13C-ethanol and 13C-acetate breath tests in normal and aldehyde dehydrogenase deficient individuals

Four normal and five aldehyde dehydrogenase (ALDH) isozyme I deficient individuals were subsequently loaded with (1-13C)ethanol and (1-13C)sodium acetate and the conversion of the label to 13CO2 was determined in expired air by isotope ratio mass spectrometry. In the 13C-acetate breath test, both groups showed virtually identical recovery of the label in expired air, namely 48.5 +/- 2.3% (mean +/- S.D.) for normal and 46.8 +/- 5.7% for deficient individuals. However, in the 13C-ethanol breath test, both the groups performed differently. On average, although a certain overlap of the single data was observed, the recovery of the label after four hours was 43.4 +/- 3.8% for the normal and 35.6 +/- 6.8% for the ALDH deficient subjects. These findings suggest a slower conversion of ethanol to carbon dioxide in aldehyde dehydrogenase deficient individuals, which may be another consequence of this deficiency besides the higher plasma acetaldehyde levels observed after ethanol loading in comparison to individuals with normal aldehyde dehydrogenase activity.     

The intravitreal penetration of ceftriaxone in man following systemic administration

Seventeen patients who underwent vitreal surgery received ceftriaxone (Rocephin) 1-2 g intramuscularly at various time intervals before surgery. Specimens of serum and vitreous were assayed for ceftriaxone concentrations both by bioassay and high pressure liquid chromatography. All patients had detectable vitreous (and serum) ceftriaxone concentrations at all time periods. Vitreous ceftriaxone levels at the first 4.5 hr following the administration of the antibiotic ranged from 1.4-19.4 micrograms/ml and averaged 5.9 micrograms/ml. At 12-13 hr following ceftriaxone administration vitreous concentrations were 11.5 (+/- 9.0) micrograms/ml. Ceftriaxone in intramuscular administration could be used as prophylaxis against ceftriaxone-susceptible microorganisms in vitreal surgery. Ceftriaxone is the first antibiotic for which reliable penetration into the vitreous is demonstrable following intramuscular administration.     

Corrective intra-articular surgery in juvenile femur head epiphysiolysis

Treatment of severely slipped capital femoral epiphysis depends on the individual pathoanatomic and pathophysiologic conditions. Since the femoral neck vessels remain intact in chronic slip, they should be preserved whenever possible. Bilateral chondrolysis developed in 1 of our 9 cervical osteotomy patients. Long-term radiologic and clinical findings after a cervical osteotomy do not differ appreciably from those after an Imh?user osteotomy, in some cases, with incomplete realignment of the femoral head-acetabulum relation. Apparently, not only the "quantitative" factor but also the "qualitative" factor plays an important role in epiphyseal separation. By contrast, severe acute slip is a severe irritation of the joint accompanied by intra-articular bleeding and rupture of the femoral neck vessels. Good results are achieved after immediate operative decompression, controlled reduction, and stable fixation of the epiphysis, providing anatomic realignment of the femoral head-acetabulum relation is not forced, but rather carried out only to the limit of tolerance without leverage maneuver and under moderate traction and vision. Epiphyseal necrosis developed after conventional open reduction in 2 of our 16 patients with acute slip. No cases of epiphyseal necrosis have been observed to date in any of our patients (N = 5) treated with this new technique of controlled reduction (i.e., partial reduction in "acute chronic slip").     

Fear conditioning and stimulus generalization in association with age in children and adolescents

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8–17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS−) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS−): four generalization stimuli depicting gradual morphs from CS+ to CS− in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS−, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

     

Influence of antacid and ranitidine on the pharmacokinetics of oral cefetamet pivoxil.

