Relationship between left ventricular diastolic function and atrial natriuretic factor in never-treated mild hypertensives.

Using digitized M-mode echocardiograms, we evaluated the relationship between plasma atrial natriuretic factor (ANF) and morphofunctional characteristics of the left ventricle (LV) in 24 mild hypertensive men, never treated, with normal renal function. For each subject we collected a blood sample for plasma ANF evaluation and, immediately after, we recorded the LV echocardiogram. All the patients had normal LV diastolic diameter and systolic function; LV hypertrophy was present in 10 patients, 7 of whom had left atrial enlargement, and 13 patients had impaired LV diastolic function. ANF was similar between patients with and without LV hypertrophy, as well as between patients with and without left atrial enlargement, whereas ANF was significantly (P < .01) higher in patients with LV diastolic dysfunction than in patients with normal diastolic function. ANF was inversely correlated with both indices of diastolic function (peak lengthening rate and peak wall thinning rate), whereas it did not correlate with blood pressure, heart rate, end-systolic wall stress, and other LV parameters. In conclusion, from our results, ANF level in never-treated mild hypertensives is related neither to the degree of LV hypertrophy nor to the afterload, expressed as blood pressure or end-systolic wall stress, whereas it is mainly influenced by LV diastolic function: the diastolic impairment induces an increase in ANF level, probably through an increased atrial stretch.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Intestinal calcium absorption in rheumatoid arthritis. A study using whole body counting.

Conflicting results are reported in the literature concerning the changes in intestinal calcium absorption in rheumatoid arthritis (RA). In the present work, intestinal calcium absorption was studied in 27 postmenopausal women with RA, using whole body counting as the study method and orally administered Ca-47 as the tracer. Nobody was on corticosteroid therapy, but all received non-steroidal anti-inflammatory drugs and hydroxy chloroquine or gold compounds. The mean calcium absorption was 22.3% of the dose administered, with a standard deviation of 8.0%. The results obtained were not significantly different from those of 40 age- and sex-matched controls (mean +/- SD: 22.0% +/- 6.0%). Our findings seem to exclude the hypothesis of calcium malabsorption as one of the causes leading to osteoporosis in RA.

Evaluation of the serum markers CEA, NSE, TPS and CYFRA 21.1 in lung cancer.

We investigated the role of tumor markers CEA, NSE, TPS and CYFRA 21.1 in lung cancer diagnosis and staging in 169 patients with histologically confirmed lung cancer (43 SCLC and 126 NSCLC). In SCLC patients NSE and CYFRA 21.1 showed the highest sensitivity and their combination improve significantly the diagnostic sensitivity and accuracy. In NSCLC patients CYFRA 21.1 showed the highest sensitivity and global accuracy and no markers association was as effective as CYFRA 21.1 alone. Based on data from our study it can be concluded that in patients with suspected lung cancer the serum NSE and CYFRA 21.1 assay is a suitable association to confirm the clinical hypothesis. NSE in SCLC and CYFRA 21.1 in NSCLC are useful in the evaluation of disease extent and successive treatment planning.

Tissue polypeptide-specific antigen (TPS) immunoassay in the diagnosis and clinical staging of prostatic carcinoma. Comparison with prostate-specific antigen (PSA).

UNLABELLED: This experimental study investigated the potential role of Tissue Polypeptide-Specific Antigen (TPS) in comparison with Prostate-Specific Antigen (PSA) in the diagnosis and the clinical and pathological staging of prostate cancer. Serum TPS and PSA levels were determined in 128 patients (pts) with benign prostatic hypertrophy (BPH; Group 1) and in 92 pts with prostate cancer (Group 2). TPS was also measured in a control group of 100 healthy subjects. Normal cutoff values of 85 U/l for TPS and 4 ng/ml for PSA were determined on the basis of ROC curve analysis. The sensitivity, specificity and accuracy in the diagnosis of prostate cancer were 49%, 95% and 76% for TPS, and 84%, 90% and 87% for PSA. The combination of the two markers provided a higher accuracy (88%), improving the sensitivity of PSA, since 47% of patients with normal PSA had pathological levels of TPS. TPS showed an increase in sensitivity from low to higher stages of disease and, in patients with skeletal involvement, from small to larger numbers of bone metastases (Kruskal Wallis p < 0.0001). Nevertheless, TPS serum levels are not useful in the clinical staging of prostate cancer as they have a poorer performance than PSA. TPS was ineffective (ROC curve area = 0.68) in predicting extraprostatic disease and demonstrated a reduced ability (area = 0.78) to identify skeletal involvement. Moreover, the combination of the two markers did not significantly improve the performance of PSA alone. The serum concentration of TPS in patients with localized tumors was not related to the degree of tumor cell differentiation evaluated by the Gleason score. CONCLUSION: Our preliminary experience suggests that TPS in association with PSA may be useful at the time of diagnosis of prostate cancer. However, these preliminary data have to be confirmed by larger clinical trials and the role of this association in the clinical setting needs to be analyzed with an adequate evaluation of the cost-effectiveness ratio.

