Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults.

The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m(2) receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K(12) and K(21)) of 8.04 ± 6.22 and 7.99 ± 5.46 h(-1), respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 µg · h/ml (P = 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r(2) = 0.524), adjusted body weight (r(2) = 0.587), lean body weight (r(2) = 0.495), and ideal body weight (r(2) = 0.398), but not with BMI (r(2) = 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

A rapid and sensitive method to measure the functional activity of Shiga toxins in human serum.

Shiga toxins (Stx) have a definite role in the development of hemolytic uremic syndrome in children with hemorrhagic colitis caused by pathogenic Stx-producing Escherichia coli (STEC) strains. The dramatic effects of these toxins on the microvasculature of different organs, particularly of the kidney, are well known, whereas there is no consensus on the mechanism by which Stx reach the endothelia of target organs and/or indirectly injure these body sites. We hereby describe a quick (4 h), radioactive, Raji cell-based method designed for the detection of Stx in human sera. The assay monitors the translation impairment induced by these powerful inhibitors of protein synthesis, which are identified properly by neutralizing their activity with specific monoclonal antibodies. By this method, we detected for the first time the functional activity of Stx in sera of STEC-infected patients during hemorrhagic colitis. Recent research has pointed to a dynamic process of Stx-induced renal intoxication in which concurrent and interactive steps are involved. Our rapid and specific method could be useful for studying the kinetics of Stx during the natural course of STEC infection and the interplay between Stx activity in serum and Stx presence in different blood fractions (neutrophils, monocytes, platelets, leukocyte-platelet aggregates, microvesicles, lipoproteins).

Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test.

OBJECTIVE: The steady-state kinetics of delavirdine and desisopropyldelavirdine were evaluated in human immunodeficiency virus-positive patients after escalating oral doses and after repeated oral administrations at the same dose level. STUDY DESIGN: Patients (n = 8 males) were given escalating oral doses of delavirdine mesylate, in a sequential fashion, over 14 days for phases 1 (200 mg every 8 hours), 2 (300 mg every 8 hours), and 3 (400 mg every 8 hours). Control patients (n = 4 males) were given 300 mg oral doses of drug every 8 hours for all three phases. Hepatic CYP3A activity was evaluated with the erythromycin breath test (ERMBT). RESULTS: In the escalating-dose group, delavirdine displayed nonlinear kinetics as indicated by the decreasing oral clearance, maximum steady-state plasma concentration/minimum steady-state plasma concentration ratio, and log-linear terminal rate constant, as well as by increasing half-life at higher doses; the ratio of desisopropyl-delavirdine formation clearance to elimination clearance was also reduced. In the control group, the kinetics of delavirdine and desisopropyl-delavirdine were unchanged. Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively. Hepatic CYP3A activity was markedly reduced after short- and long-term exposure to all doses of delavirdine mesylate. Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L. CONCLUSION: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform. It is likely that delavirdine will exhibit drug-drug interactions when coadministered with other CYP3A substrates.

Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers.

We developed an intranasal powder form of glucagon to improve metabolic status and fatty liver in patients with pancreatectomy. Microcrystalline cellulose, which is commonly used in commercial preparations for allergic rhinitis was used as an absorption enhancer. We compared the intranasal powder form with some spray solutions of glucagon with regard to glucagon absorption, concentration of blood glucose, stability and nasal irritation. The absorption of glucagon from the spray solution including 1.5% sodium glycocholate or 1% sodium caprate was 1.3- and 2.6-fold higher than that from the powder form mixed with microcrystalline cellulose at a ratio of 1:69, respectively. The C(max) values of plasma glucose were 2.18, 3.39 and 1.56 mmol l(-1) in the spray solutions including sodium glycocholate and sodium caprate and in the powder form, respectively. However, glucagon in spray solutions was unstable, but that in the powder form was stable at 5 and 25 degrees C for at least 84 days. The spray solution caused strong irritation, but the powder form did not. These results suggested usefulness of the powder form of glucagon for treatment of pancreatectomized patients.

