Doses Evaluated in Clinical Pharmacology Studies Investigating the Effect of Intrinsic and Extrinsic Factors on PK and Safety: Case Examples from Approved Drug Development Programs.

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Insights into the Therapeutic and Pharmacological Properties of Resveratrol as a Nutraceutical Antioxidant Polyphenol in Health Promotion and Disease Prevention.

Resveratrol (3, 5, 4'-trihydroxystilbene) is a polyphenolic derivative with herbal origin. It has attracted considerable attention in recent decades. Many studies have revealed the benefits of Resveratrol over several human disease models, including heart and neurological diseases, nephroprotective, immune regulation, antidiabetic, anti-obesity, age-related diseases, antiviral, and anticancer in experimental and clinical conditions. Recently, the antioxidant and anti-inflammatory activities of Resveratrol have been observed, and it has been shown that Resveratrol reduces inflammatory biomarkers, such as tissue degradation factor, cyclooxygenase 2, nitric oxide synthase, and interleukins. All of these activities appear to be dependent on its structural properties, such as the number and position of the hydroxyl group, which regulates oxidative stress, cell death, and inflammation. Resveratrol is well tolerated and safe even at higher pharmacological doses and desirably affects cardiovascular, neurological, and diabetic diseases. Consequently, it is plausible that Resveratrol can be regarded as a beneficial nutritional additive and a complementary drug, particularly for therapeutic applications. The present review provides an overview of currently available investigations on preventive and therapeutic characteristics and the main molecular mechanisms of Resveratrol and its potent derivatives in various diseases. Thus, this review would enhance knowledge and information about Resveratrol and encourage researchers worldwide to consider it as a pharmaceutical drug to struggle with future health crises against different human disorders.

Therapeutic dose and long-term efficacy of high-intensity focused ultrasound ablation for different types of uterine fibroids based on signal intensity on T2-weighted MR images.

OBJECTIVE: To investigate the therapeutic dose and long-term efficacy of high-intensity focused ultrasound (HIFU) ablation for different types of uterine fibroids based on signal intensity on T2-weighted MR images (T2WI). MATERIALS AND METHODS: Four hundred and one patients with a solitary uterine fibroid treated with HIFU were classified into four groups consisting of extremely hypointense, hypointense, isointense and hyperintense fibroids. Each group was further classified into two subtypes: homogeneous and heterogeneous, based on signal homogeneity of fibroids. The therapeutic dose and long-term follow-up results were compared. RESULTS: There were significant differences in treatment time, sonication time, treatment intensity, total treatment dosage, treatment efficiency, energy-efficiency factor (EEF) and non-perfused volume (NPV) ratio among the four groups (p<.05). The average NPV ratio achieved in patients with extremely hypointense, hypointense, isointense and hyperintense fibroids was 75.2 ± 14.6%, 71.1 ± 15.6%, 68.2 ± 17.3% and 67.8 ± 16.6%, respectively; the re-intervention rates at 36 months after HIFU were 8.4%, 10.3%, 12.5% and 6.1%, respectively. Sonication time, treatment intensity and total energy for heterogeneous fibroids were greater than that for homogeneous fibroids in patients with extremely hypointense fibroids (p<.05). The treatment time for heterogeneous fibroids was significantly longer than that for homogeneous fibroids in patients with isointense fibroids (p<.05). Multivariate ordered logistic regression analysis showed that the ablation volume of fibroids and treatment time were related to NPV ratio (p<.05). CONCLUSION: Every group of patients obtained satisfactory long-term results. Hyperintense fibroids are difficult to treat by HIFU. Heterogeneous fibroids are more difficult to treat with HIFU than homogeneity fibroids.

De Novo Seizures, Obsessive Compulsive Symptoms and Neutropenias in Patients on Clozapine: A Retrospective Cohort Study.

Background: Clozapine has well-documented inter-ethnic variations in pharmacokinetics. There is a paucity of data about clozapine use and associated adverse events such as seizures, obsessive compulsive symptoms, neutropenia, and agranulocytosis, from India. Methods: This retrospective cohort study followed up 228 patients initiated on clozapine in a tertiary care referral center in India for an average of 10 years. We calculated incidence rates of new-onset seizures, new-onset obsessive compulsive symptoms, agranulocytosis, and neutropenia. We collected data on doses of clozapine used and serum assays and calculated concentration-to-dose (C/D) ratios. We also collected relevant clinical details about clozapine-induced seizures. Results: In the sample, 16.8% had new-onset seizures, 12.3% had new-onset OC symptoms, 2.7% had neutropenia, and 0.9% had agranulocytosis. The mean C/D ratio was 2.09 (SD = 1.8). Almost half (46.3%) of available serum assays were in the supra-therapeutic range. Seizures were associated with a higher clozapine dose at one year (OR = 1.003; 95%CI = 1.000-1.006; P value = 0.045) and the presence of positive psychotic symptoms at one year (OR = 4.214; 95%CI = 1.894-9.373; P < 0.001). Conclusion: Compared to existing literature, Indians have a higher rate of clozapine- related seizures and need lower doses to reach therapeutic serum levels.