Immunoassay of neuron-specific enolase (NSE) and serum fragments of cytokeratin 19 (CYFRA 21.1) as tumor markers in small cell lung cancer: clinical evaluation and biological hypothesis.

NSE is a biochemical marker for small cell lung cancer (SCLC) diagnosis and management. CYFRA 21.1 is a newly developed immunoassay to detect the serum fragments of cytokeratin 19 which are also expressed in SCLC with or without neurofilaments. The aim of this study was to evaluate the diagnostic performance and prognostic role of the two markers in SCLC and their contribution to chemotherapy monitoring and patient follow-up. We studied 62 patients with pathologically proven SCLC: 28 with limited disease (LD) and 34 with extensive disease (ED), and 100 patients with non-malignant pulmonary disease. Immunoradiometric assays (IRMA) were employed to test NSE and CYFRA 21.1 in patients and control subjects. For each patient subset results were expressed as median and interquartile distribution range. NSE and CYFRA 21.1 sensitivity was 0.52 (33/62) and 0.56 (35/62), respectively. In the group of patients with LD, NSE and CYFRA 21.1 sensitivity was 0.42 (12/28) and 0.54 (15/28) and in patients with ED, NSE and CYFRA 21.1 were positive in 0.62 (21/34) and 0.59 (20/34) of cases, respectively. Combining the two markers, a sensitivity of 0.78 (22/28) in LD, 0.82 (28/34) in ED and a global sensitivity of 0.80 (50/62) was obtained. Only NSE was significantly linked to the extension of disease (Mann-Whitney U test p = 0.002) while CYFRA 21.1 did not correlate. The analysis of survival and the evaluation of the two markers at diagnosis showed CYFRA 21.1 to be strongly linked to the patients' outcome, independently of both clinical prognostic factors and NSE levels (log rank and Cox's model). The markers' performance during chemotherapy was tested in a group of 33 patients with at least one marker above cut-off. NSE can be considered a reliable marker of tumor mass modifications under chemotherapy, while CYFRA 21.1 expression seems to be relatively independent of tumor volume modifications. An applicable model of biomarkers in SCLC could be the concurrent assay of NSE and CYFRA 21.1 in pre-therapeutic assessment and therapy planning. CYFRA 21.1 does not play an important role during therapy monitoring and follow-up; in these phases NSE alone may be employed.

Clinical studies of bone metabolism using a simple model of calcium tracer kinetics.

Bone metabolism studies were performed in 44 subjects with and without bone disease using a calcium tracers kinetics model, the central feature of which is an expanding exchangeable calcium pool. In normal subjects the accretion rate and the exchangeable calcium pool ranged from 1.49 to 8.45 (mean 3.9 +/- 2.05) mg.d-1kg-1 and from 60 to 131 (mean 81.25 +/- 18.11) mg.kg-1, respectively. The patients with osteogenesis imperfecta. Pierre Marie's disease and one out of two cases of hypoparathyroidism had values which fell within the normal range. Both the accretion rate and the exchangeable calcium pool were significantly elevated in patients with Paget's disease and with hyperparathyroidism. Uremic patients with generalized bone lesions had accretion rates or both parameters elevated. As far as patients with successful renal transplant are concerned, the results suggest that this method is a very poor means for detecting bone disorders with only focal lesions. In contrast, the method can be very useful when persistent renal osteodystrophy or secondary hyperparathyroidism are suspected.

Description of a simple model for the study of bone calcium metabolism.

