Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model

Aim:   Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria.
Methods:   Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4–160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy.
Results:   No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80–120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses.
Conclusion:   ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.     

Clinical Evaluation of an Immunoradiometric Assay for CA15-3 Antigen Associated With Human Mammary Carcinomas: Comparison With Carcinoembryonic Antigen

Serum levels of CA15-3, a mammary tumor associated antigen recognizedby two different murine monoclonal antibodies (115D8 and DF3),were investigated in patients with mammary carcinoma and otherbenign or malignant diseases. The reference value of the serumCA15-3 level was obtained as 24 units/ml at the 99% confidencelimit among healthy individuals (n = 462). Elevation of serumCA15-3 levels was observed in 24.3% of overall patients withmammary carcinoma. Serum CA15-3 levels in breast cancer patientscorrelated with the clinical stage; higher percentages of positivitywere observed in those with advanced breast cancer (stage IV,64.7%, recurrent, 52.4% and metastatic, 70.3%). Furthermore,elevated serum CA15-3 levels in breast cancer patients respondedwell to the effect of therapy. Although the serum CA15-3 testgave percentages of positivity of breast cancer similar to thosefound by the serum CEA test, the serum CA15-3 test revealedlower percentages of posi-tivity than the serum CEA test amongpatients with benign breast lesions, liver cirrhosis or othercarcinomas. These results suggest that the serum CA15-3 antigenlevel provides a very useful marker for diagnosis and clinicalmonitoring of patients with breast cancer.     

Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo

PURPOSE: TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen-independent prostate cancer. We therefore investigated the antitumor effect of TAK-165 on these urological cancer cells. MATERIALS AND METHODS: Western blot analysis was performed to confirm HER2 expression in cell lines. To study in vitro efficacy, cells were treated with TAK-165 at various concentrations for 72 h and then counted using a hemocytometer. Then the IC50 value was calculated. In the xenograft model, after the tumor reached 200-300 mm3 in volume, mice were orally administered TAK-165 10 mg/kg per day or 20 mg/kg per day or saline for 14 consecutive days (n=6-8). RESULTS: HER2 expression was observed in HT1376, UMUC3, T24 (bladder), ACHN (kidney), DU145, LNCaP, LN-REC4 (prostate), although the expression level in these cells was weak compared with BT474 (a breast cancer cell line which expresses HER2 strongly). IC50 was varied from 0.09 to greater than 25 micromol/L in the bladder cancer cell line. ACHN cells were less sensitive in vitro. The prostate cancer cell lines studied were all sensitive (IC50 0.053-4.62 micromol/L). In the xenograft model, treatment with TAK-165 significantly inhibited growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect (T/C [%]=growth of TAK-165 treated tumor/average growth of control tumorx100) after 14 days treatment were 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively. CONCLUSIONS: TAK-165 may be a hopeful new agent for bladder, kidney and androgen-independent prostate cancer.     

Effectiveness of prosthetic mandibular advancement for obstructive sleep apnea:Analysis by sleep position

Abstract Fifteen patients with obstructive sleep apnea were treated using prosthetic mandibular advancement (PMA). Each patient was evaluated in the supine and lateral decubitus positions with and without PMA. After PMA treatment, the mean intraesophageal pressure (Peso) in the supine position improved from -42.6 to -27.3 cmH₂O and the mean apnea + hypopnea index (AHI) decreased from 48.8/h to 23.7/h. The mean Peso in the lateral decubitus position improved from -27.9 to -18.6 cmH₂O and the mean AHI decreased from 9.6/h to 6.6/h. With PMA, respiratory disturbance during sleep further improved by changing the body position from the supine to lateral decubitus position.     

Epstein-Barr Virus in Normal Pregnant Women*

ABSTRACT: Acquired immune suppression accompanying normal pregnancy may be associated with reactivation of Epstein-Barr virus (EBV). Pregnant women with reactivated EBV having anti-EA antibodies show high titers of antiviral capsid antigen (VCA) geometric mean titers (GMT) of 522 versus 170 in those lacking anti-early antigen (EA). Among twenty-seven seropositive women at parturition, 17 (63%) had generated antibody to EA, and all 27 (100%) demonstrated significant increases in antibody to VCA (p < 0.01). In contrast, antibody titers to cytomegalovirus, herpes hominis, varicella-zoster, and rubella viruses in the pregnant women were comparable to those found in nonpregnant controls.     

Natural Killer Activity and Antibody-Dependent Cell-Mediated Cytotoxicity in Multiple Myeloma

Natural killer (NK) activity and antibody-dependent cell-mediatedcytotoxicity (ADCC) were studied by routine methods in 11 patientswith untreated malignant monoclonal gammopathy. NK and/or ADCCactivity was clearly reduced in three patients with advanceddisease. Moreover, sera from some myeloma patients impairedthe ADCC and NK activity. A large quantity of purified monoclonalIgG from one patient appeared to inhibit NK and ADCC activityas did high concentrations of pooled polyclonal immunoglobulinfrom healthy persons. In two of these 11 patients, other malignancieswere diagnosed prior to chemotherapy. One of these patients,who had nonsecretory myeloma, had marked impairment of NK andADCC activity; the other, with IgG myeloma, had normal NK andADCC activity.     

ADDITIONAL PROOF OF REDUCTION OF ETHANOL ABSORPTION FROM RAT INTESTINE IN VIVO BY HIGH ACETALDEHYDE CONCENTRATIONS

We investigated intestinal ethanol absorption in rats pretreatedwith saline, cyanamide, 4-methylpyrazole and cyanamide + 4-methylpyrazole.The value of the absorption rate constant in the cyanamide-pretreatedgroup with high acetaldehyde levels was the lowest among thefour groups, but there were no significant differences amongthe remaining groups. We found that high acetaldehyde concentrationitself clearly reduces intestinal ethanol absorption.