Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

Objective This study was undertaken to investigate the effects of hyperlipidaemia on the pharmacokinetics of clomipramine, an antidepressant, particularly addressing the change of clomipramine distribution to plasma components in poloxamer 407‐induced hyperlipidaemia model rats. Methods Clomipramine pharmacokinetic studies in hyperlipidaemic rats were performed with clomipramine continuous infusion. Furthermore, clomipramine protein binding and distribution to the brain and plasma components such as lipoproteins were investigated. Key findings Mean plasma concentration of clomipramine at steady state during continuous infusion (17.5 µg/min/kg) in hyperlipidaemic rats (0.45 ± 0.01 µg/ml) was significantly higher than that in the control rats (0.30 ± 0.02 µg/ml). However, the amount of clomipramine in the brain in hyperlipidaemic rats (0.31 ± 0.06 µg/g) was dramatically lower than in the control rats (1.89 ± 0.13 µg/g). However, the plasma unbound fraction in hyperlipidaemic rats (0.98 ± 0.05%) was significantly lower than that of the control rats (6.51 ± 0.62%). Conclusions Lower distribution to the brain and lower plasma clearance of clomipramine in hyperlipidaemic rats resulted from lower plasma unbound fraction because of higher lipid‐rich protein contents in blood. Results of this study provide useful information for dosage adjustment of clomipramine in hyperlipidaemia.     

Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats

We investigated the effects of fasudil, a Rho kinase inhibitor, in the endothelial dysfunction of aortas from spontaneously hypertensive rats (SHRs). SHRs were divided in three groups; intraperitoneally (i.p.) vehicle-treated SHRs (SHR), SHRs treated with fasudil 3mg/kg i.p. (Fas3), and SHRs treated with fasudil 10mg/kg i.p. (Fas10). Vehicle-treated Wistar rats were used as normo-tensive control group. After a six-week-treatment, blood pressure and heart rate were measured by the tail cuff method. Afterwards animals were sacrificed and aortas were examined in vitro by organ bath studies to evaluate the contraction and relaxation ability. Rho kinase activity, myosin light chain (MLC), phosphorylated MLC (phospho-MLC), eNOS, phospho-eNOS protein expression and eNOS mRNA levels were evaluated. SHR demonstrated a significant hypercontractility and impaired relaxation compared to the control. Fasudil 10mg/kg significantly corrected the hypercontractility, restored the relaxation, and significantly decreased the mean arterial blood pressure, while no change observed in the systolic blood pressure. Rho kinase activity was significantly higher in the SHR, and was significantly inhibited by the high dose of fasudil. There was a slight up-regulation in the MLC, and phospho-MLC protein levels in the SHR. eNOS and phospho-eNOS protein levels were significantly lower in the SHR, and this abnormality was significantly normalized by fasudil treatment. No significant difference was observed in the eNOS gene expression. This study suggests that fasudil by inhibiting the Rho kinase activity normalizes the eNOS expression and phosphorylation and ameliorates the endothelial dysfunction induced by hypertension in the SHR model.     

Real‐Time Monitoring of Blood Flow and Intravesical Pressure in the Rat Bladder

Objectives: Because there is little information available about blood flow in the voiding cycle of the bladder, we performed a study in which we simultaneously monitored blood flow and intravesical pressure during the micturition cycle in a rat model. Methods: Approximately 300 g male Wistar rats were used in this study. Cystometric studies were performed according to our previous report, and simultaneously blood flow was monitored. Results: Before the micturition reflex occurred, a significant increase in bladder blood flow was observed, and this increased blood flow continued during the micturition reflex. Under the maximum contraction pressure, blood flow rapidly decreased (within 10% compared to the max level). This low level of blood flow continued for more than half a minute. Conclusion: Our data indicated that the blood flow in the bladder was dynamically changed during voiding. This technique may represent a strong tool to investigate bladder function under drug administrations and/or pathophysiological conditions.     

