bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recruitment pharmacophore for interleukin 5 receptor α antagonism
Authors: Bhattacharya Madhushree , Pillalamari Udaya , Sarkhel Sanjay , Ishino Tetsuya , Urbina Cecilia , Jameson Bradford , Chaiken Irwin 
Published: October 2006

AbstractInterleukin‐5 receptor α is a therapeutic target for hypereosinophilic diseases including allergic inflammations and asthma. The cyclic peptide AF17121 (Ac‐VDE[CWRIIASHTWFC]AEE‐CONH2) has been identified as a submicromolar inhibitor of interleukin 5 (IL5)‐interleukin 5 receptor α (IL5Rα) interaction from a random peptide screen. However, this inhibitor has limitations as a drug lead because of its relatively large size. We used chemical synthesis of peptides with natural and non‐natural amino acids along with kinetic binding and cell proliferation competition assays to expand definition of structural elements in the peptide that are important for receptor antagonism and to elucidate the underlying pharmacophore. We found that the specific steric array of hydrogen bonding groups in the Arg 6 guanido side chain is critical for receptor inhibition. We also investigated noncharged structural elements in AF17121. Screening a set of five hydrophobic residues showed that peptide function is strongly sensitive to variations in several of these residues, most prominently Ile 7 and Trp 13. We postulate that presentation of charged, hydrogen bonding and hydrophobic structural elements within the disulfide‐constrained peptide drives IL5Rα recruitment by AF17121. We hypothesize from these results and previous receptor mutagenesis studies that Arg 6 recruitment of IL5Rα occurs through hydrogen bonding as well as charge–charge interactions with Asp 55 in site one of domain 1 of IL5Rα, and that this interaction is complemented by additional charged and hydrophobic interactions around the Asp 55 locus. Scaffolding a limited set of structural elements in the inhibitor pharmacophore may be useful for small molecule antagonist design inspired by the peptide. © 2006 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88:83–93, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com.
Laparoscopic incisional hernia repair with a self-centring suture
Authors: Motson R W , Engledow A H , Medhurst C , Adib R , Warren S J 
Published: October 2006

Abstract

Background
Open incisional hernia repair is associated with high morbidity and recurrence rates. Laparoscopic approaches offer improved long-term results with low complication rates.

Methods
Laparoscopic repair was attempted in 117 consecutive patients (median age 68 (range 31–91) years, 50 men) undergoing 122 operations. A novel mesh centralization technique was employed. Data were recorded prospectively. Follow-up was by clinical review or telephone consultation.

Results
One hundred and eighteen procedures (96·7 per cent) were completed laparoscopically; four required conversion. Forty-one patients (35·0 per cent) had additional, unsuspected defects. The median mesh size was 225 (range 42–600) cm2. Median follow-up was 42 months. Small bowel enterotomy occurred in six patients. Fourteen postoperative seromas were successfully aspirated. Recurrence was detected in nine patients (7·7 per cent). One patient was readmitted with small bowel obstruction that settled with conservative management. There were no enterocutaneous fistulas. One patient died after operation from myocardial infarction.

Conclusion
Laparoscopic incisional hernia repair using a self-centring suture provides good long-term results with low complication rates.
Study of the bioavailability of different formulations of 8‐methoxypsoralen in the dog
Authors: Monbaliu J. G. , Belpaire F. M. , Bogaert M. G. 
Published: October 2006

AbstractThe absolute bioavailability of 8‐methoxypsoralen in gelatin capsules and as a solution was studied in dogs. A dose of 2 mg kg−1 was given. Both for the solution and the gelatin capsules, a large variation in bioavailability was found between the different dogs. For the gelatin capsules in 1 dog out of 4 an absolute bioavailability of more than 100 per cent was found; for the solution a bioavailability of more than 100 per cent was found in all 4 dogs. Resorption was more rapid and bioavailability higher for the solution than for the gelatin capsules.Relative bioavailability of an emulsion and of a solution of 8‐methoxypsoralen was studied in 2 dogs. A faster resorption and a higher bioavailability were found for the solution.
Influence of food on the absorption of theophylline administered in the form of sustained release tablet and microgranules
Authors: Delhotal‐Landes Brigitte , Flouvat Bernard , Karpouzas Ianis , Prinseau Jacques , Boutin Marie‐Sylvie 
Published: October 2006

