The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

The management of symptoms in advanced cancer: experience in a hospital-based continuing care unit.

The treatment received by 158 patients with advanced cancer admitted over one year to the Continuing Care Unit at the Royal Marsden Hospital has been reviewed. The unit is an integral part of the hospital and this is reflected in the fact that 46 patients (29%) received radiotherapy, hormone therapy, chemotherapy or surgery in addition to symptomatic treatment for palliation of troublesome symptoms. One hundred and thirty-one patients received oral morphine in doses ranging from 2.5 mg 4-hourly to 700 mg 4-hourly. Patients with renal or hepatic impairment required lower doses of morphine and there was a highly significant inverse relationship between morphine dose and age. Eighty-five patients (54%) received parenteral diamorphine at some time due to their inability to take oral morphine. One hundred and twenty-three patients (78%) received a co-analgesic drug and anti-emetics were required by 78 patients (49% overall; 56% of those receiving morphine). Transcutaneous electrical nerve stimulation, acupuncture and relaxation were employed in selected patients, and graduated compression sleeves were used to treat lymphoedema. These data highlight the wide range of therapeutic options available to control the symptoms of advanced cancer and also indicate that tumoricidal treatments used in conjunction with symptomatic treatments may have a significant part to play.     

Cognitive estimation in traumatic brain injury.

The present study explores the construct and ecological validity of the Biber Cognitive Estimation Test (BCET) in a traumatic brain injury (TBI) sample. Participants completed the BCET in the course of a neuropsychological evaluation at 1-15 years after injury. BCET scores correlated moderately with other standard measures of executive functioning, and contrary to our hypotheses, at least as high with neuropsychological tests with minimal demands on executive functioning. Moreover, partialing out the portion of BCET variance not attributable to executive functioning markedly attenuated the former correlations. With respect to ecological validity, BCET scores did not predict concurrent functional status, as measured by the Disability Rating Scale. By comparison, standard measures of executive functioning strongly correlated with each other, correlated less strongly with nonexecutive functioning measures, and predicted functional status. In conclusion, unlike standard measures of executive functioning, the BCET demonstrated poor construct and ecological validity in TBI patients.     

Surgical alterations of the pancreas and insulin-independent glucose disposal.

Systemic drainage of pancreatic venous effluent and denervation of the pancreas that follows pancreatic transplantation has been shown to alter postoperative glucose disposal despite elevated levels of peripheral insulin in response to a glucose challenge. Since an appreciable fraction of postprandial glucose disposal takes place in the absence of insulin (insulin-independent glucose disposal--IIGD), we have investigated potential changes in this aspect of carbohydrate metabolism before and after bladder-drained pancreatic auto-transplantation (PAT/B) as well as partial pancreatectomy (PPx). The hyperglycemic clamp protocol with a background infusion of somatostatin was performed on control (PREOP) dogs as well as PAT/B and PPx animals. The rate of glucose disposal (M Value) during the period of hypoinsulinemia induced by Somatostatin (SST) was measured and reported. Whereas glucose disposal during steady state hyperglycemia was significantly diminished for both PPx and PAT/B in the absence of SST, IIGD was unaltered across all three groups studied. We therefore conclude that surgical alteration of the pancreas results in abnormal glucose disposal during steady state hyperglycemia despite apparently normal to supranormal levels of peripheral insulin, and that alterations in IIGD are not responsible for these differences.     

Recent patterns of growth in radiation therapy facilities in the United States: a patterns of care study report.

The Patterns of Care Study conducted its seventh survey of radiation oncology facilities with megavoltage equipment. The aims were to identify the basic structural characteristics of the radiation oncology specialty, to allow comparison with previous surveys, to identify trends in the patterns of equipment and personnel usage, and to measure the capabilities of facilities to deliver modern radiotherapy. All radiation oncology facilities in the United States and Puerto Rico were surveyed. Multiple mailings and calls yielded identification of and responses from virtually all facilities doing megavoltage radiotherapy. The survey collected information on equipment, patient load, personnel, and types of procedures performed. The complete census was reviewed, summarized, and compared to previous surveys. Results for 1990 showed 1321 facilities, (938 hospital based, 350 freestanding, 33 federal), 492120 new patients, and 2397 treatment machines (1893 linear accelerators or betatrons and 504 cobalt machines). The number of facilities and total machines increased rapidly with most of the increase in facilities occurring in the freestanding category. The number of cobalt units declined, while the number of linear accelerators increased. The results also showed that 6% of facilities did not have the capability of simulating patients and 7% of facilities did not have treatment planning capability. Of all facilities 9% reported doing intraoperative radiation therapy and 18% doing hyperthermia. For recent years in the specialty of radiation oncology the number of facilities and treatment machines increased at a more rapid rate than the number of new patients.     

Correlation of pre-treatment transurethral resection and prognosis in patients with stage C carcinoma of the prostate treated with definitive radiotherapy--RTOG experience

Four hundred and ninety-four patients with clinical Stage C carcinoma of the prostate, who were entered onto a phase III RTOG study, have been analyzed as to the potential effect of the pre-treatment transurethral resection (TUR) of the tumor. Treatment consisted of definitive irradiation to the prostate (6500-7000 cGy) and regional lymphatics (4500-5000 cGy). A total of 202 patients underwent pre-treatment TUR. This population was compared with the remaining 292 patients as to the rate of locoregional failure, incidence of distant metastases, disease-free survival, and survival. The TUR population fared significantly worse for all four end-points. To account for uneven distribution of recognized prognostic factors the results were then adjusted using stratified Mantel-Haenszel tests. The stratification process resulted in a reduced level of significance in the differences between the two populations. However, a trend toward a higher incidence of distant metastases could be observed within most strata. The trend was most pronounced in subpopulations characterized by Gleason score 6-7 and normal serum acid phosphatase (SAP). For the population characterized by Gleason score 6-10 and normal SAP, the differences in the incidence of distant metastases retained statistical significance. Whether these findings are secondary to tumor dissemination during TUR or are due to incompletely identified selection biases remains to be demonstrated in future (prospective) studies.