Tradeoff between the Brillouin and transverse mode instabilities in Yb-doped fiber amplifiers.

The Brillouin instability (BI) due to stimulated Brillouin scattering (SBS) and the transverse (thermal) mode instability (TMI) due to stimulated thermal Rayleigh scattering (STRS) limit the achievable power in high-power lasers and amplifiers. The pump power threshold for BI increases as the core diameter increases, but the threshold for TMI may decrease as the core diameter increases. In this paper, we use a multi-time-scale approach to simultaneously model BI and TMI, which gives us the ability to find the fiber diameter with the highest power threshold. We formulate the equations to compare the thresholds of the combined and individual TMI and BI models. At the pump power threshold and below, there is a negligible difference between the full and individual models, as BI and TMI are not strong enough to interact with each other. The highest pump threshold occurs at the optimal core size of 43 µm for the simple double-clad geometry that we considered. We found that both effects contribute equally to the threshold, and the full BI and TMI model yields a similar threshold as the BI or TMI model alone. However, once the reflectivity is sufficiently large, we find in the full BI and TMI model that BI may trigger TMI and reduce the TMI threshold to a value lower than is predicted in simulations with TMI alone. This result cannot be predicted by models that consider BI and TMI separately. Our approach can be extended to more complex geometries and used for their optimization.

Levofloxacin pharmacokinetics and serum bactericidal activities against five enterobacterial species.

After oral administration of 500 mg of levofloxacin to 12 volunteers, we investigated the pharmacokinetics and serum bactericidal activities (SBAs) against five strains of members of the family Enterobacteriaceae. Pharmacokinetic data were as follows: maximum concentration in serum, 6.36 +/- 0.57 mg/liter; area under the concentration-time curve, 43.6 +/- 6.23 mg. h/liter; elimination half-life 4.23 +/- 0.87 h. SBAs were present for 24 h against Escherichia coli and Citrobacter freundii. The SBAs at 1, 12, and 24 h after administration against E. coli were 1:108, 1:29, and 1:7, respectively, and those against Citrobacter freundii were 1:74, 1:25, and 1:7, respectively. The SBAs were present for 12 h against the other three organisms tested. The SBAs against Serratia marcescens were 1:28 and 1:9 at 1 and 12 h, respectively; the SBAs against Klebsiella pneumoniae were 1:25 and 1:7 at 1 and 12 h, respectively; and the SBAs against Enterobacter cloacae were 1:24 and 1:10 at 1 and 12 h, respectively.

Concentrations of cefpirome in cerebrospinal fluid of children with bacterial meningitis after a single intravenous dose.

A single intravenous dose of cefpirome, 50 mg/kg, was administered to 15 children with bacterial meningitis 24 to 48 h after initiation of standard antibiotic and steroid therapy. Cefpirome concentrations in serum and cerebrospinal fluid were determined at selected time intervals. The mean (standard deviation) peak concentration in cerebrospinal fluid (n = 5) was 10.8 (7.8) microg/ml. Drug concentrations in cerebrospinal fluid above the MIC for Streptococcus pneumoniae at which 90% of the isolates were inhibited were found 2, 4, and 8 h after the dose of cefpirome was given. The penetration of cefpirome into cerebrospinal fluid compares favorably with that of other extended-spectrum cephalosporins and suggests that this agent would be useful in the therapy of childhood meningitis, including cases caused by drug-resistant S. pneumoniae.

In-vitro activity of levofloxacin against clinical isolates of Legionella spp, its pharmacokinetics in guinea pigs, and use in experimental Legionella pneumophila pneumonia.

