Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Aqueous and vitreous penetration of levofloxacin after oral administration.

OBJECTIVE: To investigate the penetration of levofloxacin, an optical S-(-)isomer of ofloxacin, into the aqueous and vitreous humor after oral administration. DESIGN: Randomized, clinical trial comparing tissue levels of levofloxacin after one or two doses 12 hours apart. PARTICIPANTS: Forty-five patients undergoing initial vitrectomy between February 1997 and June 1997 at the UIC Eye Center. METHODS: Aqueous, vitreous, and serum samples were obtained and later analyzed from 45 patients after oral administration of 1 500-mg tablet (group 1, 22 patients) or 2 500-mg tablets (group 2, 23 patients) 12 hours apart before surgery. MAIN OUTCOME MEASURES: Aqueous, vitreous, and serum concentrations of levofloxacin (micrograms/milliliter). RESULTS: Group 1 achieved mean aqueous, vitreous, and serum levels of 0.59 +/- 0.48 microg/ml, 0.32 +/- 0.34 microg/ml, and 4.34 +/- 3.59 microg/ml, respectively. Group 2 achieved mean aqueous, vitreous, and serum levels of 1.90 +/- 0.97 microg/ml, 2.39 +/- 0.70 microg/ml, and 8.02 +/- 3.14 microg/ml. CONCLUSIONS: Mean inhibitory aqueous and vitreous MIC90 levels were achieved against a majority of ocular pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae (vitreous), Bacillus cereus (vitreous), Haemophilus influenzae, Moraxella catarrhalis, and most gram-negative aerobic organisms except Pseudomonas aeruginosa after two doses given 12 hours apart. Mean MIC90 levels were obtained in the vitreous for a majority of pathogens responsible for traumatic, postoperative, or bleb-related endophthalmitis.

Intraocular penetration of gentamicin after once-daily aminoglycoside dosing.

BACKGROUND: Intraocular concentrations-particularly intravitreal concentrations-after systemic administration of gentamicin are poor. Once-daily aminoglycoside dosing of intravenous gentamicin achieves peak serum levels up to five times higher than conventional dosing. Whether these increased serum levels of gentamicin improve the aqueous or vitreous concentrations in humans has not been determined. The authors sought to determine if the intraocular penetration of gentamicin would be improved using this method. METHODS: Patients undergoing vitrectomy procedures were administered intravenous gentamicin in a dose of 7 mg/kg approximately 1 hour before surgery. An adjustment in dosing was made for anyone more than 20% over his or her ideal body weight. Aqueous, vitreous, and serum samples were collected before any intraocular surgical manipulation. The samples were analyzed by fluorescence polarization immunoassay (TDx system). RESULTS: The average single gentamicin dose was 498 mg (range, 360-700 mg). The aqueous, vitreous, and serum levels averaged 1.14 microg/mL, 0.41 microg/mL, and 22.07 microg/mL, respectively. No correlation between serum level concentrations and time of administration was found for the aqueous and vitreous levels in this study. CONCLUSION: Although the average peak serum level of gentamicin was five times higher than previously reported, the vitreous levels averaged only 1.5 times higher. The blood-retinal barrier is difficult to penetrate even when higher serum levels are achieved. Due to its poor ocular penetration, gentamicin may not be among the best drugs for prophylaxis of penetrating eye injuries, surgical prophylaxis, or treatment of endophthalmitis.

Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats.

BACKGROUND: The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma-lipid emulsion mixture. METHODS: Anesthetized Sprague-Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n = 6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 ml x kg x min(-1) to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n = 6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabeled bupivacaine. RESULTS: Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P < 0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n = 3). CONCLUSIONS: Lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine.

Simultaneous rapid high-performance liquid chromatographic determination of phenytoin and its prodrug, fosphenytoin in human plasma and ultrafiltrate.

