Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

BACKGROUND: Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. METHODS: The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. RESULTS: After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. CONCLUSIONS: At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.

The optimal aminoglycoside and its dosage for the treatment of severe Enterococcus faecalis infection. An experimental study in the rabbit endocarditis model.

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3 days with a computer-regulated flow simulating human pharmacokinetics of 15 mg/kg/day for amikacin, 6 mg/kg/day for netilmicin, and 3 mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6 mg/kg/day) were compared over 1 or 3 days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3 days of treatment. After only 1 day of treatment, the high dosage of gentamicin (6 mg/kg/day) was more effective than the standard dosage (3 mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.

The evolution of nutritional status of geriatric patients without cachexia is associated with food intake in sub-acute care.

OBJECTIVES: To determine if changes in patients' nutritional status during hospitalization are related to daily energy and protein intakes when cachectic/inflammatory conditions are controlled for. DESIGN: Prospective study. SUBJECTS: A total of 32 non-cachectic patients (21 women; 65-92 y). METHODS: Nutritional status was evaluated at admission and discharge using the Protein-Energy Malnutrition Index which includes BMI, %IBW, TS, MAC, albumin, hemoglobin and lymphocyte count. Food intake was assessed 3 meals/day every other day for an average of 46.2 +/- 14.6 meals/participant. RESULTS: In all, 47% of the study sample was malnourished at admission. Nutritional status improved in 73% of patients who had been identified as malnourished and in 30 % of non-malnourished patients at admission. Total energy intake correlated with improvements in BMI, %IBW and total lymphocyte count (all p < 0.04). Improvement in PEMI score for the whole group was associated with functional status (p < 0.05). Controlling for this variable, energy (kj/kg body weight) and protein (g/kg body weight) intakes correlated positively with improvements in BMI, %IBW and MAC (Energy: partial r = 0.644, 0.624, 0.466 respectively; Protein: partial r = 0.582, 0.554, 0.433 respectively; all p < 0.05). CONCLUSIONS: Results from this study offer strong evidence that when cachectic/inflammatory conditions are controlled for, standard nutrition care is compatible with the maintenance or improvement of nutritional status during the hospital stay.

Nutritional implications of patient-provider interactions in hospital settings: evidence from a within-subject assessment of mealtime exchanges and food intake in elderly patients.

OBJECTIVE: To examine the nutritional implications of the interactions taking place between patients and care providers during mealtimes in hospital settings. Specifically, we tested research propositions that the amount and nature of interpersonal behaviours exchanged between patients and providers impact patients' food intake. These propositions were derived from prior evidence of social influences on eating behaviour and a well-established framework that identifies two fundamental modalities of human interaction: striving for mastery and power (agency) and efforts to promote union with others (communion). DESIGN: In a within-subject naturalistic study, participants were observed on multiple meals (n=1477, 46.2 meals/participant on average), during which participants' and providers' agency- and communion-related behaviours and patients' protein and energy intake were recorded. Meal-level frequency and complementarity of patients' and providers' behaviours were computed to test research propositions. SETTING: Dining room of a geriatric rehabilitation unit. SUBJECTS: Thirty-two elderly patients (21 females, mean age:78.8, 95% CI: 76.4, 81.1). RESULTS: Meal-level frequency of patient-provider exchanges (P=0.016) and patients' agency-related behaviours (P=0.029), as well as mutual reciprocation of patients' and providers' communion-related behaviours (P=0.015) on a given meal were positively linked to protein intake. Higher energy intake was found during meals where patients expressed more agency-related behaviours (P=0.029). CONCLUSION: Results present evidence that the amount and nature of patient-provider interpersonal exchanges on a given meal influence the nutritional quality of food intake in hospitalized elderly. They provide insights into how to improve the design and delivery of routine care to this malnutrition-prone population. SPONSORSHIP: This study was supported by the Canadian Institutes of Health Research (Operating grant to Laurette Dubé, Doctoral Fellowship to Catherine Paquet) the Fonds de la Recherche en santé du Québec and by the Danone Institute (Doctoral fellowship to Danielle St-Arnaud McKenzie).

Simultaneous CT angiography and whole-body CT is an effective imaging approach before multiorgan retrieval.

PURPOSE: To assess the role of whole-body computed tomography (CT) for determining morphological suitability before multiorgan retrieval (MOR) in brain dead patients. MATERIALS AND METHODS: Fifty-one clinically brain dead patients (21 women, 30 men; mean age 61 year±15) were included in this prospective, single center study. All patients had CT angiography of the brain and whole-body CT examination. CT images were evaluated for the presence of morphological abnormalities of lungs, liver and other abdominal organs and presence of vascular anatomical variants. The results of CT examinations were compared to intraoperative findings observed during organ harvesting and/or the results of histopathological analysis of biopsy specimens. The impact of whole-body CT examination on the harvesting process was evaluated. RESULTS: Ninety-five percent of vascular anatomical variants that were found intraoperatively were depicted on CT. CT density measurements predicted surgical finding of steatosis in 80% of patients. Whole-body CT changed the MOR strategy in 21/51 patients (41%) including 3 MOR cancellations and 8 grafts refusals, whereas organ harvesting was continued in 10 patients after histopathological analysis was performed. CONCLUSION: Selection of potential graft donors using whole-body CT is reliable and improves graft selection during MOR.

