Drug-related problems in hospitalized patients with chronic kidney diseases and clinical pharmacist interventions.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. METHODS: With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. RESULTS: A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist's intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. CONCLUSION: DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

Identification of differentially methylated genes as diagnostic and prognostic biomarkers of breast cancer.

BACKGROUND: Aberrant DNA methylation is significantly associated with breast cancer. METHODS: In this study, we aimed to determine novel methylation biomarkers using a bioinformatics analysis approach that could have clinical value for breast cancer diagnosis and prognosis. Firstly, differentially methylated DNA patterns were detected in breast cancer samples by comparing publicly available datasets (GSE72245 and GSE88883). Methylation levels in 7 selected methylation biomarkers were also estimated using the online tool UALCAN. Next, we evaluated the diagnostic value of these selected biomarkers in two independent cohorts, as well as in two mixed cohorts, through ROC curve analysis. Finally, prognostic value of the selected methylation biomarkers was evaluated breast cancer by the Kaplan-Meier plot analysis. RESULTS: In this study, a total of 23 significant differentially methylated sites, corresponding to 9 different genes, were identified in breast cancer datasets. Among the 9 identified genes, ADCY4, CPXM1, DNM3, GNG4, MAST1, mir129-2, PRDM14, and ZNF177 were hypermethylated. Importantly, individual value of each selected methylation gene was greater than 0.9, whereas predictive value for all genes combined was 0.9998. We also found the AUC for the combined signature of 7 genes (ADCY4, CPXM1, DNM3, GNG4, MAST1, PRDM14, ZNF177) was 0.9998 [95% CI 0.9994-1], and the AUC for the combined signature of 3 genes (MAST1, PRDM14, and ZNF177) was 0.9991 [95% CI 0.9976-1]. Results from additional validation analyses showed that MAST1, PRDM14, and ZNF177 had high sensitivity, specificity, and accuracy for breast cancer diagnosis. Lastly, patient survival analysis revealed that high expression of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 were significantly associated with better overall survival. CONCLUSIONS: Methylation pattern of MAST1, PRDM14, and ZNF177 may represent new diagnostic biomarkers for breast cancer, while methylation of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 may hold prognostic potential for breast cancer.

Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy.

Bevacizumab (BEV) is widely used for the treatment of patients with recurrent glioblastoma (GBM), but recent evidence demonstrated that BEV induced cytoprotective autophagy, which allows tumor cells to survive. Hydroxychloroquine (HCQ) inhibits lysosomal acidification and blocks autophagy via influencing autophagosome fusion and degradation. HCQ is often used to enhance the efficacy of chemoradiotherapy. However, whether HCQ sensitizes GBM cells to BEV and the molecular mechanism of this effect are not clear. We showed that high concentrations of BEV increased the LC3-II/LC3-I ratio and caused the degradation of Beclin1 in the LN18 and LN229 cell lines, indicating that high concentrations of BEV induced the autophagy of the LN18 and LN229 cells. However, BEV (100 µg/ml) did not influence the autophagy of the LN18 and LN229 cells, and HCQ at less than 5 µg/ml significantly accumulated LC3B-II and p62 proteins and blocked the autophagy process. Importantly, we found that HCQ (5 µg/ml) potentiated the anti-cancer effect of BEV (100 µg/ml). Therefore, HCQ is a novel strategy that may augment the efficacy of BEV for GBM via the inhibition of autophagy.

Prophylactic abdominal aortic balloon occlusion: An effective method of controlling hemorrhage in patients with placenta previa or accreta.

