstract":"<h3>Abstract</h3> <p>The concept of a ‘microbiota-gut-brain axis’ has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to <em>m</em>-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and <em>Helicobacter pylori</em> infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.</p> <p>This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"144 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-29DOI: 10.1007/s40263-024-01069-0
Kordula Lang-Illievich, Johanna Lang, Gudrun Rumpold-Seitlinger, Christian Dorn, Connor T A Brenna, Christoph Klivinyi, Helmar Bornemann-Cimenti
Introduction: The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances.
Objective: The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship.
Methods: This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed.
Results: A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization.
Conclusion: The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.
{"title":"The Dose-Response Relationship between Opioid Agonist Therapy and Alterations in Pain Pathways in Patients with Opioid Use Disorders: A Cross-Sectional Study.","authors":"Kordula Lang-Illievich, Johanna Lang, Gudrun Rumpold-Seitlinger, Christian Dorn, Connor T A Brenna, Christoph Klivinyi, Helmar Bornemann-Cimenti","doi":"10.1007/s40263-024-01069-0","DOIUrl":"10.1007/s40263-024-01069-0","url":null,"abstract":"<p><strong>Introduction: </strong>The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances.</p><p><strong>Objective: </strong>The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship.</p><p><strong>Methods: </strong>This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed.</p><p><strong>Results: </strong>A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization.</p><p><strong>Conclusion: </strong>The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"281-290"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-15DOI: 10.1007/s40263-024-01074-3
Rosa Cortese, Giovanna Testa, Francesco Assogna, Nicola De Stefano
Numerous therapies are currently available to modify the disease course of multiple sclerosis (MS). Magnetic resonance imaging (MRI) plays a pivotal role in assessing treatment response by providing insights into disease activity and clinical progression. Integrating MRI findings with clinical and laboratory data enables a comprehensive assessment of the disease course. Among available MS treatments, cladribine is emerging as a promising option due to its role as a selective immune reconstitution therapy, with a notable impact on B cells and a lesser effect on T cells. This work emphasizes the assessment of MRI's contribution to MS treatment, particularly focusing on the influence of cladribine tablets on imaging outcomes, encompassing data from pivotal and real-world studies. The evidence highlights that cladribine, compared with placebo, not only exhibits a reduction in inflammatory imaging markers, such as T1-Gd+, T2 and combined unique active (CUA) lesions, but also mitigates the effect on brain volume loss, particularly within grey matter. Importantly, cladribine reveals early action by reducing CUA lesions within the first months of treatment, regardless of a patient's initial conditions. The selective mechanism of action, and sustained efficacy beyond year 2, combined with its early onset of action, collectively position cladribine tablets as a pivotal component in the therapeutic paradigm for MS. Overall, MRI, along with clinical measures, has played a substantial role in showcasing the effectiveness of cladribine in addressing both the inflammatory and neurodegenerative aspects of MS.
{"title":"Magnetic Resonance Imaging Evidence Supporting the Efficacy of Cladribine Tablets in the Treatment of Relapsing-Remitting Multiple Sclerosis.","authors":"Rosa Cortese, Giovanna Testa, Francesco Assogna, Nicola De Stefano","doi":"10.1007/s40263-024-01074-3","DOIUrl":"10.1007/s40263-024-01074-3","url":null,"abstract":"<p><p>Numerous therapies are currently available to modify the disease course of multiple sclerosis (MS). Magnetic resonance imaging (MRI) plays a pivotal role in assessing treatment response by providing insights into disease activity and clinical progression. Integrating MRI findings with clinical and laboratory data enables a comprehensive assessment of the disease course. Among available MS treatments, cladribine is emerging as a promising option due to its role as a selective immune reconstitution therapy, with a notable impact on B cells and a lesser effect on T cells. This work emphasizes the assessment of MRI's contribution to MS treatment, particularly focusing on the influence of cladribine tablets on imaging outcomes, encompassing data from pivotal and real-world studies. The evidence highlights that cladribine, compared with placebo, not only exhibits a reduction in inflammatory imaging markers, such as T1-Gd+, T2 and combined unique active (CUA) lesions, but also mitigates the effect on brain volume loss, particularly within grey matter. Importantly, cladribine reveals early action by reducing CUA lesions within the first months of treatment, regardless of a patient's initial conditions. The selective mechanism of action, and sustained efficacy beyond year 2, combined with its early onset of action, collectively position cladribine tablets as a pivotal component in the therapeutic paradigm for MS. Overall, MRI, along with clinical measures, has played a substantial role in showcasing the effectiveness of cladribine in addressing both the inflammatory and neurodegenerative aspects of MS.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"267-279"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-02-28DOI: 10.1007/s40263-024-01070-7