Light-induced chaotic rotations in nematic liquid crystals.

Various nonlinear rotation regimes are observed in an optically excited nematic liquid-crystal film under boundary conditions (for the light and material) that are invariant by rotation. The excitation light is circularly polarized, the intensity profile is circularly symmetric, and the beam diameter at the sample location is a few times smaller than the cell thickness. A transition to chaos via quasiperiodicity is identified when the light intensity is taken as the control parameter. Transverse nonlocal effects are suggested to be the cause of the observed dynamics, and a simple model consisting of a collection of coupled rotators is developed to provide a qualitative explanation.

Relationship of steroid receptor, cell kinetics, and clinical status in patients with breast cancer.

The fractions of cells in the different phases of the cell cycle were determined by flow cytometry in 70 human breast tumors and six human benign breast tissues. This procedure showed that 44% of the tumors and none of the benign tissues were aneuploid as determined by mixing experiments using normal peripheral blood as a standard for DNA content per nucleus. The mean percent S-phase fraction (% S) values +/- S.D. for benign and malignant tissues were 6.9 +/- 1.6 and 13.7 +/- 6.5, respectively. By our procedure, aneuploid tumors seem to have significantly higher mean % S value than do diploid tumors. Breast cancer tissue which contained steroid receptors had a mean % S value of 11.3, while those tumors which had neither the estrogen nor progesterone receptors had a mean % S value of 17.1 (p less than 0.01). The estrogen receptor status had a better inverse relationship to the cell kinetic data than did the progesterone receptor status. The use of molecular forms of the steroid receptor was of some assistance in improving the inverse relationship between cell kinetics and steroid receptor status. A trend was observed between lack of steroid receptors and higher probability of the tumor being aneuploid. From the limited clinical data, there was no relationship between cell kinetic and aneuploid data with respect to nodal status, metastatic disease, and menopausal status. The possible use of these data is discussed.

A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group.

BACKGROUND: Zileuton, a leukotriene pathway inhibitor, was compared with slowly absorbed theophylline in a randomized, double-blind study of patients with chronic asthma. The primary efficacy measure was improvement in forced expiratory volume in 1 second (FEV1). METHODS: Eligibility criteria included FEV1 of 40% to 80% of predicted, documented reversibility of airway disease, and age 18 to 60 years. Initially, the theophylline dosage was titrated to achieve trough concentrations of 8 to 15 micrograms/mL. After washout and 1-week placebo lead-in, patients were randomly assigned to 13 weeks of the appropriate theophylline dose or zileuton, 400 or 600 mg 4 times daily. The FEV1 was measured before the morning dose at 2-week intervals and serially after the dose on days 36 and 92. Patients kept daily diaries of asthma symptoms, beta-agonist usage, and peak expiratory flow rate; on days 36 and 92, they completed quality-of-life questionnaires. RESULTS: Of 471 eligible patients at 38 centers, 377 were randomly assigned to the study; 313 completed the study. On first-dose administration, all groups showed 11% to 13% improvement in FEV1 within 30 minutes. Patients who received zileuton, 400 mg, had significantly greater improvement at several points than did theophylline-treated patients. The range of long-term maximum improvement in FEV1 in the groups was 30% to 34% (P = .40 for zileuton 600 mg; P = .90 for zileuton 400 mg vs theophylline). Initially, the theophylline group improved significantly more in symptom scores, beta-agonist usage, and peak expiratory flow rate, but at maximal effect there was no significant difference. All groups showed significant improvement in quality of life. No overall differences were observed between the zileuton dosage groups. Adverse events were comparable in all groups. CONCLUSION: Zileuton appears as effective and safe as theophylline in patients with chronic asthma.

[Anthracycline-induced heart failure aggravated by pregnancy. Survival after cardiac assistance with artificial heart device and heart transplantation]. / Myocardiopathie aux anthracyclines décompensée par une grossesse. Guérison par transplantation cardiaque après assistance temporaire par coeur artificiel.

We report a case of a young woman suffering from a steady anthracycline-induced myocardiopathy with a decreased left ventricular function on echocardiography. A pregnancy was initiated, without worsening of the cardiopathy until 34 weeks. Nine days after delivery, an acute heart failure was observed leading to heart transplantation after cardiac assistance with heart cardiac device. As pregnancy is an extended stress test for a chronic failing heart, a multidisciplinary decision of pregnancy initiation and follow up should be preferred in pre and postpartum period, when such a cardiopathy exists.