A reversed-phase high-performance liquid chromatographic assay for the simultaneous determination of phenytoin and fosphenytoin, a prodrug for phenytoin, in human plasma and plasma ultrafiltrate is described. For plasma, the method involves simple extraction of drugs with diethyl ether and evaporation of solvent, followed by injection of the reconstituted sample onto a reversed-phase C18 column. Plasma ultrafiltrate is injected directly into the HPLC column. Compounds are eluted using an ion-pair mobile phase containing 20% acetonitrile. The eluent is monitored by UV absorbance at 210 nm. The fosphenytoin standard curves are linear in the concentration range 0.4 to 400 microg/ml for plasma and 0.03 to 80 microg/ml for ultrafiltrate. Phenytoin standard curves are linear from 0.08 to 40 microg/ml for plasma and from 0.02 to 5.0 microg/ml for ultrafiltrate. No interferences with the assay procedure were found in drug-free blank plasma or plasma ultrafiltrate. Relative standard deviation for replicate plasma or ultrafiltrate samples was less than 5% at concentrations above the limit of quantitation for both within- and between-run calculations.

Stability of fosphenytoin sodium with intravenous solutions in glass bottles, polyvinyl chloride bags, and polypropylene syringes.

OBJECTIVE: To determine the stability of fosphenytoin sodium admixtures with NaCl 0.9% injection and dextrose 5% (D5W) injection when stored in glass or polyvinyl chloride (PVC) containers, to evaluate the compatibility of fosphenytoin with 11 other intravenous solutions, and to determine the stability of fosphenytoin repackaged in polypropylene syringes. METHODS: Dilutions of fosphenytoin sodium 1, 8, and 20 mg phenytoin sodium equivalents (PE)/mL were prepared in NaCl 0.9%, D5W, and 11 other intravenous fluids. Aliquots of each solution in NaCL 0.9% or D5W were transferred to three glass bottles for storage at 25 degrees C and 21 PVC bags for storage at 25, 4, or -20 degrees C. Aliquots of each admixture with the other intravenous fluids were transferred to three PVC bags and stored at 25 degrees C for 7 days. In addition, 63 syringes were filled with fosphenytoin sodium 50 mg PE/mL (undiluted) and stored at 25, 4, or -20 degrees C. Samples of each solution from the three containers were analyzed for visual compatibility, pH, and fosphenytoin concentration initially and at 0.5, 1, 2, 3, 7, 14, and 30 days during storage at 25 and 4 degrees C and at 1, 7, 14, and 30 days during storage at -20 degrees C. Following removal of containers from the freezer, additional samples were obtained after 7 days at 4 or 25 degrees C, and 7 days at 25 degrees C, and then 7 days at -20 degrees C. RESULTS: No visible precipitation or change in color or clarity was observed in any of the fosphenytoin solutions during the study. The concentration of fosphenytoin at each sampling time remained within 97-104% of initial concentration, regardless of container, concentration, intravenous admixture, or storage temperature. CONCLUSIONS: Fosphenytoin sodium, either undiluted in polypropylene syringes or diluted with NaCl 0.9% or D5W in PVC bags, remains stable for at least 30 days at room temperature, under refrigeration, or frozen. After removal from the freezer, fosphenytoin can be thawed, kept at 4 or 25 degrees C for 7 days, and then returned to the freezer for another 7 days. Admixtures of fosphenytoin sodium in various other intravenous fluids are stable for at least 7 days at room temperature.

Alterations in theophylline metabolism during the first year of life.

Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.

Efeito da idade e nível de treinamento na farmacocinética do flunixin meglumine em cavalos puro-sangue inglês / Effect of age and training status on pharmacokinecits of flunixin meglumine in thoroughbreds

A maioria das comissöes de corridas proíbem a presença de qualquer substância estranha na saliva, no sangue e na urina na amostragem feita após a corrida. A identificaçäo de uma substância proibida resulta normalmente na perda de prêmios e suspensäo do treinador. Proprietários, treinadores e veterinários necessitam orientaçäo para o momento certo de interromper a medicaçäo. Vários fatores podem influenciar este momento. O presente estudo investiga a importância da idade e o nível de exercício na eliminaçäo de flunixina meglumine, medicamento näo esteróide comumente usado na terapêutica eqüina.

Altered theophylline metabolism in patients with psoriasis.