Andreas W Wolff, Jörg Peine, Josef Höfler, Gabriela Zurek, Claus Hemker, Paul Lingor
<p><strong>Background: </strong>The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.</p><p><strong>Objective: </strong>The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.</p><p><strong>Methods: </strong>This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).</p><p><strong>Results: </strong>Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC<sub>0-tz</sub>) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.</p><p><strong>Conclusions: </strong>Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to
{"title":"SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants.","authors":"Andreas W Wolff, Jörg Peine, Josef Höfler, Gabriela Zurek, Claus Hemker, Paul Lingor","doi":"10.1007/s40263-024-01070-7","DOIUrl":"10.1007/s40263-024-01070-7","url":null,"abstract":"<p><strong>Background: </strong>The intravenous (IV) formulation of Rho-kinase (ROCK) inhibitor fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995. Additionally, fasudil has shown promising preclinical results for various chronic diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and dementia, in which long-term intravenous (IV) administration might not be suitable.</p><p><strong>Objective: </strong>The objective of this study was to assess the absolute bioavailability of oral, in comparison to IV, application of the approved formulation of fasudil (ERIL®) and to evaluate the safety and tolerability of the oral application of fasudil.</p><p><strong>Methods: </strong>This was a phase I, single-center, open-label, randomized, two period cross-over clinical trial in healthy women and men. By applying a cross-over design, each subject served as their own control. Two treatments were investigated, separated by a wash out phase of at least 3 days. Oral fasudil was administered once on day 1 to assess pharmacokinetics and three times on day 2, at an interval of 8 ± 1 h, to assess safety and gastrointestinal tolerability. For pharmacometrics of IV fasudil, it was administered once on day 1. Plasma profiles of fasudil and its active metabolite hydroxyfasudil after oral or IV administration were measured by liquid chromatography electrospray tandem mass spectrometry. Tolerability was assessed as proportion of subjects without significant drug intolerance, and safety was assessed by the proportion of subjects without clinical or laboratory treatment-associated serious adverse events. Gastrointestinal safety was assessed by applying the gastrointestinal symptom rating scale (GSRS).</p><p><strong>Results: </strong>Fourteen subjects aged 30-70 years were included in this trial. After oral administration, fasudil concentrations in blood were mostly very low [1.4 g/L; coefficient of variation (CV) 41.0%]. After IV application, the peak concentration was 100.6 µg/L (CV 74.2%); however, a high variance in peak concentrations were assessed for both treatments. The maximal concentrations of hydroxyfasudil in blood were similar after oral and IV treatment [111.6 µg/L (CV 24.1%) and 108.4 µg/L (CV 19.7%), respectively]. Exposure of hydroxyfasudil (assessed as AUC<sub>0-tz</sub>) differed between both treatments, with 449 µg × h/L after IV treatment and 309 µg × h/L after oral treatment. Therefore, the absolute bioavailability of hydroxyfasudil after the oral treatment was approximately 69% of the IV treatment. No serious adverse events (SAEs) occurred during this trial, and good tolerability of oral fasudil (90 mg/day) was documented.</p><p><strong>Conclusions: </strong>Oral fasudil was generally well tolerated in the studied population, and no safety concerns were identified. However, systemic bioavailability of oral hydroxyfasudil corresponded to 69%, and dose adjustments need to","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"291-302"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-14DOI: 10.1007/s40263-024-01075-2
Gemma Mestre-Bach, Marc N Potenza
Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.
{"title":"Current Understanding of Compulsive Sexual Behavior Disorder and Co-occurring Conditions: What Clinicians Should Know about Pharmacological Options.","authors":"Gemma Mestre-Bach, Marc N Potenza","doi":"10.1007/s40263-024-01075-2","DOIUrl":"10.1007/s40263-024-01075-2","url":null,"abstract":"<p><p>Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"255-265"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-15DOI: 10.1007/s40263-024-01076-1
Kathrine Bang Madsen, Mette Bliddal, Charlotte Borg Skoglund, Henrik Larsson, Trine Munk-Olsen, Malene Galle Madsen, Per Hove Thomsen, Veerle Bergink, Chaitra Srinivas, Jacqueline M Cohen, Isabell Brikell, Xiaoqin Liu
Background: An increasing number of women of reproductive age are treated with attention-deficit hyperactivity disorder (ADHD) medication; however, patterns of ADHD medication use for women in the perinatal period have not been well described.
