Propofol decreases ocular pressure in outpatients undergoing trabeculectomy

OBJECTIVES: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. METHODS: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a crossover fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. RESULTS AND CONCLUSIONS: Serum concentration of (+)-nicardipine was approximately 2-3 times higher than that of (-)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3-2.8 times greater than that of the (-)-nicardipine (P < 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (-)-nicardipine, respectively, for the 40-mg dose.     

The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume of distribution and the plasma clearance for S(-) phenprocoumon were less than those for R(+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S(-) phenprocoumon was more highly bound than R(+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S(-) phenprocoumon is more potent anticoagulant than R(+) phenprocoumon and that the pharmacokinetic differences between the enantiomers are due mainly to differences in their distribution.     

Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration

The pharmacokinetics of methylprednisolone and prednisolone were evaluated in 24 healthy men after oral administration of single and multiple doses for 3 days. For each drug, 6 different administration regimens with doses ranging from 1 to 80-mg of methylprednisolone and 1.25 to 100-mg of prednisolone, and administration intervals ranging from 3 to 24 hours for both were investigated. Plasma was assayed using a normal phase high-performance liquid chromatography (HPLC) method. Methylprednisolone showed linear pharmacokinetics with no apparent dose or time dependency. Prednisolone showed marked dose dependency with higher clearance and volume of distribution for higher doses. This can be explained by its saturable protein binding of plasma, because unbound clearance and unbound volume of distribution were not dose-dependent. After multiple administration, prednisolone showed significant time-dependent pharmacokinetics with increased unbound clearance and increased unbound volume of distribution. Due to the complicated pharmacokinetic properties of prednisolone, it is extremely difficult to determine the dose needed to obtain a desired target concentration. The pharmacokinetics of methylprednisolone are more predictable because methylprednisolone concentrations are proportional to dose, and no determination of plasma protein binding is needed.     

Tenoxicam: acute dose-dependent disposition studies in rats

Single intravenous bolus doses of tenoxicam of 2.5, 5, and 10 mg/kg were administered to male Wistar rats to determine the effects of dose on tenoxicam pharmacokinetics. Predicted apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL) were, respectively, 42 and 45% higher in the animals given 10-mg/kg dose than the animals given 2.5- and 5-mg/kg doses. Binding of tenoxicam to plasma proteins showed saturability, with a 33% higher unbound fraction of tenoxicam in plasma when total drug concentration in plasma was 36 mg/L (high dose group) in comparison with animals given the low doses (12 and 20 mg/L). The blood-to-plasma concentration ratio of tenoxicam was concentration independent and therefore did not account for the observed dose-dependent changes in Vdss and CL.     

Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects

The pharmacokinetics of moxifloxacin were investigated in six studies after oral administration of 50, 100, 200, 400, 600, and 800 mg. Eight healthy male volunteers were included in each study. With doses of up to 200 mg the study was performed as a double-blind, randomized group comparison (n = 6 verum and n = 2 matched placebo); with the higher doses the study was conducted with a double-blind, randomized, crossover design. Safety and tolerability were assessed by evaluation of vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, results of urinalysis, and adverse events. The drug was well tolerated. The concentrations of moxifloxacin in plasma, urine, and saliva were determined by a validated high-pressure liquid chromatography assay with fluorescence detection. In addition, plasma and urine samples were analyzed by a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of moxifloxacin in plasma (Cmax) ranged from 0.29 mg/liter (50-mg dose) to 4.73 mg/liter (800-mg dose) and were reached 0.5 to 4 h following drug administration. After reaching the Cmax, plasma moxifloxacin concentrations declined in a biphasic manner. Within 4 to 5 h they fell to about 30 to 55% of the Cmax, and thereafter a terminal half-life of 11 to 14 h accounted for the major part of the area under the concentration-time curve (AUC). During the absorption phase concentrations in saliva were even higher than those in plasma, whereas in the terminal phase a constant ratio of the concentration in saliva/concentration in plasma of between 0.5 and 1 was observed, indicating a correlation between unbound concentrations in plasma and levels in saliva (protein binding level, approximately 48%). AUC and Cmax increased proportionally to the dose over the whole range of doses investigated. Urinary excretion amounted to approximately 20% of the dose. Data on renal clearance (40 to 51 ml/min/1.73 m2) indicated partial tubular reabsorption of the drug. The pharmacokinetic parameters derived from compartmental and noncompartmental analyses were in good agreement. The kinetics could be described best by fitting the data to a two-compartment body model.     

