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The objectives of this study were two-fold: (1) a 4-week multicentre, randomized, double-blind efficacy comparison of placebo and guanabenz acetate, a new centrally acting antihypertensive drug, in 168 hypertensive out-patients and (2) a more accurate determination of the incidence of drug-related, non-specific side-effects. Both treatment groups were comparable: 68% female, 63% black, mean age 53 years; 57% mild, 32% moderate, 11% moderately severe hypertensives. Seventy-six placebo patients completed 4 weeks and had a mean supine diastolic blood pressure (SDBP) decrease from 105 to 101 mm Hg (p < 0.01). Seventy-nine guanabenz patients completing 4 weeks had a mean SDBP decrease from 104 to 92 mm Hg (p < 0.01). All of the placebo responses and 10/12 mm Hg of the guanabenz response occurred during Week 1. Clinically significant individual SDBP decreases occurred in thirty-one (41%) placebo and fifty-five (70%) guanabenz-treated patients (p < 0.01). Mean daily guanabenz dose was 24 mg. Drug-related biochemical or electrocardiographic abnormalities were absent. Side-effects of sedation and dry mouth were recorded two and three times more frequently, respectively, in guanabenz as compared to placebo patients. Side-effects usually occurred within Week 1 and diminished in incidence thereafter. Consequently, in these patients it appeared that: (1) guanabenz was an effective, well-tolerated drug, (2) placebo effects on efficacy were significant, occurred early and remained stable, and (3) placebo and guanabenz side effects were mainly sedation and dry mouth.

The acute and chronic renal effects of indoramin, an alpha 1-adrenoceptor antagonist, were investigated in six normotensive men (mean +/- SEM age, 36 +/- 3 years). Renal clearance studies were done during steady-state water diuresis before administration of indoramin (baseline), 3-4 h after a single 50-mg oral dose (acute study), and after 7 days of treatment with 25 mg twice daily (chronic study). After a single 50-mg oral dose, mean supine blood pressure decreased from 117/76 mm Hg at baseline to 109/74 mm Hg (NS), and glomerular filtration rate and renal blood flow were unchanged. There were small decreases (0.05 less than p less than 0.1) in the fractional excretion of sodium and potassium. After chronic administration (7 days) of indoramin, no significant changes in blood pressure, renal function, renal hemodynamics, or fluid and electrolyte excretion were observed. Mean body weight tended to decrease and fractional sodium excretion increased slightly (NS) after 7 days of indoramin. Plasma renin and aldosterone concentrations tended to increase (NS) after chronic indoramin administration. The results of this study indicate that acute and chronic administration of indoramin does not adversely affect renal function, renal hemodynamics, or fluid and electrolyte excretion in normotensive subjects.

To determine the effects of methyldopa on renal function, clearance studies were performed on hypertensive subjects during sustained steady-state water diuresis. The data reveal an acute fall in glomerular filtration rate and sodium clearance, whereas renal blood flow was unchanged. The antinatriuresis was the result of decreased filtration of sodium and possibly enhanced proximal tubular sodium reabsorption. These changes occurred before any demonstrable fall in systemic blood pressure; thus a direct effect of the drug on arteriolar resistance within the renal circulation is suggested. Chronic administration of methyldopa for 1 wk induced sustained reduction in blood pressure and resulted in the same changes in renal hemodynamics and sodium excretion noted after acute administration. These data suggest that methyldopa, like other antihypertensives, reduces glomerular filtration rate and increases sodium retention.

