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Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults.

Objective The primary objective of this study was to assess the kinetics of ketoprofen in synovial fluid and intra-articular tissues in relation to plasma. The secondary objective was to study whether intra-articular tissues act as reservoirs. Methods The ketoprofen concentration was analysed in plasma, synovial fluid and intra-articular tissues after single application of a 30 mg plaster (n = 40), multiple applications for 5 days (n = 30) or oral intake of 50 mg (n = 30) in patients undergoing knee arthroscopy. Results Median CMax values after topical application were 12.8 ng/ml in synovial fluid, 56.7 ng/g in synovial tissue, 349.3 ng/g in meniscus and 568.9 ng/g in cartilage. Conclusion Topical applications of ketoprofen allow the attainment of high intra-articular tissue concentrations.

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

This trial aimed at studying the effects and possible interactions between forage particle size and feeding frequency on the site and extent of digestion and ruminal fermentations throughout the day in dairy cows fed mixed diets. Two forage particle sizes (chopped, C, or ground and pelleted, G, dehydrated alfalfa) and two feeding frequencies (two (2) or six (6) times daily) were combined in a 2×2! arrangement. Four mid-lactation cows with cannulae in the rumen and proximal duodenum were used in a 4×4 Latin square design. They were fed at 95% of ad-libitum intake with three hours access to the manger after each meal distribution. On a dry-matter (DM) basis, the four diets consisted of 40% dehydrated whole-crop maize, 4% long perennial ryegrass hay, 25% dehydrated alfalfa and 31% concentrate (69% wheat). Dry-matter intake averaged 22.2 kg day−1. No interaction between forage particle size and feeding frequency was found. Feeding G rather than C diets reduced chewing time (22.4 vs. 26.2 min kg−1 DM), total and ruminal digestibilities of organic matter (OM) and cell-wall constituents (p Increasing feeding frequency did not affect carbohydrate digestion and mean ruminal parameters, although post-feeding variations of pH, osmolality and ammonia concentration were much less pronounced. It is concluded that reduced forage particle size can sharply affect the quantity and the nature of digestive end-products by altering chemical and physical conditions in the rumen. However, the magnitude of this effect is not dependent on the amount of fermentable OM entering the rumen in one meal.

Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60 %. Maximum plasma concentration (C max ) and area under the concentration -time curve (AUC) values were linearly related to dose for the range studied. C x occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (t max = 2 hours compared with 0.8 hours; C x = 216 ng . mL I compared to 387 ng . mL'') and extent of absorption (AUC = 1,047 ng . hr . mL -1 versus 1,269 ng.hr.mL -1 . With multiple-dose administration, riluzole showed dose-related tibsoption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although A UC values did not differ.

Les auteurs presentent un cas de keratite fongique survenue chez une jeune femme porteuse depuis deux ans de lentilles corneennes jetables journalieres. Ce cas, qui a evolue favorablement sous therapeutique specifique et pour lequel aucun facteur de risque n’a pu etre mis en evidence, souligne l’importance de l’education des patients a l’hygiene et au respect des conditions d’emploi de ce type de lentilles.

The indirect effect of diet on the single-and multiple-dose pharmacokinetics of sustained-release ketoprofen was studied in 16 healthy male volunteers. In an open, cross-over design, 200 mg ketoprofen was administered as a gastric-juice-resistant, sustained-release tablet once daily during two periods of 5 days. A low-calorie/low-fat diet (LCFD) was given in the first period and a high-calorie/high-fat diet (HCFD) in the second period. The first meal on each day was given 4 h after drug intake. Ketoprofen plasma concentrations were measured over 24 h after the first dose on day 1 and over 36 h after the final dose on day 5 of each period. On average, plasma concentrations of ketoprofen were higher with the LCFD than with the HCFD. With the HCFD there was a tendency to longer absorption-lag times on day 5. The maximum concentration and the area under the curve over one 24-h dosage period (AUC0–24) were significantly higher with the LCFD, both on day 1 and on day 5. For AUC0–24 the differences were on average 15% (day 1) and 24% (day 5). The same tendency was observed for the amount excreted in urine over 24 h (Ae), but the difference was only significant on day 1 (14%). The elimination rate constant (Kβ) and the mean residence time were similar for the two diets, both on day 1 and on day 5. From these results, we conclude that there was an acute indirect effect of diet when a meal was had 4 h after intake of the medication. This resulted in a greater extent of ketoprofen absorption with the LCFD than with the HCFD. The absorption rate was apparently not influenced by this acute effect. The longer gastric residence time of ketoprofen with the HCFD may be the result of a long-term indirect effect on gastric emptying rate. If the extreme difference between the diets in this study is taken into account, it seems unlikely that the observed indirect effects have implications for clinical practice.

