Handbook of experimental pharmacology最新文献

{"title":"Sex Differences in Pharmacokinetics.","authors":"Irving Zucker,&nbsp;Brian J Prendergast","doi":"10.1007/164_2023_669","DOIUrl":"10.1007/164_2023_669","url":null,"abstract":"<p><p>Because women have been excluded from most clinical trials, assessment of sex differences in pharmacokinetics is available for a minority of currently prescribed drugs. In a 2020 analysis, substantial pharmacokinetic (PK) sex differences were established for 86 drugs: women given the same drug dose as men routinely generated higher blood concentrations and longer drug elimination times than men. 96% of drugs with higher PK values in women were associated with a higher incidence of adverse drug reactions (ADRs) in women than men; in the small number of instances when PKs of men exceeded those of women, this sex difference positively predicted male-biased ADRs in only 29% of cases. The absence of sex-stratified PK information for many medications raises the concern that sex differences in pharmacokinetics may be widespread and of clinical significance, contributing to sex-specific patterns of ADRs. Administering equal drug doses to women and men neglects sex differences in pharmacokinetics and body weight, risks overmedication of women, and contributes to female-biased ADRs. Evidence-based dosing adjustments are recommended to counteract this sex bias.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"25-39"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9773481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ca_V3.2 (CACNA1H) in Primary Aldosteronism.","authors":"Hoang An Dinh,&nbsp;Gabriel Stölting,&nbsp;Ute I Scholl","doi":"10.1007/164_2023_660","DOIUrl":"https://doi.org/10.1007/164_2023_660","url":null,"abstract":"<p><p>Aldosterone is a steroid hormone produced in the zona glomerulosa (ZG) of the adrenal cortex. The most prominent function of aldosterone is the control of electrolyte homeostasis and blood pressure via the kidneys. The primary factors regulating aldosterone synthesis are the serum concentrations of angiotensin II and potassium. The T-type voltage-gated calcium channel Ca_V3.2 (encoded by CACNA1H) is an important component of electrical as well as intracellular calcium oscillations, which govern aldosterone production in the ZG. Excessive aldosterone production that is (partially) uncoupled from physiological stimuli leads to primary aldosteronism, the most common cause of secondary hypertension. Germline gain-of-function mutations in CACNA1H were identified in familial hyperaldosteronism, whereas somatic mutations are a rare cause of aldosterone-producing adenomas. In this review, we summarize these findings, put them in perspective, and highlight missing knowledge.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"249-262"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9919953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Disease Modeling with Engineered Heart Tissue.","authors":"Lin Cai, Ruxiang Wang, Donghui Zhang","doi":"10.1007/164_2023_681","DOIUrl":"10.1007/164_2023_681","url":null,"abstract":"<p><p>The rhythmically beating heart is the foundation of life-sustaining blood flow. There are four chambers and many different types of cell in the heart, but the twisted myofibrillar structures formed by cardiomyocytes are particularly important for cardiac contraction and electrical impulse transmission properties. The ability to generate cardiomyocytes using human-induced pluripotent stem cells has essentially solved the cell supply shortage for in vitro simulation of cardiac tissue function; however, modeling heart at the tissue level needs mature myocardial structure, electrophysiology, and contractile characteristics. Here, the current research on human functionalized cardiac microtissue in modeling cardiac diseases is reviewed and the design criteria and practical applications of different human engineered heart tissues, including cardiac organoids, cardiac thin films, and cardiac microbundles are analyzed. Table summarizing the ability of several in vitro myocardial models to assess heart structure and function for cardiac disease modeling.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"235-255"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9977248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Medicine in Therapy of Non-solid Cancer.","authors":"Ines Schmidts,&nbsp;Torsten Haferlach,&nbsp;Gregor Hoermann","doi":"10.1007/164_2022_608","DOIUrl":"https://doi.org/10.1007/164_2022_608","url":null,"abstract":"<p><p>The development and approval of the tyrosine kinase inhibitor imatinib in 2001 has heralded the advance of directed therapy options. Today, an armamentarium of targeted therapeutics is available and enables the use of precision medicine in non-solid cancer. Precision medicine is guided by the detection of tumor-specific and targetable characteristics. These include pathogenic fusions and/or mutations, dependency on specific signaling pathways, and the expression of certain cell surface markers. Within the first part, we review approved targeted therapies for the compound classes of small molecule inhibitors, antibody-based therapies and cellular therapies. Particular consideration is given to the underlying pathobiology and the respective mechanism of action. The second part emphasizes on how biomarkers, whether they are of diagnostic, prognostic, or predictive relevance, are indispensable tools to guide therapy choice and management in precision medicine. Finally, the examples of acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia illustrate how integration of these biomarkers helps to tailor therapy.