Prediction of the Efficacy of Lumbar Sympathetic Block in Patients with Lower Extremity Complex Regional Pain Syndrome Type 1 Based on the Sympathetic Skin Response.

INTRODUCTION: Complex regional pain syndrome type 1 (CRPS-1) is prevalent after trauma, with intractable pain being the most prominent clinical symptom. The impact of sympathetic block on CRPS is unclear. The goal of this study was to explore the characteristics that predict successful symptom relief with lumbar sympathetic block (LSB) in patients with lower extremity CRPS-1. METHODS: The study was designed as a prospective cohort study. Ninety-eight patients diagnosed with lower extremity CRPS-1 between March 2021 and March 2022 were enrolled as participants. All of the patients received two LSB treatments within a month. Sympthetic skin response (SSR) and numeric rating scale (NRS) were recorded before and after LSB treatment. The procedure was judged as a clinically positive response if the patients a 50% or greater reduction in NRS scores. Patients were divided into positive response and negative response groups after LSB treatment: LSB (+) and LSB (-), and the different characteristics and examination findings of the two groups of patients were compared. Furthermore, a multivariable logistic regression model was utilized to evaluate the predictors of successful symptom relief following LSB treatment. RESULTS: A total of 43.9% (43/98) of patients experienced successful symptom relief, while 56.1% (55/98) had unsuccessful symptom relief. After LSB treatment of all subjects, the overall NRS score decreased, the SSR amplitude increased, and the SSR latency shortened in the affected extremity (P < 0.05). There was a significant difference in the change in SSR amplitude between the LSB (-) and LSB (+) groups (P = 0.000). A 12-month disease duration had an OR (odds ratio) of 4.477 (P = 0.009), and a 510-µV baseline SSR amplitude of the affected extremity had an OR of 7.508 (P = 0.000) in the multivariable analysis that included these explanatory variables. CONCLUSIONS: Patients with lower extremity CRPS-1 can experience significant pain relief after LSB treatment. The predictors of successful symptom relief after LSB treatment were a baseline SSR amplitude of the affected extremity < 510 µV and a disease duration < 12 months. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (ID: ChiCTR2000037755, date of registration: September 4, 2020).

Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0-24h, 106.79 vs. 97.07 h µg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 µg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0-48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0-48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.

Single-Ascending-Dose, Food-Effect, and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Pangenotypic Anti-Hepatitis C Virus Drug Holybuvir in Healthy Chinese Subjects.

Holybuvir is a novel pangenotypic hepatitis C virus NS5B inhibitor. This first in-human study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of holybuvir and its metabolites and the effect of food on the PK of holybuvir and its metabolites in healthy Chinese subjects. A total of 96 subjects were enrolled in this study which included (i) a single-ascending-dose (SAD) study (100 to 1,200 mg), (ii) a food-effect (FE) study (600 mg), and (iii) a multiple-dose (MD) study (400 and 600 mg once daily for 14 days). The results showed that single oral administration of holybuvir at doses up to 1,200 mg was well tolerated. Holybuvir was rapidly absorbed and metabolized in the human body, which was consistent with the characteristics of holybuvir as a prodrug. PK analysis showed that Cmax and area under the curve (AUC) increased with dose in no dose-proportional manner after a single-dose administration (100 to 1,200 mg). Although high-fat meals did change the PK of holybuvir and its metabolites, clinical significance of changes in PK parameters induced by eating a high-fat diet would be further confirmed. Following multiple-dose administration, accumulation of metabolites SH229M4 and SH229M5-sul was observed. The favorable PK and safety results support the further development of holybuvir for patients with HCV. (This study was registered at Chinadrugtrials.org under identifier CTR20170859.).

The Effects of Fluid Hydration Status on Ultrasound Muscle Measurement in Hemodialysis Patients.

