Pharmacokinetics and tissue penetration of orally administered lomefloxacin.

The pharmacokinetics of the quinolone lomefloxacin were determined following a single 400-mg oral dose given to each of six male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were determined by a microbiological assay. Samples from two volunteers were also assayed by high-performance liquid chromatography. The mean peak level in serum, 4.7 micrograms/ml, was attained within 1 h of administration. The mean elimination half-life from serum was 7 h. Inflammatory fluid was penetrated rapidly, with a mean peak level of 3.5 micrograms/ml occurring after 2.7 h. The mean recovery of lomefloxacin from urine over 48 h was 76% of the administered dose. There was a minor peak on the high-performance liquid chromatography trace, suggesting a small amount of unidentified metabolite. This was present only in urine; no detectable metabolites were found in serum. This study suggests that either once-daily or twice-daily dosage of lomefloxacin should be sufficient to treat urinary or systemic infections, respectively, caused by susceptible pathogens.     

Effect of orally administered activated charcoal on vancomycin clearance.

Vancomycin is a narrow-spectrum antibiotic that has concentration-dependent efficacy and toxicity. Recent literature indicates that orally administered activated charcoal can enhance the clearance of intravenously administered drugs. To evaluate the effects of activated charcoal on vancomycin clearance, six healthy male volunteers received vancomycin (1 g) intravenously with and without activated charcoal coadministration. In a randomized crossover sequence, subjects were given 50 g of activated charcoal immediately before the vancomycin infusion was begun and 15 g at 2, 4, 6, and 8 h afterwards, or an equal volume of water. Multiple doses of charcoal did not have a statistically significant effect on any pharmacokinetic parameter for vancomycin. Mean control values +/- standard deviation for vancomycin clearance, elimination half-life, and 24-h urinary recovery were 6.4 +/- 1.0 liters/h, 6.6 +/- 1.5 h, and 856 +/- 116 mg, respectively. Mean values for the same parameters were 6.4 +/- 1.0 liters/h, 6.0 +/- 0.9 h, and 897 +/- 130 mg when activated charcoal was given. We conclude that multiple doses of orally administered activated charcoal do not enhance vancomycin clearance in subjects with normal renal function when serum concentrations are within the therapeutic range. The results of this investigation cannot be extrapolated to patients with toxic vancomycin concentrations or renal dysfunction. The use of activated charcoal in these populations warrants further study.     

Hemodynamic effects of orally administered Sunitang in humans

The hemodynamic effects of Sunitang, an ancient Chinese remedy for general weakness, weak pulse, and cold extremities, were studied. In study, 1, 10 patients with left ventricular failure received Sunitang in single oral doses of 250, 500, and 1000 mg in a double-blind manner. Sunitang showed dose-related positive inotropic, chronotropic, and vasodilator effects. The effects reached their maximum within 30 to 60 minutes and lasted for 6 hours. In study 2, 77 patients with left ventricular failure who had not been treated satisfactorily by the conventional methods entered a controlled (parallel design), double-blind study for 1 month. When they entered the study they were in steady states. They continued their original medications throughout the month. Sunitang showed additional positive inotropic, chronotropic, and vasodilator effects. In this study no apparent adverse effects of Sunitang were noted. We conclude from these results that Sunitang may be useful in heart failure and bradycardia.     

Pharmacokinetics of dexamethasone administered orally in obese patients

Dexamethasone pharmacokinetics was studied after oral administration of two Décadron tablets in six healthy controls and in eight obese patients whose weight was at least 20% above that of the ideal body weight. The absorption (0.30 +/- 0.09 h and 0.29 +/- 0.08 h) and elimination (4.52 +/- 0.57 h and 3.71 +/- 1.05 h) half-lives were not significantly different. Maximum plasma concentrations were similar (11.95 +/- 1.00 micrograms/l and 10.93 +/- 0.94 micrograms/l) but the lag-time was significantly higher in the obese patients (0.49 +/- 0.12 h and 0.13 +/- 0.04 h). A positive correlation was observed between the AUC and the total body weight (r = 0.738, p less than 0.01). Mean predexamethasone cortisol level was significantly lower in the obese patients (189.20 +/- 52.7 micrograms/l and 256.90 +/- 58 micrograms/l). The pharmacokinetics modifications were not sufficient to explain the increased false positive frequency in the dexamethasone suppression test of the hypothalamic-pituitary-adrenal axis in obesity.     