Postpartum hemorrhage is considered to be a serious complication in patients with pernicious placenta. Approaches employing abdominal aortic balloon occlusion to control hemorrhage are extremely effective for such patients. The present study analyzed 9 patients with pernicious placenta previa in a single hospital from June 2016 to November 2017. Prior to cesarean hysterectomy, an abdominal aortic balloon catheter was placed in all patients. The balloon was inflated and evacuated alternately using saline following delivery of the fetal head. The X-ray dose, bleeding volume and complications during the procedure were observed. Balloon catheterization was successfully performed in all 9 patients. The dose of X-rays ranged from 15.8 to 24.5 mGy, with a mean of 19.3±2.7 mGy; the volume of blood loss ranged from 50 to 4,000 ml, with a mean of ~1,800 ml. Uterine artery embolization was successfully performed in 2 cases due to bleeding following the cesarean hysterectomy, and every uterus was retained. Abdominal aortic balloon occlusion can effectively reduce the amount of bleeding during cesarean hysterectomy in patients with pernicious placenta previa. This may serve as technical support for patients in whom retention of the uterus is expected. However, it is necessary to identify any abnormal uterine tissue above the level of the renal artery in order to avoid ineffective balloon occlusion.

Silibinin: an old drug for hematological disorders.

INTRODUCTION: Silibinin (silybin), a non-toxic natural polyphenolic flavonoid, is the principal and the most biologically active component of silymarin. It is efficient in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol, hepatitis, and gall bladder disorders. Further, in our previous studies, we explored the anti-cancer efficacy in common cancers, such as lung, prostatic, colon, breast, bladder, as well as, hepatocellular carcinoma. Interestingly, silibinin is still not solely limited to the treatment of these diseases. Recent research endeavors suggest that silibinin may function diversely and serve as a novel therapy for hematological disorders. AREAS COVERED: It discovered several interesting viewpoints in the widely studied mechanisms of silibinin in the hematological disorders. EXPERT COMMENTARY: In this report, we review the up-to-date findings of more potency roles of silibinin in ß-thalassemia (ß-TM), acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL) and multiple myelomas (MM) therapy and attempt to clarify the mechanisms underlying its effects. There are two viewpoints: First, The functional mechanisms of silibinin in AML cells via regulating cell differentiation to exert anti-cancer effect; Second, combination treatment strategy may be a good choice.

Statins in conditions other than hypocholesterolemic effects for chronic subdural hematoma therapy, old drug, new tricks?

Chronic subdural hematoma (CSDH) is one of the most common intracranial hematomas worldwide with a high incidence in the general population. However, the optimum treatment for CSDH is Burr-hole drainage with or without rinse Considering the poor outcomes of CSDH in aged patients, and ambiguous prediction of recurrence in many sides of recurrent CSDHs who have been analyzed, new effective therapies are needed for those CSDHs who are predicated to have poor prognosis for surgery and/or have a higher risk of recurrence. Statins, which is the first-line treatment for patients with high cholesterol and coronary heart disease. However, statins are still not solely limited in the treatment of these diseases. It has been demonstrated that statins could improve CSDH due to its effect of regulation of angiogenesis and inflammation. In this review, in order to provide potential new treatment for CSDH we summarize the recent findings of statins in CSDH in order to try to clarify the mechanisms of this effect.

Iron oxide nanoclusters for T 1 magnetic resonance imaging of non-human primates.

Iron-oxide-based contrast agents for magnetic resonance imaging (MRI) had been clinically approved in the United States and Europe, yet most of these nanoparticle products were discontinued owing to failures to meet rigorous clinical requirements. Significant advances have been made in the synthesis of magnetic nanoparticles and their biomedical applications, but several major challenges remain for their clinical translation, in particular large-scale and reproducible synthesis, systematic toxicity assessment, and their preclinical evaluation in MRI of large animals. Here, we report the results of a toxicity study of iron oxide nanoclusters of uniform size in large animal models, including beagle dogs and the more clinically relevant macaques. We also show that iron oxide nanoclusters can be used as T 1 MRI contrast agents for high-resolution magnetic resonance angiography in beagle dogs and macaques, and that dynamic MRI enables the detection of cerebral ischaemia in these large animals. Iron oxide nanoclusters show clinical potential as next-generation MRI contrast agents.

Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population.

BACKGROUND: Genome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. METHODS AND RESULTS: The association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan-Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. CONCLUSION: rs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.

Transjugular intrahepatic portosystemic shunt combined with esophagogastric variceal embolization in the treatment of a large gastrorenal shunt.

