Investigation of the influence of acetylsalicylic acid on the steady state of long-term therapy with theophylline in elderly male patients with normal renal function.

The risk inherent in the clinical control of patients with theophylline is widely recognized. Elderly patients may present an additional risk because of altered pharmacokinetics and the use of concomitant medication. Acetylsalicylic acid has been proposed for primary and secondary prevention of myocardial infarction and possible strokes. This investigation was undertaken to determine if concomitant administration of acetylsalicylic acid in elderly patients would alter steady-state levels of theophylline. A population of smoking male patients older than 60 years of age under long-term control of chronic obstructive pulmonary disease (COPD) with theophylline were evaluated for a baseline period of 3 days. Serum levels were measured at 6:00 AM and 6:00 PM. An enteric-coated acetylsalicylic acid preparation, 650 mg by mouth, was added to the daily slow-release theophylline, 6:00 AM hour dose regimen for 4 weeks. The serum levels of theophylline and salicylates were measured at 6:00 PM after dosing and at 6:00 AM the following day, at weekly intervals for 4 weeks. Urine specimens collected before administration of medication at 6:00 AM were analyzed for salicylates to further confirm dosage compliance. All volunteers continued to be clinically controlled throughout the treatment period and no symptoms of either overdose or underdose of either medication occurred. Plateau or trough theophylline serum levels did not change significantly during the salicylate treatment period. Salicylate serum levels did show during treatment self-induced metabolism. It is concluded that in elderly male patients, a daily concomitant therapeutic salicylate regimen does not alter steady-state serum theophylline levels and therefore does not per se necessitate the assay of theophylline blood levels in elderly patients.

Pharmacokinetics and bioavailability of the RRR and all racemic stereoisomers of alpha-tocopherol in humans after single oral administration.

The plasma and red blood cell pharmacokinetics and bioavailability of the natural source (RRR, d) and all racemic (all rac, dl) stereoisomers of alpha-tocopherol were studied in 12 men in a double-blind randomized crossover study. Subjects were administered two 400-mg soft-gelatin capsules of either RRR or all rac alpha-tocopherol. Plasma alpha-tocopherol concentrations were determined by high-performance liquid chromatography at various time intervals for up to 96 hours postadministration. Pharmacokinetic modeling of the data showed that alpha-tocopherol was absorbed after a 2 to 4 hour lagtime and maximum plasma concentration occurred from 12 to 14 hours postadministration. There were no significant differences in the Ka, t1/2 a, beta, or t1/2 beta between RRR and all rac. Mean plasma alpha-tocopherol concentrations were greater for RRR than all rac from 10 to 96 hours postadministration and significantly greater at 24 hours (P < .05). The red blood cell alpha-tocopherol concentration from the RRR preparation was significantly greater than from the all rac preparation from 24 to 96 hours postadministration with Cmax for RRR (4.8 micrograms/mL) significantly greater than for all rac (4.0 micrograms/mL, P < .05). The RRR AUC0-96 for both plasma and red blood cells were significantly greater than the all rac AUC0-96 (P < .05) indicating a greater bioavailability of RRR versus all rac alpha-tocopherol. This difference in overall bioavailability was apparently not due to a single pharmacokinetic component.

Effects of MPTP and vitamin E treatments on immune function in mice.

The effects of treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and vitamin E, an antioxidant, on immune functions were examined. Male C57/B1 mice were fed daily with natural vitamin E for 12 weeks, subsequently injected i.p. with MPTP or its vehicle, and sacrificed 1 week later. Control mice received the stripped corn oil vehicle daily, in place of vitamin E. Oral vitamin E feeding increased cerebral vitamin E content by 60% (P = 0.05). However, MPTP attenuated this rise in cerebral vitamin E content when measured 1 week after treatment with the neurotoxin (P = 0.05). MPTP also produced an 80-90% reduction in striatal dopamine content in both the stripped corn oil control group and the vitamin E-treated group (P = 0.0000). One week after MPTP injection, the numbers of peripheral blood lymphocytes and the percent of spleen T-cells, but not B-cells, were decreased in those groups receiving MPTP alone or MPTP plus vitamin E (P less than 0.05 and 0.02, respectively). The Con A-induced IL-2 production of spleen cells was decreased in all treated groups (P less than 0.005). There was no difference in the mitogenic stimulative response to PHA, Con A or LPS. However, the response to PWM was increased in both MPTP and MPTP plus vitamin E-treated groups (P less than 0.05 and 0.001, respectively). On the other hand, the one-way mixed lymphocyte response of the splenocytes from the MPTP-treated group was increased (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin E supplements fail to protect mice from acute MPTP neurotoxicity.

The effect of chronic treatment with vitamin E (VE) on acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, as assessed by striatal dopamine (DA) depletion, was studied. Male C57B1/6J mice were fed VE (48 mg kg-1 per day, intragastric) for 4, 8, or 12 weeks prior to administration of MPTP (20 mg kg-1, i.p. x 3, 2 h intervals) or its diluent. Brain VE concentration was increased by exogenous supplements for 12 weeks. Striatal DA content was reduced by 85% to 90% after MPTP in control and VE-treated mice. Mice with elevated cerebral VE were not protected from MPTP toxicity, with DA content as an indicator. In conclusion, these findings indicate that moderate elevation of brain VE is not adequate for protecting DA-containing neurons against the toxic actions of a high dose of MPTP.

Bioequivalence study of nabumetone: tablet versus suspension.

