Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom?

OBJECTIVES: The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype. METHODS: This is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline. RESULTS: Mean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024). CONCLUSION: Response to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI.

Posterior-superior insular deep transcranial magnetic stimulation alleviates peripheral neuropathic pain - A pilot double-blind, randomized cross-over study.

OBJECTIVES: Peripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief. METHODS: We explored the intensity and short-term duration of the analgesic effects produced in pNeP patients by 5 days of neuronavigated deep rTMS targeting the posterior superior insula (PSI) with a double-cone coil in a sham-controlled randomized cross-over trial. RESULTS: Thirty-one pNeP patients received induction series of five active or sham consecutive sessions of daily deep-rTMS to the PSI in a randomized sequence, with a washout period of at least 21 days between series. The primary outcome [number of responders (>50% pain intensity reduction from baseline in a numerical rating scale ranging from 0 to 10)] was significantly higher after real (58.1%) compared to sham (19.4%) stimulation (p = 0.002). The number needed to treat was 2.6, and the effect size was 0.97 [95% CI (0.6; 1.3)]. One week after the 5th stimulation day, pain scores were no longer different between groups, and no difference in neuropathic pain characteristics and interference with daily living were present. No major side effects occurred, and milder adverse events (i.e., short-lived headaches after stimulation) were reported in both groups. Blinding was effective, and analgesic effects were not affected by sequence of the stimulation series (active-first or sham-first), age, sex or pain duration of participants. DISCUSSION: PSI deep-rTMS was safe in refractory pNeP and was able to provide significant pain intensity reduction after a five-day induction series of treatments. Post-hoc assessment of neuronavigation targeting confirmed deep-rTMS was delivered within the boundaries of the PSI in all participants. CONCLUSION: PSI deep-rTMS provided significant pain relief during 5-day induction sessions compared to sham stimulation.

Model informed precision dosing: China expert consensus report / 中国临床药理学与治疗学

Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.

Exploration of early food effect study of innovative drugs based on physiologically-based pharmacokinetic absorption model / 中国临床药理学与治疗学

Since the impact of food on innovative drugs exposure will increase the risk of evaluation failures for safety and effectiveness, food effect study is routinely completed before multiple ascending dose (MAD) trials for innovative drugs. The prediction performance of physiologically-based pharmacokinetic absorption model (absorption PBPK model) in the application of food effect prediction has improved, we proposed a new strategy to explore food effect based on the absorption PBPK model. Based on the accurate prediction by absorption PBPK model, the food effect studies for qualified innovative drugs would be nested in MAD clinical trials to intend replacing the early independent food effect study. That would be promising to reduce costs and time for drug development, and also to provide the template for early food effect study in China.

Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used in treating COVID-19 patients recently. However, both drugs have some contradictions and rare but severe side effects, such as hypoglycemia, retina and cardiac toxicity. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in 8 cell lines, and further adopted the physiologically-based pharmacokinetic models (PBPK) to predict the tissue risk respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ respectively. The proliferation pattern was monitored in 0-72 hours by IncuCyte S3, which could perform long-term continuous image and video of cells upon CQ or HCQ treatment. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. The CC50 at 24 h, 48 h, 72 h of CQ and HCQ decreased in the time-dependent manner, which indicates the accumulative cytotoxic effect. HCQ was found to be less toxic in 7 cell types except cardiomyocytes H9C2 cells (CC50-48 h=29.55 M; CC50-72 h=15.26 M). In addition, RTTCC is significant higher in CQ treatment group compared to HCQ group, which indicates that relative safety of HCQ. Both CQ and HCQ have certain cytotoxicity in time dependent manner which indicates the necessity of short period administration clinically. HCQ has the less impact in 7 cell lines proliferation and less toxicity compared to CQ in heart, liver, kidney and lung.

