ADCdb: the database of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a class of innovative biopharmaceutical drugs, which, via their antibody (mAb) component, deliver and release their potent warhead (a.k.a. payload) at the disease site, thereby simultaneously improving the efficacy of delivered therapy and reducing its off-target toxicity. To design ADCs of promising efficacy, it is crucial to have the critical data of pharma-information and biological activities for each ADC. However, no such database has been constructed yet. In this study, a database named ADCdb focusing on providing ADC information (especially its pharma-information and biological activities) from multiple perspectives was thus developed. Particularly, a total of 6572 ADCs (359 approved by FDA or in clinical trial pipeline, 501 in preclinical test, 819 with in-vivo testing data, 1868 with cell line/target testing data, 3025 without in-vivo/cell line/target testing data) together with their explicit pharma-information was collected and provided. Moreover, a total of 9171 literature-reported activities were discovered, which were identified from diverse clinical trial pipelines, model organisms, patient/cell-derived xenograft models, etc. Due to the significance of ADCs and their relevant data, this new database was expected to attract broad interests from diverse research fields of current biopharmaceutical drug discovery. The ADCdb is now publicly accessible at: https://idrblab.org/adcdb/.

Alterations of the bile microbiome is associated with progression-free survival in pancreatic ductal adenocarcinoma patients.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited. METHODS: Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm. RESULTS: PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification. CONCLUSION: PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.

Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

OBJECTIVE: This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. METHODS: A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. RESULTS: The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. CONCLUSION: The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Exploring the effect of Wuzhi capsule on the pharmacokinetics of regorafenib and its main metabolites in rat plasma using liquid chromatography-tandem mass spectrometry.

Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (Cmax ), delayed the time to reach Cmax , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.

Signal differentiation models for multiple microRNA detection: a critical review.

MicroRNAs (miRNAs) are a class of small, single-stranded non-coding RNAs which have critical functions in various biological processes. Increasing evidence suggested that abnormal miRNA expression was closely related to many human diseases, and they are projected to be very promising biomarkers for non-invasive diagnosis. Multiplex detection of aberrant miRNAs has great advantages including improved detection efficiency and enhanced diagnostic precision. Traditional miRNA detection methods do not meet the requirements of high sensitivity or multiplexing. Some new techniques have opened novel paths to solve analytical challenges of multiple miRNA detection. Herein, we give a critical overview of the current multiplex strategies for the simultaneous detection of miRNAs from the perspective of two different signal differentiation models, including label differentiation and space differentiation. Meanwhile, recent advances of signal amplification strategies integrated into multiplex miRNA methods are also discussed. We hope this review provides the reader with future perspectives on multiplex miRNA strategies in biochemical research and clinical diagnostics.

Reply to "A better interpretation of data regarding the opioid switching to methadone".

In our article ?Methadone switching for refractory cancer pain' (BMC palliative care, 2022) we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.'s comments one by one.

[Characteristic changes of blood stasis syndrome in rat model of steroid-induced femoral head necrosis based on the combination of disease, syndrome, and symptom].