The activities of levofloxacin and ofloxacin against 22 clinical legionella isolates was determined by microbroth dilution susceptibility testing. Growth inhibition of two Legionella pneumophila strains grown in guinea pig alveolar macrophages by levofloxacin, ofloxacin, or erythromycin was also determined. The drug concentrations required to inhibit 90% of strains tested was 0.032 mg/L for levofloxacin or ofloxacin, and was 0.016 mg/L for ciprofloxacin. BYE alpha broth significantly inhibited the activities of all three drugs tested, as judged by the susceptibility of control Escherichia coli strains. Levofloxacin (0.25 mg/L) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 1 log10, but regrowth occurred over a 3 day period; levofloxacin (1 mg/L) reduced bacterial counts by 2-3 log10 cfu/mL. Levofloxacin was significantly more active than erythromycin, and as active as ofloxacin or ciprofloxacin in this assay. Pharmacokinetic and therapy studies of levofloxacin and ofloxacin were performed in guinea pigs with L. pneumophila pneumonia. For the pharmacokinetic study, levofloxacin was given (10 mg/kg) by the intraperitoneal route to infected guinea pigs; mean peak plasma and lung concentrations were 3.4 mg/L and 1.4 micrograms/g, respectively, at 0.5 h and 2.6 mg/L and 0.6 micrograms/g at 1 h. The terminal half-life phase of elimination from plasma and lung was c. 1 h. All 15 infected guinea pigs treated with levofloxacin (10 mg/kg/day given ip once daily) for 5 days survived for 9 days after antimicrobial therapy, as did all 14 guinea pigs treated with the same dose of ofloxacin. None of 13 animals treated with saline survived. Levofloxacin is effective against L. pneumophila in vitro and in a guinea pig model of legionnaire's disease. Levofloxacin should be evaluated as a treatment of human legionnaires' disease.

Pharmacokinetics of levofloxacin in comparison to the racemic mixture of ofloxacin in man.

After oral administration of a single dose of 200 mg of levofloxacin and 400 mg racemic mixture of ofloxacin to 6 healthy male volunteers in a double-blind, randomised cross-over study, concentrations of the unchanged isomers were determined at various times in serum and urine, over 28 hours and 48 hours, respectively. Each dosing was followed by a wash-out period of one week. Ofloxacin concentrations were determined using an enantioselective and a non-enantioselective high pressure liquid chromatography (HPLC) assay. The two measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. Maximum serum concentration (Cmax) of levofloxacin after the administration of 200 mg of the levo-isomer was 2.42 mg/l (chiral derivatization HPLC, mean values); the corresponding area under the serum concentration-time curve (AUC0-28) was 17.0 mg x h/l. The corresponding Cmax values after the administration of 400 mg (+/-)-isomer (chiral derivatization HPLC and reversed phased HPLC, mean values) were 2.05 mg/l, 1.98 mg/l and 4.41 mg/l for (-)-, (+)- and (+/-) isomer, respectively. The AUCS0-28 were 17.0, 14.6 and 32.7 mg x h/l, respectively. The pharmacokinetics of the (-)- and (+)-isomer were shown to be almost equal. In serum and urine no reracemisation of the (-)-isomer to a racemic mixture was observed. General tolerability was good; no side effects were reported.

Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride (Amaryl) after intravenous administration.

Glimepiride is a new sulphonylurea which is eliminated by the formation of a hydroxy-metabolite (hydroxy-gli) and a carboxymetabolite (carboxy-gli). Animal studies have shown hydroxy-gli to exhibit some hypoglycaemic effects while carboxy-gli does not appear to have any pharmacological activity. Pharmacokinetic and pharmacodynamic effects of hydroxy-gli were assessed in humans. 12 healthy male volunteers received an intravenous injection of hydroxy-gli (1.5 mg) or placebo in a single blind, randomised, cross-over study. Samples were collected for up to 24 hours (blood) or 48 hours (urine) following administration of hydroxy-gli or placebo. Hydroxy-gli significantly decreased the minimum serum concentration (Cmin) of glucose by 12% and the average serum glucose concentration over the first four hours of treatment (Cavg0-4) by 9% compared with placebo (P < or = 0.05). In addition, maximum serum C-peptide concentration (Cmax) and Cavg0-4 were both increased by 7% after hydroxy-gli (p < or = 0.05). Serum insulin concentrations (Cmax and Cavg0-4) increased by 4% but the differences from placebo were not statistically significant. No adverse events were reported during the study. In conclusion, the hydroxymetabolite of glimepiride shows pharmacological activity in human subjects.