Effect of experimental diabetes mellitus and arthritis on the pharmacokinetics of hydroxychloroquine enantiomers in rats

PURPOSE: To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. METHODS: The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. RESULTS: Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 +/- 0.15 and 1.3 +/- 0.19 l/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 +/- 0.32 and 1.93 +/- 0.34 l/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. CONCLUSIONS: Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.     

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.     

Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions

The most widely used long-acting amide local anaesthetic is bupivacaine, a racemic mixture of 2 stereoisomers. However, there is evidence that the use of single enantiomer compounds offers advantages over racemic agents. Ropivacaine, the recently introduced propyl homologue of bupivacaine, is a pure S-(-)-enantiomer. It is associated with a reduced incidence of both cardiovascular and central nervous system toxicity, a concern with racemic bupivacaine, in preclinical studies. The relevant pharmacokinetic differences include a lower lipid solubility, a slightly higher plasma clearance and shorter elimination half-life (t 1/2 beta) compared with racemic bupivacaine, with a similar degree of plasma protein binding. More recently levobupivacaine, the pure S-(-)-enantiomer of bupivacaine, has been produced. Stereoselective differences have been observed between the 2 enantiomers and the racemic mixture, with levobupivacaine exhibiting a slightly higher degree of plasma protein binding, a lower volume of distribution, a higher plasma clearance, and a shorter t 1/2 beta than the R-(+)-enantiomer. In common with ropivacaine, levobupivacaine has been shown to have a reduced incidence of toxicity in comparison the R-(+)-enantiomer in preclinical studies, explained in part by a reduced affinity to both brain and myocardial tissue. Racemic bupivacaine is increasingly administered by continuous infusion to provide prolonged postoperative analgesia. The pharmacokinetic profile of the drug administered in this manner has only recently been elucidated and indicates a slow rise in total plasma concentration with increasing duration of infusion, mitigated by changes in plasma protein concentrations during the postoperative period. This appears to be the predominant reason why complications related to systemic toxicity are rarely observed with this technique. However, continuous administration of individual enantiomers may potentially serve as a safer option in the future.     

Reversal of stereoselectivity in the hepatic availability of verapamil in isolated perfused rat livers. Role of protein binding

The effects of serum proteins on the stereoselective kinetics of the high clearance drug verapamil (VER) and its metabolite, norverapamil (NOR), were studied in isolated perfused rat livers (IPRLs). Livers were perfused, in a recirculating manner, with a solution containing human serum albumin (HSA), bovine serum albumin (BSA), or no serum albumin (N = 5 for each group). After presystemic administration of a single dose of racemic VER (2 mg), the concentrations of VER and NOR enantiomers in the perfusate were measured over 90 min. In addition, the fraction of the enantiomers bound to the plasma of perfusate was determined. Perfusate concentrations of both VER and NOR were stereoselective in all of the perfusates studied. However, the direction of stereoselectivity in the concentrations of VER enantiomers in the BSA perfusate (S-VER > R-VER) was opposite that in the HSA and albumin-free perfusates (R-VER > S-VER); this was associated with an opposite stereoselectivity in the concentrations of NOR in the BSA perfusate was higher than that in the HSA and albumin-free perfusates, an observation in agreement with the higher stereoselectivity in the binding of NOR to BSA. These data, along with other kinetic parameters such as apparent hepatic availability and intrinsic clearance, suggest that the apparent stereoselectivity in the presystemic elimination of VER by IPRLs is significantly influenced by the stereoselectivity in the protein binding of the drug.     

False-negative rates of tumor metastases in the histologic examination of bone marrow

The phenomenon of enantioselectivity in the metabolism of mexiletine (MEX) conjugation was investigated in eight female patients with the arrhythmic form of chronic Chagas' heart disease treated with racemic mexiletine hydrochloride (two 100 mg capsules every 8 hr). Blood samples were collected up to 24 hr after the administration of the morning dose, with discontinuation of the subsequent doses during the study period. Plasma concentrations of N-hydroxymexiletine glucuronide were calculated as the difference between the concentrations of unchanged and total (unchanged + conjugated) MEX enantiomers. Total plasma MEX concentrations were analyzed by HPLC after enzymatic hydrolysis with beta-glucuronidase, the formation of diastereomeric derivatives with the chiral reagent N-acetyl-L-cysteine/o-phthalaldehyde, and fluorescence detection. The differences in the pharmacokinetic parameters of the enantiomers were evaluated by the paired t-test. The plasma concentrations of the (+)-(S)-MEX did not differ before and after enzymatic hydrolysis. The pharmacokinetic parameters calculated for (-)-(R)-N-hydroxymexiletine glucuronide are presented as means (95% confidence interval): maximum plasma concentration Cmax = 194.0 ng.ml-1 (154.3-233.7), time to maximum plasma concentration tmax = 1.4 hr (0.3-2.5), area under the plasma concentration versus time curve AUC0-24 = 2099.2 ng.h.ml-1 (1585.6-2612.6), elimination half-life t1/2 beta = 12.8 hr (9.9-15.6) and extent of conjugation of 31.6% (24.3-38.9%). The present data indicate stereospecific conjugation of (-)-(R)-N-hydroxymexiletine in the female patients with the arrhythmic form of Chagas' heart disease.     