In Outpatients Receiving Parenteral Vancomycin, Dosing Adjustments Produced by Area Under the Curve-Based and Trough-Based Monitoring Differ Only at the Extremes of the Therapeutic Trough Range.

Area under the curve (AUC)-based vancomycin dosing reduces nephrotoxicity but is burdensome. Reviewing 115 adults receiving ≥2 weeks of outpatient vancomycin, we found AUC-based and trough-based dose adjustments discordant only for troughs <12 or >16 mg/L. Selective versus universal outpatient AUC calculation would likely offer similar benefit with reduced workload.

Use of a neural network-based prediction method to calculate the therapeutic dose in boron neutron capture therapy of patients with glioblastoma.

BACKGROUND: Boron neutron capture therapy (BNCT) is a binary radiotherapy based on the 10 B(n, α)7 Li capture reaction. Nonradioactive isotope 10 B atoms which selectively concentrated in tumor cells will react with low energy neutrons (mainly thermal neutrons) to produce secondary particles with high linear energy transfer, thus depositing dose in tumor cells. In clinical practice, an appropriate treatment plan needs to be set on the basis of the treatment planning system (TPS). Existing BNCT TPSs usually use the Monte Carlo method to determine the three-dimensional (3D) therapeutic dose distribution, which often requires a lot of calculation time due to the complexity of simulating neutron transportation. PURPOSE: A neural network-based BNCT dose prediction method is proposed to achieve the rapid and accurate acquisition of BNCT 3D therapeutic dose distribution for patients with glioblastoma to solve the time-consuming problem of BNCT dose calculation in clinic. METHODS: The clinical data of 122 patients with glioblastoma are collected. Eighteen patients are used as a test set, and the rest are used as a training set. The 3D-UNET is constructed through the design optimization of input and output data sets based on radiation field information and patient CT information to enable the prediction of 3D dose distribution of BNCT. RESULTS: The average mean absolute error of the predicted and simulated equivalent doses of each organ are all less than 1 Gy. For the dose to 95% of the GTV volume (D95 ), the relative deviation between predicted and simulated results are all less than 2%. The average 2 mm/2% gamma index is 89.67%, and the average 3 mm/3% gamma index is 96.78%. The calculation takes about 6 h to simulate the 3D therapeutic dose distribution of a patient with glioblastoma by Monte Carlo method using Intel Xeon E5-2699 v4, whereas the time required by the method proposed in this study is almost less than 1 s using a Titan-V graphics card. CONCLUSIONS: This study proposes a 3D dose prediction method based on 3D-UNET architecture in BNCT, and the feasibility of this method is demonstrated. Results indicate that the method can remarkably reduce the time required for calculation and ensure the accuracy of the predicted 3D therapeutic dose-effect. This work is expected to promote the clinical development of BNCT in the future.

Genetic variants associated with ALT elevation from therapeutic acetaminophen.

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined. METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Dose-response analysis of aripiprazole in patients with schizophrenia in Taiwan.

Background: Aripiprazole is a third-generation antipsychotic agent with acceptable efficacy and a good safety profile. Previous studies have indicated the therapeutic serum concentration of aripiprazole to be 100 to 350 ng/ml; however, most of these studies examined a Western population. Patients with schizophrenia from Tungs' Taichung MetroHarbor Hospital in central Taiwan were recruited to analyze the dose-response relationship of aripiprazole in the Chinese population. Objective: We aimed to investigate whether a serum concentration of aripiprazole higher than the current suggested range leads to higher response rates. Design: A prospective cohort study was designed to investigate the response rates in different studied cohorts grouped by serum concentration of aripiprazole. Data Sources and Methods: Data of 64 patients who presented to a single medical center in central Taiwan and who received therapeutic drug monitoring (TDM) were obtained. Serum concentrations of aripiprazole were correlated with the clinical response of patients by using the Clinical Global Impressions (CGI) scores. Results: The mean concentration of aripiprazole was 432.1 ± 275.1 ng/ml in the study cohort. Among the much-improved patients, the mean serum concentration of aripiprazole was 494 ± 273 ng/ml (25th-75th percentiles 264-666 ng/ml), which was higher than the current recommended therapeutic target of 100-350 ng/ml for aripiprazole. The response rate in the severe group (baseline CGI score of 6 or 7) was significantly higher than in the moderate group (baseline CGI score of 4 or 5; 86.7% versus 55.9%, p = 0.007). Conclusion: A significantly higher response rate was observed in the study cohort with serum aripiprazole concentrations over 300 ng/ml. Therefore, dosing higher than the current recommended range may potentially improve the treatment efficacy in the Chinese population. Because the serum concentration varies among patients due to multiple intrinsic and extrinsic factors, TDM, especially in outpatients, is recommended if the clinical response is limited.

