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Experience and expectations of pharmacogenetic tests in France 法国对药物基因检测的经验和期望。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.07.002
Simon Verdez , Marc Bardou , Yannis Duffourd , Maxime Luu , Christel Thauvin-Robinet , Laurence Faivre , Nicolas Picard

Although French genomic medicine is reaching a turning point in its history and the implementation of genome sequencing in routine is being implemented as part of the France Genomic Medicine 2025 Plan (FGMP), many questions about secondary data management remain to be addressed. In particular, the use of pharmacogenetic (PGx) information that can be extracted from genome data is a concern. We sought to analyze the opinion of French health professionals on their desire to have access to this information. For this purpose, we created a 22-item questionnaire on the experiences, attitudes, expectations, and knowledge of French physicians and pharmacists about PGx. We collected the responses in different groups and determined a knowledge score with the last 3 questions of the questionnaire. Then, we built a prediction model for this score and determined which factors may influence it. Half of the responders were physicians (158/311) and the other half were pharmacists (153/311), and the majority of them worked in a hospital (265/311). Almost two third (62.7%, 195/311) of the responders thought that pharmacogenetic data should be communicated with genomic results for the primary indication within the framework of FGMP, and 89.1% (277/311) of them that PGx tests could be an interesting tool to optimize patients’ drug therapy in the future. Only 11.2% (35/311) of the responders reached the maximum knowledge score, while 25.4% (76/311) had already prescribed or recommended a PGx test. This study identified a need for training for French physicians and pharmacists in PGx, particularly given the interest of health professionals in it.

法国基因组医学正处于历史的转折点,作为法国基因组医学 2025 计划(FGMP)的一部分,法国正在实施常规基因组测序,但二次数据管理的许多问题仍有待解决。从基因组数据中提取的药物遗传学(PGx)信息的使用尤其令人担忧。我们试图分析法国医疗专业人员对获取这些信息的愿望的看法。为此,我们制作了一份包含 22 个项目的调查问卷,内容涉及法国医生和药剂师对 PGx 的经验、态度、期望和知识。我们收集了不同组别的回答,并根据问卷的最后 3 个问题确定了知识得分。然后,我们为该分数建立了一个预测模型,并确定了可能影响该分数的因素。一半的回答者是医生(158/311),另一半是药剂师(153/311),其中大多数人在医院工作(265/311)。近三分之二(62.7%,195/311)的受访者认为,在 FGMP 框架内,药物基因数据应与主要适应症的基因组结果一起交流,其中 89.1%(277/311)的受访者认为,PGx 检测可能是未来优化患者药物治疗的一个有趣工具。只有 11.2%(35/311)的受访者达到了最高知识分数,而 25.4%(76/311)的受访者已经开具或推荐了 PGx 检测。这项研究发现,有必要对法国医生和药剂师进行 PGx 方面的培训,尤其是考虑到医疗专业人员对 PGx 的兴趣。
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引用次数: 0
Neurotoxicity following atezolizumab in a patient with tolerated rechallenge atezolizumab对耐受性再激发患者的神经毒性。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.03.007
Yasmine Salem Mahjoubi , Imen Aouinti , Ons Charfi , Ahmed Zaiem , Widd Kaabi , Ghozlane Lakhoua , Riadh Daghfous , Sihem El Aidli
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引用次数: 0
Acute angle closure glaucoma following COVID-19 vaccination 接种 COVID-19 疫苗后出现急性闭角型青光眼。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.06.002
Yasmine Salem Mahjoubi , Israa Dahmani , Ines Souilem , Imen Aouinti , Sarrah Kastalli , Riadh Daghfous , Sihem El Aidli
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引用次数: 0
Statins and immune-mediated necrotizing myopathy: Variability in the risk 他汀类药物与免疫介导的坏死性肌病:风险的变异性。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.07.005
Thierry Trenque , Jed Hadjoudj , Agathe Trenque , Federica Tralongo , Salomé Martin , Brahim Azzouz

Introduction

Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti HMGCR).

Objectives

The aim of this study was to investigate the relationship between the different statins and the risk of IMNM.

