Barry R. Walker

Reassessment of verbal and visual analog ratings in analgesic studies

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.

Renal disease, age, and oxazepam kinetics

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 (t½), 10 hr; area under the curve (AUC), 6.0 μg·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 llhrlkg. Less than 1% of the dose was excreted intact in urine. Age differences had no influence on results. In renal insufficiency patients, t½ 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 t½. In dialysis patients, t½ 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.

Effects of two nonsteroidal anti‐inflammatory drugs, indomethacin and oxaprozin, on the kidney

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 in 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.

Guanabenz effects on blood pressure and noninvasive parameters of cardiac performance in patients with hypertension

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 welt as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statisticalty and clinically significant decrease in blood pressure during a 4‐wk placebo‐controlted 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 (ECG) abnormalities. Noninvasive parameters of cardiac performance in JO 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.”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 welt as peripheral adrenergic neuron blockade. In this study, the drug was shown to produce a statisticalty and clinically significant decrease in blood pressure during a 4‐wk placebo‐controlted 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 (ECG) abnormalities. Noninvasive parameters of cardiac performance in JO 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.

Effects of Increased Sodium Delivery on Distal Tubular Sodium Reabsorption with and without Volume Expansion in Man

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.

Oxaprozin disposition in renal disease

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 (Vssd), and elimination half‐life (tl/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 Vssdu 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.

Fanconi Syndrome with Renal Tubular Acidosis and Light Chain Proteinuria

A patient is described with Sjogren’s syndrome, the Fanconi syndrome, proximal and distal renal tubular acidosis, and elevations of both blood and urine gamma globulin and light chains. Triamterene ha

Disposition of 14C-guanabenz in patients with essential hypertension.

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.

Multiple-Dose Kinetics and Dialyzability of Oxazepam in Renal Insufficiency

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

Cystinuria, Hyperuricemia and Uric Acid Nephrolithiasis

A patient was reported who illustrates the importance of early diagnosis of cystinuria. Hyperuricemia and uric acid lithiasis also were present. This association with cystinuria has been reported prev