The monoamine-containing neurons in avian brain: I. A study of the brain stem of the chicken (Gallus domesticus) by means of fluorescence and acetylcholinesterase histochemistry.

The distribution of monoamine (MA)-containing nerve cell bodies in the brain stem of the chicken (Gallus domesticus) was studied by means of paraformaldehyde and glyoxylic acid fluorescent histochemical methods. The MA neurons were further characterized morphologically and histochemically in material prepared for the demonstration of acetylcholinesterase (AChE). In the rostral midbrain of the chicken, two large collections of catecholamine (CA)-containing cells are found: one located in the ventromedial and the other in the dorsolateral (pedunculopontine nucleus) portions of the tegmentum. On the basis of their topographic location, CA content, and fiber connections, these ventromedial and dorsolateral cell groups can be tentatively associated with the CA-containing neuronal populations of the mammalian ventral tegmental area and pars compacta of the substantia nigra, respectively. In the caudal midbrain of the chicken, numerous CA-containing cells are intermingled with serotonin (5HT)-containing perikarya beneath as well as within the decussation of the superior cerebellar peduncles. At isthmus levels, abundant, closely-packed CA-containing cells are encountered along the lateral border of the central gray. These neurons, which display a very high AChE activity, appear to be equivalent to those of the mammalian locus coeruleus. A multitude of medium-sized 5HT-containing neuronal somata occurs within the raphe region of the isthmus. Some of these somata closely surround the medial longitudinal fasciculus. This 5HT-containing cell group also massively invades the lateral tegmentum, where it becomes closely intermingled with the CA-containing neurons of the locus coeruleus and subcoeruleus. All of these 5 HT-containing neurons display a moderate to high AChE activity. In the medulla the number of MA-containing neurons is much smaller than in the upper brain stem. Nevertheless, 5HT-containing cells are present within the raphe region, particularly in the upper two-thirds of the medulla, and CA-containing perikarya can be found along the lateral border of the medulla and within the confines of the nucleus solitarius. The findings of the present study reveal that the MA-containing neuronal systems in the avian brain stem are organized according to a pattern that is much more complex than the one disclosed in reptiles or in other nonmammalian vertebrates. This complexity arises in large part from the fact that the 5HT-containing systems undergo a prominent lateralization in birds, which leads to a close intermingling of 5HT-containing and CA-containing neuronal elements at various levels of the neuraxis.

Identification of synaptic terminals of thalamic or cortical origin in contact with distinct medium-size spiny neurons in the rat neostriatum.

In order to determine what types of neurons in the striatum receive direct synaptic input from corticostriatal and thalamostriatal fibres and whether these afferents converge on individual striatal neurons, double anterograde labelling of axon terminals was combined with Golgi impregnation at both the light and electron microscopic levels. The area of the central neostriatum that receives input from both the parafascicular nucleus of the thalamus and the somatosensory cortex was identified by retrograde transport of a conjugate of horseradish peroxidase and wheat germ agglutinin (HRP-WGA). The same region of the neostriatum was studied in rats that had received multiple electrolytic lesions in the somatosensory cortex and also an injection of HRP-WGA in different parts of the parafascicular nucleus. Sections of this part of the neostriatum were impregnated by the single-section Golgi procedure after revealing anterogradely transported HRP-WGA. Twelve Golgi-impregnated spiny neurons were recovered and examined in the light and electron microscope after gold-toning. Ten of these neurons were typical very densely spiny medium-size neurons and they were all found to receive asymmetric synaptic input on dendritic spines from degenerating corticostriatal boutons. However, even though numerous boutons labelled anterogradely by HRP-WGA from the parafascicular nucleus were found within the dendritic fields of neurons that received cortical input, none of the terminals from the thalamus made synaptic contact with these neurons. Instead, all 96 thalamostriatal boutons studied were found in asymmetric synaptic contact with dendritic shafts of other neurons. Two such neurons that received input from the parafascicular nucleus were Golgi-impregnated and appeared to be medium-size spiny neurons, but they had a lower density of spines than the typical very densely spiny neurons. An independent confirmation that the targets of thalamostriatal neurons originating in the parafascicular nucleus are dendritic shafts was provided by studying the boutons labelled following electrolytic lesioning or injection of the lectin Phaseolus vulgaris-leucoagglutinin (PHA-L) into this nucleus: these boutons were also found to form asymmetric synaptic contacts with dendritic shafts within the neostriatum. It is concluded that although afferents from the somatosensory cortex and from the parafascicular nucleus converge upon the same part of the neostriatum, they probably do not converge upon the same spiny neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

The organization of monoamine-containing neurons in the brain of the sunfish (Lepomis gibbosus) as revealed by fluorescence microscopy.