A simple model for the study of bone calcium metabolism is proposed. It describes the kinetics of a radioactive tracer in terms of an open single compartment system with an expanding volume for a finite period of time. In addition to the simplicity of the hypotheses introduced, the model is able to give a good description of the biological processes which regulate calcium kinetics. Moreover the functional parameters can be easily calculated, even just graphically. 15 normal subjects and 22 patients affected by various bone diseases were studied. The results were compared with those obtained by using the model proposed by Burkinshaw et al. and the method described by Reeve et al.

Semi-quantitative assessment of 99Tcm-sestamibi uptake in lung cancer: relationship with clinical response to chemotherapy.

The objectives of this study were to measure semi-quantitatively uptake of 99Tcm-sestamibi (99Tcm-MIBI) by tumour tissue in patients with lung cancer and to investigate its relationship with clinical response to chemotherapy. 99Tcm-MIBI single photon emission tomography was performed at the time of diagnosis in 31 patients with biopsy-proven lung cancer (19 small cell carcinomas, 12 non-small cell carcinomas), all of whom were undergoing chemotherapy. Fifteen patients were also investigated 2 weeks after the first and third cycles of chemotherapy. To quantify 99Tcm-MIBI uptake, a tumour/lung (T/L) ratio was calculated for the tomographic slices. The response to chemotherapy was rated as complete remission, partial remission or no remission using dimensional criteria. The results were expressed as the median and inter-quartile range; non-parametric statistical analyses were used. Forty one neoplastic localizations (31 primary tumours and 10 hilar or mediastinal lymph node masses) were assessed. The median T/L ratio of the primary tumours was 1.85 (range 1.7-2.4). Patients with a different response to chemotherapy had a significantly different median T/L ratio before chemotherapy: complete remission (n = 8), T/L ratio = 2.95 (range 2.20-3.25); partial remission (n = 10), 2.15 (range 1.77-2.40); no remission (n = 13), 1.70 (range 1.47-1.75) (Kruskal-Wallis, P < 0.0001). A T/L ratio of 1.80 gave sensitivity of 83%, specificity of 85% and accuracy of 84% in the prediction of the response to chemotherapy. The patients with small cell carcinomas demonstrated greater 99Tcm-MIBI uptake than those with non-small cell carcinomas: T/L ratio, median 2.30 (range 1.76-3.00) vs 1.70 (range 1.50-1.78) (Mann-Whitney U-test, P = 0.001). No significant difference in 99Tcm-MIBI uptake was observed between the 10 lymph node metastases and the corresponding primary tumours: T/L ratio, median 2.30 (range 1.75-2.50) vs 2.15 (1.77-3.00) (Wilcoxon's paired samples rank test, N.S.). Of the 15 patients who were monitored with scintigraphy during chemotherapy, 10 showed complete or partial remission and a parallel reduction in their T/L ratio. The other five patients showed no response to chemotherapy and their T/L ratio was either unaffected or increased. We conclude that the semi-quantitative assessment of 99Tcm-MIBI uptake may have a significant role to play in the management of lung cancer, providing an effective means of predicting the efficacy of chemotherapy and of selecting subgroups of patients requiring radiotherapy or combined protocols before the start of treatment. 99Tcm-MIBI imaging may also be of use in monitoring clinical response to chemotherapy.

Nuclear medicine imaging in a case of hyperfunctioning parathyroid carcinoma associated with a parathyroid adenoma.

This report describes a rare case of parathyroid carcinoma associated with an adenoma. Nuclear imaging provided the most specific information about localization of the primary carcinoma and cervical metastasis, but failed to demonstrate evidence of a parathyroid adenoma. This could be explained by a partial inhibition of hormonal biosynthesis due to the high level of circulating parathormone produced by the carcinoma.

[Study of intestinal absorption of calcium using 47Ca and whole body counter in renal calculosis with hypercalciuria]. / Studio dell'assorbimento intestinale del calcio mediante 47Ca e misure con whole body counter nella calcolosi renale con ipercalciuria.