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (.., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Normal range of hepatic hemodynamic for uncomplicated children with living donor liver transplantation (LDLT) at early postoperative period / 中华超声影像学杂志

Objective:To analyze hepatic hemodynamic parameters detected by Doppler ultrasound (DU) of uncomplicated children who underwent left lateral segment(LLS) LDLT (LLS-LDLT), explore their change trends over time and determine the normal reference intervals.Methods:This retrospective study involved the data from 261 pediatric LLS-LDLT cases in Tianjin First Central Hospital from June 2014 to January 2018. Hemodynamic parameters included peak systolic velocity (PSV), end diastolic velocity (EDV), resistivity index (RI), and pulsation index (PI) of hepatic artery (HA), and portal vein velocity (PVV) during intra-operative and on the 1st, 3rd, 5th and 7th days after operation were collected. Among whom, 232 cases with uncomplicated and normal recovery were finally involved in our study, with 200 cases who were collected from June 2014 to August 2017 as test group. Those collected from September 2017 to January 2018, totally 32 cases were set as validation group. The change trends and normal ranges of hemodynamic parameters over time were analyzed in test group, and the results were further tested in the validation group.Results:In the test group, PSV HA, EDV HA showed a similar change trend at one week after surgery, with an overall decrease-rise trend; RI HA, PI HA also changed similarly with an overall rise-decrease trend. PVV at surgery was lower than at all time points after surgery. In addition, this study provided the normal reference intervals of hemodynamic parameters for LDLT patients at early postoperative period, which at intra-operation they were PSV HA 18.4-98.3 cm/s, EDV HA 0-43.3 cm/s, RI HA 0.41-1.0, PI HA 0.51-2.0, PVV 19.0-83.7 cm/s. Within 1 week after surgery: PSV HA 21.0-97.7 cm/s, EDV HA 0-32.7 cm/s, RI HA 0.47-1.0, PI HA 0.62-2.0, PVV 23.0-92.0 cm/s. By using those results, the coincidence rate of Doppler parameter change trend was 84.3%(27/32), 84.3%(27/32), 78.1%(25/32), 78.1%(25/32), 87.5%(28/32) for PSV HA, EDV HA, RI HA, PI HA, PVV in the validation group, respectively. As for the normal reference intervals of blood flow parameters, RI HA and PI HA in one case in the validation group were lower than the lower limits of the normal reference intervals, accounting for 3.1% of the total. PSV HA in two cases was lower than the lower limit of normal reference interval, accounting for 6.2% of the total. Conclusions:The hepatic hemodynamic in post-transplanted children detected by DU has specific changing trends and normal ranges, which provides valuable reference values for ultrasonologists and pediatric transplant clinicians.

General considerations of model-based meta-analysis / 中国临床药理学与治疗学

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.

Current trends in drug metabolism and pharmacokinetics

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Mechanism underlying the inhibitory effect of overexpression of tumor suppressor gene DKK3 on migration and invasion of human cutaneous malignant melanoma cells / 中华皮肤科杂志

Objective To investigate the expression of DKK3 in human cutaneous malignant melanoma cells and tissues,and to evaluate the effect of transfection with DKK3 gene on migration and invasion of a malignant melanoma cell line A375.Methods Western blot analysis was performed to measure the relative expression of DKK3 in human cutaneous melanoma cell lines HM,A375,WM451,SK-MEL-1,Hs-695T,MDA-MB-435s and WM35,as well as pigmented nevus tissues.Real-time fluorescence-based quantitative PCR (RT-PCR) was conducted to determine the mRNA expression of DKK3 in 58 melanoma tissues (including primary melanoma and metastatic melanoma) and 30 pigmented nevus tissues from Chongqing Traditional Chinese Medicine Hospital between August 2014 and June 2017.The pcDNA3.1 (+)-Flag-Vector (control group) and pcDNA3.1 (+)-Flag-DKK3 (transfection group) were transfected into A375 melanoma cells separately.RT-PCR and Western blot analysis were performed to verify the overexpression of DKK3,and to evaluate the effect of DKK3 overexpression on the expression of molecules related to the migration and invasion of melanoma cells.Cell scratch assay,Transwell migration and invasion assay were conducted to assess the effect of DKK3 on the migration and invasion of A375 cells.Statistical analysis was done by a two-sample t-test for comparisons between two groups,one-way analysis of variance (ANOVA) for intergroup comparison,and least significant difference (LSD)-t test for multiple comparisons with the SPSS 13.0 software.Results DKK3 protein was absent or lowly expressed in the human melanoma cell lines,but highly expressed in the pigmented nevus tissues.There were significant differences in the mRNA expression of DKK3 among the primary melanoma tissues (2-ΔΔCt:[0.325 ± 0.150] × 10-3),metastatic melanoma tissues ([0.142 ± 0.210] × 103) and pigmented nevus tissues ([0.634 ±:0.120] × 10-3,F =46.57,P ＜ 0.05).In addition,the mRNA expression of DKK3 was significantly lower in the metastatic melanoma tissues than in the primary melanoma tissues and pigmented nevus tissues (LSD-t =2.48,3.12,both P ＜ 0.05).After transfection with DKK3,cell scratch assay showed that the migration rate was significantly lower in the transfection group (22.11％ ± 5.11％) than in the control group (54.36％ ± 23.22％,t =2.36,P ＜ 0.001).Transwell migration and invasion assay revealed that the number of A375 cells crossing the Transwell chamber was significantly lower in the transfection group (265 ± 33,76 ± 18 respectively) than in the control group (429 ± 41,135 ± 21 respectively;t =1.24,1.35 respectively,both P ＜ 0.001).After overexpression of DKK3 in the A375 cells in the transfection group,the mRNA and protein expression of E-cadherin were up-regulated,while the mRNA and protein expression of N-cadherin,vimentin,matrix metalloproteinase 2 (MMP2),MMP7 and MMP11 were down-regulated compared with the control group.Conclusions The expression of DKK3 is down-regulated in the melanoma cell lines and tissues,and the migration and invasion of A375 cells are markedly inhibited by overexpression of DKK3.DKK3 may be a target for inhibiting the metastasis of cutaneous malignant melanoma.

