An in situ tensile test apparatus for polymers in high pressure hydrogen.

Degradation of material properties by high-pressure hydrogen is an important factor in determining the safety and reliability of materials used in high-pressure hydrogen storage and delivery. Hydrogen damage mechanisms have a time dependence that is linked to hydrogen outgassing after exposure to the hydrogen atmosphere that makes ex situ measurements of mechanical properties problematic. Designing in situ measurement instruments for high-pressure hydrogen is challenging due to known hydrogen incompatibility with many metals and standard high-power motor materials such as Nd. Here we detail the design and operation of a solenoid based in situ tensile tester under high-pressure hydrogen environments up to 42 MPa (6000 psi). Modulus data from high-density polyethylene samples tested under high-pressure hydrogen at 35 MPa (5000 psi) are also reported as compared to baseline measurements taken in air.

Long-term treatment of multiple sclerosis with interferon-beta may be cost effective.

Multiple sclerosis (MS) is a devastating disease that can occur in early life, progressing to rapid disability and loss of physical, psychosocial and economic functioning, significantly affecting quality of life. The traditional treatment for MS has been symptomatic, treating acute relapses without affecting the underlying disease. The introduction of interferon-beta (IFN beta) has offered significant clinical benefits by reducing the frequency of relapses and slowing disease progression. Although the costs of this treatment are high, the costs to society of caring for a patient disabled by MS are greater, and if IFN beta can delay disease progression in the longer term, the economic impact would be substantial. Previous pharmacoeconomic studies of IFN beta have suggested that benefits can only be achieved at extremely high cost, with reported cost-effectiveness measures of up to 1 million pounds sterling (Pound) per quality-adjusted life year (QALY) [1995 values]. However, these studies have considered only the short term benefits of IFN beta treatment: over 2 to 3 years, the impact of treatment on patients' quality of life is relatively small, and cost-utility analyses that do not consider longer term benefits nor include societal costs may be misleading. The model reported here is based on the hypothesis that the delay in disease progression seen in short term clinical trials is likely to continue if treatment is continued. The model also assumes that the delay in disease progression, which represents a reduction in brain atrophy, will result in lasting clinical benefits even if treatment is stopped. These assumptions are strongly supported by clinical trial data and the treatment hypothesis itself. A delay in disease progression will result in a significant improvement in functioning and quality of life, and if the costs associated with increased disability can be postponed, even long term treatment of MS with IFN beta can be shown to be cost effective. Using resource utilisation costs derived from an economic evaluation of MS in the UK, it was possible to calculate the impact of delaying disease progression in terms of both health service and societal costs. An estimate of mean disease progression in patients with MS treated with IFN beta-1a compared with patients who did not receive disease-modifying agents suggested that significant cost savings would be realised after about 12 years' treatment with IFN beta-1a. The application of utility scores to the disease progression curves also facilitated estimates of cost effectiveness, with cost per QALY values ranging from 27,036 Pounds after 2 years' treatment with IFN beta-1a to 37,845 Pounds after 20 years' treatment (1995 values).

Strategies to improve burn center utilization.

Burn units/centers are under increasing pressure to improve resource utilization because of decreasing financial support for hospitals in general and low reimbursement for burn patients specifically. After review of occupancy and admission profiles, three strategies were implemented at the North Carolina Jaycee Burn Center to improve utilization: (1) an outreach program to attract additional burn patient referrals; (2) admission of routine plastic surgery patients to the burn center acute beds; and (3) admission of off-service ICU patients to critical care beds, depending upon availability. These strategies, especially admission of off-service ICU patients, led to an increased patient census despite an unchanged number of burn admissions and a decrease in the number of burn patient days because of earlier discharge. Policies for control of nonburn patients were essential, as were programs to educate nurses in management of other critically ill patients. These measures resulted in increased utilization and commitment of additional personnel to the burn center.

An early phase I study to determine the tolerance, safety and pharmacokinetics of idebenone following multiple oral doses.

