Effects of sevelamer carbonate versus calcium acetate on vascular calcification,inflammation, and endothelial dysfunction in chronic kidney disease

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Non‐calcium‐based phosphate binders are effective in the patients with end stage kidney disease for lowering serum phosphorus and have demonstrated anti‐inflammatory effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study demonstrates a favorable reduction in systemic, vascular, and bone‐related inflammatory markers from treatment with sevelamer carbonate (SC) in the patients with chronic kidney disease (CKD) not on dialysis with normal serum phosphorus levels.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that patients with CKD not on dialysis may benefit from SC phosphate binders despite having a normal serum phosphorus level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study offers insight to the role phosphates binder may play in lowering inflammation and vascular calcification in patients with CKD not on dialysis.     

A rational approach to migraine diagnosis and management in primary care

Migraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.

Key messages

• Migraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.
• A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.
• The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.

     

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC₅₀) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Buprenorphine has demonstrated efficacy for the pharmacologic treatment of neonatal opioid withdrawal syndrome (NOWS).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study sought to explore a variety of buprenorphine dose regimens using modeling and simulation. A revised dose approach was explored in an open label clinical trial.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The study explored the exposure response of buprenorphine in controlling the symptoms of NOWS. The exposure response relationship was described.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The model of buprenorphine response will allow the optimization of dose regimens that may reduce the length of pharmacologic treatment and length of stay for infants treated for NOWS.     

Triple Vectors Expand AAV Transfer Capacity in the Retina

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Unruptured cerebral aneurysms in elderly patients: key challenges and management

Unruptured cerebral aneurysms are increasingly identified in elderly patients as the global life expectancy continues to rise and non-invasive vascular imaging becomes more prevalent. The optimal management of unruptured aneurysms in elderly patients remains controversial. Variability in life expectancy, comorbidities and rupture risk coupled with heterogenous endovascular and surgical treatments contribute to a paucity of clear guidelines, and current management is highly individualized. Elderly patients present unique considerations including frailty, cognitive dysfunction, vasculopathy, reduced life expectancy and overall worse prognosis in case of rupture which shape the risks and likelihood of success of endovascular and microsurgical treatment. In this review, we provide a comprehensive overview of unruptured cerebral aneurysms in the elderly, with a particular focus on the natural history, key challenges associated with advanced age, management and future innovations to further refine treatment.

Key Messages

1. The management of unruptured cerebral aneurysms in elderly patients remains controversial.
2. Key challenges including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis with aneurysm rupture add complexity to endovascular and surgical decision making not encountered with younger demographics.
3. A thorough understanding of available treatment options, likelihood of treatment success and associated risks weighed against the risk of aneurysm rupture informs patient discussion and management.

     

Metabolomics analysis of the serum from children with urolithiasis using UPLC‐MS

Pediatric urolithiasis is a common urologic disease with high morbidity and recurrence rates. Recent studies have shown that metabolic dysfunction plays a vital role in the pathogenesis of urolithiasis, especially in children, but the specific mechanism is still unclear. Metabolomics is an ideal technology for exploring the mechanism of metabolic disorders in urolithiasis. In the present study, a serum metabolomics based on ultra‐performance liquid chromatography mass spectrometry was performed. A total of 50 children subjects were recruited for the study, including 30 patients with kidney stones and 20 normal controls (NCs). Principal component analysis and orthogonal partial least‐squares determinant analysis were carried, and 40 metabolites were found to be significantly altered in patients with kidney stones, mainly involving retinol metabolism, steroid hormone biosynthesis, and porphyrin and chlorophyll metabolism. The kidney stone group appeared to have a lower serum level of bilirubin, but a relative higher level of retinal, all‐transretinoic acid, progesterone, and prostaglandin E2 compared with those of the NC group. All the findings suggest that patients with urolithiasis have several metabolic characteristics, which are related to stone formation or compensation. These metabolites and pathways are very likely associated with development of kidney stones and should be considered as potential novel targets for treatment and prevention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Metabolic disorders can be found in most children with kidney stones, suggesting that it plays a vital role in the pathogenesis of pediatric urolithiasis. Metabolomics is an ideal strategy to explore the mechanism of metabolic disorders in kidney stones.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We aimed to identify the changes of serum metabolites in children with urolithiasis compared with normal controls by using ultra‐performance liquid chromatography mass spectrometry.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We found the special metabolic characteristics in patients with pediatric urolithiasis, which are related to stone formation or compensation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings indicate that the metabolic phenotype of serum in pediatric patients with urolithiasis is significantly different from that in normal controls. These metabolites and metabolic pathways associated with stone formation will help to develop novel therapeutic strategies and preventive interventions.     