Effects of dietary n-3 fatty acid supplementation versus thromboxane synthetase inhibition on gentamicin-induced nephrotoxicosis in healthy male dogs.

OBJECTIVE: To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin. DESIGN: Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration. ANIMALS: Eighteen 6-month-old male Beagles, 6 in each group. RESULTS: After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs. TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1a (PGF1a) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF(in)-to-TXB2, ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs. CONCLUSION: Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis. CLINICAL RELEVANCE: Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis.

Purification and some properties of an oxydative inhibitor in rabbit reticulocyte lysates.

Protein synthesis in rabbit reticulocyte lysates in the presence of heme is inhibited by 50% by the addition of 4 mM GSSG (oxidized glutathione). The incubation of the rabbit reticulocyte lysate with 4 mM GSSG at 30 degrees C for 30 min will cause activation of an inhibitor of protein synthesis which could be purified from the lysates through a five-step procedure. The inhibitor results in a 70-80% inhibition after a 1 h incubation. The inhibitor consists of one polypeptide of 23 kDa apparent molecular weight and is 90% pure as judged by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. However, in the presence of cAMP (10 mM) or GEF (guanine nucleotide exchange factor) (0.3 microgram), protein synthesis in the inhibited reticulocyte lysate will be already recovered.

Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine.

BACKGROUND: Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine. AIM AND METHODS: The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4 days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h. RESULTS: Clarithromycin increased the mean C(max) of ketamine by 3.6-fold (p<0.001) and the mean AUC(0-infinity) of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected. CONCLUSIONS: Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine.

Animal pharmacokinetics and interspecies scaling of sordarin derivatives following intravenous administration.

Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine Candida albicans, Histoplasma capsulatum, and Coccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, < or =5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.

Lack of evidence for systemic toxicity following topical chloramphenicol use.

There has been considerable controversy regarding the safety of topical chloramphenicol in ophthalmic practice. The evidence for associated haematopoietic toxicity in idiosyncratic and dose-dependent forms was reviewed. The 7 cases of idiosyncratic haematopoietic reactions associated with topical chloramphenicol reported in the literature are refutable evidence for the existence of such a response. In Scotland, despite extensive prescription of topical chloramphenicol, the incidence of acquired aplastic anaemia was found to be low, as were associated reports of blood dyscrasias throughout the UK. The epidemiology of acquired aplastic anaemia failed to make an association with topical chloramphenicol use. High-performance liquid chromatography (minimum detection limit 1 mg/l) was used to investigate whether serum accumulation of chloramphenicol occurred after topical therapy in 40 patients. The mean dose of chloramphenicol eye drops used after 1 week of treatment was 8.0 mg, and after 2 weeks, 15.3 mg. As expected, chloramphenicol failed to accumulate to detectable levels. This supported the view that topical chloramphenicol was not a risk factor for inducing dose-related bone marrow toxicity. Calls for the abolition of treatment with topical chloramphenicol based on current data are not supported.

High concentrations of 2-5A, the interferon intracellular mediator, in the blood of children with acute viral infections.

We measured the concentration of 2-5A (2',5'-oligoadenylate), an intracellular mediator of the antiviral action of interferon, in the blood of children with acute viral and bacterial infectious diseases. 2-5A concentration was found to be elevated in several children with viral diseases. This elevation seemed transient and was not specific for viral infections. We provide arguments for the use of 2-5A as a marker of the evolution of diagnosed viral diseases.

In vivo and in vitro pharmacokinetics of 4,6-benzylidene-D-glucose (BG) in rats.