AbstractTwo sustained‐release formulations of theophylline, tablets (T) and microgranules (MG) forms, were administered in a randomized order to 8 healthy subjects in fasting or with a high‐protein test meal (50 per cent). Blood was collected for 32h post‐dose. In fasting subjects, absorption of theophylline was significantly faster for T (tmax 5 h) as compared with MG (tmax 8 h, p<0‐05), but Cmax and AUC were comparable; intersubject variability was higher with T. Administration of a high‐protein test meal with T produced a significant decrease of the zero‐order absorption rate constant of theophylline (Ko 37·8±9 1 mgh−1 after meal versus 58·8±13mgh−1 in fasting, p=0·01), tmax was doubled to 10 h, and Cmax increased by 25 per cent (6·33±2·16 mgl−1 versus 504±1·28 mgl−1p <0 02); with MG, tmax were the same (8 h), Cmax were not significantly increased (4·79±0·84 mgl−1 versus 4·55±0·67 mgl−1), absorption was delayed (lag‐time 1·28±0·58 h) and the absorption was slightly accelerated (Ko 50·4±10·4 mgh−1 versus 42·3±11·9 mgh−1, NS). For each form bioavailability was not significantly modified by food. This study demonstrated that food rich in protein modifies the absorption rate of theophylline in a sustained‐release tablet formulation but is without influence in a pH‐independent, sustained‐release microgranule formulation.
Dose‐dependent pharmacokinetics of probenecid in the rat
Authors: Emanuelsson B‐M. , Paalzow L. K. 
Published: October 2006

AbstractThe basic pharmacokinetics of probenecid was studied by administration of three different i.v. bolus doses (50, 75, and 100 mg kg−1) to rats. The protein binding of probenecid in pooled rat serum was estimated by equilibrium dialysis. The unbound fraction was found to increase non‐linearly with increasing total concentration, yielding a maximum free fraction of 49 per cent. The plasma concentration data obtained were described by a two‐compartment model with Michaelis‐Menten elimination. The maximal rate of elimination (Vm) remained unchanged between different doses irrespective of whether it was calculated in total or free concentrations (mean 187·2±8·3 (SD) μg min−1). The Michaelis‐Menten constant (Km) decreased slightly with increasing dose, while the unbound Michaelis‐Menten constant (Km, u) did not change between the doses (mean 37·1±1·3 (SD) μg ml−1 ). The volume of distribution of the central compartment (Vc, u) did not alter when the dose was increased from 50 to 100 mg kg−1 (mean 56·5±4·3 (SD) ml), but the unbound volume of distribution of the central compartment (Vc, u) decreased from 186·5±15·6 (SD) to 89·8±6·9 (SD) ml, which is in accordance with the reduction to be expected for drugs that only distribute in the extracellular fluid.
Pharmacokinetics and bioavailability of etintidine in beagle dogs: Effects of routes of administration, doses, dosage forms, and chronic dosing
Authors: Huang Shiew‐Mei , Abrams Larry S. , Marriott Thomas B. , Weintraub Howard S. 
Published: October 2006

AbstractEtintidine HCl is an H2 receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are:

Plasma levels of etintidine after i.v. administration of 200mg of E followed a 3‐exponential decay with a terminal t½ of 1.7 h.
Following oral administration of 200mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first‐pass elimination.
A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg−1 and this relationship did not change with repeated dosing.
Some accumulation of etintidine took place during the 52 weeks of chronic dosing.
Bioequivalence study of two liquid formulations of benzydamine
Authors: Catanese B. , Del Bosco M. , Lagana A. , Curini L. , Colloca A. 
Published: October 2006