Efficient Non-viral Gene Delivery into Human Hematopoietic Stem Cells by Minicircle Sleeping Beauty Transposon Vectors

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Projection of global burden and risk factors for aortic aneurysm – timely warning for greater emphasis on managing blood pressure

RationaleAortic aneurysm (AA) is a serious condition that largely increases the risk of aortic dissection and sudden death. Exploring the global burden of disease and changes in risk factors for AA is essential for public health policy development.ObjectiveTo project the death burden from AA and its attributable risk factors in the following decade based on the epidemiological data over the past 30 years.Methods and ResultsWe analysed the death burden of AA and trends of four risk factors from 1990–2019 using the updated 2019 Global Burden of Disease study database by Joinpoint regression analysis. Furthermore, we project the AA-related death burden for the next decade using the Bayesian age-period-cohort model. This study discovered that the global burden of death attributable to AA began to increase after decreasing for two decades. This upward trend will continue in the subsequent decade (average annual percent change: 0.318%, 95% CI: 0.288 to 0.348). Meanwhile, the disease burdens in all economic regions except high-middle socio-demographic index (SDI) regions will continuously increase in the next decade, with the fastest acceleration in the low-middle SDI region (average annual percent change: 1.183%, 95% CI: 1.166 to 1.200). Notably, high systolic blood pressure will surpass the contribution of smoking to become the most important risk factor for mortality due to AA.ConclusionThis study discovered a rebounding trend in the aortic aneurysm-related death burden globally. High systolic blood pressure will be the top risk factor attributed to death from AA. Therefore, it should be considered as the first-degree risk factor in the guidance of AA management and criteria for population-based screening programs.

Key messages

• The death burden of aortic aneurysms is beginning to rebound globally, and the trend will continue for the next decade.
• High systolic blood pressure will replace smoking as the most important risk factor associated with aortic aneurysm death.

     

Comparison between the world health organization (WHO) and international society of hypertension (ISH) guidelines for hypertension

The global burden of hypertension remains an unsolved problem, especially in low- and middle-income countries (LMICs). For this reason, clinical practice guidelines containing the latest evidence-based recommendations are crucial in the management of hypertension. It is noteworthy that guidelines simply translated from those of high-income countries (HICs) are not the solution to the problem of hypertension in LMICs. Among the numerous guidelines available, those of the World Health Organisation and the International Society of Hypertension are the latest to be published as of the writing of this article. In this review, we conducted both general and specific comparisons between the recommendations supplied by both guidelines. Differences in aspects of hypertension management such as the timing of antihypertensive initiation, assessment of comorbidities and cardiovascular risk factors, pharmacological therapy selection, and blood pressure target and reassessment are explored. Lastly, the implications of the differences found between the two guidelines in both LMICs and HICs are discussed.

Key messages

• Currently, with low treatment and control rates, hypertension remains a burden in low- and middle-income countries (LMICs).
• The lack of customised guidelines for LMICs cannot be solved simply by adopting guidelines from high-income countries.
• The World Health Organisation (WHO) recently published a clinical guideline for the pharmacological management of hypertension in LMICs. We compare select recommendations from the guidelines to those published by the International Society of Hypertension.

