Inline fluid dynamics in piggyback and manifold drug delivery systems.

Inline mixing characteristics of primary and secondary i.v. solutions were evaluated for the piggyback and manifold systems. Dextrose (5%) and sodium chloride (0.9%) were used as markers for the primary and secondary solutions, respectively. With a 120-mL/hr flow rate, samples (up to 180) were collected over 36 minutes to quantify the change in concentration of each marker when the primary solution was changed to the secondary solution (phase 1) and when the secondary solution was changed to the primary solution (phase 2). The relative concentration data for each marker were fitted to a Weibull mathematical model to describe the disappearance and appearance of the two solutions over time. These data were then used to calculate the volume of secondary solution that was mixed with the primary solution in phases 1 and 2. With the piggyback system, the total mixing volume was 13.5 mL, with 11.1 mL contributed by the secondary solution (phase 1). In phase 2, the total mixing volume decreased to 6.6 mL, with 2.0 mL contributed by the secondary solution. The mixing volumes for the manifold system were markedly reduced; 5.8 mL of the secondary solution became mixed with 1.9 mL of the primary solution. The total mixing volume during phase 1 was reduced from 13.5 to 5.6 mL. The mixing volumes for the primary, secondary, and total solutions in phase 2 were comparable to those with the piggyback system. The use of manual clamps or automated line closures as part of a manifold system can substantially reduce the mixing of solutions inline, compared with a piggyback system.

Variance estimates and individuality ratios of 25 serum constituents in beagles.

Variance components and individuality ratios for each of 25 chemical constituents of serum were estimated in a population of beagles. Ten blood samples were obtained from each of 14 beagles, seven of each sex, approximately weekly during three months. Glucose and phospholipid displayed marked inter-dog variation, as compared with intra-dog variation (individuality ratio less than 1). Triglycerides and nonesterified fatty acids had large intra-dog variances relative to their inter-dog variances (individuality ratio greater than 1). Overall, the estimated individuality ratios exceeded 1 for 20 of the 25 constituents. We conclude that subtraction of pretreatment values in the statistical analysis of the data from assays with individuality ratios greater than 1 may mask small clinically or biologically important changes between treatment groups. When the individuality ratio is greater than 1, pretreatment values should only be used as a population screening tool before a study.

The effects on beagles of long-term administration of 20% Travamulsion fat emulsion.

The tolerance of 20% Travamulsion intravenous fat emulsion (Travenol Laboratories, Inc., Deerfield, IL) was studied using male beagle dogs. Physiologic (0.9%) saline, USP, was used as the control, and 10% Travamulsion Intravenous fat emulsion (Travenol Laboratories) as the reference article. The 20 and 10% emulsions were administered intravenously to each of eight animals for 91 days at 20 and 40 ml/kg/day, respectively. These dosages were administered over 4 hr and they correspond to approximately 4 g of lipid as soybean oil per kilogram of body weight. The saline was administered to eight animals at 40 ml/kg/day. On day 92, one-half of the animals in each group were necropsied. The remaining dogs were observed and necropsied on day 122. Toxicity was assessed on animal survival; changes in body weight, urinalysis, and hematologic, and serum biochemical analyses; ophthalmologic examination; gross pathology; and histopathology. The results obtained for the 20% Travamulsion fat emulsion correlated well with those for the 10% Travamulsion fat emulsion. The emulsions were well tolerated and all animals survived and gained weight. The 20% Travamulsion fat emulsion administered provided about 45% of the total caloric requirement of the dog, which is equal to an often used clinical dose. However, caloric administration in the form of lipid emulsion in relation to total energy required was performed at three to six times the indicated clinical rate. In addition to demonstrating that it is safe for prolonged administration, the 20% Travamulsion fat emulsion offers an advantage over the 10% Travamulsion fat emulsion in providing the same amount of calories because it produces lower serum levels of phospholipid, cholesterol, and triglyceride, and the volume of emulsion required is reduced.

The effects of intravenous administration of 10% travamulsion fat emulsion to beagle dogs for 91 consecutive days.