Guanabenz, a centrally acting alpha-adrenergic antihypertensive agent, produces neither the sodium retention seen with other centrally acting agents nor the metabolic abnormalities characteristic of diuretics. In this study, which involved 204 hypertensive out-patients, the additive effects of guanabenz and hydrochlorothiazide were compared with the effects of hydrochlorothiazide therapy alone. Before randomization to the 6-month blinded addition of either guanabenz or placebo, hydrochlorothiazide (50 or 100 mg/day; mean, 70 mg/day) was administered as sole therapy for 6 weeks. During this time, mean supine diastolic blood pressure (SDBP) decreased from 102 to 94 mm Hg (p less than 0.01), with a satisfactory clinical response rate of 62% and a mean weight loss of 2 lbs (p less than 0.01). No further change in mean SDBP occurred during the next 6 months of diuretic therapy, whereas the addition of guanabenz (mean dose, 24 mg/day) caused a further decrease in mean SDBP to 88 mm Hg (p less than 0.01), an increase in the response rate to 86%, and no weight change. Pulse rates in both groups were unchanged. The principal side-effects in both groups were dry mouth, drowsiness, weakness, and dizziness, with a greater incidence of each during the combination therapy. The usual laboratory abnormalities were associated with hydrochlorothiazide. Guanabenz was found to enhance the antihypertensive efficacy of hydrochlorothiazide without compromising its natriuretic properties or producing additional metabolic abnormalities.

Nonsteroidal antiinflammatory drugs (NSAIDs) are known to exert numerous effects on renal function ranging from actions on renal hemodynamic parameters to direct alterations in renal endocrine and tubular transport. Whereas many of these effects result from the capacity of these agents to alter the production of prostaglandins (PGs) in the renal vasculature as well as in the renal tubular cells, some of the observed actions may be due to the direct pharmacologie effects of these agents. In this review, we will discuss the actions of NSAIDs on renal hemodynamics and tubular transport. Particular emphasis will be placed on the comparative effects of Oxaprozin on these various parameters, using data obtained in specific studies designed to evaluate the renal pharmacology of this agent.

The effect of renal disease on lorazepam kinetics was assessed in three groups: six normal subjects, six patients with renal impairment, and four functionally anephric patients. Subjects received single 1.5- or 3-mg intravenous and oral doses; eight subjects (four normal and four with renal impairment) also received 0.5-mg oral doses three times a day. Lorazepam and lorazepam glucuronide were determined in plasma, urine, and feces by a highly sensitive gas chromatographic method. After single doses, t1/2 and V beta increased in patients, but Cls in the patients (about 85 ml/min) did not differ significantly from that in normals (71 ml/min). Absorption of oral dose was more than 90% and was not impaired by the disease state. Renal and fecal excretion of intact lorazepam accounted for only about 2% of the dose. The major route of drug elimination was hepatic biotransformation to lorazepam glucuronide, an inactive, nontoxic metabolite eliminated by the kidney. In both the normal and renally impaired groups, about 64% of the dose was recovered as glucuronide in urine and less than 0.4% in feces. Fecal excretion contributed very little to the overall elimination of lorazepam and its glucuronide in all groups. Only 8% of the intact drug was removed by 6-hr hemodialysis, but 40% was removed as glucuronide conjugate. Lorazepam kinetics after subchronic dosing were linear. The difference in Clo between the normal and renally impaired groups was not significant. Since the mean steady-state concentration depends on drug clearance only, and since clearance is not altered, no dosage adjustment appears necessary for patients with renal disease.

The incidence of potentially serious drug-related elevations of BUN or serum creatinine was examined among 1468 patients with rheumatoid arthritis or osteoarthritis who took daily therapeutic doses of aspirin, ibuprofen, or Oxaprozin, an investigational nonsteroidal antiinflammatory drug (NSAID), in multicenter clinical trials. Algorithms were developed to identify patients with potentially important elevations of these renal laboratory parameters and to assess the possible relation between these elevations and the study drugs. All three drugs were associated with a low (4% to 6%) incidence of potentially significant elevations in renal function parameters. Changes considered serious occurred in only three (

Mazindol is chemically unrelated to the phenethylamines and has not shown the side-effects or abuse potential of the amphetamine anorectics. To further define its potential for causing weight loss, a six-week double-blind placebo controlled study was undertaken in four centres. A common protocol was used except that in one centre, behavioural modification also was employed, whereas in the other centres, no additional measures were used to cause weight loss. Two hundred and forty-five obese patients were assigned randomly to two mazindol groups and one placebo group in each centre. Ninety-eight and forty patients receiving mazindol and placebo respectively completed the protocol. The conclusions were: (a) no significant clinical or laboratory abnormalities occurred from mazindol therapy, (b) the placebo therapy patients did not lose weight without behavioural modification, (c) the placebo therapy group had a higher drop-out rate compared to the mazindol therapy group attributable to the patients' dissatisfaction with failure to lose weight, (d) mazindol therapy without behavioural modification and behavioural modification alone both resulted in a statistically significant mean weight loss of 1 pound/patient/week and (e) mazindol plus behavioural modification resulted in a greater mean weight loss of 1/2 pound/patient/week than with behavioural modification alone. Hence, mazindol is of value in the initial therapy of obesity.

