Differentiation of myxoid liposarcoma by magnetic resonance imaging: a histopathologic correlation.

BACKGROUND: Myxoid liposarcomas represent a heterogeneous group of soft tissue tumors in which prognosis is dependent on differentiation. PURPOSE: To identify magnetic resonance imaging (MRI) criteria to distinguish low-grade from high-grade myxoid liposarcomas. MATERIAL AND METHODS: MR images of 30 histologically proven myxoid liposarcomas were retrospectively reviewed. Tumors were evaluated according to size, localization, tumor border, and structure as well as tumor composition. These imaging criteria were correlated with histopathological findings. RESULTS: Nineteen myxoid liposarcomas were histologically classified as low-grade myxoid liposarcomas, whereas 11 were considered high-grade myxoid liposarcomas. Mean tumor volume of low-grade myxoid liposarcomas (710.1 ± 960.1 ccm) was significantly smaller as compared to high-grade myxoid liposarcomas (2737.0 ± 3423.7 ccm; P = 0.04). In addition to necrotic areas, three tumor components - fatty, myxoid, as well as contrast-enhancing non-fatty, non-myxoid - could be identified. The mean fraction of fatty tumor areas in low-grade myxoid liposarcomas was 10 ± 11% as compared to 6 ± 4% for high-grade myxoid liposarcomas (P = 0.66). Myxoid components accounted for 88 ± 16% in low-grade myxoid liposarcomas, but only for 45 ± 25% in high-grade myxoid liposarcomas (P < 0.0001). The non-fatty, non-myxoid tumor fraction was significantly higher in high-grade myxoid liposarcomas (50 ± 25%) as compared to low-grade myxoid liposarcomas (2 ± 9%; P < 0.0001). A proportion of > 5% of this tumor fraction was found to be a precise unique predictor for high-grade myxoid liposarcomas with a sensitivity of 100% and a specificity of 95%. CONCLUSION: Tumor components with contrast-enhancing non-fatty, non-myxoid imaging features were predominantly found in high-grade myxoid liposarcomas, which may histologically resemble round cell clusters.

Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and Gd-EOB-DTPA enhanced MR imaging.

OBJECTIVE: To compare diffusion-weighted imaging (DWI) and Gd-EOB-DTPA-enhanced magnetic resonance (MR) imaging for the detection and characterisation of focal liver lesions (FLLs) in patients with colorectal carcinoma. METHODS: Seventy-three patients underwent MR imaging including echoplanar DWI (MR-DWI) and dynamic (MR-Dyn) and hepatobiliary phase (MR-Late) Gd-EOB-DTPA-enhanced images. Two blinded readers independently reviewed 5 different image sets using a 5-point confidence scale. Accuracy was assessed by the area (A(z)) under the receiver operating characteristic curve, and sensitivity and specificity were calculated. RESULTS: A total of 332 FLLs were evaluated. Detection rates were significantly higher for MR-Late images (94.4% for benign and 100% for malignant lesions) compared with MR-DWI (78.3% and 97.5%) and MR-Dyn images (81.5% and 89.9%). Accuracy was 0.82, 0.76 and 0.89 for MR-DWI, MR-Dyn and MR-Late images while sensitivity was 0.98, 0.87 and 0.95, respectively. For characterisation of subcentimetre lesions sensitivity was highest for MR-DWI (0.92). Combined reading of unenhanced and contrast-enhanced images had an identical high accuracy of 0.98. CONCLUSION: Late-phase Gd-EOB-DTPA-enhanced images were superior for the detection of FLLs, while DWIs were most valuable for the identification of particularly small metastases. Combined interpretation of unenhanced images resulted in precise characterisation of FLLs.

Elemental tracers of distant regional pollution aerosols.

A seven-element tracer system shows that regional pollution aerosols of both North America and Europe have characteristic signatures that can be followed into remote areas up to several thousand kilometers downwind. In aerosols of mixed origin, regional contributions to the tracer elements can be resolved by least-squares procedures. After transport of several hundred kilometers, secondary sulfate can also be apportioned satisfactorily. Regional elemental tracers thus offer a way to determine the sources of pollution aerosol in important areas such as the northeastern United States, Scandinavia, and the Arctic.

Pollution aerosol in the northeast: northeastern-midwestern contributions.