Cedar Pollen Aggravates Atopic Dermatitis in Childhood Monozygotic Twin Patients with Allergic Rhino Conjunctivitis

We report a case of 7-year-old monozygotic twin patients with atopic dermatitis. The HLA haplotypes were HLA A2, A11, B27, B61, DR1, and DR4. Both serum IgE levels and cedar pollen radioallergosorbent test (RAST) scores were high in the twins (elder/younger sister: IgE: 5170/3980 IU/ml and Japansese cedar pollen: > 100/64.0) in contrast to low mite and food RAST scores (Dermatophagoides Pterygonium; 0.59/0.4 and egg white 9.24/4.6). The patients showed positive immediate (20 min in both sisters) and delayed (24 hours in elder sister, 24, 48, 72 hours in younger sister) reactions to a scratch test with Japanese cedar pollen. Skin lesions on the face were aggravated and extended to the trunk and extremities during the Japanese cedar pollen season and gradually subsided in summer. Oral provocation with egg white or cow milk showed no exacerbations, and topical corticosteroid did not improve the eczema. In contrast, successful protection from severe scratching behaviors was achieved by use of topical anti-allergic eye drops and wearing nightgowns made by the mother.     

Second-line combination chemotherapy with docetaxel and nedaplatin for metastatic or recurrent squamous cell carcinoma of the esophagus refractory to chemotherapy with 5-fluorouracil plus cisplatin

Background  

There is no standard second-line chemotherapy regimen after failure of the standard 5-fluorouracil and cisplatin in the treatment of esophageal cancer. We retrospectively investigated the efficacy and toxicity of combination chemotherapy using docetaxel and nedaplatin for patients with metastatic or recurrent squamous cell carcinoma of the esophagus refractory to prior chemotherapy with 5-fluorouracil and cisplatin, and evaluated the prognostic significance of clinical factors in these patients.     

Examination of factors influencing continuity of S-1 adjuvant chemotherapy for gastric cancer patients

After Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer(ACTS-GC), adjuvant chemotherapy with S-1 is a standard treatment for stage II or III gastric cancer patients. In this study, we retrospectively examined factors that influence the continuity of S-1 adjuvant chemotherapy. We analyzed the clinical documentation of 27 gastric cancer patients being treated with S-1 adjuvant chemotherapy. Patients who completed the treatment without reduction dose were classified into a complete group(n=14), and those for whom S-1 was discontinued or reduced due to adverse reactions were classified into a reduced/discontinuation group(n=13). First, we examined the background factors at baseline between these two groups. Univariate logistic regression analysis revealed that the operative procedure, leukocyte count, and serum creatinine level at baseline were identified as factors that influence the continuity of S-1 chemotherapy. Next, we investigated the hematological and nutritional conditions of these patients during the treatment period. The loss of body mass index(BMI)during the treatment period was remarkable in the reduced/discontinuation group regardless of the operative procedure. This result suggests that an early nutritional intervention might be important for gastric cancer patients undergoing S-1 adjuvant chemotherapy.     

Clinical features of extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue

We newly diagnosed 131 patients with extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue lymphoma between 1998 and 2010. We retrospectively studied 124 patients for whom complete clinical data were available at presentation and who had minimally undergone tumour staging by physical examination, computed tomography (CT), bone marrow aspiration, and biopsy. A slight female predominance (men, 58; women, 66) was observed in the study population; the median age was 67 years. The primary locations at presentation were the stomach (38%), orbita (20%), lung (12%), intestinal tract (8%), thyroid gland (6%), others (14%), and unknown (2%). Seventy per cent of patients had localized disease. Of the 124 patients, 14 (11%) had lymph node involvement, and 5 (4%) had bone marrow involvement. Five (4%) patients had both lung and gastric involvement. The 5‐year overall survival rate for the 124 patients was 96.1%. The overall vital prognosis was excellent. Moreover, gastro‐intestinal fiberscopic examination is essential, especially in cases with lung involvement at presentation. Copyright © 2012 John Wiley & Sons, Ltd.