Oxaprozin, a new long-acting, antiinflammatory agent, and aspirin were compared utilizing gastroscopic evaluation and photography of the gastric mucosa in a double-blind, crossover study in normal volunteers. Submucosal hemorrhages or mucosal bleeding was observed in seven of eight subjects on aspirin and in only two of eight on oxaprozin (P = 0.061). Adverse effects were experienced by seven of eight subjects after the aspirin treatment period--tinnitus in five and gastrointestinal symptoms in four. Only one patient had mild diarrhea on oxaprozin. The incidence of adverse effects was found significantly higher with aspirin therapy (P less than 0.001). No laboratory abnormalities of clinical significance were attributed to either drug administration. Results after ten days of treatment show that oxaprozin in therapeutic dose levels (1200 mg once a day) produces significantly fewer changes in the gastric mucosa than aspirin (975 mg administered four times a day, total daily dose 3.9 Gm) in the same subjects, who received both drugs in this double-blind, crossover experiment with a four-week washout period between treatments.

The effects of oxaprozin, a new investigational propionic acid analogue, and indomethacin on uric acid metabolism were compared in 12 healthy volunteers receiving either agent, first as a single dose and then daily for seven days. While indomethacin did not alter either serum or urinary uric acid values, oxaprozin caused a fall in serum uric acid levels from 5.8 +/- 0.2 mg/dL to 4.8 +/- 0.4 mg/dL (P less than 0.01). Urinary uric acid excretion rose from a baseline of 673 +/- 47 mg to 825 +/- 66 mg/24 h by day 7 of treatment (P less than 0.01). Since oxaprozin was associated with no change in glomerular filtration rate in these studies, the hypouricemic effect of oxaprozin is most likely a result of its direct uricosuric action. Because indomethacin and oxaprozin both are inhibitors of urinary prostaglandin E2 excretion, the data suggest that prostaglandin inhibition per se is not associated with changes in uric acid excretion.

Capsules containing either 16 or 32 mg of 14C-guanabenz were given to 8 hypertensive patients. Maximum concentrations of guanabenz in plasma (1.2 to 5.2 ng/ml) were reached at 2 to 5 hr after dosing. 14C elimination into urine was 79.7 ± 10.6% (SD) and 76.7 ± 7.4% of the dose after the 16- and 32-mg doses, respectively, while guanabenz accounted for less than 1% after either dose. Kinetic parameters for guanabenz were estimated by fitting the plasma and urinary data to a 2-compartment model. After the 16-mg dose, the elimination half-life (t½) was 14 ± 5 hr, volume of distribution in the central compartment (Vc) was 5.0 ± 2.2 kl, and total plasma clearance (Clp) was 8 ± 4 l/min. After the 32-mg dose, t½ was 12 ± 3 hr, Vc was 7.5 ± 1.8 kl, and Clp, was 17 ± 6 l/min. No statistically significant difference, except of total plasma clearance, was observed between any of the parameters followed after the 2 doses. (E)-p-Hydroxyguanabenz (unconjugated and as a glucuronide) was the major metabolite and accounted for 35.4 ± 3.0% of the urinary radioactivity. Minor amounts of guanabenz and 2,6-dichlorobenzyl alcohol after β-glucuronidase hydrolysis indicated that N-glucuronidation and cleavage at the benzol carbon were minor metabolic pathways. The drug effectively lowered blood pressure in the hypertensive patients; no other significant effects were noted. Clinical Pharmacology and Therapeutics (1980) 27, 44–52; doi:10.1038/clpt.1980.7

