Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects.

BACKGROUND: The pharmacokinetics of polyethylene glycol 3350 (PEG-3350) have not been fully described because of lack of a sufficiently sensitive analytical method. AIM: To describe the pharmacokinetics of PEG-3350 in humans. METHODS: A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. RESULTS: Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. CONCLUSIONS: For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG-3350 in humans. These studies confirmed that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study.

BACKGROUND: Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM: To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS: This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS: Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS: In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

Constancy of bond strength in 5 single-bottle dentin bonding systems.

OBJECTIVE: Historically, wide variations in the shear bond strength of resin composite bonded to dentin have been reported. The purpose of this study was to compare 5 commercially available single-bottle dentin bonding systems while controlling several sources of variation in shear bond strengths. METHOD AND MATERIALS: Extracted molars were stored for 2 weeks in 0.5% Chloramine T. The teeth were mounted, the occlusal enamel was removed to expose middle dentin, and the exposed dentin was etched and treated according to 1 of 6 protocols. Finally, a cylinder of resin-based composite was bonded to the dentin. After 24 hours, specimens were fractured under shear force, and the results were recorded in megapascals. RESULTS: The type of product used was significantly associated with the mean shear bond strength observed. All products exhibited some degree of variation from specimen to specimen. One product, PQ1, exhibited less variation than the other 4 products. CONCLUSION: PQ1 was found to have a significantly higher mean shear bond strength than the other 4 products tested. There was no significant difference between specimens bonded to dry dentin and specimens bonded to wet dentin when using PQ1.

Population pharmacokinetics of aminoglycosides in critically ill trauma patients on once-daily regimens.

BACKGROUND: Once-daily dosing regimens of aminoglycosides are routinely used in critically ill trauma patients. However, the pharmacokinetic parameters are variable in these patients. The purpose of this study was to evaluate the pharmacokinetics of aminoglycosides in critically ill trauma patients receiving once-daily dosing regimens. METHODS: At least two aminoglycoside concentrations were measured in each patient. Population pharmacokinetic parameters were estimated on the basis of a one-compartment structural model and the program nonlinear mixed effects modeling. RESULTS: Fifty-three aminoglycoside concentrations from 19 patients were analyzed. The aminoglycoside clearance was 5.47 L/h. The mean volume of distribution was 22.2 L (0.3 L/kg). The mean half-life was 2.9 hours. Serum-aminoglycoside concentrations were undetectable for longer than 12 hours in 4 of 19 patients. Weight, age, or serum creatinine did not significantly explain the variability. CONCLUSION: There is marked variability in aminoglycoside pharmacokinetic parameters in critically ill trauma patients. This may lead to prolonged drug-free intervals. Individualized dosing of critically ill trauma patients on the basis of at least two serum-aminoglycoside concentrations seems indicated when using once-daily dosing regimens.

Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.

Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers.

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.

Pharmacodynamic interactions of antibiotics alone and in combination.

Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with beta-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination.

Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers.

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

Pharmacodynamic activity of five oral cephalosporins against Haemophilus influenzae.

STUDY OBJECTIVES: To determine the time above minimum inhibitory concentration (T > MIC) and serum bactericidal activity of five oral cephalosporins against two strains of Haemophilus influenzae. DESIGN: Randomized, crossover study. SETTING: University-associated research center. SUBJECTS: Ten healthy volunteers. INTERVENTIONS: Each subject received a single dose of cefpodoxime 200 mg, cefuroxime 500 mg, cefaclor 500 mg, cefprozil 500 mg, or loracarbef 400 mg each week for 5 weeks. Blood for serum levels was obtained at time zero and 1, 2, 3, 4, 6, 8, and 12 hours after each dose. MEASUREMENTS AND MAIN RESULTS: Cefpodoxime produced serum concentrations above the MIC for more than 90% of the time for both beta-lactamase-negative and -positive strains of H. influenzae. Moreover, it had serum bactericidal activity for 12 hours against both isolates. Cefuroxime was the second most active cephalosporin, with serum concentrations above the MIC of both isolates for 60% of the time. Cefuroxime provided serum bactericidal activity for 12 hours against the beta-lactamase-negative strain and 6 hours against the beta-lactamase-positive strain of H. influenzae. Even though the T > MIC was less than 50% of the study period for the other cephalosporins, all but cefaclor provided serum bactericidal activity for 12 hours against the beta-lactamase-negative isolate. Cefaclor provided measurable serum bactericidal activity for only 3 hours. The duration of serum bactericidal activity of cefprozil, loracarbef, and cefaclor against the beta-lactamase-positive isolate was 4, 2, and 0 hours, respectively. CONCLUSION: Cefpodoxime was the most active cephalosporin studied based on T > MIC and serum bactericidal activity against isolates of H. influenzae.