     

Model‐based approach to sampling optimization in studies of antibacterial drugs for infants and young children

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The clinical trials in vulnerable populations, such as infants, face challenges, including the limited blood volume due to the small bodies. In Japan, the necessity of pediatric indications has been discussed against the background of a lack of Japanese pediatric data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This simulation study aimed to apply a model‐based approach to the development of antibiotics for pediatric patients to reduce practical and ethical constraints.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The model‐based approach to sampling optimization provided a maximization of pharmacokinetic information with a minimum burden on infants and young children.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The approach will support future pediatric clinical trials and investigator‐initiated trials, as well as provide the valuable information for therapeutic drug monitoring and the administration plans for antibiotics in clinical settings.     

Strengthening systems of care for people with or at risk for HIV,HCV and opioid use disorder: a call for enhanced data collection

BackgroundThe syndemic between opioid use disorder (OUD), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) results in excessive burdens on the healthcare system. Integrating these siloed systems of care is critical to address all three conditions adequately. In this implementation project, we assessed the data capacity of the health system to measure a cascade of care (COC) across HIV, HCV and OUD services in five states to help guide public health planning.Materials and methodsData for this study were gathered from publicly available datasets and reports from government (SAMSHA, CMS, HRSA and CDC) sites. We created, where possible, COCs for HIV, HCV, and OUD spanning population estimate, diagnosis, treatment initiation, treatment retention, and patient outcomes for each of five states in the study.ResultsThe process of data collection showed that baseline COCs examining the intersections of OUD, HIV, and HCV cannot be produced and that there are missing data in all states examined. Collection of specific data points is not consistent across all states. States are better at reporting HIV cascades due to federal requirements. Only gross estimates could be made for OUD cascades in all states because data are separated by payer source, leaving no central point of data collection from all sources. Data for HCV were not publicly available.ConclusionIt is difficult to assess the strategies needed or the progress made towards increasing treatment access and decreasing the burden of disease without the ability to construct an accurate baseline. Using integrated COCs with relevant benchmarks can not only guide public health planning, but also provide meaningful targets for intervention.

KEY MESSAGES

• While HIV COCs are available for most states at least annually, they are not disaggregated for populations with co-occurring OUD or HCV.
• Data to calculate HCV COC are not available and data to calculate OUD COC are partially available, but only for specific payers.
• States do not have systems in place to measure the scope of the syndemic or to identify targets for quality improvement activities.

     

Serum ferritin is a good indicator for predicting the efficacy of adult HLH induction therapy

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome with a high mortality rate. There is no biomarker to predict the early therapeutic response.Objective: Our study explores the significance of serum ferritin in predicting the response of induction therapy.Methods: We retrospectively analyzed the clinical data of 102 adult patients with HLH admitted to our hospital. These patients received HLH-94 regimen for induction therapy. The patients were divided into remission group and non-remission group according to the response of induction therapy. Results: Ferritin values between 1–4 weeks post induction were predictive of remission (p<.05), which were higher in the non-remission group than in the remission group. Ferritin obtained 2 weeks post-induction had the highest ROC for predicting remission, with a cut-off value of 1188.5 µg/L. And patients with ferritin lower than 1188.5 µg/L had better response of induction therapy.Conclusion: Our study suggests that serum ferritin is a good indicator to predict the efficacy of induction therapy for adult HLH.

KEY MESSAGES

• Serum ferritin is a good indicator for predicting the efficacy of adult HLH induction therapy.
• Serum ferritin two weeks after treatment may be a better indicator to judge the early curative effect.
• Serum ferritin after treatment also had a predictive significance for the survival of HLH.

