Population pharmacokinetics of mizoribine in pediatric patients with kidney disease

Background

The present study aimed to obtain information enabling optimisation of the clinical effect of mizoribine (MZR) in pediatric patients with kidney disease.

Methods

A total of 105 pediatric patients with kidney disease treated at our institutions were enrolled. Kidney transplant patients were excluded. Population pharmacokinetic analysis of MZR was performed based on serum concentration data. Area under the curve from time zero to infinity (AUC_∞) and maximal concentration (C _max) were calculated by Bayesian analysis.

Results

In children, the appearance of MZR in the blood tended to be slower and the subsequent rise in blood concentration tended to be more sluggish, compared to healthy adults. Apparent volume of distribution and oral clearance were also higher in children compared to adults. A significant positive correlation was observed between patient age and AUC_∞. There were significant differences of AUC_∞ and C _max by age group. No relationship was observed between the administration method of MZR and serum concentration.

Conclusion

The pharmacokinetics of MZR was different in children compared to adults. To obtain the expected clinical efficacy, the regular MZR dosage schedule (2–3 mg/kg/day) might be insufficient for pediatric patients. In particular, younger patients might require a higher dosage of MZR per unit body weight.

     

Interferon-beta reduces the mouse liver fibrosis induced by repeated administration of concanavalin A via the direct and indirect effects

Type I interferons (IFNs), IFN-alpha and IFN-beta, are widely used for treating chronic hepatitis C. Although retrospective studies have suggested that type I IFNs have direct antifibrotic effects, little is known about these mechanisms. The present study was designed to clarify the preventive mechanisms of type I IFNs in the progression of fibrosis for the establishment of a more effective therapy. A murine fibrosis model comprising immunological reactions was induced by the administration of concanavalin A (0.3 mg/body) into mice once a week for 4 weeks. Liver injury and the degree of fibrosis were determined by measuring the serum alanine aminotransferase activities and liver hydroxyproline contents with or without IFN-beta pretreatment. IFN-beta suppressed the hepatocellular injury and increased the hydroxyproline content induced by repeated concanavalin A injections, but had no effect on established fibrosis. Furthermore, IFN-beta reduced the expressions of transforming growth factor-beta, basic fibroblast growth factor, collagen type I A2 and tissue inhibitor of metalloproteinase 1 messenger RNAs, which are related to the progression of liver fibrosis. The IFN-beta reduced the liver injury and fibrosis induced by immunological reactions. These data suggest that type I IFNs suppress the progression of cirrhosis through inhibition of repeated hepatocellular injury and/or factors that promote the liver fibrosis induced by hepatitis virus infection.     

Doppel induces degeneration of cerebellar Purkinje cells independently of Bax

Doppel (Dpl) is a prion protein paralog that causes neurodegeneration when expressed ectopically in the brain. To investigate the cellular mechanism underlying this effect, we analyzed Dpl-expressing transgenic mice in which the gene for the proapoptotic protein Bax had been deleted. We found that Bax deletion does not alter either clinical symptoms or Purkinje cell degeneration in Dpl transgenic mice. In addition, we observed that degenerating Purkinje cells in these animals do not display DNA fragmentation or caspase-3 activation. Our results suggest that non-Bax-dependent pathways mediate the toxic effects of Dpl in Purkinje cells, highlighting a possible role for nonapoptotic mechanisms in the death of these neurons.     

Quantitative analysis of the anti-inflammatory activity of orengedokuto II: berberine is responsible for the inhibition of NO production

Orengedokuto is a Kampo formula that has been used for removing “heat” and “poison” to treat inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases. We report here our analysis of the anti-inflammatory effect of the component crude drugs of orengedokuto and their constituents using the inhibition of nitric oxide (NO) production in the murine macrophage-like cell line J774.1. An initial comparison of NO production inhibitory activities of the extracts of the component crude drugs and their combinations revealed that the activity could be attributed to Phellodendron Bark and Coptis Rhizome. Berberine (1), the major constituent of these crude drugs, showed potent activity (IC₅₀ 4.73?±?1.46 μM). Quantitative analysis of 1 in the extracts of all combinations of component crude drugs revealed that the amount of 1 in each extract of the combination of Scutellaria Root with either Phellodendron Bark and/or Coptis Rhizome was lower than that in the corresponding mixtures of the extracts of the individual crude drugs and that 1 was present in the precipitates formed during the decoction process. To the contrary, the differences in the amounts of 1 were smaller in the extracts containing Gardenia Fruit. These results indicated that the constituents of Scutellaria Root precipitated with 1 and that the constituents of Gardenia Fruit dissolved the precipitates. To identify the constituents affecting the solubility of 1, we fractionated the hot-water extracts of Scutellaria Root based on solubility tests of 1 to give baicalin (2), wogonin (3) and oroxyloside (4), which formed precipitates with 1.     

Synergistic effect of baicalein,wogonin and oroxylin A mixture: multistep inhibition of the NF-κB signalling pathway contributes to an anti-inflammatory effect of Scutellaria root flavonoids

Journal of Natural Medicines - Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids...     

