Combining stem cell-derived hepatocytes with impedance sensing to better predict human drug toxicity

Background: The liver plays a central role in human drug metabolism. To model drug metabolism, the major cell type of the liver, the hepatocyte, is commonly used. Hepatocytes can be derived from human and animal sources, including pluripotent stem cells. Cell-based models have shown promise in modeling human drug exposure. The assays used in those studies are normally ‘snap-shot’ in nature, and do not provide the complete picture of human drug exposure.

Research design and methods: In this study, we employ stem cell-derived hepatocytes and impedance sensing to model human drug toxicity. This impedance-based stem cell assay reports hepatotoxicity in real time after treatment with compounds provided by industry.

Results: Using electric cell-substrate impedance Sensing (ECIS), we were able to accurately measure drug toxicity post-drug exposure in real time and more quickly than gold standard biochemical assays.

Conclusions: ECIS is robust and non-destructive methodology capable of monitoring human drug exposure with superior performance to current gold standard ‘snapshot’ assays. We believe that the methodology presented within this article could prove valuable in the quest to better predict off-target effects of drugs in humans.     

Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

Introduction: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer.

Areas covered: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials.

Expert opinion: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.     

A drug safety evaluation of abiraterone acetate in the treatment of prostate cancer

Introduction: To evaluate the safety profile characteristics of abiraterone acetate (AA) in the treatment of metastatic prostate cancer (mPCa).

Areas covered: In this literature review the authors evaluate safety data from phase III trials investigating the combination of abiraterone acetate plus prednisone (AAP) in patients with metastatic prostate cancer. In particular, the aim was to clarify its toxicity profile, long-term exposure impact, and the correlation with general health-related quality of life (HRQoL).

Expert opinion: Based on the studies reviewed, it appears that abiraterone acetate has favourable outcomes, is effective and well tolerated, mostly in asymptomatic or slightly symptomatic patients, and has recognised toxicity profile characteristics. Incidence of adverse events (AEs), such as mineralocorticoid- and corticosteroid-releated AEs, and hepatotoxicity is well known and widely described. Understanding the toxicity profile of AA could assist decision-making in clinical practice.     

Siponimod for the treatment of secondary progressive multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic central nervous system immune-mediated disease with an important inflammatory component associated with focal demyelination and widespread neurodegeneration. In most cases, the clinical presentation is relapsing-remitting, followed by a secondary progressive phase, characterized by disability accrual unrelated to relapses. In a minority, the phenotype is progressive from the beginning. Major therapeutic achievements have been made concerning the relapsing phase but modifying the evolution of progressive MS remains an unmet need.

Areas covered: This review covers siponimod (BAF312), a new sphingosine 1-phosphate receptor modulator, and its role in the treatment of secondary progressive MS. The authors reviewed PubMed English literature using the keywords ‘siponimod’ or ‘BAF312’ and ‘multiple sclerosis.’ They also present the pharmacological profile of siponimod, as well as clinical efficacy and safety, with emphasis on the recently published results of a Phase III trial. Phase II data in relapsing MS are also summarized.

Expert opinion: Siponimod may reduce the activity of the disease and has a modest effect on the gradual disability accrual. If approved, it may become one of the few available therapy options for secondary progressive MS.     

Ginsenoside Rg1 prevents acetaminophen-induced oxidative stress and apoptosis via Nrf2/ARE signaling pathway

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. Ginsenoside Rg1 is a major active ingredient in processed Panax ginseng, which is proved to elicit biological effects. We hypothesized the beneficial effect of Rg1 on APAP-mediated hepatotoxicity was through Nrf2/ARE pathway. The study was conducted in cells and mice, comparing the actions of Rg1. Rg1 significantly improved cell survival rates and promoted the expression of antioxidant proteins. Meanwhile, Rg1 reduced the excessive ROS and the occurrence of cell apoptosis, which were related to Nrf2/ARE pathway. Expression of Nrf2 has a certain cell specificity.

     

Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease

Introduction: Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder. Despite the severe motor, psychiatric and cognitive symptoms and the great socioeconomic burden caused by the disease, available treatment is mainly symptomatic.

The kynurenine pathway (KP) is the main metabolic route of tryptophan degradation, in the course of which several neuroactive compounds are generated. The imbalance of the neurotoxic and neuroprotectant metabolites can lead to excitotoxicity and overproduction of reactive oxygen species, which both contribute to the progression of HD. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of the KP that has various immune modulatory roles.

