Pharmacokinetics of naproxen in elderly patients.

The pharmacokinetics of naproxen have been examined in 13 elderly patients (mean age 84.2 years) and in 9 younger patients (mean age 53.9 years) at the end of a 21 day course of therapy with naproxen 500 mg b.d. The mean pre-dose concentration on days 19, 20 and 21 was significantly higher in the elderly patients than in the controls (60.1 vs. 43.3 micrograms X ml-1). The AUC (0-24) was significantly higher in the elderly subjects only when normalized for body weight (9.1 vs. 5.4 micrograms X ml-1 X h kg-1 p less than or equal to 0.02). The AUC was significantly higher in the elderly group compared to the control group also in the normalized form. The apparent clearance of naproxen was reduced in the elderly compared to the control patients (315 vs. 628 ml X h-1). The percentage protein binding of naproxen was the same in both groups (99.8%) but the free concentration of naproxen was significantly higher in the elderly patients than in the control patients (141 vs. 89.8 ng X ml-1). Although there was no excess of side effects in the elderly patients it is suggested that when naproxen is given to elderly patients, therapy should be started at the lower end of the dosage range.

The pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol in patients with moderate hypertension.

1 The effects on heart rate and blood pressure after single and multiple dosing (1 month) of a long acting formulation of propranolol 160 mg daily, and conventional propranolol, 80 mg twice daily, or 160 mg daily were compared in 11 moderately hypertensive subjects previously shown to respond to propranolol. 2 After acute dosing all three treatments produced significant reduction in blood pressure. After multiple dosing all three treatments maintained significant reductions in lying, standing and exercise heart rate and blood pressure throughout the 24 h. At 24 h, after multiple dosing, the fall in resting and standing systolic BP was significantly greater with LA propranolol than with conventional propranolol 80 mg twice daily or conventional propranolol 160 mg once daily (P at least less than 0.05). 3 The plasma propranolol concentration time curve after LA propranolol showed slowed absorption, and the area under the curve was significantly lower than after conventional propranolol (acute dosing; LA propranolol 160 mg 560 mg ml-1 h, conventional propranolol 80 mg twice daily 1135 mg ml-1 h, conventional propranolol 160 mg daily 1414 mg ml-1 h).

The influence of urinary pH on the disposition of indomethacin in healthy volunteers.

The influence of urinary pH on the plasma levels and renal elimination of unchanged indomethacin has been studied in seven healthy volunteers with the use of a specific and sensitive gas-liquid chromatographic method assay for indomethacin in plasma and urine. There is a wide variation in the terminal t1/2 (2.5-10.3 h) and the AUC (5264-12693 ng/ml h) of indomethacin after a standard oral dose (50 mg) under 'normal' urinary condition. Such variation is probably, in part, due to an intersubject difference in extrarenal elimination of the drug. The urinary recovery of unchanged indomethacin is highest at alkaline pH (15.7 +/- 5.3%), lowest at acidic pH (3.5 +/- 2.0%) and the 'normal' value is 7.1 +/- 1.6%. These differences are statistically significant. Despite such influence there is no apparent change in plasma levels of the drug under uncontrolled and controlled (acidic and alkaline) conditions of urinary pH. The clinical implication is that possible changes in urinary pH during long-term treatment of arthritic patients may not affect the overall kinetics of indomethacin which is extensively eliminated by the extrarenal route.

A clinical and pharmacokinetic study of indomethacin in standard and slow release formulations.

Fifteen patients with rheumatoid arthritis received indomethacin in three treatment schedules; indomethacin retard 75 mg twice daily; indomethacin capsules 50 mg three times daily; and indomethacin 100 mg suppository at night with 50 mg by mouth each morning. The study was a double-blind, double-dummy one with each treatment being given for 2 weeks after a washout period of 3 days. After the washout period, and at the end of each 2 week active treatment period, blood samples were taken during a dosage interval for assay of indomethacin concentrations in plasma. Clinical assessments were also performed. All three treatment period produced significant clinical improvements in the assessments compared with the placebo washout period. However, no differences were seen between the treatments. Side effects occurred with equal frequency in all three periods, and the anticipated reduction in central nervous system side effects during the indomethacin retard period was not seen. Plasma concentrations of indomethacin were significantly higher during indomethacin retard therapy with a peak concentration of 2500 +/- 25 ng ml-1 during indomethacin retard therapy (mean +/- s.d.) and 1900 +/- 200 ng ml during conventional oral therapy. Indomethacin retard is as effective as the other formulations of indomethacin but appears to offer no significant advantages.