The peripheral distribution of spiramycin and metronidazole, which are combined in the proprietary drug "Rodogyl", has been studied in gingival fluid, saliva and blood after a single administration to 12 healthy volunteers and after repeated administration to 4 patients with recurring severe periodontitis. Analysis of the 2 antibiotics have been performed at regular intervals during the 24-h period immediately following the administration to the volunteers and after the 1st and the 15th days of repeated administration to the patients. The results show that gingival fluid contains concentrations of spiramycin and metronidazole higher than those needed to inhibit the growth of periodontopathic bacteria. Spiramycin was found at higher concentrations in GCF than in blood, although this feature was not found for metronidazole, which was administered simultaneously and showed similar concentrations in both fluid and serum. Such high concentrations persist for a long time, and suggest the potential of this compound in the treatment of severe cases of periodontitis.

Usually sample surface structures generate large flunctuations of the photothermal response due to local variations of optical, thermal and geometrical properties which mask the crack signal when using single detection ir radiometry. Demonstrated experimentally and theoretically is the ability of a differential stimulated ir detection scheme to obtain a better contrast in crack detection on real samples. A finite element simulation confirms the magnitude and shape of the signals for vertical and slanted cracks.

A cryogenic refractometer is described. It enables preparation of liquefied samples and measurement of their refractive index at low temperatures (down to 20 K). The liquid sample can be a pure liquefied gas or a mixture. The composition of the liquid mixture can be estimated from the volume and pressure of each gas measured during the liquefying process. The determination of absolute values of the refractive index necessitates a calibration, therefore the accuracy is limited to 10−3 index unit. Sensitivity and reproductibility are better (5× 10−4) and could be improved to 10−4. The refractive index of pure liquid methane was determined at several temperatures (91–106 K) and 670 nm. The results obtained agree with the published data. The refractive index of mixtures of liquid methane and ethane, with and without dissolved nitrogen, was also determined at 94 K and 1.5 bar total pressure, for which conditions no data were previously available.

The tolerance and pharmacokinetic behaviour of a new injectable streptogramin antibiotic, RP 59500 were evaluated on 26 healthy male volunteers in a double-blind, placebo-controlled, phase I study. The doses used were 1.4, 2.8, 4.6, 7.0, 9.8, 12.6, 16.8, 22.4 and 29.4 mg/kg; each dose was administered as a 1 h infusion to eight subjects, two of them receiving placebo. Blood levels of RP 59500 were measured by both microbiological and HPLC assays. At the end of the infusion, Cmax for RP 59500 ranged from 0.95 +/- 0.22 to 24.20 +/- 8.82 mg/L. The apparent elimination half-life of the compound ranged from 1.27 to 1.53 h. RP 59500 did not significantly affect any of the laboratory or clinical assessments (blood pressure, pulse rate, ECG, peak expiratory flow rate). Reported adverse effects were of mild intensity; the most frequent event was mild pain or burning at the infusion site with doses of 7 mg/kg or higher. These results support further studies of RP 59500 in phase II clinical trials.

Pefloxacin and rifampin are frequently associated in the antibiotic therapy of deep-seated, and especially bone-located, infections. The influence of rifampin, a potent drug metabolism enzyme inducer, on the pharmacokinetics of pefloxacin was studied in a randomized crossover trial involving eight young healthy male volunteers. Every volunteer received either pefloxacin alone (period A) or pefloxacin after a 10-day induction by rifampin (period B) given as a 900 mg daily oral dose, and both periods were separated by a 3-week washout period. During both periods, pefloxacin was given during 3 days as a 400 mg b.i.d. oral dose (six doses) followed by a 400 mg intravenous dose on the fourth day. The kinetics of pefloxacin are significantly influenced by rifampin: The minimum (12-hour) plasma concentration, area under the concentration-time curve, and elimination half-life decreased respectively from 4.26 ± 1.57 to 2.70 ± 1.00 mg/L, 78.91 ± 22.82 to 57.81 ± 16.69 mg · hr/L, 14.46 ± 3.46 to 10.08 ± 2.44 hours(p

A case of fungal keratitis was diagnosed in a young female who had been wearing daily disposable soft contact lenses for 2 Years. No risk factor was demonstrated and specific treatment was effective. This case emphasizes that patients must be aware of the importance of hygiene as daily disposable contact lenses must be discarded daily.