AbstractA bioequivalence study of two liquid formulations containing benzydamine hydrochloride was carried out to evaluate the influence of a change of the excipients and the addition of a flavouring agent, ICEBERG AR 84/05/15, on the absorption of benzydamine.No statistically significant differences were observed suggesting that the two formulations are bioequivalent.
On the absorption of clavulanic acid
Authors: Allen G. D. , Coates P. E. , Davies B. E. 
Published: October 2006

AbstractIt was not possible to computer fit oral clavulanic acid data using exponential or model equations incorporating a single exponential defining the absorption phase. Using the Loo‐Riegelman method three phases of the absorption process became apparent, an initial slow phase, a more rapid phase and a final slow phase, contributing approximately 20, 70, and 5%, respectively, to the overall absorption process. Statistical moment analysis of clavulanic acid data following intravenous and oral solution administration gave mean values for the mean residence time, mean absorption time, and volume of distribution steady‐state of 56 min, 43 min, and 14.01, respectively. Weibull analysis of the oral solution data gave mean values for lag‐time and mean absorption time of 8 min and 46.8 min, respectively. Administration of clavulanic acid in a capsule formulation increased the lag‐time before absorption but had no significant effect on the mean absorption time.
Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease
Authors: Eradiri Okponanabofa , Jamali Fakhreddin , Thomson Alan B. R. 
Published: October 2006

AbstractThe influence of prednisone( PR ), sulfasalazine( SZ ), cimetidine( CM ), and pheno‐barbital(PB) on the pharmacokinetics of metronidazole was investigated in six Chrohn's patients. Metronidazole was first administered alone ( 250 mg bid, po ) and then with prednisone ( 10mg bid, po), sulfasalazine (lg bid, po), cimetidine ( 600mg bid ) or phenobarbital ( 60 mg bid, po). Each regimen was followed for 6 days and sampling of blood and urine was carried out on the 7th day after the first dose of each regimen. Plasma and urine samples were analysed for the drug and its two principal metabolites, hydroxymetronidazole and metronidazole‐1‐acetic acid, by HPLC. When given alone, metronidazole had a mean volume of distribution of 0.667 ± 0.15 1kg−1, a half‐life of 9.7 ± 3.1 h and an oral clearance of 0.852 ± 0.23 ( ml−1min ) kg−1. The disposition kinetics of metronidazole and its metabolites was not altered by CM and SZ. Induction of metabolism of metronidazole by PR was made manifest in significant increases in oral clearance of the former and urinary excretion of the hydroxy metabolite, and significant decrease in AUC of the parent compound. PB also induced the metabolism of metronidazole. This induction was reflected in significant increases in the oral clearance of metronidazole and AUC of the hydroxy metabolite as well as significant decreases in AUC, half‐life, and urinary excretion of the parent drug.
Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers
Authors: Day Richard O. , Furst Daniel E. , Dromgoole Sydney H. , Paulus Harold E. 
Published: October 2006

AbstractSteady‐state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentisic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg−1 and during multiple dosing with ASA 56 mg kg−1 day.−1 Steady‐state SA concentrations fell 23 per cent during the 4‐week study period (mean ± SD: 239 ± 35 to 183 ± 23 μg ml−1;p < 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean VmaxSU increased from 0.93 to 1.68 mg kg−1 h−1 (p < 0.05) and mean Vmax SPG increased from 009 to 019 mg kg−1h−1 (p<005). First‐order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high‐dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.
Pharmacokinetics of caffeine in breast milk and plasma after single oral administration of caffeine to lactating mothers
Authors: Stavchansky S. , Delgado M. , Joshi A. , Combs A. , Sagraves R. 
Published: October 2006

