A case of tacrolimus nephrotoxicity appearing in a second renal transplantation patient

Oka K, Moriyama T, Imai E, Kyo M, Toki K, Tanaka T, Hori M, Kokado Y, Okuyama A, Takahara S. A case of tacrolimus toxicity appearing in a second renal transplantation patient. Clin Transplantation 2001: 15 (Supplement 5): 30–34. ©Munksgaard, 2001
We experienced a case of a second renal trans- plantation patient. With the use of cyclosporin, he lost his first graft because of chronic rejection; with the use of tacrolimus, his second graft suffered from drug nephrotox- icity. On his second renal transplantation, his graft function deteriorated and required haemodialysis with the use of tacrolimus. Repeated biopsies did not reveal the typical characteristics of acute tacrolimus nephrotoxicity and acute rejection. His tacrolimus trough level was not high during the clinical course; however, by reducing tacrolimus dosage, his graft function eventually recovered to mild renal dys- function. This observation was helpful for clinical diagnosis of the functional toxicity of tacrolimus. The case is interest- ing in considering the functional toxicity of tacrolimus and the difference between tacrolimus and cyclosporin in terms of immunosuppressive and nephrotoxic actions.     

Is the cardiovascular profile of BRL 34915 characteristic of potassium channel activators?

To see whether the cardiovascular profile of BRL 34915, a potent vasodilator, is characteristic of potassium channel activators, we investigated its cardiac effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. BRL 34915 was injected intraarterially. It produced an increase in (coronary) blood flow in all preparations. In paced papillary muscle preparations, BRL 34915, although in large doses, produced a decrease in the force of contraction, leading nearly to abolition. The negative inotropic effect of BRL 34915 was accompanied by a marked acceleration of the repolarization of field cardiac action potentials. In some preparations, fibrillation occurred after profound negative inotropy and subsided spontaneously. In unpaced papillary muscles, BRL 34915 in large doses decreased rate of ventricular automaticity. In SA node preparations, BRL 34915 in large doses reduced sinus rate down to approximately 64% of the basal rate and produced atrial standstill in some. In AV node preparations, BRL 34915 in large doses slightly prolonged AV conduction time only when injected into the AV node artery. Nevertheless, it produced third-degree AV block in some. These cardiac effects of BRL 34915 are very similar to those of nicorandil and pinacidil, whose cardiac effects result exclusively from an increase in membrane K conductance in cardiac muscle cells. Like nicorandil and pinacidil, BRL 34915 was highly vasoselective.     

A Randomized Phase III Study Comparing Carboplatin With Nab-Paclitaxel Versus Docetaxel for Elderly Patients With Squamous-Cell Lung Cancer: Study Protocol

Background

Treatment with carboplatin (CBDCA) with weekly paclitaxel (PTX) has shown survival benefits compared with vinorelbine or gemcitabine in elderly patients with non-small-cell carcinoma (NSCLC). Docetaxel (DOC), however, remains a standard treatment in NSCLC. The 130-nm albumin-bound formulation of PTX (nab-PTX) has shown activity in NSCLC. Treatment with CBDCA with weekly nab-PTX showed significantly higher efficacy than CBDCA with PTX in patients with squamous histology and significantly increased overall survival (OS) in patients aged 70 years and older.

Modulation of extracellular glutamate concentration by nitric oxide synthase inhibitor in rat transient forebrain ischemia

The purpose of the present study was to clarify the effect of topical administration of a nitric oxide synthase inhibitor on extracellular glutamate concentration in transient forebrain ischemia. Two microdialysis probes were inserted into the bilateral striata of Wistar rats. N^G-Nitro-l-arginine (l-NNA) with or withoutl-arginine was topically administered into the unilateral striatum through one of the microdialysis probes, while Ringer's solution was perfused into the contralateral striatum as the control, and 14 minutes of forebrain ischemia was applied. The extracellular glutamate concentration during ischemia and subsequent reperfusion was statistically significantly higher on the 100 μMl-NNA-perfused side than on the control side, but 1 MMl-NNA was ineffective. When 100 μMl-NNA was perfused together with 500 μMl-arginine, the glutamate concentration did not differ from that on the control side. Moreover, administration of 500 μMl-arginine significantly suppressed the glutamate elevation after reperfusion. The fact that the lower dose ofl-NNA increased the accumulation of glutamate during ischemia and reperfusion without altering the blood flow may indicate that nitric oxide affords protection against ischemic neuronal damage. However, since the higher dose ofl-NNA did not affect the glutamate concentration, it appears that the effect of nitric oxide on extracellular glutamate concentration in forebrain ischemia differs, depending on the degree of the inhibition of NOS activity.     

USEFULNESS OF ENDOSCOPIC TREATMENT FOR DUODENAL ADENOMA

In recent years, due to the increasing prevalence of upper gastrointestinal endoscopy, there have been an increasing number of reports on duodenal adenoma and early stage cancer. However, endoscopic techniques for the resection of duodenal adenomas are difficult, due to the anatomical features of the duodenum, and the long distance to the lesion. There have only been a few reports on the use of endoscopic techniques for duodenal adenomas compared to those focused on the stomach and large intestine. For duodenal adenomas, we used a conventional endoscope for lesions proximal to the major duodenal papilla, and a short‐type double balloon endoscope for lesions distal to the papilla. The en‐bloc resection rate was 93.8%. There was only one case of microperforation. Endoscopic manipulation is considered difficult in the deep areas of the duodenum, but double balloon endoscopy enabled stable manipulation and successful resection of the tumor in the majority of cases.     

Negative effects of anemia on quality of life and its improvement by complete correction of anemia by administration of recombinant human erythropoietin in posttransplant patients

Background

Anemia is a common complication in posttransplant patients (posttransplant anemia: PTA). We tested the hypothesis that targeting hemoglobin (Hb) over 13.3 g/dl by administration of recombinant human erythropoietin (rHuEPO-ad) has positive impact on quality of life (QOL).

Methods

Twenty-four patients, whose initial Hb and estimated glomerular filtration rate (eGFR) were 10.5 ± 0.2 g/dl and 48.5 ± 2.7 ml/(min 1.73 m²), respectively, were enrolled in the present study. Physical and mental QOL in these patients before and after rHuEPO-ad were acquired and summarized as physical summary sore (PSC) and mental summary sore (MSC), respectively, by the 36-item Short Form (SF-36), an international questionnaire for analysis of QOL.

Results

Before rHuEPO-ad, posttransplant patients had preserved MSC (54.1 ± 2.3) but impaired PSC (32.6 ± 3.2). rHuEPO-ad for 6 months increased their Hb to 13.7 ± 0.3 g/dl. This was accompanied by improvement of PSC (49.1 ± 2.1: P < 0.01 versus before rHuEPO-ad). MSC was preserved during rHuEPO-ad (54.4 ± 1.6: NS versus before rHuEPO-ad). There was inverse correlation between initial PSC or MSC and responses of these parameters to rHuEPO-ad (PSC, P = 0.007; MSC, P = 0.009). Patients whose initial PSC was lower than 39.6 or whose initial MSC was lower than 39.4 were expected to improve their PSC or MSC by more than 10 by rHuEPO-ad.

Conclusions

Anemia in posttransplant patients has negative impacts on their QOL. Scoring mental and physical QOL by SF-36 in posttransplant patients is useful to identify groups of patients whose QOL could be improved by rHuEPO-ad.     

Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Purpose

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo.

Methods

MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography.

Results

Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts.

Conclusions

These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.