In recent years, atmospheric scientists have been endeavoring to determine the relative contributions of local and distant sources to pollution aerosol in eastern North America. Elemental analysis of aerosol from various sites in the northeastern United States has revealed a persistent northeastern "foreground" upon which pulses of midwestern aerosol are superimposed every few days, in response to large-scale meteorological features. Regional apportionment of tracer element and sulfate in summer and winter samples from Narragansett, Rhode Island, and Underhill, Vermont, shows that most of the elements come predominantly from northeastern sources. Notable exceptions include arsenic and indium, for which Canadian nonferrous smelters are important sources, and sulfur and selenium, for which the Midwest is an important source. During 1982 and 1983, the Northeast and the Midwest contributed comparably to aerosol sulfate at Narragansett and Underhill, in spite of the fact that the emissions of sulfur dioxide in the Midwest were ten times those in the Northeast; Canadian smelters accounted for less than 10 percent of the total sulfate. During a major pollution episode in July 1982, northeastern and midwestern sources produced comparable sulfate concentration in Rhode Island, whereas midwestern sources dominated northeastern sources in Vermont. Thus, although distant midwestern sources affect the quantity of pollution aerosol in the Northeast and may dominate episodically, nearer northeastern sources are comparably important on the long term.

Sources of volatile organic compounds in Cairo's ambient air.

The greater Cairo area suffers from extreme levels of gas and particulate phase air pollutants. In order to reduce the levels of ambient pollution, the USAID and the Egyptian Environmental Affairs Agency (EEAA) have supported the Cairo Air Improvement Project (CAIP). As part of this project, two intensive ambient monitoring studies were carried out during the period of February 22 to March 4 and October 27 to November 27, 1999. Volatile organic compounds (VOCs) were measured on a 24-h basis at six sampling stations during each of the intensive periods. During the February/March study, samples were collected daily, while in the October/November study samples were collected every other day. The six intensive measurement sites represented background levels, mobile source impacts, industrial impacts, and residential exposure. High levels of NMHC were observed at all locations. NMHC concentrations ranged from 365 ppb C at Helwan to 1,848 ppb C at El Qualaly during winter, 1999 and from 461 ppb C at Kaha to 2,037 ppb C at El Qualaly during fall, 1999. El Qualaly, the site chosen to represent mobile emissions, displayed the highest average NMHC concentrations of any site, by a factor of 2 or more. The highest mobile source contributions were estimated at this site. The major contributors to NMHC at all sites were mobile emissions, lead smelting, and compressed natural gas.

Kinetics of salicylate elimination by anephric patients.

The objectives of this research were to determine the kinetics of salicylate elimination in anephric patients and particularly to establish if these patients form the major metabolite of salicylic acid, salicyluric acid, at a normal rate. This investigation was initiated because of conflicting reports concerning the contribution of the kidneys to the formation of salicyluric acid in man. Six patients, 20-44 yr old, three of whom were anatomically anephric while the other three were physiologically anephric, received an intravenous injection of 500 mg salicylic acid (as sodium salicylate)/1.73 m(2) body surface area on an interdialysis day. Serial blood samples were obtained for 12 or 16 h after injection and the plasma was assayed for salicylic acid, salicyluric acid, total protein, albumin, and creatinine. Detailed pharmacokinetic analysis based on an open, two-compartment linear model revealed no significant differences in apparent volume of distribution and apparent first-order distribution and elimination rate constants between the anephric patients and normal adult subjects. An estimate of salicyluric acid formation rate by the anephric patients, based on the initial rate of increase of salicylurate concentrations in plasma, indicates that the metabolite is formed at a normal rate. These results suggest that the kidneys do not contribute significantly to the formation of salicyluric acid from salicylic acid in man.

Phase I clinical and pharmacological study of merbarone.

Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.

Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas.