The purpose of this investigation was to assess the influence that treatment with antacid and ranitidine had on the pharmacokinetics of oral cefetamet pivoxil in 18 healthy male volunteers. Each subject received, in an open-labeled, randomized, three-way crossover design, a single oral dose of 1,000 mg (two tablets) of cefetamet pivoxil 10 min after a standard breakfast during each of the following treatments: treatment A, control period; treatment B, antacid (80 ml of suspension; Maalox 70) administered on the evening before cefetamet pivoxil dosing (-12.5 h) and again 2 h before and 2 h after a standard breakfast; treatment C, ranitidine (150 mg) administered twice a day for 4 days and again 1 h and 10 min prior to cefetamet pivoxil dosing. Plasma and urine samples were collected over a 24-h period following cefetamet pivoxil administration. Cefetamet was analyzed by high-performance liquid chromatography. Oral bioavailability parameters (area under the concentration-time curve from 0 to 12 h, area under the concentration-time curve from 0 h to infinity, time to maximum concentration of drug in plasma, and maximum concentration of drug in plasma) were obtained by noncompartmental techniques. The results showed that none of these bioavailability parameters was significantly (P greater than 0.05) affected by antacid or rantidine coadministration. A compartmental analysis showed no significant differences. In addition, the terminal elimination half-life and the fraction of cefetamet excreted unchanged in the urine was also not significantly (P greater than 0.05) affected by antacid or ranitidine exposure. Relatively wide intrasubject variability was observed for time to maximum concentration of drug in plasma and terminal elimination half-life in several of the 18 subjects studied. Although these irregularities did not appear to be strongly associated with a particular treatment, they increased in subjects in both the antacid and H2-receptor antagonist treatment groups compared with those in subjects in the control treatment group. We conclude that antacid and ranitidine treatment likely does not alter the bioavailability of oral cefetamet pivoxil.     

Osteodensitometrie

Osteodensitometrie ist inzwischen eine allgemein anerkannte Methode zur Beurteilung des Frakturrisikos und klinisch unerl?sslich im Rahmen einer Osteoporosediagnostik. Die radiologischen Verfahren wie die duale R?ntgenabsorptiometrie (DXA) und quantitative Computertomographie (QCT) sind Ultraschallverfahren wie der quantitativen Ultrasonometrie und -graphie (QUS) in Bezug auf die Frakturpr?diktion ebenbürtig. Entscheidend dabei ist, diskrepante bzw. konkordante Werte für die Patientin im Sinne der Fragestellung richtig zu interpretieren. Diskrepanzen zwischen zwei Messungen bei der gleichen Patientin k?nnen durch Fehlinterpretation der Messwerte verschiedener Methoden entstehen, die durch die Variabilit?t der Anteile von Compacta und Spongiosa im menschlichen Skelett an unterschiedlichen Messstellen und den unterschiedlichen Einflüssen von Messtechnologie und Biologie bedingt sind.     

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.     

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency.

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.     

Regulation of carbohydrate metabolism by 2,5-anhydro-D-mannitol.

In hepatocytes isolated from fasted rats, 2,5-anhydromannitol inhibits gluconeogenesis from lactate plus pyruvate and from substrates that enter the gluconeogenic pathway as triose phosphate. This fructose analog has no effect, however, on gluconeogenesis from xylitol, a substrate that enters the pathway primarily as fructose 6-phosphate. The sensitivity of gluconeogenesis to 2,5-anhydromannitol depends on the substrate metabolized; concentrations of 2,5-anhydromannitol required for 50% inhibition increase in the order lactate plus pyruvate less than dihydroxyacetone less than glycerol less than sorbitol less than fructose. The inhibition by 2,5-anhydromannitol of gluconeogenesis from dihydroxyacetone is accompanied by an increase in lactate formation and by two distinct crossovers in gluconeogenic-glycolytic metabolite patterns-i.e., increases in pyruvate concentrations with decreases in phosphoenolpyruvate and increases in fructose-1,6-bisphosphate concentrations with little change in fructose 6-phosphate. In addition, 2,5-anhydromannitol blocks the ability of glucagon to stimulate gluconeogenesis and inhibit lactate production from dihydroxyacetone. 2,5-Anhydromannitol decreases cellular fructose 2,6-bisphosphate content in hepatocytes; therefore the effects of the fructose analog are not mediated by fructose 2,6-bisphosphate, a naturally occurring allosteric regulator. 2,5-Anhydromannitol also inhibits gluconeogenesis in hepatocytes isolated from fasted diabetic rats, but higher concentrations of the analog are required.