Prognostic Significance of Hiatal Hernia in Patients with Gastric Cancer Located within the Upper-Third of the Stomach

World Journal of Surgery - Gastric cancers located within the upper-third of the stomach (UGC), especially the esophagogastric junction GC (EGJGC), have distinct clinicopathological features due to...     

Prognosis following emergency surgery for ulcerative colitis in elderly patients

Purpose

Since 2000, the incidence of ulcerative colitis (UC) in patients over 60 years old has been rapidly increasing. We reviewed our surgical experience of elderly patients with UC treated at our hospital.

Methods

Patients aged 60 years or older at the time of surgery were defined as “elderly”. The medical records of all elderly patients who underwent surgery for UC during a 26-year period were retrospectively analyzed.

Results

The prognosis of elderly patients who underwent emergency surgery was extremely poor: 8 (26.7 %) of 30 such patients died within 30 postoperative days (PODs), whereas only 1 (0.88 %) of 114 who underwent elective surgery died within 30 PODs. Respiratory tract infection and sepsis resulting from methicillin-resistant Staphylococcus aureus or mycotic infection were the most common causes of death after emergency surgery.

Conclusion

The prognosis of elderly UC patients undergoing emergency surgery is very poor; thus, physicians and surgeons should collaborate to treat severe and fulminant disease, to optimize the timing of surgery. Early decisions about emergency surgery for UC will reduce postoperative mortality, especially in elderly patients.     

Effect of body mass index on the outcomes of patients with upper and lower urinary tract cancers treated by radical surgery: Results from a Canadian multicenter collaboration

ObjectiveTo evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery.Materials and methodsData were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998–2008) or radical nephroureterectomy (RNU) (1990–2010). Various parameters among subsets of patients (BMI<25, 25≤BMI<30, and BMI≥30 kg/m²) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS).ResultsAmong the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (<25 kg/m²) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI≥30 kg/m²; however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI≥30 kg/m² was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148–2.196; P = 0.0052).ConclusionsIncreased BMI did not influence survival among RC patients. BMI≥30 kg/m² is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation.     

Extraduodenal Papillectomy: a Feasible Alternative Method of Total Papillectomy

Rational treatment for neoplasms of the duodenal papilla (NDPs) is still controversial, especially for early stage lesions. Total papillectomies are indicated in patients expected to have adenomas, adenocarcinoma in an adenoma, or mucosal adenocarcinomas with no lymph node metastases. However, the preoperative pathological evaluation of NDPs is still challenging and often inaccurate, mainly because of the complicated anatomical structures involved and the possibility of an adenocarcinoma in an adenoma. Herein, we introduce a new method of total papillectomy, the extraduodenal papillectomy (ExDP). In this method, papillectomy is undertaken from outside of the duodenum, instead of resection from the inside through a wide incision of the duodenal wall as is done in conventional transduodenal papillectomy (TDP). The advantages of ExDP are precise and deeper cutting of the sphincter and shorter exploration time of the tumor compared to conventional TDP. We demonstrate three representative patients, all of whom had an uneventful postoperative course. One of them subsequently underwent a pylorus preserving pancreatoduodenectomy after detailed postoperative pathological evaluation. Including that patient, no recurrence has occurred with 37–46 months of follow-up. In conclusion, ExDP is regarded as a “total biopsy” for early stage borderline lesions and a feasible, less demanding alternative method for the treatment of NDPs.     

Risk factors of middle lobe bronchus kinking following right upper lobectomy

BackgroundThe incidence rate of kinking of the middle lobe bronchus following right upper lobectomy is higher compared to that with residual lung bronchus following other lobectomies. Bronchial kinking was presumed to be caused by the displacement of the residual lung lobes, but its etiology is unclear. Moreover, prevention methods and effective treatments have not yet been established. The purpose of this study was to investigate the risk factors and etiology of middle lobe bronchus kinking and discuss prevention methods.MethodsPatients who underwent right upper lobectomy in our hospital were retrospectively evaluated. Patient clinical characteristics, lung function, and lung lobe volume, surgical procedure were analyzed in association with the incidence of middle lobe bronchus kinking. The association between the displacement of residual lung lobes after operation and the incidence of middle lobe bronchus kinking was analyzed to assess the etiology.ResultsA total of 175 patients were enrolled in the risk analysis. Middle lobe bronchus kinking was observed in 5 patients (2.9%). The low percentage of forced expiratory volume percentage in 1 second (P=0.021), the low volume ratio of the right middle lobe (RML) to the right thoracic cavity (RTC) (P=0.016), and the low volume ratio of RML to right upper lobe (RML/RUL) (P=0.006) were significant risk factors of middle lobe bronchus kinking. In the patients who underwent CT at 6 months after surgery, the degree of the cranial displacement of RML was associated with the incidence of middle lobe bronchus kinking (P=0.025).ConclusionsThe risk of middle lobe bronchus kinking could be assessed preoperatively by calculating the volume ratio of RML/RTC and RML/RUL. The displacement of RML could be associated with the incidence of middle lobe bronchus kinking.