The approach combining disease, syndrome, and symptom was employed to investigate the characteristic changes of blood stasis syndrome in a rat model of steroid-induced osteonecrosis of the femoral head(SONFH) during disease onset and progression. Seventy-two male SD rats were randomized into a healthy control group and a model group. The rat model of SONFH was established by injection of lipopolysaccharide(LPS) in the tail vein at a dose of 20 µg·kg~(-1)·d~(-1) on days 1 and 2 and gluteal intramuscular injection of methylprednisolone sodium succinate(MPS) at a dose of 40 mg·kg~(-1)·d~(-1) on days 3-5, while the healthy control group received an equal volume of saline. The mechanical pain test, tongue color RGB technique, gait detection, open field test, and inclined plane test were employed to assess hip pain, tongue color, limping, joint activity, and lower limb strength, respectively, at different time points within 21 weeks of modeling. At weeks 2, 4, 8, 12, 16, and 21 after modeling, histopathological changes of the femoral head were observed by hematoxylin-eosin(HE) staining and micro-CT scanning; four coagulation items were measured by rotational thromboelastometry; and enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of six blood lipids, vascular endothelial growth factor(VEGF), endothelin-1(ET-1), nitric oxide(NO), tissue-type plasminogen activator(t-PA), plasminogen activator inhibitor factor-1(PAI-1), bone gla protein(BGP), alkaline phosphatase(ALP), receptor activator of nuclear factor-κB(RANKL), osteoprotegerin(OPG), and tartrate-resistant acid phosphatase 5b(TRAP5b) in the serum, as well as the levels of 6-keto-prostaglandin 1α(6-keto-PGF1α) and thromboxane B2(TXB2) in the plasma. The results demonstrated that the pathological alterations in the SONFH rats were severer over time. The bone trabecular area ratio, adipocyte number, empty lacuna rate, bone mineral density(BMD), bone volume/tissue volume(BV/TV), trabecular thickness(Tb.Th), trabecular number(Tb.N), bone surface area/bone volume(BS/BV), and trabecular separation(Tb.Sp) all significantly increased or decreased over the modeling time after week 4. Compared with the healthy control group, the mechanical pain threshold, gait swing speed, stride, standing time, and walking cycle of SONFH rats changed significantly within 21 weeks after modeling, with the greatest difference observed 12 weeks after modeling. The time spent in the central zone, rearing score, and maximum tilt angle in the open field test of SONFH rats also changed significantly over the modeling time. Compared with the healthy control group, the R, G, and B values of the tongue color of the model rats decreased significantly, with the greatest difference observed 11 weeks after modeling. The levels of total cholesterol(TC), total triglycerides(TG), low-density lipoprotein-cholesterol(LDL-C), and apoprotein B(ApoB) in the SONFH rats changed significantly 4 and 8 weeks after modeling. The levels of VEGF, ET-1, NO, t-PA, PAI-1, 6-keto-PGF1α, TXB2, four coagulation items, and TXB2/6-keto-PGF1α ratio in the serum of SONFH rats changed significantly 4-16 weeks after modeling, with the greatest differences observed 12 weeks after modeling. The levels of BGP, TRAP5b, RANKL, OPG, and RANKL/OPG ratio in the serum of SONFH rats changed significantly 8-21 weeks after modeling. During the entire onset and progression of SONFH in rats, the blood stasis syndrome characteristics such as hyperalgesia, tongue color darkening, gait abnormalities, platelet, vascular, and coagulation dysfunctions were observed, which gradually worsened and then gradually alleviated in the disease course(2-21 weeks), with the most notable differences occurred around 12 weeks after modeling.

The impact of ibuprofen on valproic acid plasma concentration in pediatric patients.

The combination of valproic acid (VPA) and ibuprofen are common in children with epilepsy. Three case reports investigated that ibuprofen might decrease the plasma concentration of VPA, however, no cohort study was published to evaluate the interaction of ibuprofen on VPA plasma concentration in pediatric patients.Data from patients with measured VPA trough concentrations (C0) were retrospectively collected in a Chinese teaching and tertiary Children's Hospital from January 2017 to June 2019. The samples measured within 6 weeks of the last ibuprofen administration were considered ibuprofen combination samples. Patients with paired samples before and after ibuprofen administration were additionally analysed. The effects of ibuprofen on the VPA through concentration to dose (C0/D) ratio were investigated. The proportion of samples with achieved target concentrations of VPA (50-100 mg/L) and the corresponding required dosage were compared. Moreover, subgroup analysis according to the interval between the last ibuprofen dosage and C0 measurement was performed.A total of 616 samples from 434 patients, of whom 16 had paired samples, were included. VPA C0/D decreased when ibuprofen was administered by 7.5% and 30.6% of the total samples and paired samples, respectively. The interaction was significant within 1 week of the last ibuprofen dose. No significant differences were observed in the proportion of target concentration achieved and VPA dose requirement when ibuprofen was combined.A moderate effect of ibuprofen on VPA C0/D was observed within 1 week of ibuprofen administration; the target concentration and required doses of VPA were comparable.