Dose-dependent plasma clearance of MK-826, a carbapenem antibiotic, arising from concentration-dependent plasma protein binding in rats and monkeys

After intravenous administration of MK-826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmacokinetics in rats and monkeys. In both species, time-averaged plasma clearance (based on total concentrations) increased about 5-fold over the 10- to 180-mg/kg dose range. MK-826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK-826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.     

Comparative repellency of commercial formulations of deet, permethrin and citronellal against the mosquito Aedes aegypti, using a collagen membrane technique compared with human arm tests

The plasma concentrations and urinary excretions of bisoprolol enantiomers in four Japanese male healthy volunteers after a single oral administration of 20 mg of racemic bisoprolol were evaluated. The AUC(infinity) and elimination half-life of (S)-(-)-bisoprolol were slightly larger than those of (R)-(+)-bisoprolol in all subjects. The metabolic clearance of (R)-(+)-bisoprolol was significantly (P < 0.05) larger than that of (S)-(-)-bisoprolol (S/R ratio: 0.79+/-0.03), although the difference was small. In contrast, no stereoselective in vitro protein binding of bisoprolol in human plasma was found. An in vitro metabolic study using recombinant human cytochrome P450 (CYP) isoforms indicated that oxidation of both bisoprolol enantiomers was catalyzed by the two isoforms, CYP2D6 and CYP3A4. CYP2D6 metabolized bisoprolol stereoselectively (R > S), whereas the metabolism of bisoprolol by CYP3A4 was not stereoselective. The S/R ratio of the mean clearance due to renal tubular secretion was 0.68, indicating a moderate degree of stereoselective renal tubular secretion. These findings taken together suggest that the small differences in the pharmacokinetics between (S)-(-)- and (R)-(+)-bisoprolol are mainly due to the stereoselectivity in the intrinsic metabolic clearance by CYP2D6 and renal tubular secretion.     

Clinical pharmacokinetics of oxaprozin

Oxaprozin is a nonsteroidal anti-inflammatory drug which reaches peak plasma concentrations 2 to 6 hours after oral administration. Oxaprozin binds extensively, in a concentration-dependent manner, to plasma albumin. The area under the plasma concentration-time curve (AUC) of oxaprozin is linearly proportional to the dose for oral doses up to 1200 mg. At doses greater than 1200 mg there is an increase in the unbound fraction of drug, leading to an increased clearance and volume of distribution (Vd) of total oxaprozin. Accumulation of the drug at steady state is between 40 and 58% lower than predicted by single dose data. After administration of multiple doses, the apparent oral clearance (CL/F) and Vd of total oxaprozin increased while those of the unbound drug decreased significantly. Substantial concentrations of oxaprozin are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships between total plasma, unbound plasma and synovial concentrations, and therapeutic and toxicological effects have yet to be established. Oxaprozin is eliminated following biotransformation to glucuroconjugated metabolites which are excreted in urine and bile, with little drug being eliminated unchanged. Two hydroxylated metabolites have been shown to possess anti-inflammatory activity. Hepatic disease and rheumatoid arthritis do not significantly alter the disposition of oxaprozin. Patients with renal impairment demonstrate an increase in unbound plasma concentrations of oxaprozin. A significant drug interaction has been demonstrated between oxaprozin and aspirin (acetylsalicylic acid).     

A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.     

Single- and multiple-dose pharmacokinetics of riluzole in white subjects

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 (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax 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 (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) 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 absorption, 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 AUC values did not differ.     

Pharmacokinetic approach to the clinical use of lidocaine intravenously

The time course of lidocaine plasma concentrations following various modes of administration were predicted by computer. Initiating therapy with a single intravenous bolus dose was unsatisfactory; plasma levels during the first hour were potentially toxic after a 200-mg bolus and subtherapeutic after a 50- to 100-mg bolus. After two bolus doses of 100 mg, separated by 20 to 30 minutes, or a rapid loading infusion over 15 to 60 minutes, therapeutic concentrations were achieved and maintained. Pharmacokinetic principles can be of value in devising rational approaches to lidocaine dosage.     