The orally administered tablet and suspension of the analgesic drug nabumetone (Relafen), a novel naphthylalkanone, were tested for bioequivalence. Nabumetone is rapidly metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (BRL 10720). The pharmacokinetics of the metabolite were studied in 24 healthy adult male volunteers. Each received a 1-g dose of the nabumetone formulations in a balanced, randomized, two-way crossover investigation. Serum metabolite concentrations were determined over a 120-hour interval by high-performance liquid chromatography. The values of the pharmacokinetic parameters computed for tablet and suspension are presented in that order: area under the curve = 1,269:1,338 mg.hour/ml; absorption half-life = 1.04:0.83 hour; elimination half-life = 27.16:25.15 hours; lag time = 0.19:0.07 hour; peak concentration = 27.56:31.91 micrograms/ml, and time to peak concentration = 4.99:4.17 hours. The mean concentration of BRL 10720 was found to be higher during the first eight hours for the suspension than for the tablet. Using criteria for statistical significance, the values for peak concentration, time to peak concentration, elimination half-life, and lag time were found significant (p less than 0.05). These results may well be reflecting the increased absorption characteristics of the suspension due to the pharmaceutical characteristics of the preparation. The formulations were found to be bioequivalent when compared on the premise that no significant difference was detected when area under the curve and all other parameters were compared, based upon the 75/75 rule analysis.

Effect of cisplatin on hair cell morphology and lateral wall Na,K-ATPase activity.

The dose-response ototoxic effects of cisplatin were studied in guinea pigs. Loss of Preyer reflex and suppression of the N1 amplitude occurred in cisplatin-treated animals and was described as dose-related. Drug-induced hair cell damage, as observed with scanning electron microscopy, occurred sporadically throughout the turns of the cochlea and the incidence increased with dose. Na,K-ATPase activity in the lateral wall tissues was not significantly different between treatment groups. The results reported here indicate that cisplatin ototoxicity was dose-dependent, but was not directly related to Na,K-ATPase activity in the lateral wall.

Pharmacokinetics and urinary excretion of clavulanic acid after oral administration of amoxicillin and potassium clavulanate.

Clavulanic acid is a beta-lactamase inhibitor which prevents microbial lactamase inactivation of beta-lactam antibiotics. The pharmacokinetics and urinary excretion of clavulanic acid were studied in eight healthy adult volunteers after oral administration of 500 mg amoxicillin and 125 mg potassium clavulanate. Serum and urine clavulanic acid concentrations were assayed using high-performance liquid chromatography. Pharmacokinetic parameters were: t 1/2 beta = 1.019 +/- 0.090 hour, t 1/2 alpha = 0.276 +/- 0.031 hour, lag time = 0.321 +/- 0.018 hour, tmax = 1.042 +/- 0.80 hour, Cmax = 2.098 +/- 0.441 micrograms/ml, and AUC = 4.897 +/- 0.979 micrograms X hr/ml. Cumulative urinary excretion of clavulanic acid (as percentage of dose administered) was: 14.05 +/- 2.87 within 2 hours, 25.77 +/- 3.98 within 4 hours, and 27.85 +/- 4.27 within 6 hours after administration.

Differential stereoselectivity of methotrimeprazine enantiomers for selected central nervous system receptor types.

Optical isomers of methotrimeprazine, an analgesic/neuroleptic, were investigated with respect to their ability to interact with six receptor types or subtypes. Bovine caudate nucleus tissue homogenates provided the dopamine, opiate, and serotonin receptor populations studied in these experiments. The radioligands used in saturation and binding competition experiments were tritiated dopamine, spiperone, dihydromorphine, 5-L-methionine enkephalin, naloxone, and 5-hydroxytryptamine. Saturation experiments verified acceptable performance of these in vitro receptor assay systems and indicated that a one-site binding model was adequate for each of these ligands under the experimental conditions employed. The competition experiments exhibited statistically significant (p less than 0.05) differences in isomeric effects only for dopamine and 5-hydroxytryptamine receptors. The more active isomer, levorotatory methotrimeprazine, was shown to be pharmacodynamically equivalent to chlorpromazine at these receptor types. When the magnitude of receptor stereoselectivity is plotted against an estimate of the more active isomer's affinity for that particular receptor, an excellent correlation is observed. This suggests that a high degree of stereoselectivity characterizes a highly specific drug/receptor interaction. These findings are compatible with the conclusion that methotrimeprazine does not produce analgesia via a direct action upon opiate receptors.

The relationship between serum and saliva trimethobenzamide concentrations in man.

Six healthy volunteers provided simultaneous serum and mixed saliva specimens at various time intervals after receiving three different concentrations of trimethobenzamide HCI (total dose 800 mg) via rectal syringe on three separate occasions. Specimens were analyzed for trimethobenzamide content and the results subjected to pharmacokinetic analysis and other statistical procedures to identify characteristics of the relationship between distribution processes in these specimen types. On the basis of linear regression analysis there was a significant correlation (P less than 0.01) between saliva and serum drug content for both mean values (r = 0.94) at each sampling time and all individuals' paired data points (r = 0.72). Because of the large degree of scatter in individual pairs, the data were subjected to analysis of variance in an attempt to determine a potential source of this divergence. The relationship between serum and saliva drug concentrations was found to depend upon the time after drug administration. We conclude that a nonuniform process determines the relative degree of partitioning trimethobenzamide between serum and saliva.