Methadone switching for refractory cancer pain.

BACKGROUND: Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain. METHODS: A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated. RESULTS: Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0-10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3-46.2) to $10.8 (IQR: 7.1-18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30-8.76, p = 0.013). CONCLUSION: Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

Spectrum-Effect Relationship-Based Strategy Combined with Molecular Docking to Explore Bioactive Flavonoids from Sceptridium ternatum.

Sceptridium ternatum is a herbaceous plant with significant potential for pharmaceutical and cosmetic applications. In this study, we established a spectrum-effect relationship-based strategy to investigate the bioactive basis and tissue distribution in S. ternatum. First, a phytochemical analysis on the ethanol extracts from roots, stems, and leaves of S. ternatum was performed using the colorimetric method, high-performance liquid chromatography-ultraviolet (HPLC-UV), and high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS/MS). Then, radical scavenging assays and the lipopolysaccharide-stimulated RAW 264.7 cell model were used to estimate the antioxidant and anti-inflammatory activities, respectively. Spectrum-effect relationship analysis and molecular docking were further employed to evaluate the correlation between the phytochemical profile and anti-inflammatory activity. Our results demonstrate that S. ternatum leaves contained the most abundant flavonoids and exerted the best biological activities. Their IC50 values for scavenging 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radicals were 2.43 ± 0.13 and 5.36 ± 0.54 mg/mL, respectively. In lipopolysaccharide-stimulated RAW 264.7 cells, the leaf extract caused the greatest reduction in nitric oxide production (38.15%) and interleukin-6 release (110.86%). Spectrum-effect relationship analysis and molecular docking indicated that quercetin 3-O-rhamnoside-7-O-glucoside possessed high anti-inflammatory activity by binding with interleukin-6. In conclusion, S. ternatum is a rich source of bioactive flavonoids with potential for exploitation in the prevention and treatment of oxidative stress and inflammation-related pathologies.

[Effect of Jianpi Huogu Formula on function damage of vascular endothelial cells induced by glucocorticoid].

This study aimed to observe the intervention effect of Jianpi Huogu Formula(JPHGF) on the functional damage of vascular endothelial cells caused by glucocorticoid, and explore its action mechanism from the PI3 K/Akt and mitogen activated protein kinase(MAPK) signaling pathways. The extracted thoracic aorta ring of normal SD rats were intervened first with vascularendothelial growth factor(VEGF, 20 µg·L-1) and/or sodium succinate(MPS, 0. 04 g·L-1) in vitro and then with JPHGF(8, 16, and 32 µg·L-1) for five mcontinuous ethylpdays, rednisolofollowed nebythe statistics of the number, length, and area of microvessels budding fromvascular rings. In addition, the human umbilical vein endothelial cells(HUVECs) induced by VEGF(20 µg·L-1) were added with MPS(0. 04 g·L-1) and then with JPHGF(8, 16, and 32 µg·L-1) for observing the migration, invasion, and luminal formation abilities of HUVECs in the migration, invasion and luminal formation experiments. The protein expression levels of PI3 K, p-Akt, p-JN K, and p-ERK in HUVECs were assayed by Western blot. The results showed that JPHGF dose-dependently improved the num-ber,length, and area of microvessels in MPS-induced rat thoracic aortic ring, reversed the migration, invasion and lumen formation abiliti es of HUVECs reduced by MPS, and up-regulated the protein expression levels of PI3 K, p-Akt, and p-JNK in HUVECs. All thesehave suggested that JPHGF exerts the protective effect against hormone-induced damage to the angiogenesis of vascular endothelial cells by activating the PI3 K/Akt and MAPK signaling pathways, which has provided reference for exploring the mechanism of JPHGF in treating s teroid-induced avascular necrosis of femoral head(SANFH) and also the experimental evidence for enriching the scientific connotationof spleen-invigorating and blood-activating therapy.