Preliminary study of lateral cerebral angiography with reverse rotation in the digital image registration and subtraction / 中华放射学杂志

ObjectiveInvestigate the value and feasibility of image registration with reverse rotation in lateral cerebral DSA.Methods ( 1 ) Experimental study:the target images were subtracted directly,and subtracted again after reverse rotation.Software of registration and subtraction with reverse rotation edited by the author utilizing Visual Basic.The function of the automatic angle detection by the software were evaluated to see whether it detected the angle of line.The subtraction function of DSA by the software was evaluated.(2) Clinical retrospective study:the untreated mask and target inages of 15 patients with motion along vertical axis during lateral cerebral DSA were uploaded to the software.The target images were processed with and without the software to get two sets of images.( 3 ) Evaluation:four experienced radiologists read and compared the two sets of the images,and graded their findings.Results ( 1 ) The automatic detection by the software suggested that the target images should be rotated counterclockwise 1.3°. The subtraction result of the software was satisfactory.(2)In the 15 sets of images,there were only three sets of images deemed optimal after traditional subtraction.After reverse rotation,artifacts were significantly reduced and the image sharper. There were ten cases with significant artifacts after traditional subtraction,and those images were sharper and showed more peripheral vessels after reverse rotation. The traditional subtraction images of two sets could not be interpreted,the reverse rotation registration images reached the diagnostic quality.(3)Subjective evaluation: there were more information and less noise and distortion in the registration images with reverse rotation than in the traditional subtraction. But the image resolution decreased slightly after reverse rotation registration.ConclusionThe registration of digital angiography with reverse rotation can improve the image quality in lateral cerebral DSA.

Expression of inositol 1,4,5-triphosphate receptor type Ⅰ in the myocardial tissue of rats with endotoxic shock / 中国小儿急救医学

Objective To investigate the changes of inositol 1,4,5-triphosphate receptor typeⅠ(IP3RⅠ)expression in the myocardial tissue of rats with endotoxic shock and probe the possible mechanisms of myocardial depression.Methods Thirty-three male Wistar rats were divided into four groups:control group (n=6) were injected normal saline(4ml/kg),and the other 3 groups (n=9) were injected endotoxin via femoral vein with a different dose of 10mg/kg,5mg/kg,and the artificial sacrificed group(10mg/kg,the rats were sacrificed when the mean arterial pressure was first rapidly decreased,then gradually increased to the normal level).IP3RⅠexpression in the myocardial tissue of rats was detected by immunohistochemistry,Western blot and colloidal gold immunoelectron microscopy technique.Results IP3RⅠexpressions were increased significantly in each group of rats with endotoxic shock than in the control group (P<0.01),and most obviously enhanced in the the artificial sacrificed group.The expression of IP3RⅠwas related to the level of mean arterial pressure.Ectopic expression of IP3RⅠwas observed around the cell membrane of the cardiac myocytes.Conclusion (1)The expression of IP3RⅠenhances in the myocardial tissue of rats with endotoxic shock,and exists ectopic expression.(2) The expression of IP3RⅠwas related to the level of mean arterial pressure.(3) IP3RⅠ may be related to the cardiac contractility and involved in the regulation of mean arterial pressure.