Areas covered: Current knowledge of the involvement of KP in HD pathogenesis with a particular focus on IDO1. By reviewing the diverse roles of the enzyme in kynurenine production, immune modulation, and serotonin metabolism, we elucidate the factors that make this enzyme a therapeutic target.

Expert opinion: Due to the complexity of HD and the various effects that IDO1 exerts, targeting this enzyme, while highly profitable, may be a great challenge. Through IDO1 activity, neurodegeneration, inflammatory processes and depressive symptoms, often related to HD, can be modulated. Ongoing trials of IDO1 inhibitors in other areas of medicine offer advantages for initiating approaches toward this enzyme as a therapeutic target.     

Metabolic profiles of corydaline in rats by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry

1. Corydaline, an isoquinoline alkaloid obtained from the rhizomes of Corydalis yanhusuo, exhibits anti-acetylcholinesterase, anti-angiogenic, anti-allergic and gastric-emptying activities. In this study, a rapid and reliable ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) method was developed and employed for the comprehensive study of the metabolites of corydaline in rats.

2. Altogether, 43 metabolites were identified in the plasma (11), bile (9), urine (34) and feces (21) of rats after oral administration of corydaline at a dose of 4.5mg/kg.

3. It was demonstrated that demethylation, hydroxylation, sulfation and glucuronidation were the major metabolic transformation pathways. Among these, two metabolites were identified as tetrahydropalmatine and isocorybulbine, and 33 phase I and phase II products were inferred to be new metabolites arising from the in vivo metabolism of corydaline.

4. Importantly, this research provides scientific and reliable support for full understanding of the metabolic profiles of corydaline and the results could help to elucidate its safety and efficacy.     

Factor XI inhibition fulfilling the optimal expectations for ideal anticoagulation

Introduction: Thromboembolic diseases are leading cause of mortality accounting for an estimated 1 in 4 deaths all over the world. Anticoagulation remains the mainstay of prevention and treatment of venous thromboembolic disorders. Conventional anticoagulants have been efficiently used over the last decades, but their clinical use encounters safety and convenience issues. To overcome these limitations, research have focused on development of new targets for anticoagulation leading to a relatively new class of drugs, non-vitamin K antagonist oral anticoagulants, specifically targeting activated factor X and thrombin. However, the search for more potent anticoagulant agents with reduced bleeding risk is still continuing.

Areas covered: In this review, we provide an overview on emerging investigational anticoagulant drugs targeting factor XI in the coagulation cascade. We review data about the role of intrinsic pathway in thrombosis and haemostasis and the rationale of different pharmacodynamic approaches targeting factor XI.

Expert opinion: Recent evidence suggests that the contact pathway plays a significant role in thrombosis by thrombus stabilization and growth without perturbing haemostasis. Factor XI might be a promising drug target to develop highly effective antithrombotic therapy with safety bleeding profile. Most of these investigational agents are in early development phases, only few have reached early phase clinical trials.     

AdipoRs- a potential therapeutic target for fibrotic disorders

Introduction: Fibrotic disorders are a leading cause of morbidity and mortality; hence effective treatments are still vigorously sought. AdipoRs (AdipoR1 and Adipo2) are responsible for the antifibrotic effects of adiponectin (APN). APN exerts antifibrotic effects by binding to its receptors. APN concentration and AdipoR expression are closely associated with fibrotic disorders. Decreased AdipoR expression may reduce APN-AdipoR signaling, while the upregulation of AdipoR expression may restore the anti-fibrotic effects of APN. Loss of APN signaling exacerbates fibrosis in vivo and in vitro.

Areas covered: We assess the relationship between APN and fibrotic disorders, the structure of receptors for APN and the pathways accounting for APN or its analogs blocking fibrotic disorders. This article also discusses designed APN products and their therapeutic prospects for fibrotic disorders.

Expert opinion: AdipoRs have a critical role in blocking fibrosis. The development of small-molecule agonists toward this target represents a valid drug development pathway.     

Benefits versus risk profile of buparlisib for the treatment of breast cancer

Introduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination.

Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.

Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials.     

Pharmacokinetics and distribution of schisandrol A and its major metabolites in rats

1.?Schizandrol A is an active component in schisandra, also the representative component for the identification of schisandra.