[Mechanism of Panlongqi Tablets intervening in vertebral artery type of cervical spondylosis in rats through PI3K/AKT signaling pathway based on network pharmacology and experimental verification].

This study aimed to further explore the relevant mechanism of action by network pharmacology integrated with animal experimental verification based on previous proven effective treatment of vertebral artery type of cervical spondylosis(CSA) by Panlongqi Tablets. Bionetwork analysis was performed to establish drug-disease interaction network, and it was found that the key candidate targets of Panlongqi Tablets were enriched in multiple signaling pathways related to CSA pathological links, among which phosphatidylinositol 3-kinase(PI3 K)/serine-threonine kinase(AKT/PKB) signaling pathway was the most significant. Further, mixed modeling method was used to build the CSA rat model, and the rats were divided into normal, model, Panlongqi Tablets low-, medium-and high-dose(0.16, 0.32, 0.64 g·kg~(-1)) and Jingfukang Granules(positive drug, 1.35 g·kg~(-1)) groups. After successful modeling, the rats were administered for 8 consecutive weeks. Pathological changes of rat cervical muscle tissues were detected by hematoxylin-eosin(HE) staining, and the content of interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), vascular endothelial cell growth factor(VEGF) and chemokine(C-C motif) ligand 2(CCL2) in rat serum and/or cervical tissues was determined by enzyme-linked immunosorbent assay(ELISA). Western blot was employed to detect the protein expression levels of chemokine(C-C motif) receptor 2(CCR2), PI3 K, AKT, phosphorylated AKT(p-AKT), I-kappa-B-kinase beta(IKK-beta/IKKß), nuclear factor kappa B(NF-κB P65) and phosphorylated nuclear factor kappa B(NF-κB p-P65) in rat cervical tissues, and positive expression of p-NF-κB P65 in rat cervical muscle tissues was detected by immunofluorescence. The results showed that Panlongqi Tablets at different doses improved the degree of muscle fibrosis and inflammation in cervical muscle tissues of CSA rats, and reduced the content of inflammatory factors IL-1ß, TNF-α, VEGF, CCL2 and CCR2 in serum and/or cervical tissues. The protein expression levels of PI3 K, p-AKT, IKKß and p-NF-κB P65 as well as the nuclear entry of p-NF-κB P65 in cervical tissues were down-regulated. These findings suggest that Panlongqi Tablets can significantly inhibit the inflammatory response of CSA rats, and the mechanism of action may be related to the down-regulation of the activation of PI3 K/AKT signaling pathway.

[Therapeutic effect of Baimai Ointment on peripheral sensitization of chronic inflammatory pain in mice].

Chronic inflammatory pain is mainly manifested by peripheral sensitization. Baimai Ointment(BMO), a classical Tibetan medicine for external use, has good clinical efficacy in the treatment of chronic inflammatory pain, while its pharmacodynamics and mechanism for relieving peripheral sensitization remain unclear. This study established an animal model of chronic inflammatory pain induced by complete Freund's adjuvant to explore the mechanism of BMO in the treatment of chronic inflammatory pain by behavioral test, side effect assessment, network analysis, and experimental verification. The pharmacodynamics experiment showed that BMO increased the thresholds of mechanical pain sensitivity and thermal radiation pain sensitivity of chronic inflammatory pain mice in a dose-dependent manner, and had inhibitory effect on foot swelling, inflammatory mediator, and the expression of transient receptor potential vanilloid-1(TRPV1) and transient receptor potential A1(TRPA1). The results of body weight monitoring, pain sensitivity threshold detection in normal mice, rotarod performance test, and forced swimming test showed that BMO had no obvious toxic or side effect. The network analysis of 51 candidate active molecules selected according to the efficacy of BMO, content of main components, and ADME parameters showed that the inhibitory effect of BMO on chronic inflammatory pain was associated with the core regulatory elements of tumor necrosis factor(TNF) and T cell receptor signaling pathways. BMO down-regulated the protein levels of mitogen-activated protein kinase 14(MAPK14), MAPK1, and prostaglandin-endoperoxide synthase 2(PTGS2), and up-regulated the phosphorylation le-vel of glycogen synthase kinase 3 beta(GSK3 B) in the plantar tissue of mice. In conclusion, BMO can effectively relieve peripheral sensitization of chronic inflammatory pain without inducing tolerance and obvious toxic and side effects. The relevant mechanism may be related to the regulation of BMO on core regulatory elements of TNF and T cell receptor signaling pathways in surrounding tissues.

