Search PubMed⌕ Search

Biomedical subjects

R E Polk

Publications and source records attributed to R E Polk.

At least 37 records · Page 2Linked to original sources
PubMed1990

Vancomycin-induced histamine release and "red man syndrome": comparison of 1- and 2-hour infusions.

Vancomycin-induced "red man syndrome" (RMS) is mediated in part by histamine release, and its severity is correlated with the area under the plasma histamine concentration-time curve. Ten adult male volunteers participated in a randomized, double-blind, two-way crossover trial (1-week washout interval between regimens) to determine the effect of 1- and 2-h infusions of vancomycin (1.0 g) on histamine release and on the frequency and severity of RMS. The severity of RMS was classified a priori as mild, moderate, or severe from a combined score of pruritus and extent of erythema. Serial concentrations of histamine in plasma and concentrations of vancomycin in serum were measured at baseline and during and after each infusion. Of 10 subjects, 8 had evidence of RMS during the 1-h infusion (3 mild, 3 moderate, and 2 severe), whereas only 3 of the 10 subjects (all mild) had RMS during the 2-h infusion (P less than 0.05). The 1-h infusion was associated with a significantly greater peak concentration of histamine in plasma (1.8 +/- 0.7 versus 1.0 +/- 0.3 ng/ml, P = 0.004) and a greater total release of histamine (74.3 +/- 54.1 versus 36.4 +/- 22.6 ng.min/ml, P = 0.017) than was the 2-h infusion. These data suggest that administration of vancomycin over 2 h reduces the frequency and severity of RMS and the amount of histamine released compared with those after a 1-h infusion in healthy volunteers.

Adult↗
PubMed1990

In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes.

Some quinolone antibiotics cause increases in levels of theophylline in plasma that lead to serious adverse effects. We investigated the mechanism of this interaction by developing an in vitro system of human liver microsomes. Theophylline (1,3-dimethylxanthine) was incubated with human liver microsomes in the presence of enoxacin, ciprofloxacin, norfloxacin, or ofloxacin. Theophylline, its demethylated metabolites (3-methylxanthine and 1-methylxanthine), and its hydroxylated metabolite (1,3-dimethyluric acid) were measured by high-pressure liquid chromatography, and Km and Vmax values were estimated. Enoxacin and ciprofloxacin selectively blocked the two N demethylations; they significantly inhibited the hydroxylation only at high concentrations. Norfloxacin and ofloxacin caused little or no inhibition of the three metabolites at comparable concentrations. The extent of inhibition was reproducible in five different human livers. Inhibition enzyme kinetics revealed that enoxacin caused competitive and mixed competitive types of inhibition. The oxo metabolite of enoxacin caused little inhibition of theophylline metabolism and was much less potent than the parent compound. Nonspecific inhibition of cytochrome P-450 was ruled out since erythromycin N demethylation (cytochrome P-450 mediated) was unaffected in the presence of enoxacin. These in vitro data correlate with the clinical interaction described for these quinolones and theophylline. We conclude that some quinolones are potent and selective inhibitors of specific isozymes of human cytochrome P-450 that are responsible for theophylline metabolism. This in vitro system may be useful as a model to screen similar compounds for early identification of potential drug interactions.

Biotransformation↗
PubMed1989

Drug-drug interactions with ciprofloxacin and other fluoroquinolones.

Early investigational trials with new quinolone antibiotics revealed two important drug-drug interactions: decreased fluoroquinolone absorption when co-administered with magnesium-aluminum antacids and inhibition of theophylline metabolism. Subsequent studies have investigated the mechanisms of these interactions. With respect to the effect of antacids, the absorption of all quinolones appears to be significantly reduced by antacids containing magnesium and/or aluminum, and concomitant administration must be avoided. Other cations, such as calcium, iron, and probably zinc, appear to interact in a similar manner. Chelation between the quinolone and cation is the most likely mechanism. With respect to the effect on theophylline metabolism, quinolones inhibit specific cytochrome P-450 isozymes responsible for metabolism of methylxanthines, although there are major differences between the quinolones. Enoxacin is the most potent inhibitor, followed by ciprofloxacin, pefloxacin, norfloxacin, and ofloxacin. Caffeine metabolism is also inhibited, although the clinical significance is uncertain. Case reports describe renal failure associated with concomitant administration of cyclosporine and ciprofloxacin, although controlled trials have not demonstrated an interaction. Enoxacin has little effect on warfarin metabolism, suggesting that other quinolones may not affect warfarin disposition. Case reports of central nervous system toxicity from administration of nonsteroidal anti-inflammatory agents and quinolones need confirmation. Patients should be monitored closely when potential interacting agents are used; it is probable that not all interactions have been identified.

Antacids↗
PubMed1989

Influence of antihistamine pretreatment on vancomycin-induced red-man syndrome.