Methods

A two-time approach was used. First, we performed a descriptive analysis of the French national pharmacovigilance database (FNPV) for the period from 1985 to december2020. To identify relevant cases, we used Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) related to IMNM. We performed a quantitative and qualitative review of individual case safety reports (ICSRs) recorded in the french vigilance spontaneous reporting system. In a second time, we performed a comparative analysis with the World Health Organization global individual case safety reports database (Vigibase). The association between IMNM and statins exposure was assessed by calculating the reporting odds ratio (ROR) and its 95% confidence interval.

Results

After analysis, a total of 25 ICSRs were related to IMNM in the FNPV. The suspected statins were atorvastatin (n = 21), simvastatin (n = 2), pravastatin (n = 1) and rosuvastatin (n = 1). In Vigibase, 567 notifications were identified. A significant ROR value was found for atorvastatin, pitavastatin, simvastatin, pravastatin and rosuvastatin.

Conclusion

Atorvastatin presents the highest risk of IMNM. Our data suggest that the occurrence of IMNM is a class effect.

简介免疫介导的坏死性肌病(IMNM)是他汀类药物肌病的一种形式,其特点是存在针对3-羟基-3-甲基戊二酰辅酶A还原酶(抗HMGCR)的抗体:本研究旨在调查不同他汀类药物与 IMNM 风险之间的关系:方法:我们采用了两种时间方法。首先,我们对 1985 年至 2020 年 12 月期间的法国国家药物警戒数据库(FNPV)进行了描述性分析。为了识别相关病例,我们使用了与 IMNM 相关的监管活动医学字典 (MedDRA) 首选术语 (PT)。我们对法国警戒自发报告系统中记录的个案安全报告(ICSR)进行了定量和定性审查。第二次,我们与世界卫生组织全球个体病例安全报告数据库(Vigibase)进行了对比分析。通过计算报告几率比(ROR)及其95%置信区间,评估了IMNM与他汀类药物暴露之间的关联:结果:经过分析,共有 25 例 ICSR 与 FNPV 中的 IMNM 有关。可疑的他汀类药物为阿托伐他汀(21 例)、辛伐他汀(2 例)、普伐他汀(1 例)和罗苏伐他汀(1 例)。在 Vigibase 中,确定了 567 份通知。结论:阿托伐他汀、匹伐他汀、辛伐他汀、普伐他汀和罗苏伐他汀的ROR值都很高:结论:阿托伐他汀发生 IMNM 的风险最高。我们的数据表明,IMNM的发生是一种类效应。
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引用次数: 0
Les dispositifs de soutien à l’innovation et la structuration de l’évaluation médico-économique en France [法国的创新资金计划和卫生经济评估结构]。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.09.003
Fanny Monmousseau , Claire Cavalin , Valéry-Pierre Riche

La diffusion et le remboursement de stratégies ou produits de santé relèvent de la décision des pouvoirs publics et des autorités sanitaires. Dans un contexte de ressources collectives limitées et de contrainte budgétaire forte, la prise de décision quant aux produits de santé innovants et coûteux intègre non seulement des données d’efficacité, de sécurité mais aussi d’efficience. En France, plusieurs dispositifs existent et permettent la production de données médico-économiques éclairant sur l’efficience. Ils sont une opportunité de développement, de structuration et de financement de l’évaluation médico-économique. Toutefois, la multiplicité des sources de financement et les spécificités de chacune compliquent leur lisibilité. L’objectif de cet article est d’en dresser un panorama, tout en soulignant les avantages et les limites de certains d’entre eux. Il en ressort une nécessaire fluidification des interactions entre les industriels, les pouvoirs publics et les structures d’évaluation médico-économique des établissements de santé. L’enjeu est de pouvoir faire appel au dispositif le plus adapté pour produire les données pertinentes au moment le plus opportun.

Diffusion and reimbursement of healthcare strategies, drugs or medical devices are based on decisions made by public authorities and health authorities. In a situation of restricted resources and strict budget restrictions, decisions on innovative and costly health products must take into account not only efficacy and safety data, but also efficiency data. In France, generate health economics data to inform on efficiency can be obtain by different processes, resulting in an opportunity to develop, structure and finance health economic evaluation. However, the diversity of sources of funding and the specific requirements of each process make them difficult to understand. The aim of this article is to provide an overview of these sources, while highlighting their advantages and limitations. It also points the need to facilitate interaction between manufacturers, public authorities and the health economic evaluation organisations of health care institutions. The issue is to be able to mobilize the most appropriate system to produce relevant data at the most appropriate time.

医疗策略、药物或医疗器械的传播和报销基于公共当局和卫生当局的决定。在资源有限和预算严格限制的情况下,关于创新和昂贵的健康产品的决策不仅必须考虑疗效和安全性数据,还必须考虑效率数据。在法国,可以通过不同的过程获得生成健康经济数据以了解效率,从而为制定、构建和资助健康经济评估提供了机会。然而,资金来源的多样性和每个过程的具体要求使其难以理解。本文的目的是概述这些来源,同时强调它们的优势和局限性。它还指出,需要促进制造商、公共当局和卫生保健机构的健康经济评估组织之间的互动。问题是能够动员最合适的系统在最合适的时间产生相关数据。
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引用次数: 0
Cannabidiol and pharmacokinetics drug-drug interactions: Pharmacological toolbox 大麻二酚与药代动力学的药物相互作用:药理学工具箱。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.05.003
Clémence Lacroix , Romain Guilhaumou , Joëlle Micallef , Olivier Blin

Cannabidiol (CBD) is one of the most important components of the Cannabis sativa plant with delta9-tetrahydrocannabinol (THC). CBD is used both for medical and recreational purposes. It can be of pharmaceutical grade (Epidyolex®), and also self-service purchased in pharmacy, CBD shops and on the internet (non-pharmaceutical). CBD is almost as widespread as it is poorly understood from a pharmacological point of view and particularly in terms of drug interactions. Drug-drug interactions could lead to clinical complications, and we here gather data currently available on pharmacokinetics (PK) drug-drug interactions with CBD through a narrative review. This review shows that several PK drug-drug interactions exist with different class of medications and aims to help clinicians to better know about CBD for their practice as this product is increasingly used.

大麻二酚(CBD)是大麻植物中与δ9-四氢大麻酚(THC)一样最重要的成分之一。CBD 可用于医疗和娱乐目的。它可以是医药级(Epidyolex®),也可以在药店、CBD 商店和互联网上自助购买(非医药级)。从药理学的角度来看,人们对 CBD 的了解并不多,尤其是在药物相互作用方面。药物之间的相互作用可能会导致临床并发症,我们在此通过叙述性综述收集了目前关于 CBD 药物代谢动力学(PK)药物之间相互作用的数据。本综述显示,CBD 与不同类药物之间存在多种 PK 药物相互作用,旨在帮助临床医生更好地了解 CBD,以便在实践中更好地使用该产品。
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引用次数: 0
Augmentation des surdoses et décès en lien avec la consommation de méthadone durant la crise sanitaire liée au COVID-19 en 2020 [2020 年 COVID-19 流行期间与美沙酮有关的用药过量和死亡人数增加]。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.06.004
Elisabeth Frauger , Nathalie Fouilhé , Clémence Lacroix , Amélie Daveluy , Reynald Le Boisselier , Célian Bertin , Bruno Revol , Louise Carton , Cécile Chevalier , Céline Eiden , Valérie Gibaja , Aurélie Aquizerate , Leila Chaouachi , Emilie Bouquet , Anne Roussin , Michel Mallaret , Joëlle Micallef

Introduction

Une surveillance renforcée a été mise en place par le réseau français d’addictovigilance à la suite du premier confinement lié au coronavirus disease 2019 (COVID-19), en raison du risque d’augmentation des surdoses, notamment avec la méthadone. Dans ce contexte, une étude a été mise en place pour décrire les surdoses liées à la méthadone en 2020 au regard de l’année 2019.

Méthodes

Les surdoses liées à la méthadone ont été analysées selon deux sources : le dispositif DRAMES (décès avec analyses toxicologiques) et la base nationale de pharmacovigilance (BNPV) pour les surdoses non fatales.

Résultats

D’après les données DRAMES, la méthadone est toujours la première substance impliquée dans les décès en 2020 avec une augmentation des décès : en nombre (n = 230 en 2020 versus n = 178 en 2019), en proportion (41 % versus 35 %) et en nombre de décès pour 1000 sujets exposés (3,4 versus 2,8). D’après la BNPV, le nombre de surdoses a augmenté en 2020 par rapport à 2019 (98 versus 79 ; soit multiplié par 1,2) en particulier durant certaines périodes cibles : premier confinement, déconfinement/période estivale et deuxième confinement. En 2020, le nombre le plus important de surdoses a été observé en avril (n = 15) et mai (n = 15). Les surdoses sont survenues chez des consommateurs de méthadone dans le cadre d’un protocole de soins ou en dehors (sujets naïfs/consommateurs occasionnels ayant obtenu la méthadone via le marché de rue ou l’entourage). Les surdoses résultent de différents facteurs : surconsommation, polyconsommation avec d’autres dépresseurs ou cocaïne, injection, consommation à des fins sédatives, récréatives ou intoxication médicamenteuse volontaire.

Discussion/Conclusion

L’ensemble de ces données montre une augmentation de la morbi-mortalité liée à la méthadone pendant l’épidémie de COVID-19 en 2020. Ce phénomène a été également constaté dans d’autres pays.

Introduction

Due to the risk of overdoses increase especially with methadone, a reinforced monitoring has been set up by the French Addictovigilance Network following the first lockdown related to coronavirus disease 2019 (COVID-19). In this context, we managed a specific study to analyze overdoses related to methadone in 2020 compared to 2019.

Material and methods

We analyzed methadone-related overdoses which occurred in 2019 and 2020 from two sources: DRAMES program (deaths with toxicological analysis) and the French pharmacovigilance database (BNPV) (overdoses that did not lead to death).

Results

Data from DRAMES program in 2020 show methadone as the first drug involved in deaths as well as an increase in deaths: in number (n = 230 versus n = 178), in proportion

导言:由于用药过量(尤其是美沙酮)的风险增加,法国瘾君子警戒网络在 2019 年冠状病毒病(COVID-19)首次封锁后,加强了对用药过量的监控。在此背景下,我们开展了一项专门研究,分析与 2019 年相比,2020 年与美沙酮相关的过量用药情况:我们从两个来源分析了 2019 年和 2020 年发生的与美沙酮相关的过量用药:DRAMES计划(经毒理学分析的死亡案例)和法国药物警戒数据库(BNPV)(未导致死亡的过量用药案例):2020年DRAMES计划的数据显示,美沙酮是第一种导致死亡的药物,死亡人数也有所增加:数量(230人对178人)、比例(41%对35%)和每1000名接触者中的死亡人数(3.4人对2.8人)。根据 BNPV 的数据,与 2019 年相比,2020 年的吸毒过量人数有所增加(98 人对 79 人;即增加了 1.2 倍),特别是在几个目标期间:第一次封锁、封锁结束/夏季期间和第二次封锁。2020 年,4 月(15 例)和 5 月(15 例)的病例数较多。过量用药和死亡病例发生在参加治疗计划或未参加治疗计划的受试者身上(新受试者/从街头市场或家人/朋友处获得美沙酮的偶尔使用者)。用药过量的原因各不相同:用药过量、多次使用抑制类药物或可卡因、注射、为镇静、娱乐目的用药或自愿药物中毒:所有这些数据都表明,在 COVID-19 流行期间,与美沙酮有关的发病率和死亡率都有所上升。其他国家也出现了这种趋势。
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引用次数: 0
Could direct oral anticoagulants induce non-hemorrhagic joint disorders? 直接口服抗凝剂会诱发非出血性关节紊乱吗?
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.06.006
Johana Béné , Amélie Boinet , Michaël Rochoy , Clémentine Rousselin , Cécile Yelnik , Hélène Peyrouzet , Anne-Lise Ruellan , Audrey Fresse , Sophie Gautier , Marc Lambert
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引用次数: 0
Predictive factors for acceptance of a long-acting opiate substitution treatment studied through social representations and internalized stigma 通过社会表征和内化耻辱感研究接受长效鸦片制剂替代疗法的预测因素。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.07.006
Aurélie Lacroix , Victor Puybaret , Pierre Villéger , Juliette Zattoni-Leroy , Sylvain Cantaloube , Catherine Chevalier , Philippe Nubukpo

Objectives

Opioid use disorder is a public health problem worldwide with a treatment gap partially due to sociocultural representation and stigma. Taking the opportunity of an authorization to a subcutaneous (SC) injectable solution of buprenorphine, the first and only injectable treatment for opioid dependence available in France, we investigate potential obstacles to its implementation in France.

Methods

This study aimed to define the factors predicting the acceptance of a new SC form of opiate substitution treatment (OST) by comparing the social representations using an adapted version of the Explanatory Model Interview Catalogue (EMIC) and the internalized stigma of intravenous drug injection using the Internalized Stigma of Mental Illness Inventory (ISMI) between participants receiving OST likely to accept the SC form or not. We also observed whether the fear of an opiate withdrawal syndrome could influence this choice.

Results

Fifty OST patients were included, 54% of them accepted a new SC form of OST. Perceived causes of drug injection measured with EMIC were significantly lower among participants who would not accept the new SC form. No significant difference was found regarding the total score of the adapted ISMI or its items. The fear of opiate withdrawal syndrome did not seem to be statistically related to acceptance of a long-acting SC OST in either group. The most discriminating combination of factors in predicting patient acceptance of such treatment was related to the perceived causes of drug injection associated with a severe Diagnostic and Statistical Manual of Mental Disorders 5th version (DSM-5) diagnosis, and a lower alcohol consumption.

Conclusions

We observed significant differences in social representations but not in internalized stigma between the two groups. Moreover, the predictive factors linked to the acceptance of a new SC form of OST suggest a multifactorial combination of elements that will have to be tested in a larger and prospective study delivering long-acting high-dose buprenorphine.

目标:阿片类药物使用障碍是世界范围内的一个公共卫生问题,其治疗缺口部分是由于社会文化代表性和耻辱感造成的。丁丙诺啡皮下注射溶液是法国第一种也是唯一一种可注射治疗阿片类药物依赖的药物,我们以该药物获得授权为契机,对其在法国实施的潜在障碍进行了调查:本研究旨在通过比较使用改编版解释性模型访谈目录(EMIC)的社会表征和使用精神疾病内在化耻辱感量表(ISMI)的静脉注射毒品内在化耻辱感,确定接受新的阿片类药物替代治疗(OST)SC 形式的预测因素。我们还观察了对鸦片制剂戒断综合征的恐惧是否会影响这种选择:结果:共纳入了 50 名 OST 患者,其中 54% 的患者接受了新的 SC 形式的 OST。通过 EMIC 测量,在不接受新的 SC 形式的患者中,他们对药物注射原因的认知度明显较低。改编后的 ISMI 及其项目的总分没有发现明显差异。对鸦片制剂戒断综合征的恐惧似乎与两组受试者接受长效 SC OST 的程度均无统计学关系。在预测患者接受这种治疗的过程中,最具区分度的因素组合与注射毒品的认知原因有关,这些原因与严重的《精神疾病诊断与统计手册》第五版(DSM-5)诊断和较低的酒精消耗量有关:我们观察到两组患者在社会表征方面存在明显差异,但在内化成见方面并无明显差异。此外,与接受新的 SC 形式 OST 有关的预测因素表明,这些因素是多因素组合而成的,必须在提供长效高剂量丁丙诺啡的更大规模前瞻性研究中加以检验。
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引用次数: 0
Un outil d’adaptation individualisée des posologies de médicaments chez le patient adulte obèse [为肥胖成年人提供个性化药物剂量的在线工具]。
IF 2.6 4区 医学 Q2 Medicine Pub Date : 2024-05-01 DOI: 10.1016/j.therap.2023.07.004
Julien Gouju , Charles Jourdan , Samuel Legeay