     

A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration

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Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness

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Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis,therapeutics and vaccines

The emergence of novel and evolving variants of SARS-CoV-2 has fostered the need for change in the form of newer and more adaptive diagnostic methods for the detection of SARS-CoV-2 infections. On the other hand, developing rapid and sensitive diagnostic technologies is now more challenging due to emerging variants and varying symptoms exhibited among the infected individuals. In addition to this, vaccines remain the major mainstay of prevention and protection against infection. Novel vaccines and drugs are constantly being developed to unleash an immune response for the robust targeting of SARS-CoV-2 and its associated variants. In this review, we provide an updated perspective on the current challenges posed by the emergence of novel SARS-CoV-2 mutants/variants and the evolution of diagnostic techniques to enable their detection. In addition, we also discuss the development, formulation, working mechanisms, advantages, and drawbacks of some of the most used vaccines/therapeutic drugs and their subsequent immunological impact.

Key message

• The emergence of novel variants of the SARS-CoV-2 in the past couple of months, highlights one of the primary challenges in the diagnostics, treatment, as well as vaccine development against the virus.
• Advancements in SARS-CoV-2 detection include nucleic acid based, antigen and immuno- assay-based and antibody-based detection methodologies for efficient, robust, and quick testing; while advancements in COVID-19 preventive and therapeutic strategies include novel antiviral and immunomodulatory drugs and SARS-CoV-2 targeted vaccines.
• The varied COVID-19 vaccine platforms and the immune responses induced by each one of them as well as their ability to battle post-vaccination infections have all been discussed in this review.

     

Continuation of fibrate therapy in patients with metabolic syndrome and COVID-19: a beneficial regime worth pursuing

Based on separate protective mechanisms related to lipid metabolism, viral cell entry and inflammation, fibrate treatment might be advantageous among patients who have been taking fibrates before SARS-CoV-2 infection and continue taking them during the infection. Based on published data on hospitalized COVID-19 patients, we recommend that the clinicians should ask their patients with metabolic syndrome who are already taking fibrates to continue fibrate treatment during the COVID-19 illness. This recommendation applies to both outpatients and hospitalized patients. However, results from the ongoing randomized controlled trials (RCTs) using fenofibrate treatment for the prevention or treatment of COVID-19 have yet to prove that fenofibrate is clinically significant for this indication.

KEY MESSAGES

• The role of fibrates as a repurpose to treat SARS-CoV-2 is under investigation in at least three ongoing RCTs.
• Obesity, diabetes, hypertension and dyslipidaemia, individually or clustered as a discrete phenotype, the metabolic syndrome, typically associate with a more severe course of COVID-19.
• Fibrate treatment seems to be most advantageous among patients who have been taken fibrates before SARS-CoV-2 infection and are continuing to take them during the infection.
• We recommend that the clinicians encourage their patients who are already taking fibrate to continue using the drug throughout the COVID-19 illness.

     

Prevalence,impact and treatment of spasticity in nursing home patients with central nervous system disorders: a cross-sectional study

Purpose To assess prevalence, impact and treatment of spasticity in nursing home patients with central nervous system (CNS) disorders. Methods The Modified Ashworth Scale was used as the main indicator of spasticity to assess muscle tone of the extremities. Further information was obtained on burden of care, level of independence, sleeping pattern, complaints, restrictions in functions/activities/participation and indication for treatment. Clinical assessments included coordination/sensibility parameters and various tests to assess motor performance. Results Fifty-six out of 77 participants (73%) with CNS disorders had spasticity, of whom 38 subjects also showed pathologically enhanced reflexes and 45 subjects had contractures in various joints. A high burden of care was observed in 71% and cramps/pain, cosmetic problems or other complaints due to spasticity were seen in 46, 20 and 26%, respectively. The vast majority of subjects were dependent for daily living activities and ambulation. Extra treatment of spasticity was indicated for 36% of the patients. Conclusion A high prevalence of spasticity was observed in nursing home residents with CNS disorders associated with substantial impact in terms of caregiving, complaints and compromised clinical outcome measures. To further optimize the treatment of spasticity in this vulnerable population, regional treatment plans should be developed.