Migration of styrene from polystyrene foam food-contact articles.

Polystyrene foam is used in many food-contact articles such as plates, cups, bowls, egg cartons, meat trays and hinged 'carryout' containers. In most of these applications the food is in contact with the article for a relatively short period of time at mild temperatures (up to 130 degrees F), or for longer periods of time at refrigerated temperatures (40 degrees F). The extent of migration of residual styrene from foam articles under these conditions is of interest in order to predict potential exposure of consumers to styrene from food-contact polymers. Studies of styrene migration from all polystyrene foam articles except egg cartons were completed using food oil as the simulant. Results showed that the amount of styrene migrating from the various food-contact articles made with thermoformed polystyrene sheet into food oil was proportional to the square root of time of exposure. The mean diffusion coefficients derived from these data, assuming the migration was Fickian in nature, showed a linear relationship between the log of the diffusion coefficient and the inverse of the absolute temperature of exposure from 70 to 150 degrees F (21-66 degrees C). The mean diffusion coefficients ranged from about 4.5E-11 cm2/s at 70 degrees F to 3.4E-9 cm2/s at 150 degrees F. Among the four thermoformed articles exposed to food oil, the diffusion coefficients varied by a factor of four or less at a given temperature. The migration of styrene from egg cartons was examined using conditions simulating 'typical' exposure temperature and time with 8% ethanol as the simulant (31 days at 40 degrees F (4 degrees C)). No migration of styrene was observed under this condition, with a detection limit of < 0.01 micrograms/cm2.

Absolute bioavailability of glimepiride (Amaryl) after oral administration.

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.

Dose linearity assessment of glimepiride (Amaryl) tablets in healthy volunteers.

Twelve healthy fasting male volunteers received glimepiride in 1, 2, 4 or 8 mg single oral doses. On the days when glimepiride was taken, the subjects were given a standardised carbohydrate diet (18 bread exchange units) and drank 125 ml of water hourly. Blood and urine samples were taken before drug administration and afterwards for up to 36 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). The areas under the curve for glimepiride after oral doses of 1 to 8 mg and the urinary recovery of its metabolites M1 and M2 were dose linear. All confidence intervals were well contained within the bioequivalence range of 80-125%. There was a statistically significant difference for Cmax values of glimepiride between doses after dose normalisation. A dose-dependent increase for Cmax was nevertheless clearly observed with a correlation coefficient of r=0.90. The pharmacokinetics of glimepiride are dose linear in the dose range 1 to 8 mg, and glimepiride was safe and well tolerated in healthy volunteers.

The 'vapour-phase' migration of styrene from general purpose polystyrene and high impact polystyrene into cooking oil.

General purpose and high impact polystyrene (GPPS and HIPS, respectively) are used in many food packaging applications. In some packaging configurations, where there is no direct contact of a liquid surface with the polymer, 'vapour-phase' migration of styrene monomer from the polymer with subsequent absorption into food is thought to be a significant mode of transfer. Correlation of residual styrene concentrations in polystyrene with vapour-phase styrene migration is of interest in order to predict potential consumer exposure to styrene from food-packaging applications of this configuration. Studies of the migration of styrene from GPPS and HIPS into air with subsequent absorption of the monomer into cooking oil, 'vapour-phase' migration, was determined in a sealed system. The results showed that for both polymers the amount of styrene migrating from the polystyrene and being absorbed by the oil was proportional to the square root of the time of exposure. The diffusion coefficients calculated for the vapour-phase migration of styrene from both polymers were found to be in good agreement with the diffusion coefficients previously determined for the 'liquid-phase' migration of styrene from similar polymers where the polymers were completely submerged in the cooking oil. These results indicate that the styrene concentrations measured in both experiments were attributable to the intrinsic diffusion of styrene from polystyrene, and that contact with cooking oil did not accelerate migration in previous experiments.

