Objective To explore the effect of Evodiamine (Evo) on the immune function of allergic rhinitis (AR) rats and the regulatory mechanism on C-C motif chemokine ligand 2 (CCL2)/ C-C motif chemokine receptor 2 (CCR2) pathway. Methods The related targets of Evo-AR-immune function were screened by network pharmacology, and the protein interaction network diagram of intersecting targets was constructed. The AR rat model was established by ovalbumin (OVA) combined with aluminium hydroxide, and the rats were divided into six groups: a normal control (NC) group, a model group, a Loratadine (LOR) group, an Evodiamine low dose (Evo-L) group, a Evodiamine high dose (Evo-H) groups, and an Evo-H combined with CCL2 group. After the last administration, the symptoms of rats in each group were scored; ELISA was applied to detect the levels of histamine, immunoglobulin E (IgE), interleukin 4 (IL-4), IL-13 and interferon γ (IFN-γ); Diff-Quick staining solution was applied to detecte the number of cells in the nasal lavage fluid (NALF); hematoxylin eosin (HE) staining was applied to observe the pathological changes of nasal mucosa tissue; real-time quantitative PCR was applied to detect the levels of CCL2 and CCR2 mRNA in tissue; Western blot was applied to detect the expression levels of CCL2, CCR2 and CXC motif chemokine ligand 8 (CXCL8) proteins in nasal mucosa. Results There were eight intersection targets of EVo-AR-immune function, and protein interaction network diagram showed that CXCL8 was the core target. Compared with the NC group, the score of nasal symptoms, the levels of histamine, IgE, IL-4 and IL-13, the numbers of eosinophil, macrophages, neutrophils, lymphocytes and total cells, the mRNA and protein expression levels of CCL2 and CCR2, and the expression of CXCL8 protein in the model group were increased, while the level of IFN-γ was decreased. Compared with the model group, the score of nasal symptoms, the levels of histamine, IgE, IL-4 and IL-13, the numbers of eosinophil, macrophages, neutrophils, lymphocytes and total cells, the mRNA and protein expression levels of CCL2 and CCR2, and the expression of CXCL8 protein in LOR and Evo groups were decreased, while the level of IFN-γ was increased. Further use of CCL2 recombinant protein for compensatory experiments revealed that the improvement effect of Evo on immune function in AR rats was reversed by CCL2. Conclusion Evo can improve the immune function of AR rats, and its mechanism may be related to the inhibition of the CCL2/CCR2 pathway.
Animals ; Receptors, CCR2/immunology* ; Signal Transduction/drug effects* ; Chemokine CCL2/immunology* ; Rats ; Rhinitis, Allergic/metabolism* ; Immunoglobulin E/blood* ; Quinazolines/pharmacology* ; Male ; Interferon-gamma ; Rats, Sprague-Dawley ; Interleukin-13 ; Histamine ; Interleukin-4/immunology* ; Disease Models, Animal