Seventy previously untreated patients with stage II, III, and IV intermediate- or high-grade lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between September 1985 and November 1987. Forty-nine of these patients had diffuse large-cell lymphoma (DLCL), and eight of these patients were human immunodeficiency virus (HIV)-positive. Complete responses were achieved in 54% of all patients and 52% of those with DLCL. With follow-up extending to 36 months, 45% of all DLCL patients are alive, and 50% are still living, if the HIV-positive patients are excluded from the analysis. Chemotherapy was quite toxic. Seventy-five percent of patients had severe mucositis, 42% had peripheral neuropathy, 50% required hospitalization, and 54% experienced leukopenia with a WBC count below 1,000/microL. Seven percent (five patients) died of toxicity related to the chemotherapy. Our analysis of prognostic parameters indicated that B symptoms, a performance status below 80, and, to a lesser extent, elevation of serum lactic acid dehydrogenase (LDH) (in HIV-negative DLCL patients) were associated with an inferior survival. Advanced age, sex, and bulky disease were not found to have a statistically significant effect on survival. Our preliminary results indicate that MACOP-B chemotherapy is an effective regimen for high- and intermediate-grade lymphomas. However, the survival for patients with DLCL treated with MACOP-B is no different than that achieved with previous regimens at our institution.

Plasma norepinephrine in exercise-induced ventricular tachycardia.

The relation between plasma norepinephrine levels and the occurrence of ventricular tachycardia during exercise testing was prospectively evaluated in 17 patients. Ten patients had reproducible ventricular tachycardia exclusively during exercise or recovery, or both; 7 patients had ventricular tachycardia only during ambulatory electrocardiographic monitoring. The two groups did not differ in age, exercise duration, left ventricular ejection fraction at rest, heart rate throughout the exercise protocol, rest QTc interval, change in QTc interval during exercise, the presence of coronary artery disease or exercise-related myocardial ischemia. Furthermore, there was no difference between groups in plasma norepinephrine levels at rest, peak exercise or in the recovery period. Myocardial ischemia was detectable by thallium perfusion scan in only 2 of the 10 patients with exercise-induced ventricular tachycardia. The 10 patients with exercise-induced ventricular tachycardia underwent repeat exercise testing immediately after maximal intravenous beta-adrenergic blockade with propranolol. Although they had no change in exercise duration, ventricular tachycardia did not occur in 9 of these 10 patients. Plasma norepinephrine levels were significantly decreased compared with levels before beta-adrenergic blockade (p less than 0.0002). Thus, plasma norepinephrine levels do not distinguish patients with reproducible exercise-induced ventricular tachycardia from otherwise comparable patients. Propranolol is highly effective in abolishing this arrhythmia and this effect is associated with decreased norepinephrine levels.

Identification of predictive CT angiographic factors in the development of high-risk type 2 endoleaks after endovascular aneurysm repair in patients with infrarenal aortic aneurysms.

PURPOSE: An extensive analysis of the value of computed tomography (CT) parameters as potential predictors of the clinical outcome of type 2 endoleaks after endovascular aortic aneurysm repair (EVAR). MATERIALS AND METHODS: Initial CT scans of 130 patients with abdominal aortic aneurysms (AAAs) were retrospectively reviewed. On the basis of postoperative CT scans and angiographies, patients were stratified into a low-risk group (LRG; without or transient type 2 endoleak; n = 80) and a high-risk group (HRG, persistent type 2 endoleak or need for reintervention; n = 50). Statistical analysis comprised a univariate and multivariate analysis. RESULTS: Anatomical, thrombus-specific, as well as aortic side branch parameters were assessed on the initial CT scan. Of all anatomical parameters, the diameter of the immediate infrarenal aorta was significantly different in the univariate analysis (LRG 22.4 ±â€Š3.8 mm; HRG 23.6 ±â€Š2.5 mm; p = 0.03). The investigation of the thrombus-specific parameters showed a trend towards statistical significance for the relative thrombus load (LRG 31.7 ±â€Š18.0%; HRG 25.3 ±â€Š17.5%; p = 0.09). Assessment of aortic side branches revealed only for the univariate analysis significant differences in the patency of the inferior mesenteric artery (LRG 71.3%; HRG 92.0%; p = 0.003) and their diameter (LRG 3.3 ±â€Š0.7 mm; HRG 3.8 ±â€Š0.9 mm; p = 0.004). In contrast, the number of lumbar arteries (LAs; LRG 2.7 ±â€Š1.4; HRG 3.6 ±â€Š1.2; univariate: p = 0.01; multivariate: p = 0.006) as well as their diameter (LRG 2.1 ±â€Š0.4 mm; HRG 2.4 ±â€Š0.4 mm; univariate: p < 0.001; multivariate: p = 0.006) were highly significantly associated with the development of type 2 endoleaks of the HRG. CONCLUSION: The most important predictive factors for the development of high-risk type 2 endoleaks were mainly the number and the diameter of the LAs which perfused the AAA. KEY POINTS: • This study is a very detailed and comprehensive analysis of the value of various CT parameters as potential predictors of the clinical outcome of type 2 endoleaks after EVAR. • Anatomical as well as thrombus-specific parameters were unsuitable as predictors. • The most important predictive factors were mainly the number and the diameter of the LAs which perfused the AAA.

