Lack of effect of food on the steady state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects

An annual atmospheric pollen survey was performed for 14 consecutive years in the autumn at Sakado city, Saitama prefecture. The survey was performed on the transition of pollen dispersion of major allergen plants: ragweed (Ambrosia spp.), Humulus japonicus, Artemisia spp. and Gramineae. 1. Annual total pollen count of ragweed showed marked increases beginning from 1991. Total pollen count in 1991 was 8.8 times and that in 1996 was 18.6 times that in 1983. This increase is probably caused by marked proliferation of giant ragweed which is left without mowing as it is on a dry riverbed, and consequently produces much more pollen than short ragweed. 2. Annual increases in total pollen counts of other major plants which disperse their pollen in the same season as ragweed were 0.95 times in 1991 and 0.5 times in 1996 that in 1983 for Humulus japonicus, 0.68 times in 1991 and 1.5 times in 1996 that in 1983 for Artemisia spp. and 1.3 times in 1991 and 1.4 times in 1996 that in 1983 for Gramineae. None of these species showed a marked increase of pollen dispersion although they showed some annual variation. The above findings suggest that changes in the proliferous state of various allergenic plants due to environmental change should be considered with respect to characteristics of pollen allergy.     

Bioavailability and pharmacokinetic properties of 2 sustained-release formulations of diclofenac sodium, Voltaren vs inflaban: effect of food on inflaban bioavailability

In this study, in vitro characterization, bioavailability and pharmacokinetics of 2 different sustained-release diclofenac sodium dosage forms were compared, Voltaren (100 mg tablets), manufactured by Ciba-Geigy and Inflaban (100 mg enteric-coated tablets), manufactured by the Arab Pharmaceutical Manufacturing Company. The in vitro results demonstrated a faster rate of dissolution for Inflaban as compared to Voltaren, but both products exhibited a sustained-release pattern. The bioavailability study was conducted on 20 healthy male subjects who received a single oral dose (100 mg) of each product according to a randomized 2-way crossover design. Blood samples were obtained over a 26-hour period, and drug concentrations were determined by an HPLC method. Concentration time profiles revealed a sustained-release pattern for both products. The Tlag for Voltaren was 0.8 +/- 0.2 h, significantly shorter than for Inflaban (1.7 +/- 0.2 h) indicating a faster rate of absorption from the upper gastrointestinal tract. The Cmax obtained with Voltaren was significantly higher than that obtained with Inflaban (1,161 +/- 102 and 799 +/- 83, respectively). With respect to Tmax and AUC0-26h parameters, both products were not found to be statistically different. Tmax for Voltaren and Inflaban was 4.2 +/- 0.5 and 4.5 +/- 0.4 h, respectively, whereas AUC0-26h values for both products were 5,423 +/- 562 and 5,237 +/- 520 ng x h/ml, respectively. It is believed that the observed differences between Voltaren and Inflaban are mainly due to the fact that Inflaban is designed as an enteric-coated tablet form, with a core tablet having different sustained-release behavior. In addition, the effect of food on the bioavailability of Inflaban was evaluated in randomly selected 6 male volunteers. Our results revealed that, following light and heavy meals, the AUC0-30 and Cmax were minimally affected by food whereas a significant increase in Tmax and Tlag as compared to fasting conditions was observed.     

The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers

The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, Cmax values averaged 44 and 54 pg mL(-1), AUC(0-336 h) averaged 6392 and 5331 pg h mL(-1), Ae(0-168 h) averaged 12.7 and 11.9 micrograms, and t1/2 averaged 109.7 and 101.3 h, respectively. No statistically significant difference was found when Cmax, AUC(0-336 h), t1/2, and Ae(0-168 h) from subjects treated under fasting and fed conditions were compared. Median tmax values in subjects treated under fasting or fed conditions were identical (2.5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food.     