The effects of renal disease on the steady-state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half-lifes were not different. The mean total AUC, peak concentration, average steady-state plasma concentration, and trough concentration for total and unbound oxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozin in patients on hemodialysis. The higher dose—averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozin may not need to be reduced when albumin levels are normal. Clinical Pharmacology and Therapeutics (1988) 44, 303–309; doi:10.1038/clpt.1988.154

The pharmacokinetics of guanabenz (16 mg) and hydrochlorothiazide (25 mg), administered separately and as a fixed-combination tablet (guanabenz 16 mg/hydrochlorothiazide 25 mg), were compared in a randomized three-period crossover study in 24 healthy men. Plasma concentrations were monitored for 48 h after each administration. No statistically significant differences between the two formulations were noted in mean plasma concentrations or the rate and extent of absorption of guanabenz. The relative bioavailability (Fr) of the combination tablet compared with guanabenz alone was 96%; thus the two formulations were bioequivalent with respect to guanabenz. For hydrochlorothiazide, mean plasma concentrations were similar for 3 h after administration but were higher for the combination tablet than for hydrochlorothiazide alone from 4 through 48 h (p less than 0.05). A significant increase in the extent, but not the rate, of absorption of hydrochlorothiazide was observed for the combination tablet (mean Fr, 120%), which is not considered clinically significant. We propose that this increase may have been due to increased systemic availability of hydrochlorothiazide in the presence of guanabenz, an alpha-adrenergic agonist, which may have delayed intestinal transport of hydrochlorothiazide, resulting in enhanced gastrointestinal absorption.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to cause sodium retention and to decrease glomerular filtration rate (GFR). We studied the effects of two such drugs, indomethacin and oxaprozin, a new propionic acid derivative, on renal function of awake, normal human subjects during sustained water diuresis. Although neither drug had a long-term effect on GFR or sodium clearance (CNa), indomethacin (six subjects) but not oxaprozin (seven subjects) transiently reduced GFR and CNa. Given over the short term, oxaprozin caused a reduction in GFR from 113.7 +/- 5.7 to 99.8 +/- 4.7 ml/min (p < 0.01) and CNa from 0.84 +/- 0.07 to 0.61 +/- 0.08 ml/min (p < 0.005). The results were much the same when an additional dose of indomethacin was given to subjects who had been receiving the drug for a week. Inference from clearance data at a time when urinary osmolality (Uosm) remained constant but urine flow per GFR (V/GFR) fell suggests that both drugs stimulated proximal tubular sodium and fluid resorption. Both suppressed renin and aldosterone levels comparably and reduced potassium excretion transiently, but only indomethacin caused a sustained change in serum potassium concentration; serum potassium rose from 4.32 +/- 0.10 to 4.56 +/- 0.11 mEq/l (p < 0.05) after 1 wk. These disparate findings suggest that prostaglandin synthesis inhibition may not be the sole mechanism of action of NSAIDs.

The safety and efficacy of guanabenz and clonidine were compared in 188 hypertensive patients during a 6-month double-blind trial. Mean supine diastolic blood pressure (SDBP) decreased from 103 to 88 mm Hg (p < 0.01) among guanabenz patients and from 101 to 88 mm Hg (p < 0.01) among clonidine patients who completed 6 months of b.i.d. therapy. Clinically significant individual SDBP decreases occurred in 85% of the guanabenz patients and in 83% of the clonidine patients after 6 months. Adverse effects, consisting primarily of drowsiness, dry mouth, dizziness, and weakness, were similar in the two therapy groups. The responses obtained with guanabenz (b.i.d.) were maintained, along with a decrease in adverse effects, by an equivalent single daily dose of guanabenz during a second 6 months of therapy. Seventy-six per cent (13/17) of the patients whose blood pressure was not adequately controlled by guanabenz alone after 8 weeks of therapy subsequently responded to a combination of guanabenz and hydrochlorothiazide. Similarly, 85% (17/20) of the patients who failed to respond to clonidine alone subsequently responded to guanabenz either alone or in combination with hydrochlorothiazide. These results suggest that guanabenz or the combination of guanabenz and hydrochlorothiazide is effective therapy for the majority of hypertensive patients.