OBJECTIVE: This study aimed to explore the effects of fluid hydration status on ultrasound muscle measurement in hemodialysis (HD) patients. METHODS: Ultrasound muscle examination of the right rectus femoris and bioelectrical impedance analysis measurement of the right lower limb were performed in HD patients at the periods of predialysis and postdialysis. The correlations between the changes in the corresponding ultrasound and bioelectrical impedance analysis variables were analyzed. RESULTS: A total of 50 patients on maintenance HD were included, with mean age of 52.6 ± 13.5 years. Patients were 40% female (n = 20), and average dialysis duration was 2.62 ± 2.42 years. Compared to predialysis, the measurements of cross-sectional area, muscle thickness, echo intensity (EI), and their percentage changes all decreased significantly after the HD procedure (P < .05). The change in EI and its percentage change were significantly correlated with changes in total body water, intracellular water, and extracellular water (P < .05). CONCLUSIONS: The HD session may have significant effects on ultrasound muscle measurement. Both the indicators of muscle quantity (cross-sectional area and muscle thickness) and quality (EI) significantly decreased after HD, which may contribute to the change in fluid hydration status and the change in fluid composition.

Musical therapy attenuates neuroma pain by modifying leptin expression.

BACKGROUND: Accumulating evidence reveals that music therapy appears to help patients with pain. However, there is a limited understanding of the underlying mechanisms. Several studies indicate that leptin level has a crucial relationship with acute and chronic pain. Herein, we evaluated the effects of music stimulation and the potential roles of adipokines (leptin) in pain behaviors. METHODS: We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. Adult male Sprague-Dawley rats were randomly assigned to one of the three groups (n = 6):group 1 (GC), TNT with white noise; group 2(GM), TNT with music; and group 3(GH), TNT. White noise and music stimulation was given once a day following surgery until the end of the study (42nd day). Pain behavioral tests were carried out before surgery and on the 3rd, 10th, 14th, 21st, 28th, 35th, and 42nd days after surgery. At the end of the observation period, we analyzed the histological samples of blood, spinal cord, and prefrontal cortex to investigate the role of leptin in pain behaviors modulated by white noise and sound stimulation. RESULT: Music therapy might improve the pain of TNT rats. Music stimulation ameliorated paw withdrawal thermal latency (PWTL) from the 3rd day after the surgery while the mechanical pain was improved 21 days after the operation.Music stimulation also increased leptin expression in the spinal cord, prefrontal cortex.White noise had no obvious effect. CONCLUSION: Music therapy might improve the pain of TNT rats. Besides, music stimulation ameliorated TNT-induced pain behaviors and affected leptin expression.

The Tourniquet Ischemia Test Effectively Predicts the Efficacy of Lumbar Sympathetic Block in Patients with Lower Extremity Complex Regional Pain Syndrome Type 1.

Background: Neuropathic pain is the most common clinical sign of complex regional pain syndrome (CRPS). Currently, lumbar sympathetic block (LSB) is commonly utilized in lower extremity CRPS that has failed to respond to medication therapy and physical therapy, but its effectiveness is unknown. The tourniquet ischemia test (IT) can distinguish between two types of CRPS: IT-positive CRPS and IT-negative CRPS. Objective: The aim of the study was to investigate whether LSB improves pain scores in patients with lower extremity CRPS-1 and to screen factors to predict its efficacy. Study Design: Prospective clinical observational study. Setting: Pain management center. Subjects: Forty-three patients diagnosed with lower extremity CRPS-1 using the Budapest criteria were included as participants. Methods: Forty-three CRPS-1 patients were treated with LSB therapy, and all of them underwent a tourniquet ischemia test (IT) before undergoing LSB therapy. LSB therapy was performed using a combination of ultrasonography and fluoroscopy. Then, numeric rating scale (NRS) scores and the symptom relief rates of patients were evaluated at 1, 4, and 12 weeks. Finally, peripheral blood inflammatory cytokine samples were collected before and after the LSB treatment. Results: At 4 weeks after the treatment, the total effective symptom relief rate of LSB on CRPS-1 was 25.6% (11/43), with 52.6% (10/19) of IT(+) patients and 4.2% (1/24) of IT(-) patients. There was a significant difference between the IT(-) and IT(+) groups (P = 0.001). The multivariate binary logistic regression analysis revealed that the response to the tourniquet IT was the only significant independent predictor of sympathetic block success (p = 0.007). Conclusion: Tourniquet IT is a simple, safe and effective test to distinguish patients with lower extremity CRPS-1. The response to the tourniquet IT is a reliable predictor of LSB effectiveness in lower extremity CRPS-1 patients.