Ten healthy male volunteers participated in this Phase I multiple dose study with CV-2619 (6-[10-hydroxydecyl]-2,3- dimethoxy-5-methyl-1,4-benzoquinone, idebenone). Each volunteer received single oral doses of 100 mg CV-2619 on study days 1 and 35, and during days 2 to 34, 300 mg daily in three divided doses. Blood and urine samples were collected for pharmacokinetic analysis of CV-2619 and its two major metabolites. CV-2619 was well tolerated with regard to the subjective and objective assessments made during the study. There were no changes in clinical laboratory values which could be directly attributed to the administration of CV-2619. The elimination of CV-2619 appeared to be biphasic with a mean terminal elimination half-life of 18 h. Levels of metabolites in serum were too low to provide adequate description of their elimination kinetics. CV-2619 and its metabolites showed no tendency to accumulate over the 35-day period.

[The effect of cimetidine on the metabolism and effects of alcohol]. / Einfluss von Cimetidin auf den Abbau und die Wirkung des Alkohols.

This study was designed to show if therapeutic doses of cimetidine (Tagamet 400 Oblong-Filmtabletten; 400 mg b.i.d. and 400 mg t.i.d.) influence the elimination of alcohol. Following controlled alcohol doses to eight healthy volunteers without cimetidine and after three days cimetidine in the two dosage regimens, blood alcohol concentrations were determined and the degree of intoxication was recorded subjectively on a 100 mm scale. Statistical evaluation showed that the elimination and effects of the alcohol were similar on all three study days. One can conclude that, under these study conditions, cimetidine had no effect on the alcohol metabolism and blood concentration. Correlation between blood alcohol levels and degree of intoxication showed a significant linear relationship.

Relative bioavailability of etofibrate. A comparison of an acute and a new sustained release formulation.

The relative bioavailability of 2-(p-chlorophenoxy)-2-methylpropionic acid [2-(nicotinyloxy)-ethyl]-ester (etofibrate) from Lipo-Merz retard (500 mg) with respect to Lipo-Merz (600 mg) has been determined in 10 health volunteers in a crossover study. Etofibrate was determined in plasma after hydrolysis to clofibrinic acid. Pharmacokinetic parameters were derived to describe the plasma concentration-time profiles using a minimisation of least squares technique. The absorption was apparently delayed following the sustained release formulation with a longer time to maximum plasma concentration, which was significantly lower following the retard form. No significant differences were found in the mean apparent elimination half-lives nor areas under the plasma concentration-time curves indicating that the two formulations can be considered bioequivalent.

Disposition of 14C-loprazolam in animals and man.

The disposition of 14C-loprazolam has been studied in rat, dog, cynomolgus monkey and man using oral and parenteral dosing. In all species 14C was excreted principally in the faeces irrespective of the route of administration. In surgically prepared animals, 46% dose (rat) or 60% (dog) was excreted in bile and, together with urinary excretion, indicates that approx. two-thirds of an oral dose was absorbed. In rat there was relatively little enterohepatic circulation (approximately 26%) compared to dog (approximately 73%). Whole-body autoradiography and tissue-distribution studies in rat showed that 14C was distributed principally in liver and intestine, and was eliminated within 24 h. 14C was found in brain of rat and dog; in dog concn. levels were higher in white matter than in grey matter. In studies using pigmented animals, 14C was associated with the uveal tract of the eye and with other melanin-containing tissues. This was reversible and was eliminated from the eye of rat with a half-life of 3.4 d. Blood and plasma concn. of 14C and of unchanged loprazolam declined relatively rapidly in rat. In dog, cynomolgus monkey and man, total 14C concn. in blood fell more slowly than unchanged loprazolam. Less than 85% of loprazolam was protein bound in rat, dog or human plasma in vitro.

[Comparative studies on biologic availability and pharmacokinetics of bromazepam in tablets]. / Vergleichende Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik von Bromazepam aus Tabletten.