2.?A rapid resolution liquid chromatography coupled with quadruple–time–of–flight mass spectrometry (RRLC–QTOF/MS) was developed to investigate the pharmacokinetics of schizandrol A after its intragastric administration (50?mg/kg) in rats.

3.?Schizandrol A was rapidly absorbed (T _max = 2.07?h), with a longer duration (t _1/2 = 9.48?h) and larger apparent volume of distribution (Vz/F?=?111.81?l/kg) in rats. Schizandrol A can be detected in main organs and the order of its distribution was in the liver?>?kidney?>?heart?>?spleen?>?brain, particularly higher in the liver.

4.?Five schizandrol A metabolites were identified, including 2–demethyl–8(R)–hydroxyl–schizandrin, 3–demethyl–8(R)–hydroxyl–schizandrin, hydroxyl–schizandrin, demethoxy–schizandrin, 2, 3–demethyl–8(R)–hydroxyl–schizandrin, indicating that the hydroxylation and demethylation may be the major metabolic way of schizandrol A.

5.?This study defined the pharmacokinetic characteristics of schizandrol A in vivo, and the RRLC–QTOF/MS is more sensitive and less limited by conditions, and needs less samples, which may be a useful resource for the further research and development of schisandrol A.     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate,SHR-A1403, in rodents and non-human primates

1. The in vivo pharmacokinetics (PK) profiles of a novel c-Met antibody–drug conjugate (ADC), SHR-A1403, were investigated and characterized in mice, rats and monkeys.

2. Serum concentrations of ADC and total antibody were detected using validated ELISA methods. The results showed low systemic clearance of both ADC and total antibody in all three species as reflected by gradual decrease in serum concentrations. Half-life (t_1/2) of ADC ranged from 4.6 to 11.3?days in the three species.

3. Tissue distribution study in tumor-bearing mice showed high accumulation of ¹²⁵I-SHR-A1403 in tumor tissues over the other organs/tissues, indicating the favorable safety of SHR-A1403 and characteristics of an ADC drug.

4. Relatively low grade of anti-drug antibody (ADA) in monkeys had no impact on PK profile of the ADC.

5. During discovery stage, undesirable exposure and/or ADA incidence were observed for SHR-A1403 with high or low drug-antibody ratio (DAR), which was DAR?=?5 to 6 and DAR?=?1, respectively, and therefore prompted selection of an appropriate DAR value (DAR?=?2) for SHR-A1403 used in preclinical development and clinical trials.

6. In conclusion, our work demonstrated favorable PK characterization of SHR-A1403, and supported for investigational new drug application (IND) and the ongoing first-in-human trial in the US.     

The Notch pathway: a novel therapeutic target for cardiovascular diseases?

Introduction: The Notch pathway is involved in determining cell fate during development and postnatally in continuously renewing tissues, such as the endothelium, the epithelium, and in the stem cells pool. The dysregulation of the Notch pathway is one of the causes of limited response, or resistance, to available cancer treatments and novel therapeutic strategies based on Notch inhibition are being investigated in preclinical and clinical studies in oncology. A large body of evidence now shows that the dysregulation of the Notch pathway is also involved in the pathophysiology of cardiovascular diseases (CVDs).

Areas covered: This review discusses the molecular mechanisms involving Notch which underlie heart failure, aortic valve calcification, and aortic aneurysm.

Expert opinion: Despite the existence of preventive, pharmacological and surgical interventions approaches, CVDs are the first causes of mortality worldwide. The Notch pathway is becoming increasingly recognized as being involved in heart failure, aortic aneurysm and aortic valve calcification, which are among the most common global causes of mortality due to CVDs. As already shown in cancer, the dissection of the biological processes and molecular mechanisms involving Notch should pave the way for new strategies to prevent and cure these diseases.     

Optimisation of the microencapsulation of lavender oil by spray drying

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions.

Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated.

Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography–mass spectrometry.

Results: Lavender microparticles of size 12.42?±?1.79?µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12?mg w/w%), and encapsulation efficiency (77.89 w/w%).

Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.     

Metabolic disposition of WTX101 (bis-choline tetrathiomolybdate) in a rat model of Wilson disease

1. WTX101 (bis-choline tetrathiomolybdate) is an investigational copper (Cu)-protein-binding agent developed for the treatment of Wilson disease (WD), a rare genetic disorder caused by mutations in the ATP7B Cu-transporter and resulting in toxic Cu accumulation.