AIM: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with stomach and esophageal variceal embolization (SEVE) in cirrhotic patients with a large gastrorenal vessel shunt (GRVS). METHODS: Eighty-one cirrhotic patients with gastric variceal bleeding (GVB) associated with a GRVS were enrolled in the study and accepted TIPS combined with SEVE (TIPS + SEVE), by which portosystemic pressure gradient (PPG), biochemical, TIPS-related complications, shunt dysfunction, rebleeding, and death were evaluated. RESULTS: The PPGs before TIPS were greater than 12 mmHg in 81 patients. TIPS + SEVE treatment caused a significant decrease in PPG (from 37.97 ± 6.36 mmHg to 28.15 ± 6.52 mmHg, t = 19.22, P < 0.001). The percentage of reduction in PPG was greater than 20% from baseline. There were no significant differences in albumin, alanine aminotransferase, aspartate aminotransferase, bilirubin, prothrombin time, or Child-Pugh score before and after operation. In all patients, rebleeding rates were 3%, 6%, 12%, 18%, and 18% at 1, 3, 6, 12, and 18 mo, respectively. Five patients (6.2%) were diagnosed as having hepatic encephalopathy. The rates of shunt dysfunction were 0%, 4%, 9%, 26%, and 26%, at 1, 3, 6, 12, and 18 mo, respectively. The cumulative survival rates in 1, 3, 6, 12, and 18 mo were 100%, 100%, 95%, 90%, and 90%, respectively. CONCLUSION: Our preliminary results indicated that the efficacy and safety of TIPS + SEVE were satisfactory in cirrhotic patients with GVB associated with a GRVS (GVB + GRVS).

Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy.

PURPOSE: To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIß-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. METHODS: Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi-square test (χ (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model. RESULTS: A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4 %, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P < 0.001, r = 0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P > 0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21 months, HR 1.913, 95 % CI 1.161-3.150, P = 0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23 months, HR 1.931, 95 % CI 1.157-3.224, P = 0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P > 0.05). CONCLUSIONS: The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression.

First-line gemcitabine plus cisplatin in nonsmall cell lung cancer patients.

AIM: To evaluate the predictive value of RRM1, ERCCl, and BRCA1 expression in Chinese NSCLC patients treated with gemcitabine and cisplatin. METHODS: Real-time fluorescent quantitative PCR was used to determine the RRM1, ERCC1, and BRCA1 mRNA expression levels of peripheral blood in late-stage NSCLC patients. The relationship between peripheral blood and mRNA expression in tumor tissues was analyzed further. RESULTS: In terms of the tumor susceptibility to chemotherapy, the response rate in the low-RRM1-expression group was significantly greater than in the high-expression group (52.9% versus 5.9%, χ(2) test, P = 0.007). Subjects with low peripheral blood RRM1 expression survived longer than those with high RRM1 expression (15.5 versus 12.0 months, logrank 3.980, P = 0.046). Linear correlations were observed between peripheral blood and tumor tissue expression levels for RRM1 (R (2) = 0.045, P = 0.048) and BRCA1 (R(2) = 0.021, P = 0.001). CONCLUSION: Our study demonstrates increased survival and superior efficacy of gemcitabine and cisplatin combination chemotherapy in the treatment of NSCLC patients with low peripheral blood RRM1 expression. The linear correlations of the relative expression of mRNA were observed between peripheral blood and tumor tissue expression levels for RRM1 and BRCA1. RRM1 gene expression may contribute to chemotherapy sensitivity and may be an indicator of survival. It was significant to individual chemotherapy of patients with advanced NSCLC who do not have sufficient tumor tissue.

RRM1 and ERCC1 expression in peripheral blood versus tumor tissue in gemcitabine/carboplatin-treated advanced non-small cell lung cancer.