AbstractSix healthy lactating women ranging in age from 28 to 35 years were selected to participate in the study. The women had been nursing their infants from 3½ weeks up to 17 weeks. On the morning of the study each participant received 100 mg dose of caffeine. The oral dose of caffeine was taken with a glass of water on an empty stomach. Blood samples were collected from zero time to 24 h after caffeine administration. Each subject aseptically collected breast milk from the right and left breasts by manual expression or using a mechanical breast pump, from zero time to 24 h after caffeine administration. Caffeine in plasma and breast milk was determined by gas liquid chromatography using nitrogen phosphorous detection.Caffeine was rapidly absorbed producing plasma time to peaks ranging from 0.50 to 1.00h, with values for peak concentrations between 360 and 6.15 μgml−1 in plasma. In breast milk, time‐to peak ranged from 0.75 to 2.00 h and concentration values between 1.98 and 4.30 μgml−1 No significant differences were found between attainment of the time of the peak in plasma and breast milk, p>0.05. In addition, peak concentration for the right and left breast were not statistically different, p>0.05. However, significant differences, p>0.05, between plasma and both breasts in regards to the peak concentrations were found. The overall breast milk/ plasma ratio obtained from the respective area under the curves were 0.815 ± 0.0521 and 0.809 ± 0.202 for the right and left breast, respectively, and no statistical differences were observed between the right and left breasts, p>0.05.In summary, caffeine is rapidly transferred to breast milk. Multiple dose studies are needed to provide more information about caffeine concentration in breast milk of women who receive multiple doses of caffeine or who chronically consume caffeine.
In vitro protein binding interaction studies involving cefixime
Authors: Bialer Meir , Wu Wen Hui , Faulkner Robert D. , Michael Silber B. , Yacobi Avraham 
Published: October 2006

Abstract Cefixime is a new oral cephalosporin currently undergoing clinical trials. Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man. Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations. In contrast, both salicylic acid and probenecid resulted in concentration‐dependent increases in the free fraction of cefixime (up to 2.5‐fold). These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.
Elevation of gastric pH with ranitidine does not affect the release characteristics of sustained release ibuprofen tablets
Authors: Berardi Rosemary R. , Dressman Jennifer B. , Elta Grace H. , Szpunar Gregory J. 
Published: October 2006

AbstractThe effect of elevating gastric pH on the release characteristics of a single unit sustained release (SR) ibuprofen tablet (MOTRIN‐SR®, Upjohn) was evaluated in 12 young, healthy men. Using a randomized crossover‐type design, each subject received three treatments – ibuprofen SR 800 mg, ranitidine 300 mg followed by ibuprofen SR 800 mg, and conventional ibuprofen tablets (2 × 400 mg). Gastric pH, which was monitored radiotelemetrically, was maintained above pH 6 for at least 4 h after pretreatment with ranitidine. In absence of ranitidine, the pH remained mostly below pH 3. Serum levels of ibuprofen were measured for 24 h and urine was collected for 48 h after each treatment. Similarity of the serum levels after the two treatments with ibuprofen SR 800 mg indicated that the release of ibuprofen was unaffected by elevation in gastric pH. Comparison of profiles with the immediate release dosage form indicated that dose dumping did not occur in any subject.
Pharmacokinetics of cefazolin administered as a new drug delivery system in healthy volunteers
Authors: Lanao J. M. , Vicente M. T. , Dominguez‐Gil A. 
Published: October 2006

AbstractA study was made of the pharmacokinetic behaviour in plasma and urine of cefazolin in seven healthy volunteers following parenteral administration of sodium cefazolin (1250 mg) and a sustained release formulation containing sodium cefazolin: cefazolin‐dibenzylamine (1:4) at a total dose of 1250 mg, both formulations being administered over 1 week by the i.m. route. Cefazolin concentrations in plasma and urine were determined by a HPLC technique. Kinetic analysis of the experimental results was performed using an open single‐compartment kinetic model and a sustained release model for the drug administered as standard formulation and the sustained release formulation, respectively. The results obtained point to significant variations in the pharmacokinetic profile of the drug when administered in the DDS.The time of cefazolin at levels greater than 1 μgml was 16.03 ± 2.51 and 47.76 ± 14.18h after administration of the standard formulation and the DDS, respectively. The urinary excretion rate curves also show the existence of sustained drug levels in the urine following administration of the DDS. The renal clearance of the drug did not show statistically significant differences between the two formulations administered. The process of release of cefazolin from the cefazolin‐dibenzylamine complex proved to be a first order kinetic process. The release constant of the antibiotic was calculated according to three different methods the Wagner‐Nelson method; the statistical moments method; and the fitting of the plasma levels curves to a compartmental model considering release and absorption. The values obtained for this constant ranges from 0.026 ± 0.02 h calculated with the method of statistical moments to 0.094 ± 0.03 h as calculated by the equation derived for the plasma fitting of cefazolin administered as DDS.
Choice of optimum pharmacokinetic model of orally administered paracetamol
Authors: Pedraz J. L. , Calvo M. B. , Lanao J. M. , Dominguez‐Gil A. 
Published: October 2006