Ten male volunteers participated in a randomized crossover trial to compare the bioavailability of bromazepam (7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one) from two different preparations (Normoc, the test preparation, and a commercially available standard preparation). A single dose of 6 mg bromazepam was given. There was no difference in the USP XX rotating basket dissolution test between both preparations. The pharmacokinetic parameters elimination half-life, maximum plasma concentration and area under the curve were not significantly different. With the test preparation, however, smaller interindividual differences were seen. Only the time to peak plasma concentration showed a statistically significant difference. The test preparation yielded a flatter and smoother plasma bromazepam concentration curve compared with the standard preparation. This seems favourable in the case of subchronic dosing with regard to side effects, e.g. sedation.

Absorption and disposition of [14C]-molsidomine in laboratory animals.

14C-Labelled N-ethoxycarbonyl-3-morpholinosyndnonomine(14C-molsidomine, Corvaton) was administered orally to mouse, rat, rabbit, dog and rhesus monkey, and i.v. to rat and dog, at a dose level of 6 mg/kg-1. The rates and routes of excretion of radioactivity were determined. The oral dose was well-absorbed in all species and most (greater than 75%) of the radioactive dose was excreted in urine. In rat and dog less than 1% of the dose was present as expired 14CO2. In dog and rhesus monkey, small amounts of radioactivity were eliminated relatively slowly. In rat, dog and rhesus monkey, the three species examined in detail, radioactivity was generally distributed throughout the body 4-10 days after dosing. Levels were highest in liver, pelt, blood and the gastrointestinal tract. Whole-body autoradiographic studies in rat and rhesus monkey showed that at 4 days post-dose, radioactivity was highest in stomach wall and was distributed into other tissues in lesser amounts. In view of its mode of action, it was interesting that radioactivity was also associated with the heart muscle and aorta walls.

Plasma levels of isosorbide dinitrate and its main metabolites following oral administration of two sustained release formulations in normal man.

The plasma levels of isosorbide dinitrate (ISDN) and the two pharmacologically active metabolites were measured following administration of two oral sustained release formulations containing 40 mg ISDN in nine healthy male volunteers. The new galenic formulation (pellets in a hard gelatin capsule) resulted in generally higher plasma levels for all three assayed substances over the time period of 24 h. The pharmacokinetic interpretation of the plasma levels following administration of the sustained release capsule assuming a one-compartment body model with zero-order invasion and first-order elimination showed a constant liberation over approximately 5 h. The elimination of all three substances was not altered by the new formulation. The plasma levels after administration of the tablet formulaation showed great variations within and between individuals. These data could therefore not be interpreted by the same model.

Finger pulse plethysmographic effects of two oral sustained-release formulations of isosorbide dinitrate in normal man.

Two sustained release formulations of 40 mg isosorbide dinitrate, encapsulated pellets and a tablet, were compared double blind following oral administration of single doses in terms of response on finger pulse plethysmography in nine healthy male volunteers. Following both formulations there was a distinct effect on the depth of b-wave in the first derivative of the finger pulse up to 9 h after administration. This change of the parameter of nitrate action was significantly different from placebo for both formulations. The onset of action was more rapid and the peak response greater for the capsule than for the tablet. The overall effects in terms of area under the effect-time curves was also greater for the capsule than for the tablet, however, not statistically significant. Furthermore, the results show that the method of finger pulse plethysmography can be used to determine onset and duration of action nitrate compounds, after single dose administrations.

Relationship between the pharmacodynamics and pharmacokinetics of two oral sustained-release formulations of isosorbide dinitrate in normal man.

The relationship between the pharmacodynamics and pharmacokinetics of isosorbide dinitrate (ISDN) following oral administration of 40 mg of two different models. A model assuming an additive contribution of all active drug-related substances in plasma to pharmacological effect, i.e., finger pulse plethysmograph, resulted in estimates of relative potencies of ISDN:2-MN:5-MN (2-MN:2-isosorbide mononitrate; 5-MN:5-isosorbide mononitrate) as being 1:0.1:0.025. The data analysis using a receptor model (plasma concentration-effect curves) yielded sigmoid curves yielded sigmoid curves for 2-MN and 5-MN with similar relative potencies in the range of 20-80% of maximum response providing an upper limit for the pharmacodynamic effect due to ISDN, 2-MN or 5-MN in healthy volunteers.