PURPOSE: To comparatively evaluate the prognostic or predictive value of ribonucleotide reductase M1 (RRM1) and excision repair cross-complementation 1 (ERCC1) gene expression in peripheral blood versus tumor tissue from patients with advanced non-small cell lung cancer (NSCLC) treated by gemcitabine/platinum chemotherapy. METHODS: A total of 49 patients with advanced NSCLC receiving gemcitabine plus carboplatin chemotherapy were studied. RRM1 and ERCC1 mRNA levels in the peripheral blood and tumor tissue were determined by real-time fluorescent quantitative PCR. The relationships between gene expression and clinical and pathological factors, response to chemotherapy as well as prognosis, were evaluated. RESULTS: RRM1 expression in peripheral blood and tumor tissue, but not ERCC1 expression, was found to be positively correlated (r = 0.332, 0.258; P = 0.020, 0.073; respectively). RRM1 and ERCC1 expression levels were nearly synchronous in both peripheral blood (r = 0.351; P = 0.013) and tumor tissue (r = 0.634; P < 0.001). Neither was correlated with clinical and pathological factors. PATIENTS: with low RRM1 expression in peripheral blood or low RRM1 or ERCC1 expression in tumor tissue experienced better response to chemotherapy (50.0 vs. 16.0%, 50.0 vs. 16.0%, and 54.2 vs. 12.0%; P = 0.012, 0.012, and 0.003; respectively), longer median survival (18.5 vs. 13.0 months, 18.5 vs. 12.0 months, and 19.8 vs. 12.5 months; P = 0.043, 0.014 and 0.007; respectively), and longer progression-free survival (6.0 vs. 4.0 months, 7.8 vs. 3.9 months, and 5.8 vs. 3.8 months; P = 0.044, 0.016, and 0.008; respectively). Cox multivariate regression analysis showed that ERCC1 expression in tumor tissue was independent indicator for overall survival. CONCLUSIONS: Advanced NSCLC patients with low RRM1 mRNA expression both in peripheral blood and in tumor tissue could benefit from gemcitabine/carboplatin chemotherapy. ERCC1 mRNA expression in tumor tissue may be a predictive and prognostic indicator in advanced NSCLC patients receiving gemcitabine/carboplatin chemotherapy.

RRM1 gene expression in peripheral blood is predictive of shorter survival in Chinese patients with advanced non-small-cell lung cancer treated by gemcitabine and platinum.

OBJECTIVE: To evaluate the predictive values of gene expressions of ribonucleotide reductase M1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum. METHODS: Forty Chinese patients with advanced NSCLC were recruited and received gemcitabine 1 200 mg/m(2) on Days 1 and 8 plus carboplatin AUC 5 on Day 1. RRM1 and BRCA1 expression levels in peripheral blood were detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Kaplan-Meier survival curve and log-rank test were performed to evaluate the correlation between gene expression and overall survival for these subjects. RESULTS: No correlation was observed between gene expression of RRM1 and that of BRCA1 (P>0.05), but there was a strong correlation between the expression of RRM1 and the response to chemotherapy (P=0.003). Subjects with low RRM1 expression levels in peripheral blood had longer survival time than those with high RRM1 expression levels (16.95 vs. 12.76 months, log-rank 3.989, P=0.046). However, no significant association between BRCA1 expression levels and survival time was found (16.80 vs. 13.77 months, log-rank 0.830, P=0.362). CONCLUSIONS: Patients with low RRM1 expression levels in peripheral blood have a greater response to chemotherapy and longer survival time. Advanced NSCLC patients with low RRM1 expression levels may benefit from gemcitabine plus platinum therapy. RRM1 mRNA expression in peripheral blood could be used to predict the prognosis of NSCLC treated by gemcitabine and platinum.

[Detection of RRM1, ERCC1 and BRCA1 gene expression in non-small cell lung cancer tissues and peripheral blood by SYBR real-time fluorescent quantitative PCR].

OBJECTIVE: To develop a method for the detection of RRM1, ERCC1 and BRCA1 gene expression by SYBR real-time fluorescent quantitative PCR in non-small cell lung cancer tissues and peripheral blood. METHODS: The plasmid standard of RRM1, ERCC1, BRCA1 and ß-actin genes was constructed. SYBR real-time PCR was performed, and the standard curve was established. The expressions of RRM1, ERCC1 and BRCA1 mRNA in non-small cell lung cancer tissues and peripheral blood were detected. RESULT: The standard curve presented linearity. The liquate curves of standard gene were all single apex, indicating that a good specificity was obtained. CONCLUSION: The developed SYBR real-time fluorescent quantitative PCR has advantage of convenient operation, low cost, good specificity and high veracity.