Enhanced echo intensity of skeletal muscle is associated with poor physical function in hemodialysis patients: a cross-sectional study.

BACKGROUND: Patients on hemodialysis often suffer from reduced muscle strength and exercise capacity due to the decreased quantity and quality of muscle. Cumulative studies showed ultrasound echo intensity (EI) had great potential in evaluating muscle quality. The objective of this study was to evaluate the relationship between EI of skeletal muscle and physical function of patients on maintenance hemodialysis. METHODS: Cross-sectional area (CSA) and mean EI of the right rectus femoris were measured by ultrasound to evaluate the quantity and quality of the muscle, respectively. Physical function was measured by handgrip strength (HGS), gait speed, sit-to-stand 60 s (STS-60) test, and instrumental activities of daily living (IADL) scale. RESULTS: A total of 107 patients on hemodialysis were included, with women accounting for 37.3% (n = 40), and a mean age of 53.53 ± 12.52 years. Among the patients on hemodialysis, EI was moderately and negatively correlated with HGS (r = - 0.467, P < 0.001), gait speed (r = - 0.285, P = 0.003), and STS-60 (r = - 0.313, P = 0.001). Multiple regression analyses adjusted for CSA showed that the enhanced EI of patients on hemodialysis remained associated with worse HGS (ß = - 0.207, P = 0.047), lower gait speed (ß = - 0.002, P = 0.001), less STS-60 (ß = - 0.136, P = 0.049), and a higher likelihood of dependency in IADL (Odds Ratio: 1.070, 95% CI: [1.033-1.111], P = 0.001). CONCLUSIONS: In patients on hemodialysis, enhanced EI in the skeletal muscle measured via ultrasound was correlated with poor physical performance. The combined muscle quality and muscle quantity evaluation provide more information for assessing the level of physical function of the patients.

Clinical Pharmacology and Utility of Contezolid in Chinese Patients with Complicated Skin and Soft-Tissue Infections.

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.

Real-time ultrasound-guided stellate ganglion block for migraine: an observational study.

OBJECTIVE: To observe whether ultrasound-guided stellate ganglion block (SGB) can effectively relieve migraine pain and improve the quality of migraine patients' life. METHODS: 81 patients with migraines were enrolled in this study. The patients received SGB with 6 ml of 0.15% ropivacaine once every week for four times. Migraine was assessed with the Migraine Disability Assessment Scale (MIDAS) at baseline and three-months follow-up (Tm). The numerical rating scale (NRS) score at baseline, one day after treatment (Td) and Tm, the frequency of analgesic use in 3 months and the side effects were also recorded at the same time. RESULTS: The NRS score of migraine subjects decreased significantly from 7.0 (2.0) to 3.0 (1.0) at Td and 2.0 (2.0) at Tm (vs baseline, P < 0.01). The MIDAS total scores were 14.0 (10.5) at baseline and 7.0 (4.5) at Tm (P < 0.001). During the three months, the frequency of analgesic consumption was decreased from 6.2 ± 2.8 to 1.9 ± 1.8. There were no serious side effects. CONCLUSIONS: This study confirmed that ultrasound-guided SGB is an effective method to treat migraines. This technique can reduce pain and disability and then improve the quality of life of patients with migraines.

Ultrasound-Guided Extraforaminal Thoracic Nerve Root Block Through the Midpoint of the Inferior Articular Process and the Parietal Pleura: A Clinical Application of Thoracic Paravertebral Nerve Block.