2. Mass balance of a single intravenous WTX101 dose, measured as molybdenum (Mo), was assessed over 168?h in control (Long Evans Agouti [LEA]) and Long-Evans Cinnamon (LEC) rats, a WD model.

3. In LEC rats, Mo was partially excreted (up to 45%); 29% by renal clearance, and faecal clearance, still ongoing at 168?h, accounted for 16%. In contrast, in LEA rats, Mo was almost fully excreted (～87%); 79% was renally cleared with only 7% faecal excretion.

4. In LEC rats, the proportion of faecal to renal Mo excretion was enhanced (4:6) compared to controls (1:9).

5. Substantially more Mo was found in LEC liver and kidney compared with LEA tissues, in line with tissue Cu distribution.

6. These findings are consistent with the WTX101 mechanism of action: in the WD model, excess Cu is removed from hepatic metallothionein and retained within the stable tetrathiomolybdate-Cu-albumin tripartite complex, preventing tetrathiomolybdate degradation and resulting in less urinary elimination and greater faecal excretion than in controls.     

Emerging oral VEGF inhibitors for the treatment of renal cell carcinoma

Introduction: The incidence of renal cell carcinoma (RCC) has increased in recent years and, unfortunately, many patients initially present with metastatic disease. When surgery is not an option, treatment involves administration of targeted therapies. The vascular endothelial growth factor (VEGF) pathway has been identified as an important mediator for the development of RCC. Numerous agents target VEGF-mediated signaling, yet resistance and progressive disease still persists. Novel small molecule VEGF inhibitors with high affinity for the VEGF receptor (VEGFR) have been discovered and are currently under investigation for the management of RCC.

Areas covered: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed.

Expert opinion: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition.     

Metabolic profile elucidation of Zhi–Zi–Da–Huang decoction in rat intestinal bacteria using high-resolution mass spectrometry combined with multiple analytical perspectives

1. Zhi–Zi–Da–Huang decoction (ZZDHD) has been widely used for the treatment of alcoholic jaundice, alcoholic liver disease, and acute hepatitis in China for thousands of years. Conventionally decoctions are administered orally, after which the metabolism caused by the enzymes in intestinal bacteria may influence significantly on the curative effects or toxicity.

2. In this work, the comprehensive metabolic process of ZZDHD in intestinal bacteria was investigated reliably using high-resolution HPLC-DAD-ESI-TOF/MS. Besides, a novel strategy for major-to-trace metabolites identification which integrated information derived from diagnostic fragment ions, mass spectral similarity filter strategy, dynamic metabolic change of target compounds and relevant behavior in LC-MS was adopted.

3. As a result, 45 compounds, including 26 bio-converted prototypes and 19 newly generated metabolites were detected and tentatively identified. The metabolic profile of ZZDHD in gastro-intestinal was subsequently elucidated. Deglycosylation, oxidation, reduction, acetylation, and ring cleavage were all observed in the biotransformation of the decoction. Among the rest, deglycosylation was found to be the predominant metabolic pathway.

4. The results obtained herein provided a practical strategy for metabolic profile elucidation of traditional herbal medicines. Moreover, it would be helpful to unravel how the oral decoctions play the therapeutic role in vivo.     

Development of a list of high-risk perioperative medications for the elderly: a Delphi method

Objectives: There is a lack of direct evidence for the management of perioperative medications in elderly patients. Therefore, the authors aimed to develop a list of high-risk medications for the elderly population in China to provide indicators for clinicians to identify medication-related factors contributing to potential adverse events during the perioperative period.

Methods: The initial list of high-risk perioperative medications was developed by studying all the publications that described specific high-risk medications and their risk profiles in the elderly. Delphi consultations were performed to form a consensus among the group of experts and the list was finalized.

Results: The expert panel consisted of 36 experts from 29 tertiary hospitals and 18 provinces or municipalities. The consensus was reached after two Delphi rounds. Finally, a total of 86 medications of 13 medication classes and 120 screening items were included in the final list, along with perioperative risk profiles and risk aversion recommendations for each drug.

Conclusion: This is the first study to establish a high-risk perioperative medication list in China, which can be used as a reference for intervention and evaluation of perioperative medications for the elderly population.