• Implications for Rehabilitation

• The prevalence of spasticity in nursing home residents with central nervous system disorders is high (73%).

• The impact of spasticity is substantial in terms of increased dependency in activities of daily living, increased burden of care, sleeping problems and many complaints.

• Thirty-six percent of patients could be helped by extra specialized treatment, so the challenge for the multidisciplinary rehabilitation team is huge.

• Regional treatment plans should be developed to further optimize the treatment of spasticity in the vulnerable ageing population of nursing home residents.

     

Non‐synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban

Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole‐exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban‐related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Although rivaroxaban has been wildly used for the prevention and treatment of prevent of deep vein thrombosis without requiring routine coagulation monitoring, the adverse events, such as bleeding following rivaroxaban treatment, has not been fully addressed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The correlation between genetic variations and rivaroxaban treatment‐induced side effects (e.g., bleeding).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 confer susceptibility to adverse reactions caused by rivaroxaban.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY AND TRANSLATIONAL SCIENCE?

This study identified AKR7A3 and ABCA6 genes involved in drug metabolism and transport associated with susceptibility to rivaroxaban‐related bleeding events, and provided supporting evidence for the prevention and treatment of anticoagulant‐caused adverse effects.     

Quantitative protein expression of blood‐brain barrier transporters in the vasculature of brain metastases of patients with lung and breast cancer

This study determined absolute transporter protein abundances in isolated microvessels of human noncancerous cerebral cortex as well as brain metastases of patients with lung and breast cancer, using a validated targeted proteomics approach. As compared with those in microvessels of noncancerous cerebral cortex, the median protein abundances of glucose transporter 1 (a brain endothelial marker) and sodium‐potassium pump (Na/K ATPase, a plasma membrane marker) were decreased by ~ 80% in brain metastasis microvessels. The major efflux transporters (ABCB1 and ABCG2) fell to undetectable in microvessels of more than 80% of brain metastasis specimens. Monocarboxylate transporter 1 was undetectable in microvessels of more than 80% of brain metastases, whereas large neutral amino acid transporter 1 levels remained unchanged. In conclusion, the integrity of the physical and biochemical barrier with respect to transporter protein expression is largely disrupted in brain metastasis tumor vasculatures. Differential transporter protein abundances at the blood‐brain barrier and blood‐brain tumor barrier provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Systemic chemotherapy for brain metastases is controversial, at least partly due to the incomplete understanding of the blood‐brain barrier (BBB) and blood‐brain tumor barrier (BBTB) with respect to transporter protein expression and function.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study determined the absolute protein abundances of major BBB transporters in isolated microvessels of brain metastases from lung and breast cancer patients as well as non‐cancerous brain cortex from primary or metastatic brain cancer patients.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study complemented our previous knowledge on transporter expression in microvessels of human normal brain cortex and glioblastoma, which collectively provided a comprehensive dataset on the quantitative protein expression of BBB transporters in the vasculatures of human normal brain, primary and metastatic brain tumors.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Differential transporter protein abundances at the BBB and BBTB provided mechanistic and quantitative basis for prediction of heterogeneous drug penetration into human brain and brain tumors, which is critical not only to the understanding of the success or failure of systemic chemotherapy in the treatment of brain tumors but also to the development of more effective therapeutic strategies.     

Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors

Vascular endothelial growth factor (VEGF) inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs), are important as anticancer treatments through curbing tumour angiogenesis and growth. VEGF inhibitors have significant cardiovascular effects. By blocking VEGF receptors, ligands, or signal pathways, VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity, and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors. This review updates current understandings of VEGF inhibitors on cardiovascular toxicity, explores potential mechanisms, and clarifies whether genetic or ethnic factors contribute to their adverse effects.

• Key Messages

• VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity and activate cardiomyocyte apoptosis.

• VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia.

• Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors.