The pharmacokinetics of 125I-atrial natriuretic factor in anaesthetized rats. Effects of neutral endopeptidase inhibition with candoxatrilat and of ANF-C receptor blockade.

The effects of candoxatrilat (cis-4-([2-carboxy-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarbonyla mino)- 1-cyclohexane carboxylic acid) and the ring-deleted atrial natriuretic factor (ANF) analogue C-ANF4-23 (des[Gln18, Ser19, Gly20, Leu21, Gly22]ANF4-23-NH2) on the clearance of (3-[125I]iodotyrosyl28)ANF (125I-ANF) were studied in both intact and nephrectomized anaesthetized rats. HPLC analysis was used to verify that the 125I-labelled material isolated by solid phase extraction of rat plasma was intact ANF. In intact animals, clearance of 125I-ANF was biphasic with a T1/2 alpha of 17 sec and T1/2 beta of 95 sec. Volume of distribution (Vd) was 564 mL/kg and plasma clearance (Clp) 248 mL/min/kg. Candoxatrilat, over the dose range 0.01-10 mg/kg i.v., increased T1/2 beta (by a maximum of 56%) and decreased Clp (by up to 52%) with no effect on T1/2 alpha or Vd. C-ANF4-23 (10 micrograms/kg+1 microgram/kg/min i.v.) reduced Vd (by 57%) and Clp (by 54%) with no effect on T1/2 beta, whilst abolishing the T1/2 alpha phase in over 50% of animals. Increasing the dose of C-ANF4-23 did not increase the effect on any of these parameters, apart from a small increase in T1/2 beta. Combining the two agents resulted in a substantial decrease in Clp (76%) whilst the reduction in Vd and increase in T1/2 beta were comparable to those seen with C-ANF4-23 and candoxatrilat alone, respectively. In nephrectomized rats, the pharmacokinetics of 125I-ANF and the changes induced by candoxatrilat were similar to those observed in intact animals, whilst the effects of C-ANF4-23 alone were greater than in intact animals. The combination of C-ANF4-23 and candoxatrilat again produced a substantial increase in T1/2 beta (153%) and decreases in Vd (55%) and Clp (78%) in nephrectomized animals, although these changes could not be distinguished from those seen in intact animals treated with the same combination. Our studies indicate that neutral endopeptidase and ANF-C receptors are both major, and approximately equal, clearance mechanisms for 125I-ANF, together accounting for at least 75% of the total clearance of this peptide in the rat.     

Routinely collected general practice data aids identification of people with hyperglycaemia and metabolic syndrome.

AIMS: To assess the performance of a risk score comprising data routinely available in general practice records (age, gender, body mass index, family history of diabetes, smoking habits and prescribed anti-hypertensive drugs or steroids) in detecting diabetes, impaired glucose tolerance and metabolic syndrome. METHODS: In a population-based, cross-sectional study in a semi-rural general practice in Jutland, Denmark, Cambridge Risk Scores were calculated for 1355 patients without known diabetes (69% response rate) who completed questionnaires and underwent anthropometric measurement and an oral glucose tolerance test. RESULTS: Prevalences of diabetes, impaired glucose tolerance and metabolic syndrome were 2.29% (95% CI: 1.56-3.23), 6.64% (95% CI: 5.38-8.10) and 13.4% (95% CI: 11.5-15.2), respectively. Area under the ROC curve for the risk score and diabetes was 83.8% (75.9-91.7) and for metabolic syndrome [European Group for the Study of Insulin Resistance (EGIR)] was 78.1% (74.6-81.6). Twenty per cent of the population had a risk score above 0.246; at this threshold the sensitivity to detect diabetes was 71.0% (53.4-83.9), the specificity 81.2% (79.0-83.2), positive predictive value 8.1% (6.6-10.0) and likelihood ratio 3.77 (2.94-4.85). For metabolic syndrome (EGIR) corresponding values for sensitivity were 50.3% (43.1-57.5), specificity 84.7% (82.5-85.6), positive predictive value 33.6% (28.2-39.4), and likelihood ratio 3.28 (2.69-4.00). CONCLUSIONS: Undiagnosed hyperglycaemia and metabolic syndrome are common. The Cambridge Risk Score is a practical first step in a screening procedure to identify individuals with these disorders who might benefit from diagnostic testing or to direct preventive interventions.     