Can early computed tomography angiography after endovascular aortic aneurysm repair predict the need for reintervention in patients with type II endoleak?

PURPOSE: This study was designed to identify parameters on CT angiography (CTA) of type II endoleaks following endovascular aortic aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA), which can be used to predict the subsequent need for reinterventions. METHODS: We retrospectively identified 62 patients with type II endoleak who underwent early CTA in mean 3.7 ± 1.9 days after EVAR. On the basis of follow-up examinations (mean follow-up period 911 days; range, 373-1,987 days), patients were stratified into two groups: those who did (n = 18) and those who did not (n = 44) require reintervention. CTA characteristics, such as AAA, endoleak, as well as nidus dimensions, patency of the inferior mesenteric artery, number of aortic branch vessels, and the pattern of endoleak appearance, were recorded and correlated with the clinical outcome. RESULTS: Univariate and receiver operating characteristic curve regression analyses revealed significant differences between the two groups for the endoleak volume (surveillance group: 1391.6 ± 1427.9 mm(3); reintervention group: 3227.7 ± 2693.8 mm(3); cutoff value of 2,386 mm(3); p = 0.002), the endoleak diameter (13.6 ± 4.3 mm compared with 25.9 ± 9.6 mm; cutoff value of 19 mm; p < 0.0001), the number of aortic branch vessels (2.9 ± 1.2 compared with 4.2 ± 1.4 vessels; p = 0.001), as well as a "complex type" endoleak pattern (13.6 %, n = 6 compared with 44.4 %, n = 8; p = 0.02). CONCLUSIONS: Early CTA can predict the future need for reintervention in patients with type II endoleak. Therefore, treatment decision should be based not only on aneurysm enlargement alone but also on other imaging characteristics.

Effect of hemodialysis on kinetics of acetaminophen elimination by anephric patients.

The pharmacokinetics of acetaminophen elimination were determined in 4 anephric patients during hemodialysis and on an interdialysis day. The biologic half-life of acetaminophen ranged from 119 to 147 min on an interdialysis day and was decreased by 42% to 53% during hemodialysis. Individual mean dialyzer extraction ratios, based on assay of plasma samples from blood flowing into and out of the dialysis unit, were 0.46 to 0.78 for acetaminophen, 0.53 to 0.57 for acetaminophen glucuronide, 0.13 to 0.60 for acetaminophen sulfate, and 0.70 to 0.87 for urea nitrogen. There was a strong correlation between the extraction ratios of acetaminophen and urea nitrogen. Hemodialysis was the major or sole routine of elimination of acetaminophen glucuronide and sulfate in the anephric patients.

Effectiveness of centrally acting drugs and diuretics in adolescent hypertension.

The effectiveness and tolerance of a centrally acting antihypertensive agent (clonidine) was compared to that of a diuretic (hydrochlorothiazide) in treatment of adolescents with essential hypertension. After a phase on placebo 29 adolescents with fixed primary hypertension were randomly assigned, double blind, to one of two treatment groups. Active therapy was initiated at a low dose (0.1 mg clonidine b.i.d. or 24 mg hydrochlorothiazide b.i.d.) for 12 wk. In those in whom treatment goals for blood pressure control had not been reached, the dose was increased (clonidine to 0.2 mg and hydrochlorothiazide to 50 mg) for 12 wk. In the clonidine-treated group there was a reduction during low-dose therapy in systolic (P less than 0.05) and diastolic pressure (P less than 0.01) and heart rate (P less than 0.01). With low-dose diuretic therapy there was a reduction in systolic pressure only (P less than 0.05). Linear growth patterns were normal for both groups, but there was a reduction in serum potassium in the diuretic group (P less than 0.001). Of the two drugs investigated the centrally acting clonidine was more effective in blood pressure control (85%) than the diuretic (40%).