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"280 ","pages":"35-64"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10141945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.","authors":"Helen C Fox,&nbsp;Verica Milivojevic,&nbsp;Rajita Sinha","doi":"10.1007/164_2023_687","DOIUrl":"10.1007/164_2023_687","url":null,"abstract":"<p><p>In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this \"telescoping\" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":"127-161"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compound Identification Strategies in Mass Spectrometry-Based Metabolomics and Pharmacometabolomics.","authors":"Rylan Hissong,&nbsp;Kendra R Evans,&nbsp;Charles R Evans","doi":"10.1007/164_2022_617","DOIUrl":"10.1007/164_2022_617","url":null,"abstract":"<p><p>The metabolome is composed of a vast array of molecules, including endogenous metabolites and lipids, diet- and microbiome-derived substances, pharmaceuticals and supplements, and exposome chemicals. Correct identification of compounds from this diversity of classes is essential to derive biologically relevant insights from metabolomics data. In this chapter, we aim to provide a practical overview of compound identification strategies for mass spectrometry-based metabolomics, with a particular eye toward pharmacologically-relevant studies. First, we describe routine compound identification strategies applicable to targeted metabolomics. Next, we discuss both experimental (data acquisition-focused) and computational (software-focused) strategies used to identify unknown compounds in untargeted metabolomics data. We then discuss the importance of, and methods for, assessing and reporting the level of confidence of compound identifications. Throughout the chapter, we discuss how these steps can be implemented using today's technology, but also highlight research underway to further improve accuracy and certainty of compound identification. For readers interested in interpreting metabolomics data already collected, this chapter will supply important context regarding the origin of the metabolite names assigned to features in the data and help them assess the certainty of the identifications. For those planning new data acquisition, the chapter supplies guidance for designing experiments and selecting analysis methods to enable accurate compound identification, and it will point the reader toward best-practice data analysis and reporting strategies to allow sound biological and pharmacological interpretation.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"277 ","pages":"43-71"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9407039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CACNA1D-Related Channelopathies: From Hypertension to Autism.","authors":"Nadine J Ortner","doi":"10.1007/164_2022_626","DOIUrl":"https://doi.org/10.1007/164_2022_626","url":null,"abstract":"<p><p>Tightly controlled Ca²⁺ influx through voltage-gated Ca²⁺ channels (Cavs) is indispensable for proper physiological function. Thus, it is not surprising that Cav loss and/or gain of function have been implicated in human pathology. Deficiency of Cav1.3 L-type Ca²⁺ channels (LTCCs) causes deafness and bradycardia, whereas several genetic variants of CACNA1D, the gene encoding the pore-forming α1 subunit of Cav1.3, have been linked to various disease phenotypes, such as hypertension, congenital hypoglycemia, or autism. These variants include not only common polymorphisms associated with an increased disease risk, but also rare de novo missense variants conferring high risk. This review provides a concise summary of disease-associated CACNA1D variants, whereas the main focus lies on de novo germline variants found in individuals with a neurodevelopmental disorder of variable severity. Electrophysiological recordings revealed activity-enhancing gating changes induced by these de novo variants, and tools to predict their pathogenicity and to study the resulting pathophysiological consequences will be discussed. Despite the low number of affected patients, potential phenotype-genotype correlations and factors that could impact the severity of symptoms will be covered. Since increased channel activity is assumed as the disease-underlying mechanism, pharmacological inhibition could be a treatment option. In the absence of Cav1.3-selective blockers, dihydropyridine LTCC inhibitors clinically approved for the treatment of hypertension may be used for personalized off-label trials. Findings from in vitro studies and treatment attempts in some of the patients seem promising as outlined. Taken together, due to advances in diagnostic sequencing techniques the number of reported CACNA1D variants in human diseases is constantly rising. Evidence from in silico, in vitro, and in vivo disease models can help to predict the pathogenic potential of such variants and to guide diagnosis and treatment in the clinical practice when confronted with patients harboring CACNA1D variants.