The effect of food on bromfenac, naproxen sodium, and acetaminophen in postoperative pain after orthopedic surgery

STUDY OBJECTIVES: To evaluate the effect of a standard meal on bioavailability of bromfenac, and on the relative analgesic efficacy and adverse effect liability of bromfenac 25 mg, naproxen sodium 550 mg, and acetaminophen 325 mg in the treatment of pain after orthopedic surgery. DESIGN: Randomized, double-blind, single-dose, parallel-group. SETTING: Two wards of the orthopedic surgery department at the Central Hospital, Karlstad, Sweden. PATIENTS: Three hundred ten patients with steady, moderate, or severe pain within 72 hours after orthopedic surgery. INTERVENTIONS: Patients were randomly assigned both to receive a standard meal or remain in a fasted state, and to treatment with a single oral dose of bromfenac 25 mg, naproxen sodium 550 mg, or acetaminophen 325 mg, when they experienced steady, moderate, or severe pain that required an analgesic. Using a self-rating record, subjects rated their pain and its relief for up to 8 hours after medicating. Blood samples were obtained from all patients using one of two schedules. MEASUREMENTS AND MAIN RESULTS: The peak plasma bromfenac concentration for fed patients was only 28% of that of fasted patients. Disregarding food intake, bromfenac 25 mg and naproxen sodium 550 mg were significantly superior to acetaminophen 325 mg for all summary measures of analgesia. Bromfenac and naproxen were superior to acetaminophen by hour 1 and this difference persisted for 8 hours. Food reduced bromfenac's analgesic effect, but not that of naproxen or acetaminophen; treatment by meal interaction was significant for five measures of efficacy. Analgesic response for fed bromfenac recipients, compared with those who were fasted, ranged from 37-71%. The percentage of patients reporting an adverse effect was significantly higher for bromfenac (25%) and naproxen (24%) than for acetaminophen (12%). CONCLUSIONS: Results of analgesic studies not taking patients' food status into consideration might be misleading. Although bromfenac 25 mg and naproxen sodium 550 mg produced significant analgesia compared with acetaminophen 325 mg, bromfenac's efficacy was significantly reduced when patients ate a standard meal. Adverse effects were transient and consistent with the pharmacologic profiles of the drugs.     

The pharmacokinetics and steady state pharmacodynamics of mivacurium in children

BACKGROUND: The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable acute rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival. METHODS: We compare here in a case-control study 24 retransplantations with 47 first transplants in patients matched for date of transplantation. RESULTS: Between 1973 and 1996, 1,063 patients underwent cardiac transplantation in our institution. In this cohort, 22 patients had a total of 24 retransplantations (2 second-time retransplantations). The causes of retransplantations were primary graft failure (n=4), acute rejection (n=7), coronary graft disease (n=11), and miscellaneous (n=2). Survival at 1 and 5 years of patients with retransplantations is 45.5% and 31.2%, and survival of control patients is 59.4% and 38.8% (p=0.07). An interval between first transplantation and retransplantation shorter (n=11) or longer (n=13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively (not significant). Intervals shorter than 1 year between first transplantation and retransplantation were exclusively secondary to primary graft failure or intractable acute rejection. CONCLUSIONS: In the face of lack of donor grafts, these and other data indicate that retransplantation should be considered cautiously, especially when the interval between the first transplantation and retransplantation is short.     

Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings

In the absence of E1B, the 289-amino acid product of human adenovirus type 5 13S E1A induces p53-independent apoptosis by a mechanism that requires viral E4 gene products (Marcellus, R.C., J.C. Teodoro, T. Wu, D.E. Brough, G. Ketner, G.C. Shore, and P.E. Branton. 1996. J. Virol. 70:6207-6215) and involves a mechanism that includes activation of caspases (Boulakia, C.A., G. Chen, F.W. Ng, J. G. Teodoro, P.E. Branton, D.W. Nicholson, G.G. Poirier, and G.C. Shore. 1996. Oncogene. 12:529-535). Here, we show that one of the E4 products, E4orf4, is highly toxic upon expression in rodent cells regardless of the p53 status, and that this cytotoxicity is significantly overcome by coexpression with either Bcl-2 or Bcl-XL. Conditional expression of E4orf4 induces a cell death process that is characterized by apoptotic hallmark features, such as externalization of phosphatidylserine, loss of mitochondrial membrane potential, cytoplasmic vacuolation, condensation of chromatin, and internucleosomal DNA degradation. However, the wide-spectrum inhibitor of caspases, tetrapeptide zVAD-fmk, does not affect any of these apoptogenic manifestations, and does not alter the kinetics of E4orf4-induced cell death. Moreover, E4orf4 expression does not result in activation of the downstream effector caspase common to most apoptosis-inducing events, caspase-3 (CPP32). We conclude, therefore, that in the absence of E1A, E4orf4 is sufficient by itself to trigger a p53-independent apoptosis pathway that may operate independently of the known zVAD-inhibitable caspases, and that may involve an as yet uncharacterized mechanism.     