The relative performance of three analgesic rating scales—visual pain analog, verbal pain intensity, and verbal pain relief—was assessed in clinical trials with 1,497 patients and a variety of pain models. The scales correlated strongly with one another, with inconsistent and generally minimal differences in sensitivity. Overall, the verbal relief scale tended to be slightly more sensitive than the pain analog rating, which in turn showed a small advantage over the verbal pain intensity assessment. When the scores derived from the categorized ratings 1 hour after drug dosing (generally the time of peak effect) were analyzed, there was little difference whether a parametric or nonparametric approach was taken. When the cumulative measures of overall effect over 6 hours were considered, however, the nonparametric approach was decidedly more powerful. There was a similar pattern when the analog scores were analyzed. This unanticipated finding appears to be due to the cumulative measures (from all three scales) being more skewed toward the lower end of their respective ranges than are the 1-hour scores. A composite efficacy variable was defined, incorporating data from the three primary scales; this measure was found to be generally comparable in sensitivity to the individual scales and may be useful as a global summary of response. While our investigation provides evidence that any of the ratings considered will accurately reflect analgesic response, the verbal relief scale was the most sensitive and might be the best choice if a single measure is desired. Clinical Pharmacology and Therapeutics (1985) 38, 16–23; doi:10.1038/clpt.1985.127

Triamterene administered for 2 weeks to 16 normal volunteers increased the renal clearance of sodium and magnesium without affecting calcium or phosphate excretion. It decreased the uric acid clearance in proportion to the decrease in creatinine clearance. Triamterene induced no significant change in serum calcium, phosphate, or uric acid, but there was a slight increase in serum magnesium. The results support the hypothesis that sodium transport in the distal tubule can be inhibited without affecting calcium reabsorption. The mechanism for the increased blood and urine magnesium is not known but could be both renal and extrarenal. There was no evidence for an inhibition of tubular secretion of uric acid. On the basis of these data, it seems unlikely that triamterene could produce clinically significant hypercalcemia or hyperuricemia in nonazotemic patients. However, magnesium depletion could result from long-continued use, especially when triamterene is combined with other diuretics which also increase magnesium excretion.

Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally impaired, or who had been undergoing hemodialysis. Oral dose clearance (Cloral), volume of distribution at steady-state (V88d), and elimination half-life (t 1/2) did not substantially differ among the three groups. Mean fraction unbound oxaprozin in plasma (fup) increased from 0.08% in the normal group to 0.18% and 0.28% in the two azotemic groups. Consequently, unbound drug kinetic parameters, including intrinsic clearance (Clint) and V88du of unbound drug were reduced from 2.9 l/hr/kg and 193 l/kg in normal subjects to approximately 1.6 l/hr/kg and 91 l/kg in azotemic patients. The smaller volume of distribution is consistent with a decrease in oxaprozin tissue binding in azotemia. The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day.

7 patients with chronic renal insufficiency (4 of whom were on maintenance hemodialysis) and 6 healthy controls received single 15-mg oral doses of oxazepam for 7 consecutive days. Multiple venous blo

Effects of renal insufficiency and age on oxazepam kinetics were assessed in 13 normal subjects (21 to 72 yr old), four patients with renal insufficiency, and eight patients on hemodialysis. Normal intact oxazepam results were: mean elimination half-life (t1/2), 10 hr; area under the curve (AUC), 6.0 microgram.hr/ml; unbound oxazepam fraction (fup), 3.2%; maximum concentration of unbound oxazepam (Cmax,u), 16 ng/ml; and intrinsic (unbound drug) clearance (Clint), 2.9 l/hr/kg. Less than 1% of the dose was excreted intact in urine. Age differences had no influence on results. In renal insufficiency patients, t1/2 was prolonged to 25 hr, fup increased to 7%, and Cmax,u and Clint were unchanged. Volume of distribution of unbound oxazepam (Vu) increased, thereby prolonging t1/2. In dialysis patients, t1/2 was prolonged to 33 hr, fup increased to 6.2%, and Cmax,u and Clint again were unchanged. Oxazepam was undialyzable; since unbound oxazepam disposition kinetics are not altered, no dosage adjustment for patients is necessary.