AbstractThe present work studies the characterization of the pharmacokinetic profile of paracetamol following oral administration of DUOROL® tablets containing 500 mg of the active compound. Analysis is made of the influence of statistical weighting on the selection of the pharmacokinetic model chosen. In the model proposed, the uptake of the drug into the systemic circulation is described by two first‐order sequential kinetic processes. The values of the first order rate constants that define the absorption process have values of 4.79 and 9.73h−1. Validation of the absorption model proposed was performed by applying the Wagner‐Nelson method, according to which values of 4.63 and 10.95 h−1 were obtained for each of the constants defining the uptake of the drug into the systemic circulation.
Noncompartmental area under the curve determinations for drugs that cycle in the bile
Authors: Colburn Wayne A. , Lucek Rudolph W. 
Published: October 2006

AbstractDrugs that are involved in the enterohepatic circulation (EHC) generally exhibit complex disposition profiles and are difficult to describe by classical methods. A noncompartmental method for calculating the area under the curve from time zero to time infinity (AUC) for substances that are involved the EHC is developed and tested. Previous methods have been based on specific compartmental models and/or have been limited to a single enterohepatic cycle. The current method uses the following equations:
equation image
For an oral dose where kaR is the apparent first‐order absorption rate constant and βR is the rate constant that describes the decline in blood concentrations of drug at 24‐h intervals, i.e., 12, 36, and 60 or 24, 48, and 72 h, etc. AUC0–24 can be calculated by trapezoidal summation. The precision of this method is dependent on the number of observations during the 0‐24 h sampling period as well as the accuracy of KaR and βR. For drugs that are subject to a distinct distribution phase(s), error can be introduced into the AUC0‐00 value if pseudo‐equilibrium has not been achieved during the first 24‐hour interval. Although the method depends on a linearization process, it is truly concompartmental (‘model‐independent’) in nature.
Pharmacokinetics of 14C‐etretinate in healthy volunteers and two patients with biliary t‐tube drainage
Authors: Lucek Rudolph W. , Bugge Christopher J. L. , Crews Ted , Vane Floie M. , Cunningham W. , Colburn Wayne A. , Dickerson Janet , Carter Dean E. 
Published: October 2006

AbstractThe pharmacokinetic profile of 14C‐etretinate, a retinoid that is effective in the treatment of psoriasis, was studied in six healthy male volunteers and two biliary T‐tube patients. Following a 100 mg oral dose of 14C‐etretinate (20 microcurie), etretinate and its major blood metabolites (etretin, isoetretin) were measured by HPLC and total carbon‐14 was measured in blood, bile, urine, and feces by liquid scintillation counting. Etretinate was extensively metabolized in healthy volunteers and in T‐tube patients. During the absorption phase, 75 per cent of the total radioactivity in the blood could be accounted for as etretinate, etretin, and isoetretin whereas these compounds accounted for only approximately 12 per cent of the blood radioactivity in T‐tube patients over the same time period. The blood concentrations of etretinate, etretin, and isoetretin appeared to be substantially reduced in T‐tube patients compared to those in healthy volunteers. A higher proportion of the total drug was excreted in the feces and bile of the T‐tube patients (84 per cent) than in the feces of healthy volunteers (62 per cent). The major factor responsible for the observed decrease in etretinate blood concentrations following biliary cannulation appears to be the reduced absorption of etretinate due to the elimination of solubilizing bile salts in the duodenum. Carbon‐14 related material was detected in urine and feces for as long as 3 weeks in healthy subjects supporting the previous observation that a long terminal elimination half‐life exists for etretinate, even following a single dose of the compound.