Endotoxin shock in newborn dogs: serial hemodynamic studies

Using a newly modified dye dilution method for cardiac output determination, we successfully performed frequent serial hemodynamic measurements in newborn dogs to characterize hemodynamic changes in endotoxin shock in neonates. Sixty-seven mongrel newborn dogs (2 to 20 days old, 300 to 1500 gm) were divided into four groups: group 1 (2 to 20 days old, 300 to 1500 gm) received normal saline solution, group 2 (2 to 10 days old, 300 to 800 gm) received 1.5 mg/kg of Escherichia coli lipopolysaccharide (LPS), group 3 (2 to 10 days old, 300 to 800 gm) received 10 mg/kg of LPS, and group 4 (11 to 20 days old, 801 to 1500 gm) received 10 mg/kg of LPS. Cardiac output, heart rate, mean arterial pressure, systemic vascular resistance, and minute work were measured serially after endotoxin administration for 4 hours. Despite extensive manipulation, these measurements were stable in controls throughout the length of the study. Endotoxin, administered at two different doses of 1.5 mg/kg and 10 mg/kg, had profound effects on hemodynamic responses. These effects included a significant dose-related fall in cardiac output, minimal changes in heart rate, and a marked rise in systemic vascular resistance. The hemodynamic changes reported in this study lend additional support to the hypothesis that maturational factors are involved in the hemodynamic response to LPS.     

Comparison of abdominopelvic computed tomography results and findings at second-look laparotomy in ovarian carcinoma patients

In 35 women with epithelial carcinoma of the ovary, the results of restaging laparotomy were compared with the preoperative abdominopelvic computed tomography (CT) findings to evaluate the accuracy of CT for determining tumor status. In the 36 studies performed, enhanced CT scans at 10-mm to 15-mm intervals had a sensitivity of 84% and a specificity of 88%; in addition, there was 86% agreement between the CT and surgical findings. These results suggest that although CT is not accurate enough to completely replace the restaging laparotomy, its high accuracy in determining residual disease after treatment is helpful for patient management.     

Gold: an old drug still working in refractory pemphigus

BACKGROUND: The mainstay of treatment for pemphigus is systemic corticosteroids. Different adjuvants have been used to reduce side-effects of long-term corticotherapy. Gold is an anti-inflammatory drug used in autoimmune diseases, whose use has waned with the advent of new immunosuppressive agents. OBJECTIVE: To study the outcome of the use of intramuscular gold treatment of pemphigus vulgaris refractory to previous therapies. METHODS: Thirteen patients with pemphigus vulgaris who had failed to respond to several prior therapies were treated with aurothiomalate, as a steroid-sparing agent. Patients were monitored to assess disease activity and gold toxicity. RESULTS: Seven patients achieved complete remission. Four patients were able to taper prednisone doses, although pemphigus flared when prednisone was discontinued or reduced. Toxicity was observed in the other two patients. CONCLUSIONS: In 53.4% of the patients, the use of chrysotherapy resulted in the complete clearing of the disease, discontinuation of all systemic therapies and induced a long-term clinical remission. Prednisone doses were able to be reduced in the remaining 46.6%. Any side-effects were reversible with drug discontinuation. Gold therapy showed efficacy as a secondary line treatment in refractory pemphigus vulgaris.     

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.     

Uterine stromal sarcoma cell line. A cytogenetic and electron microscopic study.

Uterine sarcomas constitute approximately 3% of all malignant uterine corpus tumors. Of these, the tumors that originate solely in the stromal elements of the uterine wall are relatively infrequent and have not been well characterized cytogenetically. We report data from a low-grade endometrial stromal sarcoma both at the time of resection and after months in long-term tissue culture. Cytogenetic analysis showed a clonal population of cells with an abnormal karyotype of 46,XX,del(5)(q31.1),der(7)t(6;7)(p21;p22) which remained unchanged in long-term culture. Electron microscopy suggests that these cells are similar to other neoplastic cells in having immature-appearing nuclei surrounded by a relatively mature cytoplasm (with well-developed organelles). Determination of the specificity of these observations must await study of additional stromal sarcomas.     

L-arginine reverses the antinatriuretic effect of cyclosporin in renal transplant patients

BACKGROUND: Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine. DESIGN: Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h. RESULTS: The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2. CONCLUSION: These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.      

Argon laser stapedectomy using an endo-otoprobe system

In summary, we believe that the endo-otoprobe system offers several advantages to the otologist. The system is safe and relatively inexpensive. The probes are designed to provide tactile feedback similar to that of standard otologic instruments and avoid the use of a cumbersome micromanipulator. There are currently shapes that are similar to a Rosen needle, Shea pick, and bayonet. We hope most otologists will find that one of the endo-otoprobes fits their particular style of surgery.