Patients with end stage renal disease who are maintained on haemodialysis have elevated levels of many hormones, some of which may play a role in the pathogenesis of the complications of uraemia. The infusion of synthetic somatostatin reduces the circulating level of many of these same hormones in patients with normal renal function. If the elevated hormone levels in dialysis patients could be similarly lowered, study of the pathogenitic significance of the various hormonal abnormalities would be facilitated. With this in mind, the effect of synthetic somatostatin on the circulating level of growth hormone, glucagon, insulin, gastrin, parathyroid hormone, and thyroid stimulating hormone in dialysis patients was investigated. In pilot protocol, a dose of 2 mg of somatostatin infused over 24, 18, or 12 hours (two patients each) was found to have no effect on any hormonal level. Infusion of 2 mg of somatostatin over 4 hours, however, was associated with consistent fall in the level of growth hormone (13.6 ± 6.2 to 6.53 ± 2.9, p = 0.15) and glucagon (595.0 ± 73 to 441 ± 28, p < 0.05) in each of four patients. The percentage change in the level of growth hormone and glucagon during the 4-hour somatostatin infusion was significantly different from the change occurring during a 4-hour timed control period (growth hormone —45 ± 18% vs +9 ± 7%, [p < 0.05]), (glucagon −27% ± 2% vs + 8 ± 2%, [p < 0.01]). There was no change in the level of any other hormone during the 4-hour infusion. No significant adverse effects were seen. This study suggests that the intravenous infusion of somatostatin can, at least on an acute basis, lower the level of growth hormone and glucagon in patients with end stage renal failure; and, therefore, it may be useful in further study and possibly the treatment of the hormonal abnormalities of end stage renal disease.

Nafcillin (N) pharmacokinetics was studied in 27 subjectswith and without renal failure (RF) (determined by endogenous creatinine clearance, Ccr). Elimination rate constants (K) were calculated from serial serum levels of N measured from 2 to 12 hr after a single 500-mg intramuscular injection. Only 4 of 9 hemodialysis patients had measurable levels of N at 24 hr. The K values for the groups with normal renal function,moderate RF, severe RF, and on hemodialysis were 0.477 hr(-1), 0.432 hr (1), 0.369 hr(-1), and 0.306 hr (-1), respectively...

We evaluated the potential hepatic toxicity of ibuprofen, aspirin, and oxaprozin in 1468 patients with rheumatoid arthritis and osteoarthritis by slightly modifying an algorithm that was developed to evaluate the drug relatedness of renal toxicity associated with therapeutic doses of these agents in the same population. Ibuprofen proved to be the safest of these nonsteroidal antiinflammatory drugs; it was associated with no AST elevation that was considered probably drug related as determined by application of the algorithm to laboratory values and information from case report forms. The frequency of probably drug-related AST elevations was highest (5%) with aspirin; with oxaprozin, an investigational nonsteroidal antiinflammatory drug, the incidence (3%) fell between that for the other two agents. Thus our findings on the hepatic safety of ibuprofen are consistent with those in the medical literature.

Guanabenz (2,6 dichlorobenzylidene amino guanidine acetate) is a new antihypertensive whose mechanism of action appears to involve both central alpha adrenergic stimulation leading to suppression of sympathetic nervous system activity from bulbar vasoconstriction centers as well as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statistically and clinically significant decrease in blood pressure during a 4-wk placebo-controlled double-blind study. For three additional months continued efficacy and safety were shown under open conditions in 17 hypertensive patients. Mild sedation occurred, but there were no postural hypotension, tachycardia, evidence of sodium retention, gastrointestinal disturbances, or electrocardiographic (ECB) abnormalities. Noninvasive parameters of cardiac performance in 10 patients after single doses of guanabenz showed no significant changes. Although the numbers of patients were relatively small, the data suggest that this new drug may be a useful antihypertensive agent that warrants further investigation.