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"183-225"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of Vascular Ca_V1.2 Channel Regulation During Diabetic Hyperglycemia.","authors":"Miguel Martín-Aragón Baudel,&nbsp;Junyoung Hong,&nbsp;Johannes W Hell,&nbsp;Madeline Nieves-Cintrón,&nbsp;Manuel F Navedo","doi":"10.1007/164_2022_628","DOIUrl":"10.1007/164_2022_628","url":null,"abstract":"<p><p>Diabetes is a leading cause of disability and mortality worldwide. A major underlying factor in diabetes is the excessive glucose levels in the bloodstream (e.g., hyperglycemia). Vascular complications directly result from this metabolic abnormality, leading to disabling and life-threatening conditions. Dysfunction of vascular smooth muscle cells is a well-recognized factor mediating vascular complications during diabetic hyperglycemia. The function of vascular smooth muscle cells is exquisitely controlled by different ion channels. Among the ion channels, the L-type Ca_V1.2 channel plays a key role as it is the main Ca²⁺ entry pathway regulating vascular smooth muscle contractile state. The activity of Ca_V1.2 channels in vascular smooth muscle is altered by diabetic hyperglycemia, which may contribute to vascular complications. In this chapter, we summarize the current understanding of the regulation of Ca_V1.2 channels in vascular smooth muscle by different signaling pathways. We place special attention on the regulation of Ca_V1.2 channel activity in vascular smooth muscle by a newly uncovered AKAP5/P2Y₁₁/AC5/PKA/Ca_V1.2 axis that is engaged during diabetic hyperglycemia. We further describe the pathophysiological implications of activation of this axis as it relates to myogenic tone and vascular reactivity and propose that this complex may be targeted for developing therapies to treat diabetic vascular complications.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"279 ","pages":"41-58"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9899627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges Related to the Use of Next-Generation Sequencing for the Optimization of Drug Therapy.","authors":"Yitian Zhou,&nbsp;Volker M Lauschke","doi":"10.1007/164_2022_596","DOIUrl":"https://doi.org/10.1007/164_2022_596","url":null,"abstract":"<p><p>Over the last decade, next-generation sequencing (NGS) methods have become increasingly used in various areas of human genomics. In routine clinical care, their use is already implemented in oncology to profile the mutational landscape of a tumor, as well as in rare disease diagnostics. However, its utilization in pharmacogenomics is largely lacking behind. Recent population-scale genome data has revealed that human pharmacogenes carry a plethora of rare genetic variations that are not interrogated by conventional array-based profiling methods and it is estimated that these variants could explain around 30% of the genetically encoded functional pharmacogenetic variability.To interpret the impact of such variants on drug response a multitude of computational tools have been developed, but, while there have been major advancements, it remains to be shown whether their accuracy is sufficient to improve personalized pharmacogenetic recommendations in robust trials. In addition, conventional short-read sequencing methods face difficulties in the interrogation of complex pharmacogenes and high NGS test costs require stringent evaluations of cost-effectiveness to decide about reimbursement by national healthcare programs. Here, we illustrate current challenges and discuss future directions toward the clinical implementation of NGS to inform genotype-guided decision-making.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"280 ","pages":"237-260"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10138521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Implementation of Pharmacogenetics in the United Kingdom.","authors":"John H McDermott, Videha Sharma, Jessica Keen, William G Newman, Munir Pirmohamed","doi":"10.1007/164_2023_658","DOIUrl":"10.1007/164_2023_658","url":null,"abstract":"<p><p>There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":"280 ","pages":"3-32"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10198355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}