The morphological organization of the monoamine-containing neurons in the brain of the sunfish (Lepomis gibbosus) was studied by means of the Falck-Hillarp histofluorescence method. No attempt was made to distinguish between norepinephrine and dopamine, both primary catecholamines (CA) yielding a similar yellow-green fluorescence after paraformaldehyde treatment. In the brain stem of this teleost fish, three groups of CA-containing neuronal somata have been found. First, there is a small collection of CA perikarya located just caudal to the obex of the fourth ventricle. The neurons of this medullo-sinal group give rise to numerous CA fibers many of which ascend within the central portion of the medulla. Intermingled with these CA fibers are some CA cells that constitute the central medullary group. The CA perikarya of this group are scattered between the levels of cranial nerves X and VIII. The tegmentum of the isthmus also contains a small group of very closely packed CA neurons. The large-sized CA cells of the isthmal group are located dorsolateral to the medial longitudinal fasciculus, partly within the periventricular gray. High densities of CA varicosities were also disclosed in various brain stem structures such as the optic tectum, the torus semicircularis and the cerebeller valvula. In addition, numerous serotonin (5-HT)-type neuronal somata were found in the raphe region of the brain stem, particularly at caudal mesencephalic, isthmal and rostral medullary levels. A large number of CA cell bodies were visualized in the sunfish hypothalamus. Most of them form two populations of small, round cells that are located along and partly within the ependymal walls of the posterior and lateral recesses of the third ventricle. These bipolar cells possess one short club-like process protruding into the ventricle and their thin ependymofugal processes contribute to the CA innervation of numerous hypothalamic regions. Large CA neurons apparently without direct CSF contact also occur in the area of nucleus posterior tuberis, at the level of the mesodiencephalic junction. Although the hypothalamic inferior lobes are devoid of CA cell bodies they are heavily innervated by CA axons. The sunfish telencephalon also receives a strikingly massive and complex monoaminergic innervation. Numerous CA fibers which are first observed at the level of the preoptic area, ascend through the central zone of the telencephalon and arborize profusely particularly within the medial zone of area dorsalis telencephali. Other CA fibers, as well as abundant fine 5-HT varicosities were found in the lateral zone of area dorsalis. Although the exact origin of the telencephalic CA afferents in Lepomis is not known, part of it may arise from the isthmal CA cell group which appears similar to the locus coeruleus of reptiles, birds and mammals.

Pharmacokinetics and pharmacodynamics of zileuton after oral administration of single and multiple dose regimens of zileuton 600mg in healthy volunteers.

The pharmacokinetics and pharmacodynamics of zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state park plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 +/- 1.13 and 4.37 +/- 1.02 mg/L, 1.5 +/- 0.9 and 1.5 +/- 0.9 hours, 793 +/- 233 and 579 +/- 162 ml/min (47.6 and 34.7 L/h), and 179 +/- 126 and 115 +/- 29L, respectively (mean +/- SD). Trough zileuton plasma concentrations (Cmin) immediately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of zileuton. Accumulation of zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyzileuton metabolite. The q6h regimen of zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.

The effect of food on the pharmacokinetics of zileuton.

The present study was undertaken to assess the effect of food on the pharmacokinetic parameters of zileuton. In a nonblinded crossover study, 18 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of zileuton 600mg in the presence or absence of food consisting of a standardised breakfast on the following morning. The mean zileuton peak plasma concentration (Cmax) increased significantly by 27% after food intake, while the mean area under the plasma concentration versus time curve increased by only 1.4%, a difference that was not statistically significant. The mean time to Cmax was unaffected by the presence of food, as were the other pharmacokinetic parameters assessed. Overall, the results suggest that food has a relatively small effect on the rate of zileuton absorption compared with the fasting state, while the bioavailability of the drug appears to be unaffected. Thus, it is concluded that it is appropriate to administer zileuton with or without food.

Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans.

The effects of coadministration of zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases. The study results provide no evidence of any significant overall effect of zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase. Therefore, it is concluded that digoxin and zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.

The influence of multiple oral doses of zileuton on the steady-state pharmacokinetics of sulfasalazine and its metabolites, sulfapyridine and N-acetylsulfapyridine.

The effects of zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebo-controlled study enrolling 14 healthy male volunteers. All subjects received SASP 1 g every 12 hours for 8 days and zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.

Pharmacokinetic interactions between zileuton and prednisone.

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

The pharmacokinetic and pharmacodynamic interactions between the 5-lipoxygenase inhibitor zileuton and the cyclo-oxygenase inhibitor naproxen in human volunteers.

The potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance. There is no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.