Macrosegregation in continuously cast steel slabs: preliminary theoretical investigation on the effect of steady state bulging

Model for computation of macrosegregation in slabs due to bulging. Assumptions involved. Simplification for the case of no bulging. Introduction of a modified stream function for the mushy zone. Computation of macrosegregation profiles for various conditions.     

The effect of sample size on the steady state creep characteristics of Ni-6 pct W

The effects of sample size and grain morphology on the steady state creep properties of Ni-6 pct W in the temperature range of 0.55T _m to 0.74T _m have been studied. It is shown that a decrease in sample thickness results in a corresponding decrease in the number of grains per thickness and gives rise to a decrease in the measured values of bothQ _creep andn when compared to existing data on thick samples with many grains per thickness. The observed effects of sample configuration on the creep properties are explained with a model for creep deformation which is based on the interaction of free surfaces with grain boundary sliding and grain deformation. Using this model, an expression for the stress and temperature dependence of the total steady state strain rate is obtained as a function of the grain matrix strain rate and the grain boundary sliding strain rate. The results of this model are shown to correlate well with the observed deformation characteristics of the thin samples and to explain the variations ofQ{creep} andn with sample morphology. Formerly Graduate Student, Department of Materials Science and Engineering, Stanford University     

Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations

Prospective clinical studies about photocoagulation of extrafoveolar choroidal neovascularizations in focal hemorrhagic chorioretinopathy (CR) have demonstrated that the risk of visual loss years after successful treatment is related to the development of retinal pigment epithelium (RPE) atrophy around the laser scar. The reason for this event was thought to be late damage of RPE cells due to the laser treatment. However, because RPE atrophy can also be seen in untreated patients, a prospective study was started to test this pathogenetic hypothesis and to analyze the pathogenetic factors and prognostic importance of RPE atrophy in focal hemorrhagic CR. Eighty-eight patients (52 women, 36 men, 15-45 years old; mean follow-up 62 months; 26 patients treated by photocoagulation) with focal hemorrhagic CR were reexamined. Fifty-two patients (15 treated by photocoagulation and 37 untreated) showed clinically visible RPE atrophy. In these 52 patients the initial and final visual acuity, the amount of initial subretinal fluid (34.6% < 500 microns, 50% 500-750 microns, 15.4% > 750 microns) and the amount RPE atrophy (23.2% < 500 microns, 53.6% 500-750 microns, 23.2% > 750 microns) were analyzed. The development of RPE atrophy was dependent on the time of follow-up (36 patients without RPE atrophy, mean follow-up 29 months; 52 patients with RPE atrophy, mean 84 months, P < 0.001). Of the 52 patients with RPE atrophy, 15 were treated by photocoagulation. The distribution of RPE atrophy was similar to what was found in the 37 untreated patients (P = 0.4). With pronounced RPE atrophy, a decrease in final visual acuity was seen (RPE atrophy < 500 microns, mean visual acuity 0.5; 500-750 microns mean visual acuity 0.3; > 750 microns, mean visual acuity 0.1; P = 0.005). Increased RPE atrophy was also associated with a higher incidence of visual loss (p = 0.009). The amount of RPE atrophy was not dependent on the time of follow-up (P = 0.3), but only correlated with the initial amount of subretinal fluid (atrophy < 500 microns: subretinal fluid < 500 microns 15.4%, 500-750 microns 7.7%, > 750 microns 0%; atrophy 500-750 microns: subretinal fluid < 500 microns 19.2%, 500-750 microns 32.7%, < 750 microns 1.9%; atrophy > 750 microns: subretinal fluid < 500 microns 0%, 500-750 microns 9.6%, > 750 microns 13.5%; P < 0.0001). Because RPE atrophy in focal hemorrhagic CR was seen in patients both with and without photocoagulation therapy, laser treatment cannot be the causative factor. With increased follow-up the risk of the development of RPE atrophy increases in all patients. The resulting amount of RPE atrophy was only dependent on the initial amount of subretinal fluid. If the fovea is included in the exudative detachment, there is a higher risk of long-term visual loss.     