Tigecycline-Induced Tooth Discoloration in Children Younger than Eight Years.

Tetracycline may cause tooth discoloration when used in young children during tooth development. Whether tigecycline, a tetracycline derivative, has either a similar adverse event or not remains unclear. We assessed the discoloration of the permanent teeth of patients <8 years old after tigecycline exposure. These patients were identified through a retrospective chart review in a Chinese children's hospital. Those who had at least one erupted permanent tooth after tigecycline exposure were interviewed, examined, and photographed by an experienced pediatric dentist and independently assessed by another senior dentist to detect tetracycline-like tooth discoloration. We identified 101 patients who were exposed to tigecycline, 12 of whom were included. The mean daily dose of tigecycline was 2.3 mg/kg of body weight (standard deviation, 0.6), and the median duration was 12.5 days (interquartile range [IQR], 8.0 to 19.3). The median age of exposure was 5.2 years (IQR, 4.5 to 7.4), and the median age of dental examination was 9.1 years (IQR, 9.0 to 10.3). Two patients (16.7%) developed yellow discoloration: a girl having yellow discoloration with white-to-yellow opacities in the upper lateral incisors and lower incisors and a boy with a suspicious buccal yellow discoloration and enamel dysplasia in the second molars. The incidence and extent of tigecycline-associated dental adverse events remain unclear due to the small sample size and inadequate follow-up period.

Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms.

PURPOSE: To evaluate the role of diltiazem on tacrolimus sparing in pediatric primary nephrotic syndrome (PNS) and its relation to CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms. METHODS: The PNS children treated with tacrolimus and with steady-state trough concentration (C0) were retrospectively collected. The impacts of diltiazem on tacrolimus dose-adjusted C0 (C0/D), target concentration achievement, and required dose were evaluated. Meanwhile, the relationship between the polymorphisms (including CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and SCLO1B3) and dose-sparing effect were investigated. RESULTS: A total of 71 children with 535 concentrations, including 16 children with concomitant diltiazem, were involved. Significantly increased C0/D (94.0 vs 83.8 ng/mL per mg/kg, p = 0.038) and lower required daily dose of tacrolimus (0.056 vs 0.064 mg/kg, p = 0.003) were observed in patients co-administered with diltiazem. Subpopulation carrying CYP3A4*1G, CYP3A5*1, ABCB1-3435TT, or SLCO1B3-699AA was presented with enhanced increment in tacrolimus C0/D by 38.8-102.9%. CONCLUSION: Moderate effect of diltiazem on tacrolimus sparing, which might relate to the polymorphisms of CYP3A4, CYP3A5, ABCB1, and SLCO1B3, was documented.

The hyperpolarization-activated cyclic nucleotide-gated channel currents contribute to oxaliplatin-induced hyperexcitability of DRG neurons.