A mobile high-resolution gamma camera for therapeutic dose control during radionuclide therapy.

Objective.Molecular radiotherapy is the most used treatment modality against malign and benign diseases of thyroid. In that context, the large heterogeneity of therapeutic doses in patients and the range of effects observed show that individualized dosimetry is essential for optimizing treatments according to the targeted clinical outcome.Approach.We developed a high-resolution mobile gamma camera specifically designed to improve the quantitative assessment of the distribution and biokinetics of131I at patients's bedside after treatment of thyroid diseases. The first prototype has a field of view of 5 × 5 cm2and consists of a high-energy parallel-hole collimator made of 3D-printed tungsten, coupled to a 6 mm thick CeBr3scintillator readout by an array of silicon photomultiplier detectors. The intrinsic and overall imaging performance of the camera was evaluated with133Ba and131I sources. In order to test its quantification capability in realistic clinical conditions, two different 3D-printed thyroid phantoms homogeneously filled with131I were used. Both single view and conjugate view approaches have been applied, with and without scatter correction technique.Main Results.The camera exhibits high imaging performance with an overall energy resolution of 7.68 ± 0.01%, a submillimetric intrinsic spatial resolution of 0.74 ± 0.28 mm and a very low spatial distortion 0.15 ± 0.10 mm. The complete calibration of the camera shows an overall spatial resolution of 3.14 ± 0.03 mm at a distance of 5 cm and a corresponding sensitivity of 1.23 ± 0.01 cps/MBq, which decreases with distance and slightly changes with source size due to the influence of scattering. Activity recovery factors better than 97% were found with the thyroid phantoms.Significance.These preliminary results are very encouraging for the use of our camera as a tool for accurate quantification of absorbed doses and currently motivates the development of a fully operational clinical camera with a 10 × 10 cm2field of view and improved imaging capabilities.

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF).

BACKGROUND: Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. METHODS: This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. RESULTS: A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs-Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. CONCLUSIONS: PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Optimal therapeutic adropin dose intervention in mice and rat animal models: A systematic review.

BACKGROUND AND AIM: Adropin is a hormone encoded by the Enho gene, which is associated with energy homeostasis. Preclinical studies using animal models have shown that adropin plays a role in enhancing glucose homeostasis and dyslipidemia. Lately, several studies on animal models have been performed to examine the therapeutic and pathophysiological effects of adropin in many disorders. The aim of this systematic review was to identify the ideal adropin dose in mice and rat animal models. MATERIALS AND METHODS: We systematically searched PubMed, Science Direct, and Scopus databases from 2008 to 2020. The terms used in the search were "adropin," "adropin doses in animal models," "glucose homeostasis related to adropin," and "adropin therapeutic effects on rats and mice." Articles that included non-adropin doses, in vitro studies, and factors affecting adropin levels were excluded from the study. RESULTS: Of the total 179 qualified studies, six studies were included. We found that a daily injection of 450 nmol/kg of adropin for 3 days might be considered the optimum dose of effect in mice, whereas injection of 2.1 mg/kg once a day for 10 successive days might be the optimal effective dose in rats. CONCLUSION: Additional investigations are needed to determine the optimum dose of adropin to be used as a therapeutic intervention depending on the animal model.

Autopsy case of fatal hypoglycemia following ingestion of a therapeutic dose of tramadol.