Lack of effect of ranitidine on warfarin action.

1 In five volunteers taking daily subtherapeutic doses of warfarin the addition of ranitidine 200 mg twice daily for 14 days did not affect prothrombin time or plasma warfarin concentration. 2 Ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat. 3 Ranitidine had no effect on pentobarbitone sleeping time in the rat whereas cimetidine significantly prolonged the sleeping time. 4 The interaction between cimetidine and oral anticoagulants is unrelated to histamine H2-receptor antagonism.

Indomethacin in rheumatoid arthritis: comparison of oral and rectal dosing.

1 Indomethacin 100 mg nightly for 1 week has been administered to 13 patients with rheumatoid arthritis by both oral and rectal routes in a double-blind, randomized, cross-over study. 2 Clinical assessments were performed at 09.00 and 14.00 h on the last 3 days of each active treatment period and compared to the results on the last 2 days of the placebo control period. 3 Indomethacin produced significant improvements in the clinical assessments at both 09.00 and 14.00 h compared to placebo but not differences were seen between the two routes of administration. 4 No significant difference was seen in the side effects experienced in the two periods. 5 The mean (+/- s.e. mean) plasma indomethacin concentration at 09.00 h in the oral period was 200.3 +/- 27.4 ng/ml, not significantly different from that in the suppository period (220.0 +/- 28.9 ng/ml). 6 Indomethacin 100 mg nightly by mouth is as effective as a 100 mg suppository and easier to administer.

Interaction between diflunisal and warfarin.

The effect of diflunisal on steady-state warfarin dynamics and kinetics was studied in five healthy men taking daily subtherapeutic doses of warfarin. Diflunisal 500 mg twice daily for 2 wk increased the percentage unbound warfarin from 1.02% to 1.24% and lowered total warfarin from 741 to 533 ng/ml, but did not alter the anticoagulant response (prothrombin complex activity, PCA). When diflunisal was discontinued but warfarin continued, there was a loss of anticoagulant effect and a difference in the rates at which percentage unbound warfarin and total warfarin concentration returned to prediflunisal levels. There was a correlation between plasma diflunisal and percentage unbound warfarin. Diflunisal reduced both the maximum plasma protein-binding capacity for warfarin and the apparent association constant.

Propranolol in the control of blood pressure: a dose-response study.

In a double-blind crossover study, it has been shown that the hypotensive response to propranolol in 24 patients with essential hypertension was no greater at doses of 80, 160, or 240 mg twice daily than at 40 mg twice daily. A relationship was observed between dose and response as defined by the ability to achieve a standing diastolic blood pressure of 95 mm Hg. Four patients with low plasma renin activity (PRA) had no fall in blood pressure even at highest dose levels. Plasma propranolol levels in the groups were related to dose, and up to a concentration of 300 ng/ml, with degree of beta-adrenoceptor blockade; there was, however, no correlation with hypotensive response.

The effect of indomethacin on renal function in man.

Twenty-one patients with rheumatoid arthritis were given indomethacin 25 mg t.i.d. by mouth for 3 weeks followed by indomethacin 25 mg t.i.d. plus a 100 mg suppository at night, after a 5-day period on placebo capsules. The mean (+/- S.E.) 24-hour creatinine clearance was 57.8 +/- 5.7 ml/min in the placebo period and was not significantly altered during indomethacin therapy, 53.1 +/- 5.5 ml/min in the oral period and 56.6 +/- 6.4 ml/min in the oral plus suppository period (P greater than 0.1). In 6 volunteers, duplicate 2-hour creatinine clearances were performed after a single oral dose of 50 mg indomethacin. After placebo capsules the mean creatinine clearance was 133.7 +/- 9.5 ml/min and after 50 mg indomethacin it was 126.5 +/- 8.9 ml/min (P greater than 0.1). In 4 of the volunteers the mean creatinine clearance after 8 days on indomethacin 25 mg q.i.d. was 117.1+/- 5.3 ml/min (P greater than 0.1). Indomethacin plasma concentrations were in the usual range for the dose given. Indomethacin caused no reduction in the creatinine clearance in spite of causing significant inhibition of prostaglandin E synthesis.