Humans are likely to experience mechanical allodynia and cold hyperalgesia after oxaliplatin intravenous injection. The mechanism by which oxaliplatin leads to these side effects is unknown. Since the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in the automatic depolarization of action potentials, we speculated that HCN channels are involved in oxaliplatin-induced hyperalgesia through action potentials. Our results showed that the density of HCN channel currents and the excitability of dorsal root ganglion neurons both increased after oxaliplatin perfusion at the cellular level. The neuronal hyperexcitability could be alleviated by ivabradine. Ivabradine inhibited oxaliplatin-induced mechanical allodynia and cold hyperalgesia at the individual rat level. Oxaliplatin enhanced the function of HCN channels, which in turn promoted the automatic depolarization of action potentials. The acceleration of automatic depolarization excited the neurons and caused more rapid firing of action potentials. Therefore, the HCN channel is a potential therapeutic target for the hyperalgesia induced by oxaliplatin.

Evaluation of Concentration Errors and Inappropriate Dose Tailoring of Tacrolimus Caused by Sampling-Time Deviations in Pediatric Patients With Primary Nephrotic Syndrome.

BACKGROUND: Tacrolimus dosing is routinely tailored based on its trough level (C0) drawn by therapeutic drug monitoring in pediatric patients with primary nephrotic syndrome. However, this concentration is often inaccurate owing to inappropriate practice, such as deviation of sampling time (DST). The quantitative relationship between DST and C0 remains unclear. METHODS: Tacrolimus concentration at nominal sampling times (12 hours after last dose) and 32 deviation scenarios (12 ± 4 hours every 15 minutes) was predicted using a previously validated population pharmacokinetic model based on 162 scenarios of 100 primary nephrotic syndrome patients involved in the population pharmacokinetic model and derived virtual patients. Concentration error (CE) and relative CE (RCE) were evaluated, and the correlation between DST and RCE was evaluated by subgroup analysis using linear regression. Ultimately, the inappropriate dosing possibly misled by incorrect C0 was simulated in a real-patient cohort according to the target range (5-10 ng/mL). RESULTS: Approximately 7% of RCE was caused at every 1-hour of DST. DST was the most major contributor of RCE (r = 0.773-0.804). Patients with early sampling, older age, high body weight, high dose, low aspartate transaminase level, high corticosteroid dose, and without combination of azole antifungal agents were revealed to have high RCE. Approximately 7%-36% and 9%-25% of inappropriate dose tailoring may be caused by early and delayed sampling, respectively. In addition, patients with early sampling or high-dose tacrolimus had a higher risk of inappropriate dosing than patients with delayed sampling [hazard ratio = 1.53, 95% confidence interval (CI): 1.03-2.27, P = 0.048], and low-dose tacrolimus (P < 0.0001). CONCLUSIONS: A moderate bias of concentration and dose tailoring was revealed within 4 hours of DST. In addition, a high risk of bias was found in patients with early sampling and high-dose tacrolimus.

Underlying Mechanism of Insulin Resistance: A Bioinformatics Analysis Based on Validated Related-Genes from Public Disease Databases.

BACKGROUND The underlying mechanism of insulin resistance is complex; bioinformatics analysis is used to explore the mechanism based differential expression genes (DEGs) obtained from omics analysis. However, the expression and role of most DEGs involved in bioinformatics analysis are invalidated. This study aimed to disclose the mechanism of insulin resistance via bioinformatics analysis based on validated insulin resistance-related genes (IRRGs) collected from public disease-gene databases. MATERIAL AND METHODS IRRGs were collected from 4 disease databases including NCBI-Gene, CTD, RGD, and Phenopedia. GO and KEGG analysis of IRRGs were performed by DAVID. Then, the STRING database was employed to construct a protein-protein interaction (PPI) network of IRRGs. The module analysis and hub genes identification were carried out by MCODE and cytoHubba plugin of Cytoscape based on the primary PPI network, respectively. RESULTS A total of 1195 IRRGs were identified. Response to drug, hypoxia, insulin, positive regulation of transcription from RNA polymerase II promoter, cell proliferation, inflammatory response, negative regulation of apoptotic process, glucose homeostasis, cellular response to insulin stimulus, and aging were proposed as the crucial functions related to insulin resistance. Ten insulin resistance-related pathways included the pathways of insulin resistance, pathways in cancer, adipocytokine, prostate cancer, PI3K-Akt, insulin, AMPK, HIF-1, prolactin, and pancreatic cancer signaling pathway were revealed. INS, AKT1, IL-6, TP53, TNF, VEGFA, MAPK3, EGFR, EGF, and SRC were identified as the top 10 hub genes. CONCLUSIONS The current study presented a landscape view of possible underlying mechanism of insulin resistance by bioinformatics analysis based on validated IRRGs.