Objectives The objective of this study was to compare the pharmacokinetics of the low-molecular-weight heparin enoxaparin in obese and nonobese volunteers, by means of two administration regimens. Methods Enoxaparin was administered subcutaneously (1.5 mg/kg once daily for 4 days) and in a single 6-hour infusion (1.5 mg/kg) to 24 obese volunteers and 24 age-, sex-, and height-matched nonobese volunteers in a randomized, open-label, 2-way crossover design. Blood plasma was assessed for anti-Xa and anti-IIa activity and activated partial thromboplastin time. Results After subcutaneous administration, steady-state exposure was achieved after the second dose in nonobese volunteers and after the third dose in obese volunteers. Time to maximum anti-Xa activity was 1 hour longer in obese volunteers, but maximum anti-Xa activity was similar in both groups. For anti-Xa activity, exposure at steady-state was 16% higher in obese volunteers than in nonobese volunteers (90% confidence interval, 108%-125%). After intravenous infusion, total body clearance and volume of distribution at steady state were higher in obese volunteers than in nonobese volunteers, but when adjusted for weight, these values were about 10% lower in obese volunteers. Anti-IIa activity after subcutaneous administration did not differ significantly between obese and nonobese volunteers. Pharmacodynamic analysis of activated partial thromboplastin time showed similar results in obese and nonobese volunteers after both intravenous and subcutaneous administration. No deaths or serious adverse events occurred during the study. Conclusions Enoxaparin was well tolerated when administered subcutaneously or intravenously, and there appears to be no need to modify the currently recommended dose for obese volunteers. Clinical Pharmacology & Therapeutics (2002) 72, 308–318; doi: 10.1067/mcp.2002.127114

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

Quinupristin–dalfopristin (30:70, w/w) is a new streptogramin, which has been developed for intravenous use. A specific and sensitive HPLC method was developed to measure simultaneously quinupristin (RP 57669) and dalfopristin (RP 54476) and their main metabolites in human plasma. The metabolites measured by this method were RP 69012 (glutathione-conjugated) and RPR 100391 (cysteine-conjugated) from quinupristin and RP 12536 (natural pristinamycin IIA), from dalfopristin. Solid-phase extraction with disposable cartridges was combined with reversed-phase HPLC and fluorimetric detection for RP 57669, RP 69012 and RPR 100391 and UV detection for RP 54476 and RP 12536. The method provided good recovery and low limits of quantitation (0.025 mg l−1 for RP 57669, RP 54476 and RP 12536, and of 0.010 mg l−1 for RP 69012 and RPR 100391). The validated range of concentrations of the method was: 0.025–5000 mg l−1 for RP 57669, RP 54476 and RP 12536 and 0.010–0.750 mg l−1 for RP 69012 and RPR 100391.

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To assess the concentration of ketoprofen, after topical plaster application, in various tissues in relation to plasma levels in 60 patients undergoing surgery for Achilles or patellar tendinopathy; and to analyze whether tissues act as a reservoir of ketoprofen, by evaluating tissue concentrations in relation to plasma concentration at various time points after removal of the plaster. No attempt was made to study the clinical effect of treatment per se.In random order to patients applied 30 mg plasters once daily for 5 consecutive days (n = 30), or took a single oral dose 50 mg (n = 30) before surgery. Tissue samples of skin, subcutaneous fat, tendon sheath, and tendon, and plasma were collected intraoperatively at 0, 6 and 14 hours after removal of the 5th plaster, and at 2, 6, and 14 hours after oral intake. Ketoprofen concentration was determined by a validated GC/MS method. The low limit of quantification was 0.5 ng/ml plasma and 0.5 ng/50 mg tissues.High concentrations of ketoprofen were observed in fat, tendon sheath, and tendon after topical applications, whereas plasma levels of ketoprofen were low.Ketoprofen attains high concentrations in subcutaneous tissues after multiple topical applications. Subcutaneous tissues appear to act as a reservoir of ketoprofen.