Cimetidine: interaction with oral anticoagulants in man.

In 6 patients anticoagulated with warfarin, nicoumalone, or phenindione the addition of cimetidine prolonged the prothrombin-time (PT) by a mean of 12.6 s (range 5--23 s). In 7 volunteers taking daily subtherapeutic doses of warfarin the addition of cimetidine increased the PT from 19.4 to 22.9 s and the plasma-warfarin concentration from 0.96 to 1.76 microgram/ml. Cimetidine reduced the single-dose clearance of warfarin and antipyrine. The basis of the interaction between cimetidine and oral anticoagulants is probably inhibition of drug metabolism. Care should be exercised in concomitant therapy.

Indomethacin in rheumatoid arthritis: clinical effects, pharmacokinetics, and platelet studies in responders and nonresponders.

Twenty patients with definite or classical rheumatoid arthritis entered and completed a sequential study of placebo for 1 week, oral indomethacin 25 mg 3 times a day for 3 weeks, and oral indomethacin 25 mg 3 times a day plus 100 mg indomethacin suppository at night for 3 weeks. Twelve of the patients had previously been classified as responders and eight as nonresponders to indomethacin by an independent assessor. At the end of each period patients were assessed by a blind observer for duration of morning stiffness, pain score, digital joint size, grip strength, articular index, analgesic tablet usage, and the patient's own overall global assessment and comparative global assessment. In 8 of the 9 tests used responders improved on indomethacin in comparison with placebo, while nonresponders did not improve. There were no significant differences between responders and nonresponders in the plasma half-life, plasma clearance of indomethacin, protein binding of indomethacin, or urinary excretion of free or conjugated indomethacin. There were no significant differences between responders and nonresponders in the urinary excretion of 7HDPA or in the platelet aggregation or platelet malonyldialdehyde production tests. In responders there was a significant positive correlation between the plasma indomethacin concentration (r=0.44, P<0.05) and the percentage inhibition of malonyldialdehyde production by the platelets. However, in nonresponders this correlation, while significant (P<0.05), was negative (r=-0.498). Both for responders and nonresponders there was a significant correlation between plasma indomethacin concentration and the percentage reduction in 7HDPA. There was no correlation between the clinical response and the plasma concentration of indomethacin. There appears to be a biochemical difference between responders and nonresponders, which, while not necessarily causally linked with the clinical response to indomethacin, is worthy of further study.

The interaction between indomethacin and probenecid. A clinical and pharmacokinetic study.

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas-liquid chromatographic method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3-wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 +/- 213 hr ng/ml to 4,181 +/- 384 hr ng/ml when probenecid was given, but there was no change in the plasma half-life of indomethacin. There was a reduction in the mean plasma clearance of indomethacin from 174 +/- 21 ml/kg/hr to 107 +/- 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distribution from 0,927 +/- 0.16 L/kg to 0.613 +/- 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacin from 8,967 +/- 867 microgram/day to 4,760 +/- 674 microgram/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 +/- 48 ml/min to 126 +/- 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.

Quantitative gas-liquid chromatographic method for the determination of indomethacin in biological fluids.

A sensitive and specific gas chromatographic method for the analysis of indomethacin has been developed. After extraction of the drug from blood or urine with ethylene dichrloride a derivative is formed with pentafluorobenzyl bromide. 5-Fluoro-indomethacin is used as an internal standard. The overall recovery of indomethacin is 85.1 +/- 2.3% and the method can detect 10 ng indomethacin in a 1 ml plasma or urine sample. No interference in the method is seen with some commonly used drugs. The method has been used to measure plasma indomethacin concentrations in 20 patients with rheumatoid arthritis, being treated with 25 mg indomethacin three times daily. The plasma concentration ranged from 168-596 ng/ml.

May mothers given warfarin breast-feed their infants?

Warfarin was measured with a sensitive and specific method in the plasma and breast milk of 13 mothers. Less than 0-08 micronmol warfarin per litre (25 ng/ml) of breast milk was found in each instance. Seven of the mothers were breast-feeding their infants, in none of whom was warfarin detected in the plasma; furthermore, in three the British corrected ratio of the plasma was appreciably less than that of the mother and was within the expected range. We conclude that nursing mothers given warfarin may safely breast-feed their infants.