PURPOSE: Thoracic nerve root (TNR) block is performed primarily under computed tomography or X-ray fluoroscopy but is associated with radiation exposure. Ultrasound requires no radiation and distinguishes vessels, nerves, pleura, and other tissues. Few reports of ultrasound-guided TNR (US-TNR) block have been described, and the puncture end point has not been clearly defined. Herein, we evaluated the feasibility of US-TNR block using the midpoint of the inferior articular process (IAP) and parietal pleura (PP) as the puncture end point. PATIENTS AND METHODS: A prospective series of 10 patients with Herpes Zoster-associated pain underwent US-TNR-guided block performed using an in-plane technique with the midpoint of thoracic IAP and PP as the puncture end points of ultrasonography. The US-TNR block procedure was performed with ultrasound as the primary imaging tool followed by fluoroscopic confirmation. RESULTS: In all patients, the needle tips were visible at the lateral margin of the pedicle in the anteroposterior view and at the extraforaminal zone in the lateral view. The TNR and dorsal root ganglion (DRG) were delineated in all 10 patients. Furthermore, 2 mL of radiopaque agent could delineate the epidural space in 8 patients and the thoracic paravertebral (TPV) space in the other 2 patients. All patients developed numbness along the corresponding dermatome 30 min after injection of local anesthetics. The numeric rating scale (NRS) score at baseline, and at two- and four-week follow-ups were 6.50 ± 1.35, 3.50 ± 0.85 (vs NRS at baseline, P < 0.01), and 4.00 ± 0.82 (vs NRS at baseline, P < 0.01), respectively. CONCLUSION: This study demonstrated the feasibility of US-TNR block using the in-plane technique with the midpoint of thoracic IAP and PP as the puncture end point to effectively block the TNR and DRG. This technique is an accurate clinical application of TPV nerve block and provides a potential therapeutic option for the treatment of neuropathic pain.

Development and validation of ultra-performance liquid chromatography-tandem mass spectrometric methods for simultaneous and rapid determination of contezolid and its major metabolite M2 in plasma and urine samples and its application to a study in subjects with moderate liver impairment.

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.

US-Guided Transforaminal Cervical Nerve Root Block: A Novel Lateral in-Plane Approach.

OBJECTIVE: The aim of the present study was to investigate the effectiveness and safety of a novel lateral in-plane approach for ultrasound-guided transforaminal cervical nerve root block (US-guided TF-CNRB) in the treatment of cervical radiculopathic pain. DESIGN: The design of the present study consisted of an institutional, retrospective case series. SETTING: The present study was conducted at a university hospital. SUBJECTS: Thirty-two patients with cervical radiculopathy who were resistant to conservative therapies and regular US-guided CNRB were included as participants. METHODS: The included patients were treated with US-guided TF-CNRB. During the treatments, using real-time fluoroscopy, we monitored the spreading patterns of a contrast medium and double confirmed the positions of needle tips. Pain numeric rating scales (NRS) and symptom relief grades were determined via telephone interviews at one, four, and 12 weeks after the procedures. RESULTS: US-guided TF-CNRB was performed at the C5 level in six patients, the C6 level in 18 patients, and the C7 level in eight patients. Compared with NRS at baseline, pain scores decreased throughout the observation period. Symptom relief rates of US-guided TF-CNRB at one, four, and 12 weeks were 72%, 69%, and 63%, respectively. Venous blood was aspirated during the procedures in two patients, and the needle tips were corrected. No intravascular injections or neurologic injuries were observed. CONCLUSION: US-guided TF-CNRB produced circumferential spreading around the involved cervical nerve root and showed significant clinical effectiveness in patients resistant to regular US-guided CNRB.

Tamoxifen attenuates reactive astrocyte-induced brain metastasis and drug resistance through the IL-6/STAT3 signaling pathway.

Brain metastasis affects approximately 20%-30% of patients with triple-negative breast cancers (TNBCs). Even small metastatic lesions in the brain can trigger severe neurological impairments and result in extremely short survival time. Recently, active astrocytes were reported to be associated with brain metastases. However, how activated astrocytes regulate the behaviors of disseminated breast cancer cells in the brain remains unknown. In this study, human primary astrocytes were stimulated with IL-1ß to form active astrocytes to study the cross-talk between stromal cells (astrocytes) and TNBC cells in brain metastases. Our results showed that active astrocytes significantly increase the malignancy of TNBC cells and prevent them from undergoing apoptosis caused by doxorubicin. We also found that the high level of IL-6 secreted by activated astrocytes was responsible for the drug resistance of breast cancer, which could be abolished by treatment of astrocytes with tamoxifen (TAM). The blockage of active astrocyte-derived IL-6 by a neutralizing antibody resulted in the attenuation of drug resistance, consequently enhancing the sensitivity of breast cancer cells to doxorubicin. Furthermore, the possible involved TAM-modulated drug resistance mechanism may be associated with a decrease in IL-6 expression in astrocytes and the downregulation of MAPK and JAK2/STAT3 signaling in cancer cells. Our data suggested that TAMs might reduce drug resistance through the IL-6/JAK2/STAT3 signaling pathway, providing a possible therapy to treat brain metastasis in TNBCs, as estrogen receptor inhibitors (TAMs, etc.) can cross the blood-brain barrier.