Pentobarbital elimination in patients with poor renal function.

Drug oxidation is slowed in experimental uremia in animals but has been reported to be normal or accelerated in uremic patients. Eleven normal subjects and 9 uremic patients were each given 100 mg pantobarbital orally. Several blood samples were drawn over a 36-hr period starting on the morning after the dose. Plasma pentobarbital concentration was measured by GLC. The log concentration values were graphed against time elapsed after dose for each patient, and the plasma T/2 and extrapolated value of concentration at the time of drug administration (Co) were determined. The T/2 values in normals ranged from 18 to 48 hr; mean, 26.5 +/- 9.2 (SD). In uremic patients, T/2 values are 10 to 38 hr, mean, 21.3 +/- 8.7. Four of the uremic patients had T/2 values below 18 hr (which was the lowest in the normals). The apparent volumes of distribution of pentobarbital (aVD = dose divided by Co) were 62 +/- 25 L in the normal subjects and 58 +/- 24 L in the uremic patients. The four uremic patients with the short T/2 values tended to have small apparent volumes of distribution so that the metabolic clearnce rates (aVd X 0.693 divided by half-life) were normal in 3 of them. We conclude that pentobarbital elimination is normal in renal failure. Some uremic patients have short plasma T/2 values for pentobarbital, and these more likely result from low apparent volumes of distribution with normal metabolic clearance rates than from accelerated metabolism of pentobarbital.

Influence of uremia, hemodialysis, and nonesterified fatty acids on zomepirac plasma protein binding.

Zomepirac binding to plasma of uremic patients before hemodialysis and to that of healthy subjects was compared. Unbound zomepirac in plasma of uremic patients averaged 3.7% to 4.0% of the 14C-zomepirac added (0.2, 2, and 20 micrograms/ml). This was more than the percentage of unbound zomepirac observed when the same 14C-zomepirac concentrations were dialyzed against plasma from healthy subjects (mean 1.3% to 1.4%). Plasma albumin from uremic patients appeared to have lower apparent binding affinity for zomepirac. Oleic, stearic, and palmitic acids, when added to plasma at concentrations of 2.0 mM, markedly reduced zomepirac free fraction, but, there were no significant differences between uremic and normal plasma in total nonesterified fatty acid (NEFA) concentrations after equilibrium dialysis. Thus, plasma NEFAs do not contribute to the differences in zomepirac plasma binding between normal and uremic plasma. Hemodialysis increased zomepirac binding to plasma of uremic patients, but NEFA concentrations were also increased in hemodialyzed plasma. Enhanced zomepirac binding by NEFAs could not be differentiated from other effects of hemodialysis, such as the removal of endogenous inhibitors of drug plasma protein binding. The binding of zomepirac was not affected by its three known metabolites: zomepirac glucuronide, hydroxyzomepirac, and 4-chlorobenzoic acid.

Effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone in diet-controlled diabetes.

The effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone were evaluated in 10 patients with diet-controlled diabetes. Eight had mild hypertension, and 2 had normal blood pressure. Prior to receiving amiloride all were studied for renin and aldosterone responses while supine and after 2 hr ambulation. All had a normal response to change in position in the renin and aldosterone systems. Before administration of amiloride glucose tolerance tests were carried out, with simultaneous determinations for potassium and insulin. Amiloride 5 to 10 mg was given orally for 6 wk. Blood glucose and serum potassium levels were monitored weekly. After 6 wk renin and aldosterone responses were again determined, as were oral glucose tolerance and serum potassium and serum insulin levels. Amiloride did not induce hyperkalemia in these diabetic patients and did not alter the postamiloride relationship. It is concluded that amiloride is safe for patients with an intact renin aldosterone system, more especially those with normal renal function and diet-controlled diabetes mellitus.

Elimination of procainamide in end stage renal failure.