An 86-year-old female was found unconscious the day after taking a prescribed tablet containing a combination of tramadol and acetaminophen. At admission to the hospital, marked hypoglycemia (blood glucose: 4 mg/dL) was confirmed, but serum insulin and C-peptide were within the normal range, which suggested that neither endogenous hyperinsulinemia nor exogenous insulin administration was responsible for the hypoglycemia. Despite resuscitation efforts, the woman subsequently died. At autopsy, there was renal disorder, but any pathological abnormalities that could have caused hypoglycemia were not observed. Blood tramadol and acetaminophen were in the therapeutic range. We speculate that the cause of fatal hypoglycemia was tramadol intake at the therapeutic dose. Older age and renal insufficiency are factors that could have potentially caused the fatal hypoglycemia in this case despite tramadol having been taken at a therapeutic dose. This is the first case report of fatal hypoglycemia following ingestion of a therapeutic dose of tramadol.

A surrogate measure for patient reported symptom remission in administrative data.

BACKGROUND: In real-world pragmatic administrative databases, patient reported remission is often missing. OBJECTIVE: We evaluate if, in administrative data, five features of antidepressant use patterns can replace patient-reported symptom remission. METHOD: We re-examined data from Sequence Treatment Alternatives to Relieve Depression (STAR*D) study. Remission was measured using 50% reduction in Hamilton index. Pattern of antidepressant use was examined through five variables: (a) number of prior ineffective antidepressants, (b) duration of taking current antidepressant, (c) receiving therapeutic dose of the medication, and (d) switching to another medication, or (e) augmenting with another antidepressant. The likelihood ratio (LR) associated with each of these predictors was assessed in 90% of data (3329 cases) and evaluated in 10% of data (350 cases) set-aside for evaluation. The accuracy of predictions was calculated using Area under the Receiver Operating Curve (AROC). RESULTS: Patients who took antidepressants for 14 weeks (LR = 2.007) were more likely to have symptom remission. Prior use of 3 antidepressants reduced the odds of remission (LR = 0.771). Patients who received antidepressants below therapeutic dose were 5 times less likely to experience remission (LR = 0.204). Antidepressant that were augment or switched, almost never led to remission (LR = 0.008, LR = 0.002 respectively). Patterns of antidepressant use accurately (AROC = 0.93) predicted symptom remission. CONCLUSION: Within the first 100 days, antidepressants use patterns could serve as a surrogate measure for patient-reported remission of symptoms.

Inappropriate Doses of Intravenous Polymyxin B after Renal Adjustment Lead to Treatment Failure

Sub-therapeutic doses, shorter duration of therapy, female gender, bacteremia, and renal impairment were among independent predictors of polymyxin B treatment failure. In this study, we found an association between inappropriate doses of polymyxin B (<15000 or >25000 unit/kg/day) and renal impairment. Inappropriate doses of polymyxin B were significantly associated with CrCl 20-50 mL/min (p = 0.021, ORadj 6.660, 95% CI 1.326, 33.453) and CrCl <20 mL/min (p = 0.001, ORadj 22.200, 95% CI 3.481, 141.592). By conducting sub-group analysis only using subjects with appropriate dosage, renal impairment was not associated with polymyxin B treatment failure, thus indicating that treatment failure was due to an inappropriate dose of polymyxin B, rather than renal impairment. In conclusion, renal impairment was not directly associated with treatment failure but was due to an inappropriate dosage of polymyxin B after renal adjustment

The optimal therapeutic irisin dose intervention in animal model: A systematic review.

BACKGROUND AND AIM: Irisin, a novel myocyte-secreted hormone, was proposed to mediate some of the beneficial effects of exercise such as browning of adipocytes, thermogenesis, and metabolic homeostasis. Recently, several animals' models' studies have been performed to investigate the therapeutic impact of irisin in several disorders. Several interventional trials used different doses. However, optimum dose was not determined. This systematic review aims to identify the optimal dose of interventional irisin in mice and rat animal models. MATERIALS AND METHODS: Online databases PubMed, Google Scholar, and Springer were systematically searched from 2012 to 2019. The words searched were irisin, irisin and animal model, physical activity, and irisin and irisin dosage. Non-irisin doses, in vitro studies, and factors influencing irisin levels were excluded. RESULTS: Eleven of the total 391 qualifying studies were included. A daily injection of 500 µg/kg irisin may be the optimum dose of effect in mice and rats. CONCLUSION: More studies are required to determine the optimum dose of irisin to be used as a therapeutic intervention based on animal model.

The Use of Therapeutic-Dose Anticoagulation and Its Effect on Mortality in Patients With COVID-19: A Systematic Review.