Effect of orally administered probenecid on the pharmacokinetics of cefoxitin.

To characterize the effect of orally administered probenecid on the pharmacokinetics of cefoxitin in healthy male volunteers, we administered to one group of six subjects 2 g of cefoxitin by intravenous (i.v.) bolus either alone, with 1 g of probenecid concomitantly, or when 1 g of probenecid was administered 1 h previously by using a crossover design. Likewise, we administered to a second group of six subjects 2 g of cefoxitin intramuscularly (i.m.) together with 1 and 2 g of probenecid. Probenecid increased the mean terminal half-life and the area under the serum cefoxitin concentration-time curve (AUC0-24) and decreased renal clearance, but did not alter the volume of the central compartment or the total urinary recovery of i.v.-administered cefoxitin; pretreatment with probenecid produced a greater increase in cefoxitin AUC0-24 and a constant decrease in renal clearance compared to concomitant probenecid. The AUC0-24 after i.m.-administered cefoxitin was greater after 2 g than 1 g of probenecid; the AUC0-24 after i.v.-and i.m.-administered cefoxitin was similar after 1 g of probenecid was given concomitantly. Cefoxitin AUC0-24 was increased further when 1 g of probenecid was given before i.v.-administered cefoxitin or when 2 g of probenecid was given with i.m.-administered cefoxitin. The effect of probenecid was related to both timing and dose.     

Photoreaction potential of orally administered levofloxacin in healthy subjects

OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a single-center, double-blind, randomized study, 30 adults (20 men, 10 women) received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline photoexposure prior to drug administration, each subject was exposed to UVB light at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25 J/cm2). Photoexposure was repeated on day 5, two hours following final drug administration, and response was determined using both a photoreaction rating scale and investigator assessment. RESULTS: Using the photoreaction rating scale, following UVB exposure on day 5, no abnormal photoreactions were observed among levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of 24 levofloxacin-treated and three of six placebo-treated subjects, with no associated symptoms. By investigator assessment, all subjects had a negative reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal reactions were mild and similar for both treatment groups. No subject experienced an immediate wheal-and-flare reaction. There were no statistically significant differences between treatment groups for any of the comparisons. CONCLUSIONS: Levofloxacin has a low photosensitizing potential when administered to healthy subjects.     

Abnormal renal glucose handling in X-linked hypophosphataemic mice.

1. The renal handling of glucose was determined in male X-linked hypophosphataemic (Hyp/Y) mice and in control littermates (+/Y) aged 4 months. Plasma glucose concentration and urinary glucose excretion were measured before and during stepwise increase in glycaemia induced by an acute infusion of glucose. The relationship between plasma glucose concentration and urinary glucose excretion was monitored per ml of glomerular filtrate in mice fed high and low phosphate diets. 2. Hyp/Y mice fed the high phosphate diet showed a significantly higher glucosuria compared with +/Y littermates. When glycaemia was increased, Hyp/Y mice developed frank glucosuria earlier than +/Y animals. In Hyp/Y mice we could not find a threshold below which virtually no glucose was excreted in the urine, whereas this was clearly visible in +/Y mice. These differences persisted in animals fed the low phosphate diet. 3. Using the acute response to the glucoregulatory hormones, glucagon and insulin, administered exogenously, we found that the regulation of plasma glucose concentration did not differ between Hyp/Y and +/Y mice. 4. The significantly lower plasma glucose concentration observed in Hyp/Y as compared with +/Y mice decreased further during fasting. 5. We conclude that the renal reabsorptive capacity for glucose is defective in Hyp/Y mice and their low plasma glucose concentration may be explained by the renal leak. Therefore the X-linked phosphataemic mouse appears not only to be characterized by a defect in renal phosphate and calcium reabsorption but also by an altered glucose reabsorption.     