火焰原子发射光谱法直接测定钠盐表面活性剂中钠

在加热下用硝酸(1+1)-OP溶液溶解钠盐表面活性剂样品,配制成均匀透明的样品溶液。为消除电离干扰,取适量样品溶液加入消电离剂硝酸钾溶液配制成试液,喷入空气-乙炔火焰测定钠,建立了火焰原子发射光谱法直接测定钠盐表面活性剂中钠的分析方法。以空白溶液为参比,用工作曲线法测定。对样品溶解条件、电离干扰、试液与空白溶液粘度一致性进行了考察。测定结果的相对标准偏差小于2.4%,加标回收率97.8%~105.0%,线性范围0~1.6μg/mL,方法简便。     

Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects

The Salford static knee instrument (SSKI) was developed to determine the quantitative assessment of the human knee joint in vivo by utilizing the technique of applied displacement and measurement of resistive load as proposed by Butler et al. (1). The instrument was used in parallel with the device developed by Al-Turaiki (2) which utilized the opposite method of assessment. The objective of the research was to examine which of the two techniques provided the more reliable and accurate method of knee assessment. Fourteen patients with suspected isolated rupture of the anterior cruciate ligament (ACL) were subjected to anterior-posterior drawer testing on both devices. The results showed that each instrument produced results which confirmed the clinical diagnosis by indicating a significant decrease in anterior stiffness when comparing the injured and uninjured knees. [SSKI device (p = 0.000) and Al-Turaiki (2) device (p = 0.002) statistical significant difference testing with Bonferonni Alpha correction p = 0.0125]. The results showed the Salford static knee instrument indicated a 58 per cent decrease in anterior stiffness and the Al-Turaiki (2) device a 35 per cent decrease when comparing the injured and uninjured knees. In conclusion it is suggested that the application of displacement and measurement of load as proposed by Butler et al. (1) may be the most appropriate technique for precise clinical diagnosis of pathological human knee joint instability.     

Changes in the rat's preference for saccharin and sodium chloride solutions following injection of alloxan monohydrate.

Conducted 5 experiments with a total of 136 male Sprague-Dawley rats in which alloxan-diabetic rats were compared with saline-injected controls on 2-choice preference tests involving saccharin and water or NaCl and water. Previous results indicating a decrease in preference for saccharin were confirmed and extended. However, a similar pattern of preference change for NaCl was not found. Results indicate that saccharin and NaCl consumption were not affected in the same way by experimental diabetes and that the loss of palatability of saccharin during a chronic diabetic state was not consistent with learning models of taste-aversion formation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dynamic recovery during and after steady state deformation of Al-11wt%Zn

Cylindrical specimens of Al-11wt%Zn were deformed at constant stress and at 523 K in tensile creep tests. The stress dependence of the steady state deformation rate ge_s, was determined from stress change tests, ge_s shows an exponential stress dependence in the stress range above 10 MPa. The steady state values of the dislocation density in the subgrain interior (ρ_i) and of the subgrain size were determined by means of transmission electron microscopy. The fundamental equation of steady state deformation ge_s = (bM)Agr⁻ was tested by independent measurement of ge_s and gr⁻. A is of the order of the subgrain size. gr⁻ was determined from the recovery behavior of the dislocation density immediately after steady state deformation. The shape of the recovery curves did not depend on type and amount of stress reduction but was strongly dependent on ge_s. These results were confirmed by measurements of the transient creep behavior after reloading the specimens with the initial load. For the exact determination of gr⁻ an interpolation method was used, which is based on the decrease ofρ_i during stress relaxation. The shape of the recovery curves and the stress dependence of ge_s.A and gr⁻ suggest that recovery during and immediately after steady state deformation is of dynamic nature.