Richard A Reeves

Serum Concentrations of Salicylic Acid following Topically Applied Salicylate Derivatives

OBJECTIVE: To compare the rate and extent of systemic salicylate absorption following single and multiple applications of two topically applied analgesics, one containing methyl salicylate and the other containing trolamine salicylate. DESIGN: Two-period, two-treatment, randomized, crossover, multiple-dose study in healthy men and women volunteers. PARTICIPANTS: Six men and six women volunteers, 21–14 years of age. INTERVENTIONS: Subjects applied 5 g of an ointment containing 12.5% methyl salicylate twice daily for 4 days (8 doses) or a cream containing trolamine 10% twice daily for two doses, to a 10-cm2 area on the thigh. Treatment order and leg (right or left) were assigned randomly. Subjects were crossed over to the alternate treatment on the other leg after a minimum washout period of 7 days. MAIN OUTCOME MEASURES: The total amount of salicylate recovered in the urine during two dosing intervals (24 hours) on each study day, relative to the applied dose, was used to calculate the bioavailability of each product. Mean standard pharmacokinetic parameters including area under the curve, maximum concentration (Cmax), time to maximum concentration, and minimum concentrations at steady-state were determined from serum concentrations. Serum concentrations were fit to three pharmacokinetic models and the suitability of each model was evaluated. Estimates of absorption rate constant, clearance, volume, and fraction absorbed on day 1 were estimated by using the best-fitting model. RESULTS: Salicylic acid could not be detected in serum after trolamine application. However, concentrations between 0.31 and 0.91 mg/L were detected within 1 hour of the first application of methyl salicylate and Cmax, between 2 and 6 mg/L were observed following the seventh application on day 4. Both the extent and rate of absorption changed after the first 24 hours. The absorption rate constant increased significantly from the first to the seventh dose (first dose absorption rate constant: 0.16 h−1; seventh dose: 0.28 h−1; p < 0.035). Urinary recovery of total salicylate (salicylic acid and principal metabolites of salicylic acid) during the first 24 hours of the methyl salicylate phase averaged 175.2 mg, exceeding the 6.9 mg (p < 0.05) recovered during the trolamine phase. The recovery of salicylate in the urine in the first 24 hours after application of methyl salicylate was significantly greater than the 1.4% recovered after application of trolamine (p < 0.05). Furthermore, the fraction of methyl salicylate recovered in the urine increased significantly from 15.5% on day 1 to approximately 22% on the second, third, and fourth days. CONCLUSIONS: A considerable amount of salicylic acid may be absorbed through the skin after topical application of methyl salicylate products and this may increase with multiple applications. Caution is warranted in patients for whom systemic salicylate may be hazardous or problematic.

Epinephrine and left ventricular function in humans: Effects of beta‐1 vs nonselective beta‐blockade

Changes in cardiac performance in response to epinephrine administered by graded infusion were assessed by M‐mode echocardiography in normotensive healthy subjects after pretreatment with placebo, the β1‐selective blocker atenolol, or the nonselective β‐blocker propranolol. Epinephrine alone increased heart rate and left ventricular end diastolic dimension and decreased left ventricular end systolic dimension. Left ventricular performance as assessed by fractional shortening and systolic blood pressure/end‐systolic volume (P/V) ratio was also increased. Atenolol pretreatment did not significantly affect the increase in heart rate by epinephrine. However, atenolol did prevent the effects of epinephrine on left ventricular dimensions and left ventricular performance at the lower infusion rates and significantly blunted these effects at the highest infusion rate. After propranolol, epinephrine significantly decreased left ventricular end diastolic dimension despite decreasing heart rate and left ventricular emptying (associated with a high afterload). P/V ratio remained unchanged. These results indicate that β2‐receptors may play a major role in the increase in heart rate caused by epinephrine. In contrast, epinephrines positive inotropic effect appears to be mediated primarily via β1‐receptors and, at higher concentrations, possibly also through β2‐receptors. The pattern of changes in left ventricular end diastolic dimension suggests that epinephrine increases venous return via both β1 and β2‐receptor stimulation and that α‐receptor stimulation (epinephrine after propranolol) may actually decrease venous return.