Response of oral mucosal cells to glass ionomer cements.

Although glass ionomer cements are generally considered to be tissue-compatible, it has been suggested that unreacted components or setting reaction by-products can affect cell metabolism. The current study examined the effects of constituents leached out of three glass ionomer cements on growth and metabolism of oral epithelial cells. Aseptically prepared discs of Ketac-Cem Radiopaque (KCR), Ketac-Cem Maxicap (KCM) and Fuji I were incubated in Dulbecco's medium for 10 d, with daily medium changes. Cultures of hamster cheek pouch (HCP) cells, a line of hamster buccal pouch epithelial cells, were incubated in control or eluate-containing media for 24 h. Viable cell numbers were determined by the colorimetric MTS assay, and DNA and RNA syntheses were assessed using [3H]thymidine and [3H]uridine incorporation, respectively. Responses to materials were determined by comparison of cell numbers and radioisotope incorporation (counts per minute (cpm) per 1000 cells). Results were analysed by ANOVA and Duncan's multiple range test, then converted to percent control for comparison. The eluates of all three materials from the first 24 h of soaking inhibited HCP cell growth. The number of cells in cultures exposed to Fuji were 88% of control cultures, while those exposed to KCR and KCM were 58% and 59% of control, respectively. The difference between Fuji-exposed and control cultures was significant (P < 0.05). The two Ketac cements were different from Fuji-exposed and control cultures (P < 0.05) but not from each other. All of the materials caused significant increases in labelling of DNA compared to control cultures (P < 0.05) when calculated on a per cell basis, but the materials did not differ from each other. Both Ketac cements also significantly stimulated labelling of RNA per cell compared to control cultures (P < 0.05). All effects of the material decreased over time. Results suggest that leachable components of the materials may affect the rate of progression of HCP cells through the cell cycle, rather than overt toxicity that results in cell death.

Age-related changes in the tip-of-the-tongue experience.

The tip-of-the-tongue (TOT) experience was compared in younger and older adults, using picture and definition cues to elicit TOTs. Older adults (a) experienced more TOTs, (b) had less target word information available during the TOT, and (c) had more related words (blockers) come to mind during the TOT. There were no age differences in either the speed or likelihood of immediate resolution of the TOT. Picture and definition cues were equally likely to evoke TOTs, although picture cues elicited more interlopers. The idea that TOTs are more likely to be elicited by less common target words was not supported.

Food chloride distribution in nature and its relation to sodium content.

Because of growing interest in the biological and clinical effects of dietary chloride as the anion accompanying the dietary cation sodium and because the standard food composition tables used in the United States to estimate sodium content do not contain data on chloride content, we analyzed the nutrient data base of the English workers Paul and Southgate, which contains an extensive listing of both chloride and sodium contents in foods. To examine food chloride distribution in nature, we focused on the uncooked, unadulterated, discrete, primitive foods in the data base (no. = 216 food items). The findings indicate the existence of both a large variability of chloride content among foods and a high degree of coupling of chloride with sodium. The contents of chloride and sodium varied over a similarly large range (coefficients of variation, 229% vs. 263%), differed very little from each other on the average (less than 20%), and correlated (r = 0.84, p less than 0.001) to the extent that greater than two-thirds of the overall variation of chloride content was linked to that of sodium content. Those findings accord with the often posited but untested assertion that the chloride content of foods approximates and parallels that of sodium.(ABSTRACT TRUNCATED AT 250 WORDS)

A focus group study of sexually active black male teenagers.

This is a report of a focus group study conducted by the National Institute for Adolescent Pregnancy and Family Services at Temple University. It presents in detail how the study was carried out and relevant findings from the transcripts of sessions held with a group of sexually active teenage males, including excerpts from the transcripts. Also included are the characteristics of the participants and a summary of the services they requested from a model adolescent pregnancy prevention and care program.