Four diets differing in level and source of nitrogen were given in a 4 x 4 latin square design using four dairy cows canulated in the rumen and duodenum. A low N diet (T-, 17.4 g N/kg DM) with only 17 g of degradable N per kg of fermentable OM (FOM) (covering 73% of microbial requirements) was supplemented with up to 21.6 g/kg DM and 22 g/kg FOM (covering 95% of microbial requirements) of increasing levels of preformed amino acids. Three mixtures of urea and casein [100:0 (U); 50:50 (UC) and 0:100 (C)] were used in order to supply 30, 15 and 0% of the total N of the diet as urea-N. The four diets (66% maize silage) were isoenergetic and were offered 95% of ad libitum twice daily. OM and NDF digestibilities in the total digestive tract and in the rumen did not differ between T- and U diets. These digestibilities increased linearly with the proportion of casein-N in the diet but the response remained low. The levels and the source of degradable N did not affect the non ammonia nitrogen (NNA) flow into the duodenum, the microbial N flow and the efficiency of microbial synthesis. NNA flow exceeded N intake for all diets but the net recycling into the rumen was markedly higher for the LN diet (+110 vs +31 g/day). This is related to a lower excretion of urea-N in urine (22 vs 80 g/day). These results suggest that in cows fed at 95% of ad libitum, the shortage of degradable N hardly affects the digestion of the diet and that the supply of preformed amino acids is not an important limiting factor for bacterial growth when maïze silage based diets are fed. Therefore, the supplementation with such preformed carbon chains is not of practical interest.

*INRA, Station de recherche sur la vache laitiere, 35590 L'Hermitage Diffusion du document : INRA, Station de recherche sur la vache laitiere, 35590 L'Hermitage Diplôme : Dr. Ing.

Four diets differing in level and source of nitrogen were given in a 4 x 4 latin square design using four dairy cows canulated in the rumen and duodenum. A low N diet (T-, 17.4 g N/kg DM) with only 17 g of degradable N per kg of fermentable OM (FOM) (covering 73% of microbial requirements) was supplemented with up to 21.6 g/kg DM and 22 g/kg FOM (covering 95% of microbial requirements) of increasing levels of preformed amino acids. Three mixtures of urea and casein [100:0 (U); 50:50 (UC) and 0:100 (C)] were used in order to supply 30, 15 and 0% of the total N of the diet as urea-N. The four diets (66% maize silage) were isoenergetic and were offered 95% of ad libitum twice daily. OM and NDF digestibilities in the total digestive tract and in the rumen did not differ between T- and U diets. These digestibilities increased linearly with the proportion of casein-N in the diet but the response remained low. The levels and the source of degradable N did not affect the non ammonia nitrogen (NNA) flow into the duodenum, the microbial N flow and the efficiency of microbial synthesis. NNA flow exceeded N intake for all diets but the net recycling into the rumen was markedly higher for the LN diet (+110 vs +31 g/day). This is related to a lower excretion of urea-N in urine (22 vs 80 g/day). These results suggest that in cows fed at 95% of ad libitum, the shortage of degradable N hardly affects the digestion of the diet and that the supply of preformed amino acids is not an important limiting factor for bacterial growth when maize silage based diets are fed. Therefore, the supplementation with such preformed carbon chains is not of practical interest.

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A differential stimulated I.R. detection scheme is presented in order to obtain a better contrast in crack detection on real samples whose surface exhibits topographical and optical irregularities. A finite element simulation confirms the magnitude and shape of the signals for vertical and slanted cracks.

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.

The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.

Zopiclone is a new hypnotic cyclopyrrolone with a short elimination half-life (5.3 h). The pharmacokinetic profile of this drug was studied in 7 chronic renal failure (CRF) patients given 7.5 mg nocte for 7 consecutive nights. The pharmacokinetic values obtained were compared with the corresponding values found in healthy young volunteers given the same repeated dosage regimen. C max and T max were not significantly different between the two groups but the C min of unchanged zopiclone (at 24 h) post-dosing was significantly (p less than 0.001) higher in CRF patients (8.16 +/- 5.34 ng/ml) than in healthy volunteers (1.90 +/- 0.82 ng/ml). The AUC values in CRF patients were also significantly increased during the seventh day (742 +/- 212 h ng/ml) compared to healthy subjects (408 +/- 66.5 h ng/ml) and the elimination half-life of zopiclone was also longer in CRF patients (about 8 h) than in the reference group (about 5 h). Nevertheless, the accumulation ratios remained similar in the two groups (1.09 +/- 0.18 in CRF patients and 1.02 +/- 0.2 in healthy subjects). Thus no evident accumulation of zopiclone appeared in the CRF patients. As in the healthy subjects, no metabolites were detected in the plasma of the CRF patients although at steady state the urinary excretion of zopiclone and its N-oxide and N-desmethyl derivatives (2.03% +/- 1.52% and 1.99 +/- 0.65% of the dose, respectively) was significantly decreased compared to healthy subjects (3.7% +/- 2.1% and 32.6% +/- 4.5%, respectively). Zopiclone thus represents a safe alternative to benzodiazepine hypnotic therapy in patients with renal impairment.