[Clinical and angiographic characteristics of left coronaroventricular microfistula].

OBJECTIVE: To investigate the clinical and angiographic characteristics of left coronaroventricular microfistula. METHODS: In his retrospective review, clinical, electrocardiogram, echocardiography and coronary angiography data were analyzed for patients with left coronaroventricular microfistula. RESULTS: Left coronaroventricular microfistula was identified in 9 out of 8300 patients underwent coronary angiographies from 1998 to 2008 in our center. Seven patients were female (77.8%) and the average age was 71.5 years. All 9 patients had presenting symptoms of chest distress or dyspnea, coronary artery disease was documented in 5 (55.6%), hypertension in 2 (22.2%), valve disease in 1 (11.1%)and cardiomyopathy in 1 (11.1%) patient. Microfistula originated from one single coronary artery was seen in 1 patient (11.1%), from two coronary arteries in 6 patients (66.7%), from three coronary arteries in 2 patients (22.2%). The diagonal artery was involved in all patients. The characteristic sign of microfistula from CAG was intracavitary staining. CONCLUSION: Microfistula between coronary arteries and left ventricle is a rare disease, often originates from two coronary vessels and diagonal artery is involved in most cases.

[Electrocardiographic and angiographic characteristics of patients with acute solitary posterior myocardial infarction].

OBJECTIVE: To investigate electrocardiographic (ECG) and angiographic characteristics of patients with acute solitary posterior myocardial infarction. Patients complicated by inferior wall or right ventricular infarction were excluded. METHOD: ECG and angiographic changes in 11 patients with acute solitary posterior myocardial infarction admitted to our emergency room from 2001 to 2006 were analyzed. RESULTS: Besides typical ST segment elevation in V(7)-V(9) leads, other ECG manifestations in these patients included V(1)-V(2) R/S > or = 1 (9/11, 81.8%), 1 - 2 mm ST depression in V(1)-V(4) (5/11, 45.5%), 0.5 - 1.5 mm ST elevation in I, aVL leads (4/11, 36.4%) and 0.5 - 1.5 mm ST elevation in V(5)-V(6) leads (5/11, 45.5%). Coronary angiography showed that left circumflex artery (LCX) was the infarction related artery in all cases. The infarction area located before OM1 origination in 1 patient with a 95% pipe-like stenosis (1/11), after OM1 origination in 6 patients (6/11, 4 with total occlusion, 1 with sub-total occlusion and 1 with 90% long length stenosis), in OM1 in 4 patients (4/11, 2 with total occlusion, 1 with sub-total occlusion and 1 with 95% local stenosis). There were 3 patients (27.3%) with single vessel lesion, 4 patients (36.4%) combined with left anterior descending artery (LAD) lesion, 2 patients (18.2%) combined with right coronary artery (RCA) lesion and 2 patients (18.2%) combined with LAD and RCA lesions. CONCLUSIONS: Acute posterior myocardial infarction should be suspected with V(1)-V(2) R/S > or = 1 and V(1)-V(4) ST depression in standard 12 leads ECG. Besides symptoms and cardiac enzyme measurements, recording posterior leads electrocardiogram and performing coronary angiography will help to make the correct diagnosis.

[Peak concentration of gemcitabine at fixed-dose-rate and its hematological toxicity profile].