The tolerance of 10% Travamulsion Intravenous Fat Emulsion (Travenol Laboratories, Inc., Deerfield, IL) was studied using beagle dogs. Physiological (0.9%) saline, USP, was used as the control, and Intralipid 10% Fat Emulsion (Vitrum, Sweden) as the reference article. The emulsions were administered intravenously to each of 10 animals for 91 days at a dosage of 40 ml (approximately 4 g)/kg of body weight/day. The saline was administered to 10 animals at 40 ml/kg/day. On day 92, 7 of the 10 animals in each group were necropsied. The remainder were observed and necropsied at approximately day 160. Toxicity was assessed on the basis of animal survival; changes in body weight, hematology, and serum chemistry; gross pathology; and histopathology. The results obtained for the Travenol emulsion correlated well with those for the Vitrum emulsion. The emulsions were well tolerated and they did not produce any major clinical signs of toxicity. All animals survived and gained weight. The Travenol emulsion administered provided about 45% of the total caloric requirement of the dog which is equal to an often used clinical dose. However, the emulsion was infused at six times the indicated clinical rate. Thus, in addition to demonstrating the similarity of Travenol and Vitrum emulsions, the results of this study indicate that the Travenol emulsion is safe for prolonged administration.

Kinetic analysis of rat liver sorbitol dehydrogenase.

1. A steady state kinetic investigation was performed on an improved preparation of rat-liver sorbitol dehydrogenase (L-iditol: NAD-oxidoreductase, EC 1.1.1.14). 2. Data analyses indicate the enzyme follows a rapid equilibrium random mechanism in the direction of sorbitol oxidation and a random mechanism in the direction of fructose reduction. 3. Kinetic constants were: K m NAD 0.082 mM; K m sorbitol 0.38 mM; K m NADH 67 microns; K m fructose 136 mM. 4. Evidence is adduced to indicate the more rapid reverse (fructose reduction) reaction is susceptible to metabolic control by formation of abortive enzyme fructose-NAD and enzyme-NADH-sorbitol complexes.

Effects of intravenous administration of Travenol 10% lipid emulsion to miniature swine for 28 consecutive days.

The potential toxicity of Travenol 10% lipid emulsion was studied using miniature swine. Physiological (0.9%) saline, USP, was used as the control, and Intralipid 10% fat emulsion as the reference article. The emulsions were administered intravenously at dosages of 40 milliliters (approximately 4 grams of lipid) and 60 milliliters (approximately 6 grams of lipid) per kilogram of body weight per day to eight animals (four males and four females) in each treatment group on each of 28 consecutive days. The saline was administered to eight animals at 60 milliliters per kilogram per day. On day 29, one half of the male and female animals in each group were necropsied. The remaining pigs were observed and necropsied on either day 56 or 57. Toxicity was assessed on the basis of animal survival; changes in body weight, urinalyses, and hematological, and serum biochemical analyses; ophthalmological examination; gross pathology; and histopathology. The results obtained for the Travenol emulsion correlated well with those for the Intralipid emulsion. The emulsions were well tolerated, and they did not produce any major clinical signs of toxicity. All Travenol emulsion-treated animals survived. In addition to demonstrating the similarity of Travenol and Intralipid emulsions, the results of this study indicate that the Travenol emulsion demonstrated an adequate margin of safety for prolonged administration. Travenol emulsion was well tolerated by miniature swine infused at about one and one-half (40 milliliters per kilogram per day) and two (60 milliliters per kilogram per day) times the proposed clinical dose, and at three and two times the anticipated clinical rate, respectively.

Rapid affinity purification and properties of rat liver sorbitol dehydrogenase.

A 23-h affinity chromatography purification procedure for sorbitol dehydrogenase (L-iditol:NADl-oxidoreductase, EC 1.1.1.14) prepared from freshly excised rat liver has been developed that resulted in an 18% yield of an apparently homogeneous preparation (purification = 439-fold). The molecular weight of the enzyme was approx. 96 000. The enzyme was specific for NAD+ (NADH), but had no requirement for NADP+ (NADPH). The purified preparation shows significant activity with structurally related polyols and ketoses. Km values for sorbitol and fructose are 0.35 and 110 mM (at pH 7.1), respectively.