Ultrasonography-Guided Radiofrequency Ablation for Painful Stump Neuromas to Relieve Postamputation Pain: A Pilot Study.

OBJECTIVE: Postamputation pain (PAP) is a serious problem, and thus far, there is no perfect treatment strategy. Clinically, minimally invasive treatments for peripheral neuromas are simple and feasible. This study aimed to investigate the immediate and long-term effects of ultrasonography-guided radiofrequency ablation (RFA) on PAP. METHODS: Eighteen PAP subjects with painful peripheral neuromas were treated with ultrasonography-guided RFA. RESULTS: A total of 18 PAP subjects were included in the final analyses. Fourteen of the 17 subjects with residual limb pain (RLP) (82.4%) had successful outcomes. A successful outcome was noted in 9 of the 13 subjects with phantom limb pain (PLP) (69.2%). There were no significant associations between symptom relief and sex, age, or the duration of symptoms. There were no severe complications. CONCLUSIONS: Ultrasonography-guided RFA for painful stump neuromas can effectively relieve stump pain and PLP in amputees with PAP (follow-up time was 12 months). Ultrasonography-guided RFA is easy and safe and does not involve radiation exposure, making it very suitable for clinical applications.

Population Pharmacokinetics Study of Contezolid (MRX-I), a Novel Oxazolidinone Antibacterial Agent, in Chinese Patients.

PURPOSE: Contezolid (MRX-I) is a novel oxazolidinone with potent in vitro activity against gram-positive pathogens. The aim of this study was to establish the dose-pharmacokinetic (PK) exposure-pharmacodynamic (PD)-response relationship and to quantitatively evaluate the variability of MRX-I after continuous oral administration of 600 mg BID and 800 mg BID for 14 days under fed conditions in patients with skin and skin structure infections. Another goal was to evaluate the 2 dosing regimens against methicillin-resistant Staphylococcus aureus infections based on PK/PD analysis. METHODS: PK data from healthy volunteers and patients were pooled to develop a population PK model using a nonlinear mixed effect modeling method. Monte Carlo simulations were used to predict probability of target attainment (PTA) and cumulative fraction of response after single oral administration of 600 and 800 mg of MRX-I under fed conditions. FINDINGS: The PK profile of oral administration of MRX-I was described by using a 2-compartment model with first-order elimination. Absorption of MRX-I may be affected by food intake. Type of volunteers could affect absorption constant rate and volume of distribution in the peripheral compartment, and weight could affect volume of distribution in the central department. No obvious effect on PK parameters was identified for other factors such as age, sex, creatinine clearance, concomitant medicine, and baseline diseases. Based on Monte Carlo simulation, MRX-I 600 or 800 mg BID up to 14 days on ordinary fed status could produce satisfactory efficacy against methicillin-resistant S aureus, with cumulative fraction of response >90% for fAUC0-24/MIC targeted at 2.3. At MIC ≤2.0 µg/mL for MRX-I 600 mg BID, or at MIC ≤4.0 µg/mL for MRX-I 800 mg BID, with continuous administration for 14 days at fed status, both regimens could obtain satisfactory clinical and antibacterial efficacy, with PTA >90%. Hence, the MRX-I regimen of 800 mg BID for 7-14 days can be recommended for confirmative clinical trials in patients with skin and skin structure infections. IMPLICATIONS: PK profiles of MRX-I were well captured by using a 2-compartment PK model, and disease status, food intake, and weight were found to significantly affect PK profiles. A dosing regimen of 800 mg BID for 7-14 days with ordinary food intake was recommended for pivotal study based on simulated fAUC0-24/MIC and PTA values. Results suggest that dose adjustments are not necessary for patient sex in confirmatory studies. Chinese Clinical Trial Registration identifier: CTR20140056.

Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers.

Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc was slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 h postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin, at 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 by having a lower confidence bound of ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/liter (90% CI, 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose.