OBJECTIVE: To investigate the relationship between peak concentration (Cmax) of gemcitabine at fixed-dose-rate and its hematological toxicity profile in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Twenty-one patients received gemcitabine at a fixed dose rate (1200 mg/m2 over 120 min) with carboplatin. Plasma concentrations of gemcitabine were measured by ion-pair reversed-phase high-performance liquid chromatography. RESULTS: The mean value of Cmax in 21 eligible patients was(4.95+/-2.42) microg *ml(-1). The main hematological toxicity was grade III-IV thrombocytopenia and neutropenia. The mean percentages of reduction of WBC, NEC, PLTC and Hb of 21 patients were (38.3+/-38.1)%, (31.3+/-73.6)%, (31.8+/-53.5)% and (12.0+/-12.2)%, respectively. The C(max)of gemcitabine and the percentage of reduction in WBC showed a significant correlation (r2=0.4575, P<0.05). A significant correlation (r2=0.5671, P<0.05) was also observed between the percentage of reduction of PLTC and Cmaxof gemcitabine. CONCLUSION: The results of relationship between Cmax and toxicity profile suggest that gemcitabine administration should be individualized in order to decrease the occurrence of ADR.

Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of gemcitabine in combination with carboplatin at standard rate or fixed dose rate infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this prospective study, patients with chemonaive advanced NSCLC were randomized to receive gemcitabine at a standard rate (gemcitabine 1,200 mg/m2 over 30 min, the standard arm) or a fixed dose rate (gemcitabine 1,200 mg/m2 over 120 min, the FDR arm) on days 1 and 8 every 3 week cycle. In both treatment arms, carboplatin at AUC of 5 was administered over 4 h following gemcitabine on day 1 of each cycle. RESULTS: From November 2003 to June 2005, a total of 42 patients, in which 7 (17%) patients had stage III(B) disease and 35 (83%) had stage IV disease, were enrolled into this study. All patients were included in efficacy and toxicity assessment. No patient had a complete response. Seven (33%) patients in the standard arm and 10 (48%) in the FDR arm had a partial response. The median time to progression and median overall survival time in the standard arm was 5.4 months (95% CI, 3.8-7 months) and 11.5 months (95% CI, 8.2-14.8 months), respectively, while in the FDR arm was 6.5 (95% CI, 4.4-8.6 months) months, 12.0 months (95% CI, 11.3-12.7 months), respectively. The most frequently reported grade 3 or 4 hematological toxicities were thrombocytopenia (38% patients in the standard arm and 43% in the FDR arm) and neutropenia (24% in the standard arm and 33% in the FDR arm). Although hematological toxicity occurred in a little higher percent of patients in the FDR arm than in the standard arm, there were no discernible differences by statistical analysis in both treatment arms (P > 0.05). And significant nonhematologic toxicities were infrequent and tolerable in both arms. No significant difference existed also (P > 0.05). CONCLUSION: In this phase II study, gemcitabine in combination with carboplatin either at standard rate or fixed dose rate infusion was clinically effective and well tolerated in patients with advanced NSCLC.

[Effects of hypoxia on ET and NO levels in cultured umbilical venous endothelial cells of native Tibetan].

AIM: To assay ET and NO in venous blood of native Tibetan and to investigate the effects of hypoxia on ET and NO levels in cultured umbilical venous endothelial cells of native Tibetan. METHODS: ET and NO in venous blood of native Tibetan, immigrant Han and lowland Han were assayed. Umbilical venous endothelial cells (UVECs) from native Tibetan and immigrant Han newborns were cultured and divided into 4 groups: (1) Native Tibetan control group (TC), (2) Native Tibetan hypoxic group (TH), (3) Immigrant Han control group (HC), (4) Immigrant Han hypoxic group (HH). Supernatant was collected and ET and NO were detected. RESULTS: Venous blood NO was significantly higher in native Tibetan than in immigrant Han, while ET lower in native Tibetan than in immigrant Han. ET excretion from UVECs was elevated while NO decreased in both Tibetan and Han groups after exposed to hypoxia. On time-points 12 h and 24 h, ET was significantly lower in TH than in HH, while concentration of NO showed no difference in TH and HH. CONCLUSION: ET released by UVECs was higher in Han than in Tibetan after 12 h and 24 h hypoxic exposure, which may be in favor of lower vascular resistance and better fetal blood supply in Tibetan, and thus plays a role in the mechanisms of less intrauterine growth restriction (IUGR) throughout pregnancy and heavier birth weight of Tibetan newborns.