Twelve adult male volunteers participated in a double-blind study to determine the effect of pretreatment with histamine and/or histamine2 receptor antagonists on the incidence and severity of vancomycin-induced "red-man syndrome." Subjects received hydroxyzine, 50 mg, ranitidine, 300 mg, hydroxyzine plus ranitidine, or placebo at weekly intervals 2 h before a l-h infusion of vancomycin, 1,000 mg. The extent of erythema was evaluated by burn chart and pruritus was assessed by each subject using a rank scale; symptoms were thus classified a priori as mild, moderate, or severe and their summation determined a global severity score for red-man syndrome. There was no significant intrasubject variation between area under the concentration-time curves for histamine and vancomycin (P greater than .05). Pretreatment with hydroxyzine alone provided significant protection against vancomycin-induced erythema and pruritus (P less than .05) whereas the effect of ranitidine did not differ significantly from placebo. The combination of hydroxyzine and ranitidine offered no advantage over hydroxyzine alone. Similar results were observed for global severity scores. Thus in normal volunteers prior administration of a histamine antagonist (hydroxyzine) provided significant protection against vancomycin-induced red-man syndrome compared to that afforded by placebo. There was no significant benefit from the histamine antagonist alone or by its addition to a histamine antagonist.

Double-Blind Method↗
PubMed1989

Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers.

Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.

Adult↗
PubMed1989

Interaction between oral ciprofloxacin and caffeine in normal volunteers.

The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its major metabolite, paraxanthine, was investigated in healthy volunteers. Ten xanthine-free, fasting males were given 100 mg of caffeine orally 24 h before being given ciprofloxacin and again with the third dose of ciprofloxacin (750 mg administered every 12 h). Blood samples were serially collected after both doses of caffeine and after the first and last doses of ciprofloxacin. Ciprofloxacin significantly increased the half-life of caffeine (from 5.2 +/- 1.2 to 8.2 +/- 2.5 h) and the area under the caffeine concentration-time curve (from 16.3 +/- 6.6 to 25.9 +/- 7.8 micrograms.h/ml) while decreasing the total body clearance (from 106 +/- 41.6 to 58.2 +/- 28.8 ml/min per 1.73 m2). In addition, the rate of conversion of caffeine to paraxanthine was significantly delayed. There was no significant linear correlation between the urinary recovery of oxociprofloxacin at 0 to 12 h and the change in the area under the caffeine concentration-time curve. There was also a small but statistically significant increase in the area under the ciprofloxacin concentration-time curve during simultaneous administration of caffeine. We concluded that ciprofloxacin causes a significant increase in the half-life of caffeine and in the area under the caffeine concentration-time curve by reducing total body clearance. This interaction is due at least in part to a delay in the conversion of caffeine to paraxanthine. The clinical significance of these observations remains to be determined. Lastly, caffeine may alter the kinetics of ciprofloxacin, a possibility which should be more fully explored.

Adult↗
PubMed1988

Vancomycin and the red-man syndrome: pharmacodynamics of histamine release.

Two regimens for infusing vancomycin over 1 h (500 mg every 6 h for five doses or 100 mg every 12 h for three doses) were used in 11 volunteers. Subjects received both regimens one week apart; the regimen used first for each subject was randomized. Nine receiving the 1000-mg dose experienced the "red-man (neck)" syndrome; none had the reaction while receiving the 500-mg dose (P = .002). Plasma histamine concentration, measured every 10 min during the first infusion of each regimen, increased in most subjects given 1000-mg doses; there was only a slight change in histamine levels after 500-mg doses. There was a significant relation between histamine release and reaction severity; frequency and severity of the reaction declined with subsequent doses. We conclude that the red-man syndrome occurs frequently in normal adults who receive 1000 mg of vancomycin over 1 h, that vancomycin causes an infusion rate-dependent increase in plasma histamine concentration, and that the increase in plasma histamine concentration is correlated with the severity of the reaction.

Adult↗
PubMed1987

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

Adult↗
PubMed1986

Cefmenoxime kinetics during continuous ambulatory peritoneal dialysis.

The kinetics of the aminothiazolyliminomethoxy cephalosporin, cefmenoxime, were determined after a 30 min intravenous infusion of 15 mg/kg body weight in 6 adult subjects undergoing continuous ambulatory peritoneal dialysis. Concentrations of cefmenoxime in serum, urine and dialysate were determined by high-pressure liquid chromatography. The mean peak serum concentration was 92.8 +/- 11.6 micrograms/ml and the harmonic mean for the elimination half-life was 5.46 h. The volume of distribution at steady-state was 14.60 +/- 3.01 l/kg. Total body clearance of the drug was 31 +/- 7.7 ml/min with 8 +/- 5% and 5.75 +/- 2.72% of the administered dose being eliminated by renal and peritoneal clearance, respectively. Peritoneal clearance for all exchanges (n = 24) was 1.93 +/- 68 ml/min. These data suggest that peritoneal losses of this drug are minimal and doses conventionally employed in advanced renal failure can be utilized in the management of systemic infections.

Adult↗
PubMed1986

Comparative pharmacokinetics of azlocillin and piperacillin in normal adults.

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.