The incidence of venous thromboembolism (VTE) events in patients with COVID-19 treated with a standard thromboprophylaxis dose of anticoagulants remains high. We conducted a systematic review in order to explore the association between therapeutic-dose anticoagulation and its effect on mortality in patients with COVID-19. A systematic search was carried out using the electronic databases of PubMed, EuropePMC, and the Cochrane Central Database, using specific keywords. All articles that fulfilled the inclusion criteria were included in the qualitative analysis. There were 8 observational studies included in the final qualitative analysis. Quality assessment using the Newcastle-Ottawa Scale (NOS) showed a mean score of 7.5 ± 1.06, indicating moderate to high quality of the studies. Three retrospective cohort studies reported a reduction in the mortality rate, while 6 other studies showed no mortality benefits among patients with COVID-19 treated with therapeutic-dose anticoagulation. There was a slight tendency toward a reduction in the mortality rate among mechanically-ventilated patients with COVID-19 receiving therapeutic-dose anticoagulation. Bleeding events and thrombotic complications among patients receiving therapeutic-dose anticoagulation were reported in 3 studies. Although it is too soon to draw any conclusions, this systematic review draws attention to current evidence regarding the association between therapeutic-dose anticoagulation and its effect on mortality in patients with COVID-19.

First-in-patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP). OBJECTIVES: This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients. METHODS: In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks. RESULTS: Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 109 /L on day 28. CONCLUSION: Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag.

Treatment with Volanesorsen, a 2'-O-Methoxyethyl-Modified Antisense Oligonucleotide Targeting APOC3 mRNA, Does Not Affect the QTc Interval in Healthy Volunteers.

The aim of this study was to assess the effect of volanesorsen on the corrected QT (QTc) interval. This thorough QT study enrolled 52 healthy male and female subjects who were randomized at a single site in a four-way crossover study. Subjects were randomly assigned to 1 of 12 treatment sequences and crossed over into four treatment periods over the course of which each subject was to receive a single therapeutic dose of volanesorsen as a 300 mg subcutaneous (SC) injection, a single supratherapeutic dose of volanesorsen as 300 mg intravenous (IV) infusion, a single oral (PO) dose of moxifloxacin (positive control), and placebo dose. The study demonstrated that volanesorsen 300 mg SC and 300 mg IV did not have a clinically relevant effect on ΔΔQTcF exceeding 10 ms. The largest mean effect at any postdose time point was 3.0 ms (90% confidence interval [CI]: 0.8-5.2) after SC dosing and 1.8 ms (90% CI -0.4 to 4.0) after IV dosing. Volanesorsen, at the studied therapeutic and supratherapeutic doses, does not have a clinically meaningful effect on the QTc.

Different proteomic profiles of cinnabar upon therapeutic and toxic exposure reveal distinctive biological manifestations.

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnabar, a traditional Chinese mineral medicine with sedative and tranquilizing effects, is known to be toxic to the neural system, but its detailed pharmacological and toxicological mechanisms are still unclear. AIM OF THE STUDY: This study aimed to explore the potential neuropharmacological and neurotoxicological mechanisms of cinnabar by investigating the differentially expressed proteins in cerebral cortices of mice exposed to therapeutic and toxic doses of cinnabar. MATERIALS AND METHODS: Label-free quantitative proteomics and bioinformatics analysis were used to characterize the proteins, pathways, and potential targets associated with therapeutic (50 mg/kg) and toxic (1000 mg/kg) doses of cinnabar in cerebral cortices of mice. Proteomic analysis was verified by parallel reaction monitoring. RESULTS: A total of 6370 and 6299 proteins were identified in the cerebral cortices of mice after exposure to therapeutic and toxic doses of cinnabar, among which 130 and 119 proteins were differentially expressed, respectively. Functional/pathway enrichment analysis showed that both exposure doses of cinnabar could affect transport processes in the cerebral cortex through different proteins. The changes induced by the therapeutic dose included pathways involved in translation and sphingolipid metabolism. Interestingly, for the toxic dose, differentially expressed proteins were enriched for functions and pathways related to RNA splicing, transcription, synaptic plasticity regulation and developmental processes, among which RNA splicing was the most significantly affected function. ATP6V1D and CX3CL1 were shown to be possible key proteins affected by cinnabar, leading to multiple functional changes in the cerebral cortex at the therapeutic and toxic doses, respectively. Furthermore, Connectivity Map (CMap) analysis predicted LRRK2 to be a potential therapeutic target and FTase to be a potential toxic target for cinnabar. CONCLUSION: Our results suggest that the pathways and potential targets identified in the mouse cerebral cortex exposed to therapeutic and toxic doses of cinnabar are different, which provides novel insights into the potential molecular mechanisms underlying the pharmacological and toxicological effects of cinnabar.