An outbreak of Salmonella enteritidis in a maternity and neonatal intensive care unit

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2, 5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2-10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6-fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+/-)-MPD was greater than that (2.2-fold) of the same dose of (-)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (-)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (-)-isomer.     

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers

OBJECTIVE: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. RESULTS: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC0-infinity 12.6 micrograms.h.ml-1) in comparison with healthy volunteers (AUC0-infinity 39.3 micrograms.h.ml-1). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free Cmax (5.0 vs. 2.6 ng/ml) but similar free AUC0-infinity (0.13 vs. 0.11 microgram.h.ml-1) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemodialysis. CONCLUSION: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound nonsteroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free Cmax value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable.     

Light is associated with a 34 kDa ribonucleoprotein in spinach chloroplasts

Ketamine exerts antinociceptive effects in many pain tests. We investigated the antinociceptive effect of intrathecally administered racemic ketamine and its S(+)- and R(-)-enantiomer on carrageenan-induced thermal hyperalgesia with a paw withdrawal test and acute pain (hot plate and tailflick) tests. Rats were prepared with a chronic lumbar intrathecal catheter to receive either saline or ketamine enantiomers in cumulative doses. None of the ketamines (10, 50, or 100 microg) had any effect on the withdrawal latency of the contralateral, noninjected paw. In the injected paw, intrathecal saline did not alter carrageenan-induced thermal hyperalgesia, whereas intrathecally applied S(+)-, R(-)-, and racemic ketamine decreased thermal hyperalgesia. However, compared with saline, racemic ketamine had a higher efficacy than S(+)-ketamine, whereas R(-)-ketamine did not achieve statistical significance. Neither S(+)- nor R(-)-ketamine had a significant effect in the tailflick test (10, 100, or 500 microg). In the hot plate test, only the largest dose of ketamine (500 microg) caused a nonstereospecific, significant increase in hot plate latency; this dose caused supraspinal effects as well. The results demonstrate that the behavioral hyperalgesia associated with carrageenan-induced hindpaw inflammation in rats is attenuated by the intrathecal administration of racemic and S(+)-ketamine, but not R(-)-ketamine, which only displayed an insignificant trend toward a dose-response relationship. This finding warrants further studies to investigate a possible clinical advantage of preservative-free S(+)-ketamine over the currently used preservative containing racemic mixture. IMPLICATIONS: In rats, intrathecal S(+)-ketamine was effective for treating inflammatory pain. Although racemic ketamine has a greater efficacy, S(+)-ketamine is available as a preservative-free drug and might be of clinical interest for future neuraxial administration in different pain states.     

Preliminary toxicokinetic study with different crystal forms of S (+)-ibuprofen (dexibuprofen) and R,S-ibuprofen in rats

The aim of the study was to gain information on the plasma concentration-time profiles of both ibuprofen (CAS 15687-27-1) enantiomers in the rat after single oral application of two different crystal forms of S (+)-ibuprofen (dexibrufen, CAS 51146-56-6) and racemic ibuprofen in order to optimize blood-sampling times in a subsequent subchronic toxicity study. The application of either commercial racemic ibuprofen or recrystallised S (+)-ibuprofen (60 mg/kg) to two groups of 4 rats per blood sampling term was carried out in order to define Cmax and tmax and AUC of the plasma-concentrations of the ibuprofen enantiomers. The crystals of commercial (manufactured according to an usual manufacturing procedure) and recrystallised (S(+)- and racemic ibuprofen were different in respect to their shape and size. The recrystallised crystal species of S (+)- and racemic ibuprofen has better galenic (tabletting-) properties and tablets containing the modified S (+)-ibuprofen species showed favorable clinical results. The toxicokinetic behaviour of the recrystallised species was investigated in comparison to the commercial crystal species because of its slightly but significantly slower dissolution rate in simulated gastric and enteric juice. As the AUC0-24 h S-(+)-ibuprofen and the AUC0-24 h, R-(-)-ibuprofen after application of commercial and recrystallised crystal species were not different, the crystal form apparently did not exert an influence on the extent of absorption of S-(+)-ibuprofen and racemic ibuprofen in the rat. The rat has a high inversion capacity and the inversion of R-(-)-ibuprofen after application of commercial and recrystallised racemic ibuprofen was nearly complete in this study. The effects of crystallinity on solubility in simulated media in vitro did not correlate to the findings on the extent of absorption in the rat in vivo.