Objective: This study aimed to describe ADHD medication use patterns from 1 year before pregnancy to 1 year after delivery, and to describe sociodemographic characteristics and clinical features by medication trajectories.
Methods: The population-based cohort study included pregnancies in Denmark between 1997 and 2020, from the Medical Birth Register, by women who filled at least one prescription for ADHD medication from 12 months before pregnancy until 12 months after delivery. We applied group-based trajectory modeling to classify women into subgroups based on the identification of heterogeneous ADHD medication treatment patterns, and described the characteristics associated with these groups.
Results: Overall, we included 4717 pregnancies leading to liveborn singletons by 4052 mothers with a mean (standard deviation) age of 27.5 (5.6) years. We identified four treatment trajectories across pregnancy and the postpartum period: continuers (23.3%), discontinuers (41.8%), interrupters who ceased filling prescriptions during pregnancy but resumed postpartum (17.2%), and postpartum initiators (17.7%). Continuers were older at the time of conception, gave birth in more recent years, were more likely to smoke during pregnancy, and used other psychotropic medications during pregnancy. A large proportion of continuers used methylphenidate (89.1%) compared with the other groups (75.9-84.1%) and had switched ADHD medication type during the whole period (16.4% vs. 7.4-14.8%).
Conclusion: We found that approximately 60% of women discontinued or interrupted their ADHD medication around pregnancy, and those who continued differed in sociodemographic and clinical factors that may reflect more severe ADHD.
{"title":"Attention-Deficit Hyperactivity Disorder (ADHD) Medication Use Trajectories Among Women in the Perinatal Period.","authors":"Kathrine Bang Madsen, Mette Bliddal, Charlotte Borg Skoglund, Henrik Larsson, Trine Munk-Olsen, Malene Galle Madsen, Per Hove Thomsen, Veerle Bergink, Chaitra Srinivas, Jacqueline M Cohen, Isabell Brikell, Xiaoqin Liu","doi":"10.1007/s40263-024-01076-1","DOIUrl":"10.1007/s40263-024-01076-1","url":null,"abstract":"<p><strong>Background: </strong>An increasing number of women of reproductive age are treated with attention-deficit hyperactivity disorder (ADHD) medication; however, patterns of ADHD medication use for women in the perinatal period have not been well described.</p><p><strong>Objective: </strong>This study aimed to describe ADHD medication use patterns from 1 year before pregnancy to 1 year after delivery, and to describe sociodemographic characteristics and clinical features by medication trajectories.</p><p><strong>Methods: </strong>The population-based cohort study included pregnancies in Denmark between 1997 and 2020, from the Medical Birth Register, by women who filled at least one prescription for ADHD medication from 12 months before pregnancy until 12 months after delivery. We applied group-based trajectory modeling to classify women into subgroups based on the identification of heterogeneous ADHD medication treatment patterns, and described the characteristics associated with these groups.</p><p><strong>Results: </strong>Overall, we included 4717 pregnancies leading to liveborn singletons by 4052 mothers with a mean (standard deviation) age of 27.5 (5.6) years. We identified four treatment trajectories across pregnancy and the postpartum period: continuers (23.3%), discontinuers (41.8%), interrupters who ceased filling prescriptions during pregnancy but resumed postpartum (17.2%), and postpartum initiators (17.7%). Continuers were older at the time of conception, gave birth in more recent years, were more likely to smoke during pregnancy, and used other psychotropic medications during pregnancy. A large proportion of continuers used methylphenidate (89.1%) compared with the other groups (75.9-84.1%) and had switched ADHD medication type during the whole period (16.4% vs. 7.4-14.8%).</p><p><strong>Conclusion: </strong>We found that approximately 60% of women discontinued or interrupted their ADHD medication around pregnancy, and those who continued differed in sociodemographic and clinical factors that may reflect more severe ADHD.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"303-314"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}