Nonselective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine, and angiotensin II in normal man

Nonselective β‐blockers increase peripheral vascular resistance and, sometimes, blood pressure (BP); increased responsiveness to circulating pressor agents could be one of the underlying mechanisms. Heart rate (HR) and BP responses to graded intravenous infusions of epinephrine, norepinephrine, and angiotensin II were recorded after placebo and then after 4 wk of β‐blocker treatment (nadolol or propranolol, 240 mg/day) in 10 healthy young men. Adequacy of β‐blockade was demonstrated by a mean 31% decrease in HR response to bicycle exercise, with no differences between the two β‐blockers. Under placebo conditions epinephrine lowered diastolic BP and raised HR; these effects were reversed during treatment with β‐blockers. β‐Blockade potentiated BP responses to norepinephrine and angiotensin II: Thirty‐five percent less norepinephrine and 52% less angiotensin II were required to increase mean BP by 15 mm Hg. A final study 2 wk after β‐blocker cessation revealed the absence of lasting effect. These results confirm the concept of unopposed α‐constriction for epinephrine and also demonstrate increased BP responses to norepinephrine and angiotensin II during chronic β‐blockade.

Evaluation of the Pharmacokinetic and Pharmacodynamic Interaction Between Quinidine and Nifedipine

Quinidine and nifedipine appear to be subject to metabolism by the same isozyme of cytochrome P‐450. In addition, both drugs have been reported to alter the pharmacokinetics of other compounds. To investigate a potential interaction, 10 healthy subjects (five male, five female) received quinidine sulfate (200 mg orally), nifedipine (20 mg orally), or the combination of both drugs every 8 hours for 4 doses using a randomized, cross‐over study design with a 2‐week washout period between treatments. Drug concentration, heart rate, and mean arterial pressure were measured at frequent intervals after the final dose. Quinidine concentrations were unchanged by the co‐administration of nifedipine. Nifedipine area under the curve (AUC0–8) increased 36.6% from 333 to 455 μg · hr/L (P <.05) after quinidine administration. Heart rate was significantly higher in the nifedipine‐quinidine treatment at 0.5, 1.0, 1.5, and 2.0 hours when compared with either drug alone. The maximum increase in heart rate (17.9 beats/minute) occurred at 0.5 hours after nifedipine administration and was significantly correlated with serum concentrations at that time (r = .78). These results suggest that quinidine inhibits nifedipine metabolism, and this pharmacokinetic interaction results in enhanced pharmacologic response.

Reproducibility of nurse-measured, exercise and ambulatory blood pressure and echocardiographic left ventricular mass in borderline hypertension.

Objective: To compare the short-term reproducibility of four diagnostic tests: resting blood pressure, exercise blood pressure, non-invasive daytime ambulatory blood pressure and echocardiographic left ventricular mass. Design: Blinded, prospective test-retest (reliability) study. Setting: Hypertension research units in two teaching hospitals. Participants: Six normal volunteers and 22 patients with untreated borderline to mild hypertension, mean age 44 years. Main outcome measures: The intraclass correlation coefficient (R1) and standard deviation of the difference (SDD) between visits. Main results: The mean blood pressures and left ventricular mass did not differ between visits. Concordance between visits reached R1 = 0.86 systolic/0.66 diastolic for ambulatory blood pressure and R1 = 0.85 systolic/0.64 diastolic for nurse-measured random-zero sphygmomanometer resting blood pressure. The respective variabilities were SDD = 9/8 and 8/8 mmHg. Submaximal exercise systolic blood pressure (SBP) and echo left ventricular mass showed excellent reliability. Echo left ventricular mass and resting SBP or ambulatory SBP were significantly more reproducible than resting diastolic blood pressure (DBP) or ambulatory DBP. Conclusions: Despite averaging many readings within each day, clinically important between-visit variations in ambulatory blood pressure remained. The between-visit variability of daytime ambulatory blood pressure was similar to that of resting blood pressure when carefully measured by a research nurse. The echo left ventricular mass appears to be more reproducible over the short term than the current diagnostic standard for hypertension, the resting DBP.

Hemodynamic interaction of nonselective vs. beta‐1‐selective beta‐blockade with hydralazine in normal humans

To assess the effects of nonselective vs. β1‐selective β‐blockade on the hyperdynamic circulation induced by hydralazine, eight healthy volunteers received placebo, propranolol, 20 and 40 mg, and atenolol, 25 and 50 mg, on 5 separate days, followed by hydralazine (range 75 to 150 mg). Hydralazine decreased afterload (end‐systolic wall stress) and increased venous return and left ventricular performance (by M‐mode echocardiography). Both β‐blockers blunted the increases in heart rate, cardiac output, and venous return similarly, although heart rate and cardiac output were not completely normalized. Atenolol did not affect the hydralazine‐induced decrease in afterload, whereas propranolol significantly opposed this change (P < 0.03). The hyperdynamic circulation seen with hydralazine is mostly β mediated, primarily β1. When given with hydralazine the two β‐blocker types differ primarily in their effects on afterload.