PEGylated versus non-PEGylated drugs: A cross-sectional analysis of adverse events in the FDA Adverse Event Reporting System (FAERS) Database
.

OBJECTIVE: PEGylation is commonly used to optimize pharmacological properties and improve the clinical response of drugs. Due to the inherent toxicity of polyethylene glycol (PEG) and pharmacological changes induced by PEGylation, the safety may be altered and required to be explored. This study explored the adverse events (AEs) associated with PEGylation by comparing pharmacovigilance data of PEGylated and parent drugs. MATERIALS AND METHODS: We conducted a disproportionality analysis of spontaneous reports associated with PEGylated and corresponding parent medications from the FDA Adverse Event Reporting System database recorded between the 1st quarter of 2004 and the 4th quarter of 2018 at the level of preferred terms (PTs) and standard MedDRA queries (SMQs), respectively. The AEs probably different in risk due to changed pharmacological effects and inherent toxicity of PEG were analyzed. RESULTS: A total of 259,428 cases associated to six drug pairs (filgrastim, asparaginase, interferon α-2a, interferon α-2b,interferon ß-1a, and liposomal doxorubicin) were collected. Although 95% of PTs were comparable between the two groups, PTs of deep vein thrombosis, pancreatitis acute, diabetes mellitus, liver disorder, disorientation, aphasia and infection, and SMQ of embolic and thrombotic events were significantly alleviated by PEGylation. No PT was significantly enhanced by PEGylation. CONCLUSION: The pharmacovigilance profiles of PEGylated and non-PEGylated agents were similar. Further clinical assessment is required to validate the pharmacovigilance data.

Asiatic acid enhances intratumor delivery and the antitumor effect of pegylated liposomal doxorubicin by reducing tumor-stroma collagen.

Tumor-targeted drug delivery systems (Tt-DDSs) are proposed as a promising strategy for cancer care. However, the dense collagen network in tumors stroma significantly reduces the penetration and efficacy of Tt-DDS. In order to investigate the effect of asiatic acid (AA) on antitumor effect of pegylated liposomal doxorubicin (PLD) by attenuating stroma-collagen, colon cancer xenograft mice (SW620 cell line) were treated by PLD, AA, or combined regimes, respectively; the collagen levels were estimated by Sirius red/fast green dual staining and immunohistochemistry (IHC) staining; the intratumor exposure of doxorubicin was visualized by ex vivo fluorescence imaging and quantified by HPLC/MS analysis. In addition, the impact of AA on collagen synthesis of fibroblast cell (HFL-1) and cytotoxic effect of PLD and doxorubicin to cancer cell (SW620) were studied in vitro. In the presence of AA (4 mg/kg), the intratumor collagen level was restricted in vivo (reduced by 22%, from 4.14% ± 0.30% to 3.24% ± 0.25%, P = 0.051) and in vitro. Subsequently, doxorubicin level was increased by ~30%. The antitumor activity of PLD was significantly improved (57.3% inhibition of tumor growth and 44% reduction in tumor weight) by AA combination. Additionally, no significant improvement in cytotoxic effect of PLD or doxorubicin induced by AA was observed. In conclusion, AA is a promising sensitizer for tumor treatment by enhancing intratumor drug exposure via stromal remodeling.