Adult↗
PubMed1986

Comparative pharmacokinetics of two multiple-dose mezlocillin regimens in normal volunteers.

Mezlocillin was previously reported to exhibit dose-dependent pharmacokinetics. These reports suggest that it may be possible to administer a relatively large dose at a longer interval than is usual and still achieve therapeutic concentrations in serum. In a randomized, crossover study, we compared concentrations of mezlocillin in serum after a single dose and at steady state in 12 healthy volunteers who received 4 g every 6 h and 5 g every 8 h. A slight, but statistically significant, dose-dependent effect was observed upon the area under the concentration-time curve and total body clearance. No accumulation was observed with either schedule. Although concentrations in serum were higher after the 5-g dose, the more frequent administration of the 4-g dose schedule produced serum concentrations above the MIC for susceptible bacteria for a greater portion of the day. In the absence of clear guidelines from human studies which relate serum concentrations to clinical response, the available data indicate that the more frequent dosage schedule is appropriate for severe infections.

Adult↗
PubMed1986

Vancomycin pharmacokinetics in continuous ambulatory peritoneal dialysis patients with peritonitis.

Peritonitis has proven to be the major deterrent to the further growth of continuous ambulatory peritoneal dialysis (CAPD) as a treatment strategy for end-stage renal disease. The correct treatment of peritonitis remains unsettled as evidenced by the presence of advocates for oral, intravenous or intraperitoneal antibiotic administration. This study examines the pharmacokinetic parameters of intravenous vancomycin when employed in the therapy of peritonitis. One gram of intravenous vancomycin was administered during 7 episodes of peritonitis in 5 patients. Plasma and end-of-dwell dialysate levels were maintained above the minimum inhibitory concentration for Staphylococcus aureus and S. epidermidis for 7 days following this single dose of vancomycin. These data establish the existence of sustained intraperitoneal entry of intravenous vancomycin during peritonitis and raise for speculation its use as the sole therapy in most episodes of gram-positive peritonitis.

Adult↗
PubMed1986

Controversies in antimicrobial therapy: critical analysis of clinical trials.

Problems with design and statistical evaluation of clinical efficacy trials of antimicrobial agents are reviewed. Of the three major criteria used for evaluating antimicrobial agents (efficacy, toxicity, cost), the most important is efficacy. Clinical efficacy can be evaluated in uncontrolled or controlled clinical trials. Uncontrolled trials are often conducted to satisfy Food and Drug Administration requirements during premarketing testing; the response rate is typically high because only patients with susceptible infections may be treated and large doses are given. Controlled antibiotic trials should be randomized, blinded, parallel comparisons of an investigational agent versus the best available agent at an accepted dose. However, interpretation of these studies is frequently clouded by poor study design, small sample sizes, and heterogeneous patient populations. Controlled trials are usually centered around a null hypothesis (i.e., that no difference will be found between the agents being compared). All conclusions (to reject or not reject the null hypothesis) should be carefully evaluated by clinicians seeking to apply the available data to patient care. Researchers can incorrectly conclude that two therapies have equal efficacy because of insufficient statistical power (i.e., small sample size) or poor study design. Likewise, researchers may incorrectly conclude that there is a statistical difference between two therapies because of poor design or improper sample selection. For the clinician, clinical relevance takes precedence over statistical significance. Before the results of a study are allowed to affect drug use in an institution, strong similarities between subjects and methods in the study and patients and care in the institution should be demonstrated.

Anti-Bacterial Agents↗
PubMed1986

Multiple-dose pharmacokinetics of piperacillin and azlocillin in 12 healthy volunteers.

The pharmacokinetic profile of piperacillin and azlocillin after multiple-dose administration to healthy volunteers was studied. Twelve healthy volunteers received either piperacillin 4 g (as the sodium salt) or azlocillin 4 g (as the sodium salt) as a 20-minute infusion every six hours for five doses. After a one-week washout period, subjects received identical treatment with the alternate drug. Serum and urine concentrations of piperacillin and azlocillin were measured using a reversed-phase high-performance liquid chromatographic assay, and the pharmacokinetic analysis of serum concentration-versus-time data was performed using a computerized program. A standard open-model equation for i.v. infusions was used. Mean serum concentrations of piperacillin and azlocillin after dose 5 were 344 +/- 66 micrograms/mL and 414 +/- 86 micrograms/mL, respectively. The terminal elimination half-life of azlocillin (1.1 +/- 0.2 hr) was significantly longer than that of piperacillin (0.75 +/- 0.13 hr) (p less than 0.05). Total body clearance of azlocillin (125 +/- 25 mL/min) was significantly less than that of piperacillin (226 +/- 43 mL/min) after dose 5. Azlocillin showed accumulation between the first and fifth doses. Twelve hours after administration of dose 5, 75% of azlocillin and 57% of piperacillin were excreted unchanged into the urine. In healthy volunteers, azlocillin produced higher and more prolonged serum concentrations than piperacillin after administration of equivalent i.v. doses. Further studies are needed to determine the clinical importance of these observations.

Adult↗