BACKGROUND: In the real world, the plasma drug concentration range of Icotinib treated with epidermal growth factor receptor (EGFR) gene mutant non-small cell lung cancer (NSCLC) is not yet clear, and there may be a correlation between drug concentration and its efficacy, as well as adverse reactions. This study conducted therapeutic drug monitoring (TDM) of Icotinib. The aim of this study was to analyze the drug exposure of Icotinib in targeted therapy for NSCLC, and to investigate the relationship between Icotinib drug concentration and its efficacy and safety. METHODS: Prospective blood samples were collected from NSCLC patients with EGFR-sensitive mutations who received treatment with Icotinib in Peking University Cancer Hospital from April 2022 to July 2024. The drug trough concentration of Icotinib in plasma was detected, and the correlation between drug concentration and efficacy, as well as the toxic side effects, were further analyzed based on the patient's clinical medical records. RESULTS: 22 patients who were treated with Icotinib underwent TDM, but one of them did not acquire the data due to prolonged discontinuation. The remaining 21 patients, each with 1-7 blood draws, obtained a total of 32 plasma drug concentration data. The drug concentration of icotinib is a range of 126.9-2317.1 ng/mL. Among the 21 patients, 18 cases were female (85.7%), and 3 cases were male (14.3%), with an age range of 44-85 years old. The pathological types are all lung adenocarcinoma. Except for 5 patients receiving postoperative adjuvant therapy, 16 patients had assessable tumors. The objective response rate was 43.8% (7/16), and the disease control rate reached 100.0% (16/16). The median value of drug concentration is 805.5 ng/mL among those 21 patients. Compared with the patients who achieved stable disease, the median value of drug concentrations of Icotinib in patients who achieved partial response were 497.2 and 1195.5 ng/mL, respectively (P=0.017). The median value of drug concentrations for patients who did not experience adverse reactions during treatment and those who experienced adverse reactions were 997.0 and 828.6 ng/mL, respectively (P=0.538). CONCLUSIONS Icotinib demonstrates good therapeutic effect and tolerable toxicity on the EGFR gene mutant NSCLC. There is a certain negative correlation between the plasma drug concentration of Icotinib and its efficacy, while there seems no significant correlation with safety.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/metabolism* ; Lung Neoplasms/genetics* ; Male ; Female ; Crown Ethers/blood* ; Middle Aged ; Drug Monitoring ; Aged ; Quinazolines/blood* ; Mutation ; Adult ; Aged, 80 and over ; Antineoplastic Agents/blood* ; Prospective Studies

OBJECTIVETo evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib (Iressa®) and the oriental medications Guipi Decoction (, GPD, Guibi-tang in Korean) and Bawu Decoction (, BWD, Palmul-tang in Korean).

METHODSMethylcellulose (MC, control), GPD (1,200 mg/kg), or BWD (6,000 mg/kg) was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib (10 mg/kg) was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefitinib (10 mg/kg) was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis.

RESULTSGefitinib was rapidly absorbed and showed a monoexponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration (C, P<0.05) and area under the curve (P<0.05), and a delayed time to reach C (T, P<0.01) were observed in both single- and multipledose BWD-pretreated rats compared with the control rats.

CONCLUSIONSBWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.

Animals ; Chromatography, Liquid ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; Male ; Quinazolines ; administration & dosage ; blood ; pharmacokinetics ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry ; Time Factors

OBJECTIVETo investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model.

METHODSThe intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) α-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined.

RESULTSCompared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM α-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01).

CONCLUSIONRut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.

Actins ; metabolism ; Animals ; Carotid Arteries ; drug effects ; metabolism ; pathology ; Carotid Artery Injuries ; drug therapy ; genetics ; pathology ; Cyclic GMP ; blood ; Disease Models, Animal ; Gene Expression Regulation ; drug effects ; Hyperplasia ; Indole Alkaloids ; pharmacology ; therapeutic use ; Male ; Nitric Oxide ; blood ; Phosphorylation ; drug effects ; Proliferating Cell Nuclear Antigen ; metabolism ; Quinazolines ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Tunica Intima ; drug effects ; pathology

OBJECTIVETo compare the pharmacokinetic parameters of evodiamine hydroxypropyl-β-cyclodextrin inclusion complex and free evodiamine suspension in rats, and investigate the pharmacokinetic characteristics of evodiamine inclusion complex.

METHODSBoth water solubility and cumulative release percentage of EHD were tested with evodiamine as the control. Blood samples were collected from the venous plexus of SD rats after intravenous administration with evodiamine inclusion complex and free evodiamine at 100 mg/kg (equivalent evodiamine dose). Plasma concentrations of evodiamine were determined by high-performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using DAS 2.1.1.

RESULTSThe evodiamine inclusion complex showed a better water solubility (18.46±0.36 µg/mL) and a higher cumulative release percentage [(76.8±4.9)%] than free evodiamine. The pharmacokinetic parameters of evodiamine inclusion complex and free evodiamine in rats were as follows: Cmax, 252.5±12.43 vs 161.3±3.45 µg/L; T(max), 4.00±0 vs 4.07±0 h; MRT(0-∞), 8.46±0.91 vs 4.43±0.74 h; AUC(0-t), 2266.40±28.64 vs 911.92±8.53 µg·L(-1)·h(-1); AUC(0-∞), 2359.76±31.58 vs 919.16±9.73 µg·L(-1)·h(-1). The relative bioavailability of evodiamine inclusion complex was 256.73%.