In previous placebo-controlled studies, guanabenz was shown to be a safe and effective antihypertensive drug without acute effects on cardiac function. In view of its therapeutic advantages, a double-blind comparison of guanabenz with methyldopa was performed in a group of 36 patients over 6 mo. Both drugs produced statistically and clinically significant decreases in blood pressure with similar side effects. No laboratory or electrocardiographic abnormalities were found other than positive Coombs' tests which developed in 3 patients during methyldopa therapy. Cardiac performance in 26 of the patients, as measured by noninvasive techniques, showed no significant changes from either drug except for a progressive and statistically significant increase in systolic time interval (QS2) and the ratio of the pre-ejection period to left ventricular ejection time (PEP/LVET) during methyldopa therapy. For an additional 6 mo, continued efficacy and safety were shown under open conditions in those patients who had received guanabenz. The study suggests that guanabenz may be an important new antihypertensive drug because of effectiveness, absence of adverse cardiac effects, and paucity of side effects.

Preliminary clinical studies showed that oxaprozin (4,5 Diphenyl-2-oxazolepropionic acid) has anti-inflammatory and analgesic properties with a plasma half-life of about 40 hours. Consequently, a multicentre, double-blind parallel trial was conducted for 12 weeks at thirteen investigator sites, utilizing 212 patients with classic rheumatoid arthritis and comparing oxaprozin 600 mg/day, oxaprozin 1200 mg/day and aspirin 3900 mg/day. Both the oxaprozin and aspirin-treated patients had statistically significant improvement from baseline periods, in most key categories evaluated. Oxaprozin administered twice a day (b.i.d.) was as effective as aspirin administered four times a day (q.i.d.) and caused significantly less tinnitus (p < 0.001). Fewer patients receiving high dose oxaprozin (2%) dropped out of the study because of unsatisfactory response than did those receiving aspirin (10%). There were no clinically significant laboratory abnormalities in the gastro-intestinal, renal, hepatic or haematological parameters monitored. This study suggests that oxaprozin is effective and well tolerated in the treatment of rheumatoid arthritis.

Twelve healthy volunteers received single 1200-mg oral doses of oxaprozin while fasting and immediately after a standard breakfast in a two-period crossover design with three weeks between administrations. Oxaprozin plasma concentrations were monitored during a 10-day period after each dose. No statistically significant differences were noted between kinetic parameters obtained in the fasting and post-prandial states for mean peak plasma concentrations (Cmax, 103 vs. 109 micrograms/ml), absorption rate constants (ka, 1.1 vs. 0.8 h-1), or total AUC (7042 vs. 7066 micrograms/ml X hr). Compared with doses administered during fasting, postprandial doses led to a delay in the onset of absorption in the gastrointestinal tract (lag time t0, 24 vs. 9 min), but not in the peak time (tmax approximately 5 hours). Oxaprozin's mean residence time t was slightly shorter for subjects in the postprandial state (72 hours) than for those in fasting state (73 hours), probably because of the intrasubject variability in half-life (48 vs. 50 hours). The results of this study indicate that the ingestion of food has no effect on the bioavailability of oxaprozin.

To the Editor:— In the editorial, "A Nontraditional View of Heart Failure" ( JAMA 189: 57 [July 6] 1964), the statement that "the readily recognizable signs and symptoms of congestive heart failure such as dyspnea, orthopnea, restlessness, abdominal discomfort, edema, hepatomegaly, and congested veins result from circulatory congestion and are not directly related to cardiac function" implies that this is an original unequivocal conclusion of clinical significance demonstrated by Rader et al ( Circulation 29: 328 [March] 1964). This is not so. Over 60 years ago, Widal et al ( Bull Mem Soc Med Hop Paris 20: 1208 [June 12] 1903) demonstrated that the peripheral manifestations of congestive heart failure could be altered by changing the salt content of the diet. These observations, plus the fact that subjects who become edematous gain weight, indicated quite clearly that edema is due to extracardiac mechanisms which control the excretion of salt and water. A regimen