Single-dose pharmacokinetics of cefpirome in patients receiving hemodialysis and in patients treated by continuous ambulatory peritoneal dialysis.

Cefpirome is eliminated primarily by renal excretion, compelling dosage reduction in kidney failure. We studied the elimination kinetics after intravenous administration of 1 gm cefpirome in patients undergoing hemodialysis (n = 9) and after intravenous (n = 6) or intraperitoneal administration (n = 6) of 1 gm cefpirome in subjects treated by continuous ambulatory peritoneal dialysis (CAPD). Four hours of hemodialysis removed 48% +/- 9% of the drug present in the body at the start of hemodialysis. Consequently, a supplementary dose equal to 50% of the daily dose recommended in end stage renal disease (ESRD) should be administered after each hemodialysis treatment. In patients receiving CAPD, therapeutic levels in both serum and dialysate were reached after intravenous and intraperitoneal administration. The bioavailability after intraperitoneal administration was 84%. After systemic administration, the elimination of cefpirome in the dialysate was negligible. Consequently, systemic dosage of cefpirome in patients receiving CAPD and in patients with ESRD should be identical.

Studies on the pharmacokinetics and metabolism of prednicarbate after cutaneous and oral administration.

Prednicarbate (PC) is a nonhalogenated derivative of prednisolone which is used for the local treatment of corticoid-sensitive skin diseases. In this study, the pharmacokinetics and the metabolism of PC in humans are investigated after cutaneous ointment application (75 mg PC) and after systemic oral administration (40 mg PC) in 8 healthy volunteers. In addition, the possible suppression of endogenous cortisol secretion by both application forms was monitored. After oral administration no intact PC, but significant levels of the first metabolite prednisolone-17-ethylcarbonate (PRED-17-EC) were determined. PRED-17-EC was further metabolized with a half life of 1.6 h to prednisolone. After percutaneous administration neither PC nor other known metabolites could be detected systemically. The low systemic bioavailability after dermal application was also reflected in an unchanged cortisol secretion pattern. According to animal studies our metabolic studies in humans suggest that the prednisolone-17-ester PRED-17-EC, which has a receptor binding affinity comparable to that of dexamethasone is the pharmacologically active compound. As PRED-17-EC subsequently undergoes an inactivation step to the low active prednisolone this may be the reason for the dissociation of good local efficacy and low systemic side effects.

Single-dose pharmacokinetics of cefpirome in patients with renal impairment.

The pharmacokinetic parameters of cefpirome (HR 810) were examined in 22 patients with different degrees of renal impairment. HPLC was used to analyze samples of blood and urine for cefpirome; and enzymatic assay of creatinine in serum and urine was used to assess kidney function. Creatinine clearance correlated linearly with both total and renal clearance of cefpirome. The loss of kidney function resulted in a decreased renal clearance, whereas the volume of distribution remained the same. This result led to an increase in the terminal half-life of the drug, from 2 hours in healthy subjects to 14 1/2 hours in patients with uremia. This increase also resulted in a prolonged high serum concentration well above the minimum inhibitory concentration. The following dosages are thus recommended: (1) creatinine clearance greater than 50 ml/min: normal daily dose, (2) creatinine clearance from 20 to 50 ml/min: 50% of normal daily dose, and (3) creatinine clearance less than 20 ml/min: 25% of normal daily dose. An initial loading dose of 1 gm, independent of renal function, is advised. Cefpirome was safe and well tolerated.

Metamizole-furosemide interaction study in healthy volunteers.