The human utilization of orally administered 15N-glycine

In 7 convalescent patients we studied utilisation of a single dose of 15N-labelled glycine. In intervals we estimated total-N, urea-N, NH3-N and their 15N-abundances (urine). The following results were obtained. The peak of ammonium-15N appeared 25 minutes earlier than the peak of urea-15 N. The cumulative elimination of total-15N amounted to 25% of uptake after 24 hours and to 34.4% after 6 days. 12 hours after application 53% of the total amount, excreted within 6 days, were already eliminated. 24 hours after administration 80% of total-15N was urea-15N and 2.8% NH3-15N. Further we found correlations between N-balance (N-application minus excretion) and elimination of 15N-urea: If N-balance got more negative, the amount of cumulative elimination, the portion of urea-15N to total-15N and the percentage of elimination after 12 hours related to 6 days were elevated. That means that in stress condition utilisation of glycine to urea is higher and accelerated. The model seems acceptable, to get information concerning metabolic situation in a simple way.     

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.     

Modulation of mucosal immunity against Campylobacter jejuni by orally administered cytokines.

The effect of oral recombinant interleukin (rIL) treatment on the course of Campylobacter jejuni infection and the development of mucosal immunity in mice was investigated. rIL-2, rIL-5, and rIL-6 were administered to mice at 24 and 6 h before infection and at 0, 24, and 48 h after infection with C. jejuni HC, and the subsequent development of an immune response and intestinal colonization resistance were determined. In this model, orally administered cytokines retained their biological activities with no apparent side effects. Following infection, initial bacterial counts in fecal samples collected from cytokine-treated and untreated mice were similar. However, within 48 h of infection a greater than 3-log-unit reduction in the number of C. jejuni shed in the feces was found for rIL-6-treated animals. Colonization levels were similarly reduced in rIL-5-treated mice, although the rate of clearance was somewhat slower. In contrast, rIL-2 treatment had no significant effect on colonization levels compared with that in controls. Oral rIL-6 treatment was also associated with enhanced intestinal and systemic Campylobacter-specific immunoglobulin A responses compared with those observed in either rIL-5- or rIL-2-treated animals. Upon rechallenge, initial colonization in all cytokine-treated groups was approximately 2 log units lower than that in controls. However, local infection was controlled only in rIL-2-treated mice over time. rIL-5 and rIL-6 treatment had only a marginal effect on colonization resistance following rechallenge. On the basis of these results, it appears that rIL-5 or rIL-6 may function to modulate the induction and/or expression of anti-C. jejuni immunity through different mechanisms.     

Effects of orally administered sodium cromoglycate in asthma and urticaria due to foods.

Out of twenty patients with a history of asthma or urticaria attributed to food substances, ten reacted on oral challenge: seven with asthma, one with asthma and urticaria and two with urticaria alone. In five of the eight asthmatic reactors, the symptoms developed within a few sec and there was no associated rise in free venous plasma histamine. In those remaining, two with asthma, two with urticaria and one with both, the symptoms developed only after 20-30 min. A rise in free plasma histamine occurred only in the two subjects with urticaria alone. The third with urticaria and asthma did not have blood estimations performed. Sodium cromoglycate in a dosage of 800 mg a day for 1 week, or a single dose of 1.0 g by mouth, did not block any of the reactions. By inhalation it blocked the asthmatic reactions which developed within a few sec of challenge.     

Nyctohemeral variations of cyclosporine administered orally in renal transplant patients

The circadian intraindividual variations of cyclosporin blood concentrations were studied in nine renal transplant patients at steady state. The cyclosporin was administrated orally twice a day (9 a.m. and 21 p.m.). Blood concentrations were analysed by H.P.L.C. AUC = area under the drug concentration versus time curve, Cmax = maximum blood concentration, Cmin = minimum blood concentration, Tmax = Time to maximum concentration. Statistical analysis (t, Wilcoxon) shows: AUC, Cmax and Tmax are not significantly modified, Cmin (21) less than Cmin (9) (p less than 0.02). This phenomenon seems to be rather a cyclosporin metabolism variation than an absorption alteration.