Intestinal calcium absorption was studied using orally administered 47Ca and whole body counting. Using this method, we examined 82 patients suffering from recurrent calcium urolithiasis associated with idiopathic hypercalciuria, to evaluate the incidence of elevated intestinal absorption of this ion. An oral dose of 111 kBq (3 microCi) of 47Ca chloride, together with 250 mg of stable calcium as carrier, was given to each patient. Two hours and one week later, the total body radioactivity of each subject was measured. The retention of 47Ca, as percentage of the administered dose, was then calculated. The measurements were performed with a whole body counter consisting of a two-crystal moving system with shadow shield. Forty age-matched healthy volunteers were also examined. The whole body retention of 47Ca resulted significantly higher (p less than 0.0002) in the group of patients than in the control sample, whose m +/- SD was 22.0 +/- 6.0%. In particular, by defining the normality range as 10-34% (m +/- 2SD of control results), enhanced intestinal absorption of calcium was found in 28% of the examined patients. The use of this simple examination seems to be helpful in the physiopathologic assessment of subjects suffering from calcium urolithiasis and idiopathic hypercalciuria and consequently, in their appropriate management.

[Whole-body osseous scintigraphy and Ca++ kinetics in patients with renal transplants]. / La scintigrafia ossea whole-body e la cinetica del Ca++ nel paziente con trapianto renale.

Bone scintigraphy with 99mTc-diophosphonate and a whole body scanner was performed on 18 subjects with good renal function who had received a kidney transplant more than six months previously. This demonstrated scintigraphyc abnormalities in 17 of the cases. The alterations were characterized in 44,5% of the cases by focal uptake of the tracer. Diffuse alterations were observed in 4 of the 18 cases studied (22%). In these patients increases of serum alkaline phosphatase and in PTH levels were present. Ca++ exchangeable pool values and accretion rate were normal in the subjects with focal lesions. In the cases where scintigraphy showed diffuse lesions both the above parameters were much increased.

Vascular toxicity in dogs associated with overdoses of a novel benzodiazepine receptor partial agonist.

Necrotizing arteritis and periarteritis were found in Beagle and German Shepherd dogs treated for 13 or 52 weeks with the novel benzodiazepine receptor (BZR) partial agonist Ro 16-6028 (generic name bretazenil). Eight male and one female out of a total of 20 dogs treated with 40-60 mg/kg/day Ro 16-6028 developed the arteritis, predominantly in the heart or the epididymis. Two of these animals died prematurely following treatment at the initial dosing levels of 80 and 55 mg/kg/day; one of these two dogs was asymptomatic and in good general condition until death. Clinically, all but one of the dogs showed sedation, ataxia, stiff gait, body weight-loss and a deterioration of the general condition as well as changes of some laboratory parameters. No signs of arteritis and untoward clinical or laboratory findings were seen at lower doses. Possible aetiologies, as well as the mechanisms involved in arteritis in general and the genetic disposition of beagles in particular for this type of effect, are discussed. Reflections on the potential risk to man of this so far unknown finding after oral treatment with 1,4-benzodiazepines (BZs) are presented.

Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration.

During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg-1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min-1 resulted in a short elimination half-life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

Calcitonin in chronic renal failure.

The pattern of circulating calcitonin (CT) has been studied in relation to other humoral factors (PTH, calcium, phosphate and magnesium) in patients with chronic renal failure on either conservative or dialysis treatment. The latter group was studied before and after dialysis. In both groups, in basal conditions there was a significant increase in the circulating levels of CT, PTH, phosphate and magnesium and a significant decrease in calcemia compared to control group values. Positive correlations were found between increased CT and PTH and between CT and phosphate in uremic patients on conservative medical treatment, but not in those on hemodialysis. In the hemodialyzed group, the postdialysis increase in calcemia was significantly correlated to an increase in calcitoninemia. These data would indicate that even in severe uremia parafollicular cells are still able to increase CT secretion in response to physiological stimuli.

The renal plasma flow and glomerular filtration rate as estimated through double radiocompound renography.

In order to estimate the renal plasma flow and glomerular filtration rate during the course of renography, a method was developed using simultaneously 131I Hippuran and 169Yb DTPA. First results obtained in a survey of approximately 200 patients are encouraging. The method permits an accurate evaluation of the renal function. In addition, by comparing the clearance rate of the two radiocompounds one can also obtain some interesting diagnostic information which can contribute usefully to the interpretation of renographic tracings and/or gamma camera sequential images.