PIP: This is a report of a focus group study conducted by the National Institute for Adolescent Pregnancy and Family Services at Temple University. Participants were sexually active US teenage males recruited from local agencies, the school district, community groups and health agencies and paid US$15 per session to cover expenses or to use for their own self-enhancement. The 20 men ranged in age from 13 to 20 and had a total of 10 children of their own. The fathers had their 1st child between the ages of 15 and 19. 5 males were employed, 12 were at school and 3 were unemployed. About 1/2 were living below the poverty level. Questions asked included views of success, what it is like to be a teenager and how they handled peer pressure, thoughts about dating and whether dating included sex. Also discussed were what services should be offered by the Institute. Actual dialogue interchanges are given to illustrate the findings. Most young men viewed success through the work they wanted to do. They felt, in general, that the teenage years are a terrible time in their lives. Dating and sexual intercourse were synonymous in their minds although 2 of the participants were resistant to this notion. Most of the young men would refuse to use condoms and felt it was the girl's responsibility to prevent pregnancy. In discussing what services a model adolescent pregnancy prevention and care program should provide they were very adamant, almost hostile, in demanding that services be available to them. Some of this is attributed to lack of attention given to the young men by most institutions, beginning with their homes. Explicit needs were for job training and placement; vocational counseling, educational services, medical services, nutrition information, child care services, parenting education, family planning education and assistance, counseling and recreational activities.

Audible interpretation of carotid Doppler signals. An improved technique to define carotid artery disease.

Direct interrogation of the common, internal, and external carotid arteries with a bidirectional Doppler detector was performed on 199 vessels in 101 patients. Audible interpretations of normal, disturbed (stenotic), or absent (occluded) flow signals were made by vascular technologists and the results were compared with independently assessed carotid arteriograms. The sensitivity in detecting severe (greater than or equal to 50%) stenosis or occlusion was 9.2%, with correct differentiation of these two conditions in 84% of vessels. Nonobstructive (less than 50%) stenoses were detected in 30% of cases. The specificity in identifying normal carotid arteries was 91%. The predictive values of normal, abnormal, and absent flow signals were 95%, 90%, and 90%, respectively. Direct carotid Doppler signal analysis is more accurate than indirect periorbital Doppler screening in defining carotid stenosis or occlusion.

Prediction of amputation wound healing. Roles of Doppler ultrasound and digit photoplethysmography.

Segmental limb blood pressures (BPs) measured by Doppler ultrasound and digit photoplethysmography were used to define hemodynamic correlates of wound healing in 122 lower-extremity amputations for ischemia. Healing of digit or transmetatarsal amputations were influenced by the presence of diabetes and correlated better with digit pulsation and BP than with ankle pressure. Healing of below-knee amputation did not correlate with segmental limb BPs. In the absence of an absolute threshold to predict wound healing or failure, caution is urged in using hemodynamic indices to select the level of amputation of arterial insufficiency.

Noninvasive determination of carotid artery operability by Doppler ultrasound.

Indirect periorbital screening techniques may detect obstruction of the extracranial internal carotid artery, but they do not distinguish operable stenosis from inoperable occlusion. In an attempt to overcome this limitation, direct interrogation of carotid artery flow velocity by Doppler ultrasound was added to periorbital screening of 97 arteries in 53 patients. Analysis of results suggests that this assessment can improve diagnostic accuracy and distinguish stenosis from occlusion of the internal carotid arteries in stroke-prone patients.

High-Resolution CRT Optical Film Recorder Incorporating an Optical Feedback Exposure Control.

A high-resolution CRT optical film recorder incorporating an optical exposure control system is described. The recorder incorporates provisions for a highly nonlinear writing rate of up to 7 to 1 that make it uniquely suited for such applications as side-look radar or sonar. Provisions are made for spot shaping permitting line fill-in between scan lines spaced up to ten spot sizes apart. The recorder achieves a linear gray scale having sixteen equal density steps for a wide range of sweep times by means of a brightness feedback loop that automatically corrects for such problems as phosphor saturation, phosphor noise, nonlinear CRT grid transfer characteristics, variation in cathode emission, and tube aging in conjunction with film gamma correction circuitry.