Eleven patients with maturity-onset diabetes mellitus and 6 normal subjects were studied to determine whether they would develop abnormal serum potassium or glucose levels in response to triamterene, to an acute glucose load, or to an acute glucose load during triamterene therapy. The response in each case depended on the presence of diabetes and the degree of glucose intolerance before triamterene. The normal subjects and mild diabetic patients showed no change in pattern of response to glucose load after triamterene, while the moderate diabetic patients displayed certain metabolic changes under the same experimental conditions. Triamterene caused a minor, reversible increase in serum potassium in all subjects but an increase in fasting blood sugar only in the moderate diabetic patients. In all groups there was a decline in creatinine clearance after 7 days on triamtercne. In addition, the moderate diabetic patients developed hyperkalemia during an intravenous glucose tolerance test while on triamterene therapy. Only one of the moderate diabetic patients developed hyperkalemia during an oral glucose tolerance test. Possible mechanisms for these effects are discussed and the use of triamterene in diabetes mellitus is assessed.

A B S T R A C T The separate effects of volume expansion and of increased delivery of sodium on sodium reabsorption in the diluting segment of the distal nephron were studied in man. In six normal subjects during a sustained water diuresis, sodium delivery to the distal nephron was increased without volume expansion by the administration of acetazolamide. In these subjects, free water clearance rose linearly as a function of urine flow. In five patients with complete, central diabetes insipidus, distal sodium delivery was increased by the infusion of hypertonic saline during a sustained water diuresis. In four of these five patients, changes in free water clearance were also observed during hypertonic saline diuresis in the presence of distal blockade of sodium reabsorption with chlorothiazide. At high rates of distal delivery the following observations were made: (a) free water clearance was lower and fractional sodium excretion higher during saline diuresis compared to acetazolamide diuresis; (b) although free water clearance was moderately reduced by chlorothiazide at low rates of urine flow, there was no difference in free water clearance between saline loading alone and saline plus chlorothiazide at high rates of urine flow; and (c) during saline loading free water clearance rose without evidence of a limit when increased distal delivery was accompanied by spontaneous increases in glomerular filtration rate, but tended toward a limit when glomerular filtration rate remained constant. The data indicate that during acute volume expansion with saline, there is a decrease in the fraction of delivered sodium reabsorbed in the distal nephron when compared to the response of the distal nephron to comparable increases in distal sodium delivery in the absence of volume expansion.

Nine patients with sickle cell anemia (SS) and four with sickle cell trait (AS) were studied for evidence of nephropathy. Two of the SS patients died with uremia, and three others had proteinuria, including one with the nephrotic syndrome. With light microscopy, eight SS patients were found to have anatomical changes similar to those caused by a proliferative glomerulonephritis, whereas the AS patients were found to have no significant abnormalities. In cases of SS, renal function tests did not reflect the degree of pathological glomerular disease. Anatomical abnormalities seemed to correlate with the number of sickle cell crises, and may have been due to renal arteriolar ischemia. Previous reports of SS histology have not emphasized glomerular changes. It is postulated that, as the life span of SS patients increases, clinical evidence of glomerular disease will be seen more frequently.

A 42-year-old man had polycythemia, polycystic kidney disease, and azotemia. To our knowledge, this entity has not been reported.

Hyperuricemia of unknown etiology has been associated occasionally with sickle cell anemia (SS). Asymptomatic SS patients were compared to normal volunteers, with the former showing a significant increase in the ratio of total uric acid to creatinine excretion suggesting increased purine synthesis. There was no difference between the two groups in the ratio of uric acid to creatinine clearance (C Ur /C Cr ), nor were there abnormalities in peripheral lactate and pyruvate levels in the SS group. When the SS patients were separated into those with hyperuricemia and those without, there was a significant decrease in C Ur and C Ur /C Cr in the hyperuricemics. These findings suggest that hyperuricemia in SS patients occurs when defective renal function is superimposed on the excessive purine synthesis. It is not known whether the hyperuricemia or uricosuria plays any role in sickle cell nephropathy.