CONCLUSIONCompared with free evodiamine, evodiamine inclusion complex has a higher bioavailability.

2-Hydroxypropyl-beta-cyclodextrin ; Animals ; Biological Availability ; Chromatography, High Pressure Liquid ; Quinazolines ; blood ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Solubility ; beta-Cyclodextrins ; pharmacokinetics

In this study, the variation of pharmacokinetics behavior of raltitrexed (RTX) in rats after repeatedly injected with Huangqi injection was investigated. Twelve SD rats were divided into two groups: the multidose group and the RTX group. Rats in multidose group were iv. injected with Huangqi injection (dose of 1.575 mL x kg(-1)) everyday at 8 am for a week, and had free accesses for food and water. The rats were fasted for food but not water since 8 h before the eighth day. At the eighth morning, firstly, rats were injected with Huangqi injection (dose of 1.575 mL x kg(-1)), and 5 min later, were injected with RTX (dose of 0.467 mg x kg(-1)); rats in RTX group were not disposed in the previous seven days, also had free accesses for food and water, and were iv. injected with raltitrexed at the same time as Multidose group at the eighth day morning. Rat plasma was collected at different time and processed with methanol to precipitate the protein before HPLC assays. The pharmacokinetics parameters for two groups were calculated by software 3P97. Through the observation of drug concentration in plasma and time curve, we found that at almost every time point the concentration of RTX in plasma in multidose group was lower than the RTX group. When comparing the pharmacokinetics parameters between the multidose group and the RTX group, the average of AUC(0-t) and half-life(t1/2) of multidose group were decreased from 56 080 microg x min x L(-1) and 15.07 min to 35 834 microg x min x L(-1) and 8.95 min, respectively, while the clearance (CL) was increased from 0.51 to 0.83 mL x h(-1). Therefore, it could be deduced that repeatedly injected with AR injection may influence the renal excretion and glycometabolism of RTX, thus change pharmacokinetics behavior of raltitrexed in rats plasma. This result may give us a hint to prudantly manage the drug combination of RTX and Huangqi injection.
Animals ; Drugs, Chinese Herbal ; administration & dosage ; pharmacokinetics ; Female ; Injections ; Male ; Quinazolines ; administration & dosage ; blood ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Thiophenes ; administration & dosage ; blood ; pharmacokinetics

BACKGROUNDSerum expression of cytokines may provide information about the clinical outcome of advanced non-small cell lung cancer (NSCLC) patients. This study aimed to investigate the relationship between serum cytokine levels and the clinical outcome of erlotinib treatment in a second or third line setting in patients with advanced NSCLC.

METHODSA total of 162 patients with advanced NSCLC who received erlotinib as either second or third line therapy were enrolled in this study. Blood samples were collected before the initiation of erlotinib treatment, and the levels of IL-1, IL- 2R, IL-6, and tumor necrosis factor (TNF)-α were assessed by enzyme-linked immunosorbent assay (ELISA). Cutoff points were defined as the median levels of IL-1 (low (≥26.5 pg/ml) and high (>26.5 pg/ml)), IL-2R (low ( = 115 pmol/L) and high (>15 pmol/L)), IL-6 (low (≤49.5 pg/ml) and high (>49.5 pg/ml)), and TNF-α (low (≤48.5 pg/ml) and high (>48.5 pg/ml)). Kaplan-Meier analysis was used to estimate the survival time, and Cox regression analyses were used to correlate cytokines and baseline clinical characteristics with clinical outcomes, including time to progression (TTP) and overall survival (OS).

RESULTSBetween January 2007 and May 2011, 162 patients were enrolled. Their median age was 58 years. In this group, 109 were males and 53 were females, 74 were former or current smokers and 88 were non-smokers. A total of 122 patients had adenocarcinoma, 27 had squamous cell carcinoma, and 13 had tumors with other types of histology. And 139 patients had an Eastern cooperative oncology group (ECOG) performance status of 0-1, while 23 scored at 2-3. Expression of IL-1, IL-2R, and IL-6 was not significantly associated with age, gender, ECOG performance status, smoking status, or histology and stage of tumor. Only TNF-α was associated with smoking status (P = 0.045). Survival analysis showed that patients with low levels of either IL-6 or TNF-α had a statistically longer TTP and OS than patients with high expression (P < 0.05). These cytokines remained significant upon multivariate analysis (P < 0.05).