Contexte

Entre 1975 et 2014, le nombre de personnes souffrant d’obésité a triplé, jusqu’à atteindre 17 % de la population adulte en France et plus de 35 % aux États-Unis. L’obésité se définit par un indice de masse corporelle (IMC) > 30 kg/m2 et se caractérise par une accumulation importante de tissu adipeux responsable de l’augmentation du poids. Cette accumulation entraîne des changements physiologiques capables de modifier la pharmacocinétique des médicaments pouvant conduire à l’administration de doses inappropriées. Pour cette raison, certains des ajustements posologiques significatifs sont nécessaires chez le patient obèse. Cependant, les données sur ces adaptations sont peu accessibles et parfois complexes à mettre en œuvre en pratique.

Objectif

Proposer un nouvel outil en ligne permettant de calculer un ajustement de la dose d’un médicament à administrer à un patient obèse.

Méthodes

(i) réalisation d’une recherche bibliographique extensive selon la méthodologie PRISMA ; et (ii) développement d’un outil en ligne proposant une dose ajustée pour les patients obèses.

Résultats

Dans un premier temps, 49 revues de la littérature ont été évaluées concernant l’adaptation de la posologie des médicaments chez les patients obèses puis, dans un deuxième temps, 319 articles ont été sélectionnés. Parmi ces 319 articles, 204 ont été inclus dans la base de données afin de fournir des informations d’adaptation de posologie pour 84 molécules et modalités d’administration incluant des antibiotiques, des antifongiques, des anticoagulants ou encore des cytotoxiques. Cette base de données a été rendue accessible à travers le développement d’un calculateur utilisable sur le site internet Adapt’Obese. Ainsi, grâce au sexe, à la taille et au poids du patient obèse, l’outil propose au praticien une adaptation personnalisée du médicament à administrer au patient obèse.

Perspectives

D’autres principes actifs seront ajoutés prochainement, et des améliorations des fonctionnalités sont envisagées dans le but d’adapter les posologies chez le patient obèse, comme cela peut être réalisé chez les patients insuffisants rénaux.

Background

Between 1975 and 2014, the number of people suffering from obesity tripled, reaching 17% of the adult population in France and more than 35% in the United States. Obesity is defined by a Body Mass Index (BMI) > 30 kg/m2 and characterized by a significant accumulation of adipose tissue responsible for the increase in weight. This accumulation leads to physiological changes capable of modifying the pharmacokinetics of drugs, which can lead to the administration of inappropriate doses. For this reason, some significant dosage adjustments are necessary for obese patients. However, data on these adaptations are not easil

背景:1975年至2014年间,肥胖人数增加了两倍,在法国达到成年人口的17%,在美国超过35%。肥胖的定义是体重指数(BMI)>30kg/m2,其特征是脂肪组织的大量堆积导致体重增加。这种积累会导致能够改变药物药代动力学的生理变化,从而导致不适当的剂量给药。出于这个原因,肥胖患者需要进行一些显著的剂量调整。然而,关于这些调整的数据并不容易获得,有时在实践中实施起来也很复杂。目的:使用一种新的在线工具,计算并提出肥胖患者应服用的药物的调整剂量。方法:(i)根据PRISMA方法进行广泛的文献研究;以及(ii)开发一个新的网站,建议为肥胖患者调整剂量。结果:首先,对49篇关于剂量适应的综述进行了评估,其次,选择了319篇文章。其中,数据库中包含了204篇文章,以证明84种药物的调整剂量和给药方法,包括抗生素、抗真菌药物、抗凝血剂甚至癌症药物。这个数据库可以通过名为Adapt‘Obese的网站上的计算器在线获得。因此,根据肥胖患者的性别、身高和体重,Adapt’obese提出了一种个性化和调整剂量的药物。展望:其他药物将很快加入,并计划改善功能,目的是调整肥胖患者的剂量,如肾功能不全患者的剂量。
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引用次数: 0
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