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.     

Doppler echocardiography of 119 normal-functioning St Jude Medical mitral valve prostheses: a comprehensive assessment including time-velocity integral ratio and prosthesis performance index.

The purpose of this study was to provide, in a large number of patients, comprehensive Doppler echocardiographic assessment of normal St Jude Medical mitral valve prosthesis function using Doppler-derived hemodynamic variables, including the mitral valve prosthesis-to-left ventricular outflow tract time-velocity integral ratio and prosthesis performance index. The pressure half-time was less than 130 milliseconds in all patients, and all but one patient had either a peak early mitral diastolic velocity of 2 m/s or less or a mitral valve prosthesis-to-left ventricular outflow tract time-velocity integral ratio of less than 2.2. There was a significant (P < .001) negative correlation between the prosthesis performance index and prosthesis size. This negative correlation suggests that there is more efficient use of the in vitro geometric orifice area with smaller prostheses.     

Results of irradiation in the squamous cell carcinomas of the anterior faucial pillar-retromolar trigone

Between January 1966 and August 1981, 159 patients with previously untreated squamous cell carcinomas of the anterior faucial pillar or retromolar trigone received definitive radiation therapy at The University of Texas M. D. Anderson Hospital and Tumor Institute. All except 11 patients were treated by external radiation including combination of electron beams with high-energy photons or 60Co to doses ranging from 60 Gy to 75 Gy. In the N0 patients, as a rule, only the ipsilateral subdigastric nodes were treated electively to a dose of 50 Gy. The 5-year determinate survival rate for the overall group was 83%. The cumulative recurrence rate showed that 92% of the patients had recurrence by 2 years. Therefore, all patients except those who died with no evidence of local disease less than 2 years after treatment were evaluated for local control. The failure rate for the evaluable patients was 29% for T1 lesions, 30% for T2 lesions, 24% for T3 lesions, and 40% for T4 lesions. After salvage surgery, which consisted of intraoral resection in one-third of the patients and of a composite operation in the other two-thirds, the ultimate failure rate was 0% for T1 lesions, 6% for T2 lesions, 8% for T3 lesions, and 20% for T4 lesions. Whereas stage was a poor indicator for treatment outcome, there was a significantly higher failure rate for infiltrative and/or ulcerated lesions (35%) than for exophytic or superficial lesions (15%). Histologic grade was of no prognostic significance, nor was there any significant difference in the failure rate for lesions originating on the anterior faucial pillar versus that for lesions on the retromolar trigone. Following radiotherapy, 30% of the patients developed some degree of bone exposure but only 5.6% (9 patients) required a segmental mandibular resection. The probability of bone exposure was not dose related and more likely reflected tumor location on the mucoperiosteum. Of the whole group, 16 patients (10%) experienced a neck failure with 8 ultimate failures after salvage surgery. Among the 16 patients who had neck failures, 13 were originally staged N0; 6 of these patients had failures that occurred in the electively treated ipsilateral subdigastric area, but the field was too small to cover the nodes adequately. Aspects of the radiotherapy techniques with combined electron and photon beams that may influence the treatment outcome are discussed.     

Perceptions of fever among adults in a family practice setting

Febrile illnesses are common clinical problems for the family physician. A questionnaire study was conducted of 100 adult patients in a family practice clinic to gain understanding of their knowledge about fever and its management. Many misconceptions were documented among adult patients about their own fevers and those of children for whom they cared. Misconceptions included the conviction that fever is more dangerous in children than in adults and a distorted concern about bodily damage from fever. Patients demonstrated a poor understanding of normal body temperature, minimum and maximum febrile temperatures, and minimum temperatures warranting antipyresis. Though many owned thermometers, they indicated improper usage and demonstrated inaccurate temperature-reading technique. Questionnaire responses indicated that health care providers had done poorly in educating patients about fever, its consequences, and its proper treatment.     

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG-CSF (Lenograstim)

Granulocyte colony-stimulating factor (G-CSF) is being considered as adjuvant treatment for infections in non-neutropenic patients. Normal healthy donors were given rHuG-CSF (Lenograstim) at 2.5, 5.0 and 7.5 μg/kg subcutaneously daily for 5 d. Polymorphonuclear leucocyte (PMN) function tests were carried out on peripheral blood PMN before the first injection and at 24 h and 96 h. Circulating PMN levels were also measured at these time intervals and found to be significantly increased with all doses by 24 and 96 h. Investigation of cell surface antigen expression revealed no changes in β₂ integrin (CD11b/CD18) expression. L-selectin (CD62L) expression was reduced with all doses by 96 h, this being significant with the 7.5 μg/kg dose. FcγRI (CD64) levels were significantly up-regulated with the 7.5 μg/kg dose by 96 h whereas FcγRIII (CD16) expression was found to be reduced during G-CSF treatment. Superoxide anion production was significantly increased in response to N -formylmethionylleucylphenylalanine (FMLP) and opsonized Staphylococcus epidermidis stimulation at 24 h and 96 h with the 5.0 and 7.5 μg/kg doses. The initial rate of phagocytosis (0–2 min) appeared to have increased with the 7.5 and 5.0 μg/kg doses at 96 and 24 h compared with PMN responses pretreatment, although these increases were not statistically significant. These results show that G-CSF enhances the functional responses of PMN stimulated by physiological agonists and may help in the treatment of infections.