CONCLUSIONIL-6 or TNF-α may serve as potential predictive biomarker for the efficacy of erlotinib.

Adult ; Aged ; Carcinoma, Non-Small-Cell Lung ; blood ; drug therapy ; Cytokines ; blood ; Erlotinib Hydrochloride ; Female ; Humans ; Lung Neoplasms ; blood ; drug therapy ; Male ; Middle Aged ; Protein Kinase Inhibitors ; therapeutic use ; Quinazolines ; therapeutic use

PURPOSE: A prospective multi-center study was conducted to evaluate the safety and efficacy of alfuzosin (10 mg), for male lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in primary care clinics. MATERIALS AND METHODS: Three hundred twenty-four patients with complaints of LUTS associated with BPH were enrolled from 17 clinics. Patients received a 12-week course of 10 mg alfuzosin (Bearxat(R)XL Tablet) once daily, and underwent follow-up at 2~4 and 12 weeks post-treatment. The maximum flow rate (Qmax) and residual urine volume (RUV) were measured at each visit. The International Prostate Symptom Score (IPSS), Quality of Life (QoL), and International Index of Erectile Function (IIEF-5) were evaluated at baseline and post-treatment. During the study period, the presence of orthostatic hypotension was evaluated by blood pressure measurement before and after a postural change. Any adverse effects of alfuzosin including retrograde ejaculation were assessed. RESULTS: Of the 324 enrolled patients, 62 (19.1%) patients dropped out and a total of 262 patients were evaluated. Each value of Qmax, RUV, IPSS, QoL, and IIEF-5 was significantly improved from 14.19+/-8.85 ml/sec, 41.10+/-81.44 ml, 18.04+/-7.36, 3.81+/-0.86, and 11.75+/-6.91, respectively, at baseline, to 15.68+/-6.25 ml/sec, 24.29+/-29.46 ml, 12.19+/-5.59, 2.54+/-0.91, and 12.33+/-7.55, respectively, at end-point. Retrograde ejaculation was found in 2 patients (2/255, 0.78%) at 2~4 weeks and 1 patient (1/152, 0.66%) at 12 weeks. The frequency of orthostatic hypotension was 13.27% (30/226) at baseline, 13.11% (27/206, p=0.8658) at 2~4 weeks, and 14.29% (19/133, p=0.8348) at end-point. The number of patients with adverse events was 36 where the number of adverse events was 60. Among those 60 adverse events, 8 events were related to treatment, which consisted of headache (2), dizziness (2), palpitation (1), voiding difficulty (1), erectile dysfunction (1), and arthralgia (1). CONCLUSIONS: Treatment with alfuzosin (10 mg) once daily led to significant improvements in LUTS associated with BPH and QoL in primary care clinic patients. alfuzosin (10 mg) use resulted in few hypotensive events, no deleterious effect on sexual function, and no drug related SAEs during the study. The study findings suggest that alfuzosin (10 mg) can be safely prescribed in primary care clinics for male LUTS with efficacy.
Arthralgia ; Blood Pressure ; Dizziness ; Ejaculation ; Erectile Dysfunction ; Follow-Up Studies ; Headache ; Humans ; Hypotension, Orthostatic ; Lower Urinary Tract Symptoms ; Male ; Primary Health Care ; Prospective Studies ; Prostate ; Prostatic Hyperplasia ; Quality of Life ; Quinazolines

OBJECTIVETo analyze the association between the EGFR protein level and the EGFR gene mutation status in advanced non-small cell lung cancer (NSCLC), and to explore whether the EGFR protein level is related to the efficacy and survival of the EGFR-TKI drug Gifitinib-treated patients with advanced NSCLC.

