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.     

Conjugated linoleic acid evokes de-lipidation through the regulation of genes controlling lipid metabolism in adipose and liver tissue

Conjugated linoleic acid (CLA) is a unique lipid that elicits dramatic reductions in adiposity in several animal models when included at < or = 1% of the diet. Despite a flurry of investigations, the precise mechanisms by which conjugated linoleic acid elicits its dramatic effects in adipose tissue and liver are still largely unknown. In vivo and in vitro analyses of physiological modifications imparted by conjugated linoleic acid on protein and gene expression suggest that conjugated linoleic acid exerts its de-lipidating effects by modulating energy expenditure, apoptosis, fatty acid oxidation, lipolysis, stromal vascular cell differentiation and lipogenesis. The purpose of this review shall be to examine the recent advances and insights into conjugated linoleic acid's effects on obesity and lipid metabolism, specifically focused on changes in gene expression and physiology of liver and adipose tissue.     

Urinary tract injuries during obstetric intervention

A retrospective case record review of obstetric urinary tract injury in the Grampian region from 1976 to 1993 identified 16 cases of bladder injury (0.1 per 1000 deliveries, 1.4 per 1000 caesarean sections and four cases of ureteric injury (0.03 per 1000 deliveries, 0.27 per 1000 caesarean sections). Diagnosis of bladder injury was immediate, but of ureteric injury often delayed. Although the injury rates are lower than previously reported and previously reported risk factors not confirmed, this audit has resulted in guidelines for junior staff, compliance with which will be monitored, and every case of urinary tract injury will be reviewed.     

The hydration question. Hydration or dehydration of terminally ill patients.

Hydration of terminally ill patients is a controversial issue. This study assesses the reasons why doctors and nurses in hospital and hospice settings do or do not undertake this procedure.     

Exposure of humans to a volatile organic mixture. I. Behavioral assessment.

Exposure to a low-level mixture of volatile organic compounds, typical of those found in new buildings, has been reported to impair neurobehavioral function in persons who have experienced sick building syndrome (SBS). Sixty-six healthy young males who had no history of chemical sensitivity were exposed for 2.75 h to a complex mixture of volatile organic compounds at 0 and 25 mg/m3. Even though subjects reported more fatigue and more mental confusion following exposure to volatile organic compounds than to clean air, performance on 13 neurobehavioral tests was not affected. Practice or learning effects were observed if administration of many behavioral tests were repeated. Further studies are needed to clarify the relationship of exposure to volatile organic chemicals, neurobehavioral performance, and subject characteristics, e.g., age, gender, and chemical sensitivity.     

Age, socioeconomic status, and health

Analysts dispute what roles biomedical, psychosocial, and other factors play in determining the duration of morbidity and disability over the life course. Cross-sectional data from two national surveys of adults aged 25 years and over not only show, however, that age and socioeconomic status (SES) are significant predictors of self-reported physical health; they also demonstrate that the relation of age to health varies with SES features. Longitudinal research is needed to test the finding that enduring functional limitations in terms of time are actually compressed in higher SES groups. To improve well-being in our society, moreover, requires specifying why SES differences occur, and perhaps ultimately reducing socioeconomic inequality itself.     

Phase III double-blind comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based chemotherapy.

BACKGROUND. Ondansetron hydrochloride is a selective serotonin subtype 3 (5HT3) receptor antagonist that has been shown to be an effective antiemetic in patients receiving cisplatin chemotherapy. METHODS. This double-blind study compared the safety and efficacy of intravenous ondansetron with metoclopramide in patients receiving a 4- or 5-day regimen of cisplatin (20-40 mg/m2/day) combination chemotherapy. Forty-five patients were enrolled, and efficacy of the drug therapy could be studied for all 45. Patients were randomly assigned (1:1) to receive three daily intravenous doses of either 0.15 mg/kg ondansetron or 1 mg/kg metoclopramide. All patients were monitored daily for the number of emetic episodes (vomiting or retching), severity of nausea, adverse events, and laboratory safety parameters. RESULTS. Seven (30%) patients who received ondansetron had no emetic episodes throughout the entire study period compared with two (9%) who received metoclopramide (P = 0.077). The greatest difference in antiemetic efficacy was seen on day 1, when 18 (78%) patients who received ondansetron had no emetic episodes compared with 3 (14%) patients who received metoclopramide (P < 0.001). Significantly fewer antiemetic treatment failures (more than five emetic episodes or withdrawal from the study) occurred with patients given ondansetron (9%) than with those given metoclopramide (50%) during the entire study period (P = 0.002). The most commonly reported adverse event associated with ondansetron therapy was headache (controlled with acetaminophen), whereas diarrhea and restlessness were the most commonly reported adverse events associated with metoclopramide therapy. Extrapyramidal symptoms were judged to have occurred in 13 patients who received metoclopramide and 1 patient who received ondansetron. However, the patient who received ondansetron subsequently was judged to have had an anxiety attack. In patients with low or normal baseline transaminase values, a greater percentage who received ondansetron had transient increases as great as twice the upper limit of normal in aspartate transaminase (5% versus 0%) and alanine transaminase (17% versus 6%) than those who received metoclopramide. CONCLUSIONS. Ondansetron is superior to metoclopramide as antiemetic therapy for multiple-day cisplatin-based chemotherapy.     

A prospective study of colposcopy in women with mild dyskaryosis or koilocytosis

Summary. Colposcopy was performed in 91 women who had cervical cytology suggesting mild dyskaryosis or showing koilocytosis, all previous cytology having been normal. The final histological diagnosis was C1N III in 22%, CINII in 18%, CINI in 31%, koilocytosis alone in 14% and no abnormality in 15%. These results indicate that even with mild cytological atypia, a high proportion of patients will have more advanced disease when colposcopy-directed punch biopsy is performed.     

Tympanosclerosis of the stapes: hearing results for various surgical treatments.

When tympanosclerosis involves the tympanic membrane or the lateral ossicles, treatment is usually straightforward and uncomplicated. When the stapes is involved, therapy is more controversial and may be more difficult. We report our results in 154 patients who underwent different surgical procedures for tympanosclerosis of the stapes. Followup was up to 10 years. Pure-tone average threshold was significantly improved (p < 0.05) in patients who underwent mobilization procedures or stapedectomy for definitive treatment. The air-bone gap was less than 20 dB at 6 months postoperative in 72% of patients and less than 30 dB in 90%. At 6 months, 2 years, and 5 years there were no statistically significant differences in hearing results between stapedectomy and mobilization patients, some of whom were followed for up to 10 years. No patient had a profound hearing loss after surgery. Surgical treatment for tympanosclerosis of the stapes is a safe procedure, with hearing results similar to those of surgery for other chronic ear diseases involving the ossicular chain.