Pyrroloquinoline quinone delays inflammaging induced by TNF-α through the p16/p21 and Jagged1 signalling pathways.

Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor-alpha (TNF-α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti-inflammaging effect. More senescent cells were detected with the addition of TNF-α than without (P < .01). The ratio of senescent cells to non-senescent cells in the TNF-α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF-α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF-α, a well-known pro-inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF-α -induced cellular senescence and has anti-inflammaging properties.

Promotion of Mitochondrial Biogenesis via Activation of AMPK-PGC1ɑ Signaling Pathway by Ginger (Zingiber officinale Roscoe) Extract, and Its Major Active Component 6-Gingerol.

Several studies indicated that ginger (Zingiber officinale Roscoe) enhances thermogenesis and/or energy expenditure with which to interpret the beneficial effects of ginger on metabolic disorders. It is well known that mitochondrial activity plays an essential role in these processes. Thus, this study aimed to investigate the effect of ginger extract (GE) and its major components, 6-gingerol and 6-shogaol, on mitochondrial biogenesis and the underlying molecular mechanisms. Our results showed that GE at dose of 2 g/kg promoted oxygen consumption and intrascapular temperature in mice. The mitochondrial DNA (mtDNA) copy number in muscle and liver increased. Expression levels of oxidative phosphorylation (OXPHOS) related proteins and AMP-activated protein kinase ɑ/proliferator-activated receptor gamma coactivator 1 ɑ (AMPK/PGC1ɑ) signaling related proteins in the muscle, liver, and brown adipose tissue (BAT) increased as well. In HepG2 cells, GE at concentration of 2.5 and 5 mg/mL increased mitochondrial mass and mtDNA copy number. GE promoted ATP production, the activities of mitochondrial respiratory chain complex I and IV, and expression levels of OXPHOS complex related proteins and AMPK/PGC1ɑ signaling related proteins. The antagonist of AMPK eliminated partly the effect of GE on mitochondrial biogenesis. 6-Gingerol increased mitochondrial mass, mtDNA copy number and ATP production, and the activities of mitochondrial respiratory chain complexes in HepG2 cells as well. However, both 6-gingerol at high concentration of 200 µM and 6-shogaol at 10 to 200 µM inhibited cell viability. In conclusion, GE promoted mitochondrial biogenesis and improved mitochondrial functions via activation of AMPK-PGC1ɑ signaling pathway, and 6-gingerol other than 6-shogaol, may be the main active component. PRACTICAL APPLICATION: Ginger (Zingiber officinale Roscoe) is a food seasoning and also used as a medical plant in alternative medicine throughout the world. Here, we demonstrated that ginger extract (GE) promoted mitochondrial biogenesis and mitochondrial function via activation of AMPK-PGC1ɑ signaling pathway both in mice and in HepG2 cells, and 6-gingerol may be its main active component. Ginger, with anticipated safety, is expected to be a long-term used dietary supplement and be developed into a new remedy for mitochondrial dysfunctional disorders.

Concentration-response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent.

The effects of contezolid (MRX-I, an oxazolidinone antibacterial agent) on cardiac repolarization were evaluated retrospectively using a population modeling approach in a Phase I study incorporating single ascending dose, multiple ascending dose, and food effect assessments. Linear mixed effect models were used to assess the relationships between MRX-I plasma concentrations and QT/QTc/∆QTc (baseline-adjusted), in which different correction methods for heart rate have been included. The upper bound of the one-sided 95% confidence interval (CI) for predicted ∆∆QTc was < 10 ms (ms) at therapeutic doses of MRX-I. Model performance/suitability was determined using diagnostic evaluations, which indicated rationality of one-stage concentration-QT model, as well as C-QT model suggested by Garnett et al. The finding demonstrated that MRX-I may have no clinical effects on the QT interval. Concentration-QT model may be an alternative to conventional thorough QT studies.

Tolerability and Pharmacokinetics of Contezolid at Therapeutic and Supratherapeutic Doses in Healthy Chinese Subjects, and Assessment of Contezolid Dosing Regimens Based on Pharmacokinetic/Pharmacodynamic Analysis.

PURPOSE: This study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. METHODS: A Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. FINDINGS: Single-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC50 and MIC90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). IMPLICATIONS: Contezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.