In vivo pharmacokinetics of 4,6-benzylidene-D-glucose (BG) was investigated in rats following an i.v. bolus injection of 85 mg BG/kg body weight. High performance liquid chromatography (HPLC) was used to characterize and quantitate BG in whole blood or serum samples. It was found that BG rapidly disappeared with a half-life (t1/2) on the order of 10 min. At the same time a metabolite appeared which eluted before the double isomer peaks of BG. It increased in concentration from 0 to 30 min after initial i.v. injection of BG. Thereafter the metabolite was slowly removed or cleared from the animals. The t1/2 of the metabolite calculated from the time of maximum concentration was found to be about 1 h. BG was also metabolized by whole rat blood at 37 degrees C, but on a different time scale in vitro. The t1/2 of BG in the in vitro assays was now about 4 h, as compared to 10 min in vivo. BG was not metabolized in rat plasma or rat serum. In contrast to in vivo data, the metabolite of BG was not reduced upon further incubation, but remained in blood samples with no reduction for at least 24 h. In addition, we found that protein synthesis was inhibited by approximately 50% when isolated rat hepatocytes were incubated with 3.2 mM BG. BG was slowly metabolized by hepatocytes to produce a metabolite indistinguishable (by HPLC) from that found in blood samples. Analysis of the metabolite by combined gas chromatography-mass spectrometric (GC-MS) methods identified it as being 1,3-benzylidene-D-glucitol.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of the ochratoxin A-induced cytotoxicity in Vero cells by aspartame.

Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus ochraceus as well as other moulds. This mycotoxin contaminates animal feed and human food and is nephrotoxic for all animal species studied so far. OTA is immunosuppressive, genotoxic, teratogenic and carcinogenic. Recently lipid peroxidation induced by OTA has been reported. OTA, a structural analogue of phenylalanine, inhibits protein synthesis by competition with phenylalanine in the phenylalanine-tRNA aminoacylation reaction, constituting the main mechanism of OTA-induced cytotoxicity. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, investigation is required for preventing the toxicity of OTA. An attempt to prevent its toxic effect, mainly the inhibition of protein synthesis, has been made using aspartame (L-aspartyl-L-phenylalanine methyl ester) a structural analogue of both OTA and phenylalanine. Protein synthesis was assayed in monkey kidney cells (Vero cells) treated by increasing concentrations of OTA (10-100 microM). After 24 h incubation, protein synthesis was inhibited by OTA in a concentration dependent manner (the 50% inhibitory concentration, IC50, was c. 14.5 microM). Aspartame (A19), at tenfold higher concentrations than OTA (100-1000 microM), was found to partially protect against the OTA-induced inhibition of protein synthesis in Vero cells, and more efficiently when added 24 h prior to the toxin (IC50 34 microM) than together (IC50 22 microM). As expected A19(250 microM) prevented the OTA-induced leakage of certain enzymes, including lactate dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, into the culture medium, and the concomitant decrease of their intracellular activity in OTA (25 microM)-treated cells. In order to investigate the effect of aspartame (A19) on OTA-protein binding as explanation of the above results, the mycotoxin time- and concentration-dependent binding to human samples was studied in static diffusion cells with two compartments separated by a dialysis membrane. When A19 (34 microM) was added to the upper compartment containing plasma before installing OTA (50, 250, 1240 microM) in the lower one. OTA binding was largely prevented (95-98%). When A19 (34 microM) was added to the lower compartment simultaneously with the toxin (50, 250, 1240 microM), for the lowest concentration of OTA, the same efficiency was shown in preventing OTA binding, but at the two high concentrations A19 seemed less efficient.

Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.

OBJECTIVE: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. METHODS: Twelve healthy young male subjects received single oral doses of 300 microg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. RESULTS: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). CONCLUSIONS: Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 microg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.

Blood clearance and organ distribution and tissue concentration of native, homopolymerized and IgG-conjugated ribosome-inactivating proteins.

1. The blood clearance, organ distribution and tissue concentration of several native, homopolymerized, and IgG-conjugated 125I-labelled ribosome-inactivating proteins (RIPs) were determined in mice. 2. Native RIPs were cleared rapidly from blood, with half-lives of 4-8 min, and were concentrated mainly in the kidneys. 3. After conjugation to IgG the three RIPs studied showed increased blood half-lives and decreased concentrations in the kidneys. 4. The two homopolymers studied had blood half-lives and kidney concentrations intermediate to those of free and conjugated RIPs. 5. These results indicate that after IgG-conjugation the increased half-lives of the RIPs studied were at least in part due to the larger molecular size of the conjugates and to their lower renal excretion.