METHODSNinety-nine cases were enrolled in this study. Pathological tissue specimens and paired peripheral blood samples were collected. Exons 19 and 21 of the EGFR gene mutation were detected by direct sequencing. The concentration of plasma EGFR protein was detected by ELISA. Univariate and multivariate statistical analyses of the efficacy and survival were performed using SPSS 13.0 software.

RESULTSThe response rate (RR) and clinical benefit rate (CBR) of Gefitinib-treated patients were 51.5% and 79.8%, respectively. There were 35 (35.4%) with positive EGFR gene mutation of the 99 samples. The concentration limit of EGFR protein was 55.42 µg/L. The RR and CBR of patients with EGFR gene mutation was significantly higher than those without mutation (65.7% vs. 43.8%, P = 0.037; 94.3% vs. 71.9%, P = 0.008). The median PFS was prolonged (23 months vs. 10 months, P = 0.014). The CBR of patients with high EGFR protein expression (concentration ≥ 55.42 µg/L) was significantly higher than those with low expression (90.0% vs 64.1%, P = 0.004), and the median PFS was prolonged (21 months vs. 8 months, P = 0.016). EGFR protein level was an independent factor affecting the EGFR gene mutation status. The Correlation between EGFR gene mutation status and EGFR protein level was positive.

CONCLUSIONSGefitinib is effective in the treatment of advanced NSCLC patients with EGFR gene mutation and high EGFR protein expression. EGFR protein level in peripheral blood may be a molecular biomarker in prediction of efficacy and survival of the Gefitinib treatment in patients with advanced NSCLC.

Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; blood ; drug therapy ; genetics ; pathology ; Disease-Free Survival ; Exons ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; blood ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; blood ; genetics ; Remission Induction ; Survival Rate

OBJECTIVEThe aim of this study was to detect the pre- and post-treatment serum carcinoembryonic antigen (CEA) levels after 4 weeks of EGFR-TKIs treatment in advanced non-small cell lung cancer (NSCLC) patients to evaluate the clinical value of CEA in the prediction of chemotherapy response and prognosis in those patients.

METHODSPre- and post-treatment serum CEA levels of the patients were measured with immunoradiometric kits after 4 weeks of EGFR-TKIs treatment to evaluate the relationship between chemotherapy response and prognosis.

RESULTSAfter 4 weeks of EGFR-TKIs treatment, one patient in the total of 75 patients (1.3%) achieved complete response (CR), 17 patients (22.7%) achieved partial response (PR), 31 patients (41.3%) achieved disease stable (SD) and 26 patients had progressive disease (PD). The radiological objective response rate(ORR) and disease control rate (DCR) were 24.0% and 65.3%, respectively. The median survival time (MST) of all patients was 8.1 months. The MST of SD patients was similar to that in the OR patients (P = 0.06), but both longer than that in the PD patients (P < 0.001). The MST of DC patients was similar to that in OR patients (P = 0.358), but longer than that in PD patients (P < 0.001). Serum CEA levels decreased ≥ 32% and ≥ 61% were closely related with the objective response and disease control. The median survival time (MST) of patients with serum CEA decreased ≥ 32% was longer than those with CEA decreased < 32% (9.5 months vs 6.7 months, P < 0.0001). The MST of patients with serum CEA decreased ≥ 32% was similar to those with CEA decreased ≥ 61% (9.5 months vs 10.5 months, P = 0.370), but both longer than those with CEA decreased < 32% (6.7 months, P < 0.001). Cox multivariate survival analysis confirmed that serum CEA level decreased ≥ 32%, CEA level decreased ≥ 61%, PS score, and DC are independent prognostic factor, but not OR.

CONCLUSIONSTo advanced NSCLC patients, the disease control rate (DCR) may be more suitable than objective response rate (ORR) as an indicator in predicting the efficacy and prognosis in advanced NSCLC patients. Serum CEA levels decreased ≥ 32% may be a reliable indicator to determine the therapeutic efficacy of EGFR-TKIs.

Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoembryonic Antigen ; blood ; Carcinoma, Non-Small-Cell Lung ; blood ; drug therapy ; pathology ; Erlotinib Hydrochloride ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; blood ; drug therapy ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Proportional Hazards Models ; Protein Kinase Inhibitors ; therapeutic use ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Remission Induction ; Survival Rate