The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3 x 1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml.min-1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI.ml-1.h-1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F2 alpha (by 70-81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.

Ofloxacin pharmacokinetics in chronic renal failure and dialysis.

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), are reviewed. In addition, a large pool of data obtained in patients with a wide range of renal dysfunction is provided. The good absorption of ofloxacin after oral administration is not influenced by renal failure. Total plasma clearance (CL) is largely dependent on renal elimination of the drug, and renal clearance (CLR) and urinary recovery are reduced in parallel with reductions in renal function. Consequently, the serum half-life progressively increases when creatinine clearance decreases. Although there is wide variation in the published absolute values for the CL and CLR of ofloxacin, all studies show a similar pattern in the pharmacokinetic behaviour of the drug in chronic renal failure. A proposed protocol for ofloxacin dosage adjustment in chronic renal failure is reported which differs slightly but significantly from that recommended by the manufacturer. This new dosage regimen was derived from the pharmacokinetic results after single and multiple oral administration of the drug to patients with chronic renal failure. Since no clinically relevant losses of ofloxacin occur during haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the same protocol should be followed in these patients as in undialysed patients with terminal chronic renal failure.

The migration of Irganox 1010 antioxidant from high-density polyethylene and polypropylene into a series of potential fatty-food simulants.

Alternatives to highly-volatile ethanol or analytically complex cooking oil were examined as potential fatty-food simulants which would undergo high-temperature exposures to food-packaging polymers in food-packaging evaluation studies. The alternatives consisted of alcohols containing four to eight carbons. As test cases, the migration of Irganox 1010 antioxidant from high-density polyethylene and polypropylene into the higher alcohols was compared to the migration of Irganox 1010 into aqueous ethanol solutions and cooking oil, the US Food and Drug Administration's currently recommended fatty-food simulants. The data obtained showed slightly greater migration of the antioxidant into 95% ethanol than into cooking oil, and slightly less migration into 50% ethanol than into cooking oil. The migration of the antioxidant into the alcohols consisting of four or more carbons was much greater than the migration observed in cooking oil. In many experiments the polymers became depleted of the antioxidant prior to the end of the short, high-temperature exposure period (i.e. 2 h at 250 degrees F) to the higher alcohols. Also, for all experiments run under the same time/temperature/simulant conditions, migration of the antioxidant was greater from polypropylene than from high-density polyethylene. Diffusion coefficients generated for 95% ethanol and corn oil from these data compare closely with data from the literature.

Simultaneous determination of the sulphonylurea glimepiride and its metabolites in human serum and urine by high-performance liquid chromatography after pre-column derivatization.

A sensitive and selective high-performance liquid chromatographic method has been developed for a new sulphonylurea, glimepiride, and its metabolites. The assay involves extraction with diethyl ether, thermolysis of the sulphonylureas at 100 degrees C and trapping of the resulting amines with 2,4-dinitrofluorobenzene. The derivatives were quantitated on a reversed-phase column by absorbance at 350 nm using a step gradient for the three compounds in serum and an isocratic run for the metabolites in urine. Analogous compounds were used as internal standards. The detection limit was 5 ng/ml for glimepiride and metabolite II and 10 ng/ml for metabolite I using 1 ml of serum. The method has been applied to the analysis of serum and urine samples from pharmacokinetic studies in humans.

Quantification of the enantiomers of ofloxacin in biological fluids by high-performance liquid chromatography.

Two methods for the determination of (+)- and (-)-ofloxacin in biological fluids by high-performance liquid chromatography are described. The first method is separation on a chiral stationary phase with bovine serum albumin immobilized on silica gel. The second is the coupling of ofloxacin to L-leucinamide via diphenylphosphinyl chloride activation. The diastereoisomeric derivatives are then separated on a common reversed-phase column. The second method revealed only slight differences in the pharmacokinetics of (+)- and (-)-ofloxacin in humans after an intravenous administration of racemic ofloxacin.