To investigate the effect of end stage renal insufficiency and hemodialysis on the serum half-life of procainamide, 500 mg of procainamide was given orally to control subjects and dialysis patients on interdialysis days. Procainamide was assayed by spectrophotometry and spectrophotofluorometry. Mean half-life in normal subjects was 3.2 hr by spectrophotometry and 3.5 hr by spectrophotofluorometry. Mean half-life in patients was 11.3 hr by spectrophotometry and 16.0 hr by spectrophotofluorometry (p less than 0.001 compared to control subjects). Half-life of procainamide during dialysis in patients given 500 mg of procainamide 1 hr before dialysis was 4.3 hr and 9.6 hr on a nondialysis day (p less than 0.001). Both methods of assay gave higher levels of procainamide when the metabolite, N-acetylprocainamide, was present in serum and the extract allowed to stand in 1 N HCl, but spectrophotometry was less affected. Thus, end stage renal insufficiency greatly prolongs the half-life of procainamide, procainamide is readily dialyzable, and N-acetylprocainamide is hydrolyzed in 1 N HCl to procainamide during routine serum determinations.

Biochemical and dynamic responses to single and repeated doses of methyldopa and propranolol during dynamic physical activity.

Our purpose was to describe changes in potassium disposition with antirenin antihypertensives during dynamic physical activity in normal subjects receiving methyldopa and propranolol. Before the study, 2 hr after dosing and coincident with immediate preexercise on treadmill (at graded increases of exercise), and 2 hr after exercise, blood was sampled for determination of potassium, renin, aldosterone, and catecholamine levels. Blood pressure and heart rate were measured. The results demonstrate no greater increase in potassium after single or multiple doses of methyldopa than after placebo. After the first dose of propranolol there was a greater rise in potassium over that with placebo, but it was not observed after multiple doses, which may be related to the low doses. There were minor, but significant, changes in norepinephrine, renin, and systolic pressure with multiple-dose methyldopa and in renin, heart rate, and systolic and diastolic pressure with propranolol. Overall, the adrenergic responses to exercise win methyldopa and propranolol were biochemically altered rather than functionally impaired. The latter is related to dose and the underlying age and state of health of our subjects. Methyldopa (or clonidine) may be useful in patients with hypertension who exercise and are predisposed to pertubations in potassium disposition.

Dynamic and biochemical responses to single and repeated doses of clonidine during dynamic physical activity.

Beta-adrenoceptor blockade increases serum K, which may be related to renin inhibition, hypoaldosteronism, and exercise-induced skeletal muscle release of serum K. We report on the dynamic and biochemical response to clonidine (C) after single (S) 0.2-mg and repeated (R) 0.1-mg bid doses of C to six normal subjects at rest, 2 hr after dosing and immediately before dynamic physical activity (DPA) on a treadmill, and at peak activity and 2 hr after DPA. Blood pressure (BP), heart rate (HR), plasma renin concentration (PRC), aldosterone (ALD), serum K, epinephrine (E), and norepinephrine (NE) were measured in standing subjects before and 2 hr after placebo or C (S or R), at peak DPA, and 2 hr after exercise. K, BP, and HR were also determined during all stages of DPA. Results show a parallel rise in K at peak over rest after C (S or R) and after placebo. NE, E, and PRC decreased after 1 wk of C (P less than 0.01), but the fall of ALD was only slight. The fall in NE at rest suggested a relationship to the decrease in systolic BP and rate pressure product after 1 wk on C. With DPA there is a normal yet smaller increase in systolic BP and also a smaller rise in HR with S- and R-dose C. There is no adverse rise in K in C-treated subjects during DPA.

Prazosin kinetics and effectiveness in renal failure.

Single and repeated doses of prazosin were given to 17 hypertensive patients, 5 with normal renal function and 12 with impaired renal function. Blood for prazosin assay was drawn after a 1-mg single dose and after patients reached steady-state levels with their long-term maintenance dose. As blood was drawn blood pressure was recorded. Prazosin absorption was not altered in patients with impaired renal function, and there is no cumulation of the drug when given repeatedly to patients with impaired renal function. Elimination kinetics were virtually identical regardless of degree of renal function. Effect on blood pressure was significantly better at the dosage range of 3 to 8 mg/day than at higher doses of 9 to 20 mg/day. There does not appear to be a direct relationship between the peak plasma prazosin level and the nadir of antihypertensive response. This would seem to indicate that the drug leaves the plasma and goes to the vascular smooth muscle receptor site of action. There appears to be no impairment in prazosin elimination in patients with impaired renal function, and its effectiveness (with diuretic or dialysis) is optimum at 3 to 8 mg/day.