We observed two patients on theophylline therapy with concomitant severe psoriasis and a two- to threefold greater theophylline clearance than that reported in healthy, nonsmoking adults. There were no factors known to induce theophylline clearance. In both cases, the induction of theophylline metabolism was relatively selective for the 1-methyluric acid pathway. The altered metabolism in these patients appeared to correlate with the clinical severity of the disease. The data suggest the possibility that an observed lack of efficacy for theophylline in psoriasis may be related to pharmacokinetic effects. The concept that altered drug metabolism may occur in the presence of skin disease has important implications for pharmacotherapeutics in dermatology.

Effect of age and training status on pharmacokinetics of flunixin meglumine in thoroughbreds.

The effect of age and training status on the pharmacokinetics of flunixin meglumine was evaluated in 16 Thoroughbreds. Horses were assigned to 1 of 3 groups on the basis of age and training status: group A (n = 6), horses in active training and less than or equal to 5 years old; group B (n = 5), horses out of training for a minimum of 6 weeks and less than or equal to 5 years old; and group C (n = 5), horses out of training for at least 2 years and greater than or equal to 9 years old. After administration of 500 mg of flunixin meglumine IV, multiple serum and urine samples were obtained over 24 hours and assayed for flunixin by high-performance liquid chromatography. Although the mean distribution rate constant and volume of distribution were similar for the 3 groups, mean total body clearance and elimination rate constant were significantly (P less than 0.05) greater and half-life significantly (P less than 0.01) less in groups A and B, compared with group C. Differences in pharmacokinetic values were not observed between the horses in group A and B. In addition, the changes in clearance, elimination rate constant, and half-life of flunixin were found to significantly (P less than 0.05) correlate with age. The results of this investigation indicated that age, but not training status, influences disposition of flunixin meglumine in Thoroughbreds.

Stability of nizatidine in commonly used intravenous fluids and containers.

The stability of nizatidine in commonly used i.v. fluids stored in glass and plastic containers was studied. Stock solutions of nizatidine 0.75, 1.5, and 3.0 mg/mL in 15 i.v. fluids were prepared using nizatidine injection 25 mg/mL. Six 50-mL aliquots of each solution were transferred to separate glass infusion bottles and stored at room temperature or under refrigeration. Twenty-one 40-mL aliquots of additional stock solutions of nizatidine 0.75 and 3.0 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection were transferred to polyvinyl chloride (PVC) bags and stored at room or refrigerated temperature; some of these solutions were frozen, thawed, and refrigerated before analysis. Samples of each admixture were analyzed after 0.5, 1, 2, 3, and 7 days of storage for nizatidine concentration using a stability-indicating high-performance liquid chromatographic assay and also for visible changes and pH. The concentration of nizatidine in each admixture remained within 92%-106% of actual initial storage concentration throughout the study period, with the exception of nizatidine 3.0 mg/mL in 8.5% amino acid injection. The stability of nizatidine in admixtures stored in polyvinyl chloride bags was similar to that of admixtures stored in glass bottles. In the i.v. fluids, concentrations, and containers studied, nizatidine admixtures are stable for at least 7 days at either room or refrigerated temperature and 30 days when stored frozen in polyvinyl chloride bags. Admixtures of nizatidine 3.0 mg/mL in 8.5% amino acid injection should not be stored at room temperature for longer than four days.

Quantitative determination of tolazoline in serum and urine.

A high-performance liquid chromatographic procedure is described for the analysis of tolazoline in serum and urine. This assay procedure is suitable for the analysis of micro-samples (50 or 100 microliters serum and 100 microliters urine). Samples are extracted in a single step and injected into a reversed-phase high-performance liquid chromatography system for detection at 210 nm. The clinical applicability of this assay is demonstrated by the determination of tolazoline serum and urine concentrations in neonates. In addition, the presence of urine conjugates and the extent of serum protein binding were investigated. This assay procedure has the required sensitivity (0.1 microgram/ml), accuracy and precision for both routine monitoring and pharmacokinetic characterization of tolazoline in neonates and adults.