Postprandial responses of individual fatty acids in subjects homozygous for the threonine- or alanine-encoding allele in codon 54 of the intestinal fatty acid binding protein 2 gene

BACKGROUND: The affinity of intestinal fatty acid binding protein (FABP) for fatty acids is regulated by the polymorphism at codon 54 of the FABP2 gene (alanine-to-threonine shift). We found earlier that the threonine-encoding allele (Thr54) is associated with an increased postprandial lipemic response. OBJECTIVE: We studied the postprandial responses of individual fatty acids in subjects homozygous for the Thr54 or alanine-encoding allele (Ala54). DESIGN: Oral-fat-loading tests were performed in 8 subjects homozygous for Thr54 and in 7 subjects homozygous for Ala54. RESULTS: The postprandial responses of most of the 14-18-carbon fatty acids in chylomicron and VLDL triacylglycerols were significantly elevated in the Thr54 homozygotes whereas the relative increases in these fatty acids were not significantly different in both groups. The amounts of 20- and 22-carbon polyunsaturated fatty acids started to increase later than the amounts of shorter ones after the test meal, and the differences between the groups were mostly insignificant. The responses of chylomicron fatty acids correlated positively with postprandial insulin response in the Thr54 homozygotes and inversely in the Ala54 homozygotes. VLDL fatty acid responses correlated with fasting triacylglycerol concentrations in the Ala54 homozygotes but not in the Thr54 homozygotes. CONCLUSION: The threonine-encoding allele of the FABP2 gene is associated with an increased postprandial response of 14-18-carbon fatty acids but not with changes in the relative amounts of individual fatty acids introduced to chylomicron triacylglycerols.     

Starch acetate as a tablet matrix for sustained drug release.

The aim of this study was to investigate the effect of a high degree on substitution (DS) on starch acetate (SA) and SA concentration on tablet properties. SAs with a DS of 2.6 and 3.0 were used as matrix formers with propranolol hydrochloride (PH) as a model drug. The SA-3.0 powder had better compactibility than the SA-2.6 powder. A decrease in SA concentration decreased compactibility of PH/SA blended powders when compared to neat SA powders. In general, drug release was considerably slower from SA-3.0 matrices than from SA-2.6 matrices. Also, a decrease in SA concentration increased the drug release rate. Water penetration into 80% (w/w) SA-3.0 matrices was incomplete during 24-h dissolution tests. Diffusion path length increased with time and PH was released by Fickian diffusion. However, all other PH/SA tablets were completely hydrated during dissolution tests. Macroscopic cracks were formed during dissolution, which increased area available for Fickian diffusion and resulted in slow attenuation of the drug release rate. Crack formation, not been reported earlier, must be taken into account in order to understand drug release from SA matrices.     

Pulmonary Deposition and Clinical Response of99mTc-Labelled Salbutamol Delivered from a Novel Multiple Dose Powder Inhaler

Pulmonary deposition of ^99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler^®). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with ^99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler^® powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV₁ curve, maximum FEV₁ and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler^® powder inhaler and the aerosol delivery through the spacer are equally effective.     

Absorption of ascorbic acid from a film-coated tablet and from a new enteric-coated pellet preparation in subjects with inadequate plasma levels of ascorbic acid.

The effects of a film-coated tablet and a novel enteric-coated pellet preparation of ascorbic acid (CAS 50-81-7) on the plasma concentration and on the urinary excretion of ascorbic acid were investigated. The pharmacokinetic properties of these dosage forms were also compared both after a single dose and in steady state. The study was carried out as a randomized, single blind parallel group trial in 11 volunteers with inadequate plasma levels of ascorbic acid. The duration of the treatment period was 7 days. After the first dose, higher plasma ascorbic acid concentration as well as AUC and Cmax values were achieved with the film-coated preparation. After the multiple dosing in steady state, plasma ascorbic acid concentration as well as AUC and Cmax values were higher with the new pellet preparation. In addition, the plasma ascorbic acid concentration remained on higher level with pellet preparation on the 7th day. Tmax values for the pellet preparation were also slightly higher on both of the pharmacokinetic test days. The amount of ascorbic acid excreted in urine was higher with the film-coated tablet. According to the results of this study it can be supposed that during the long-term supplementation the more complete absorption can be achieved with the new enteric-coated pellet preparation.     

Comparison of beclomethasone dipropionate delivery by easyhaler dry powder inhaler and pMDI plus large volume spacer.

Dry powder inhalers (DPIs) provide a means of delivering inhaled asthma drugs without the use of propellants. Easyhaler is a multidose DPI, delivering 200 doses of beclomethasone dipropionate (BDP), 200 microg/dose. A gamma scintigraphic study has been carried out in 10 healthy volunteers to compare the deposition of BDP from Easyhaler with that from a pressurized metered dose inhaler (pMDI) coupled to a Volumatic spacer device delivering 250 microg BDP per dose. The spacer was used without any pretreatment to reduce static charge on the spacer walls. The study was conducted according to an open, randomized, crossover design. The volunteers inhaled the study drug using optimal inhalation technique for both devices. Lung deposition of 99mTc-labeled BDP averaged 18.9% (SD 9.5%) of the metered dose for Easyhaler, and 11.2% (SD 5.3%) for pMDI plus spacer (p < 0.05); when the data were expressed as mass of BDP deposited in the lungs, the difference in lung deposition just failed to reach statistical significance (Easyhaler 37.8 microg; pMDI plus spacer 28.0 microg). Oropharyngeal deposition was significantly reduced by use of the spacer. The results of this study show that Easyhaler delivers drug more efficiently to the lungs than pMDI plus Volumatic spacer when no measures are taken to eliminate static charge on the spacer walls.     

Effect of the new spacer-device on the deposition of the inhaled metered dose aerosol

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.     

Postprandial lipemic response and lipoprotein composition in subjects with low or high cholesterol absorption efficiency

BACKGROUND: The purpose of this study was to investigate the effect of differences in cholesterol absorption efficiency on the postprandial lipemia and lipoprotein composition. METHODS: Fifteen healthy subjects were divided into low and high cholesterol absorbers on the basis of serum cholestanol to cholesterol ratio. A high-performance liquid chromatographic method with evaporative light scattering detection was developed for quantitation of free and esterified cholesterol, triglycerides and major phospholipids from the same lipid extract in two runs utilizing the same internal standard. RESULTS: The free cholesterol to phosphatidylcholine ratio of chylomicrons was higher in the high cholesterol absorption group. The total increase of cholesterol in combined chylomicron and very low density lipoprotein (VLDL) fraction was also higher in this group. Chylomicron free cholesterol and cholesterol ester responses correlated with fasting low density lipoprotein (LDL) cholesterol. VLDL and VLDL1 triglyceride responses correlated inversely with fasting insulin and homeostasis model assessment of insulin resistance. CONCLUSIONS: High cholesterol absorption efficiency was seen in chylomicrons as higher cholesterol to phosphatidylcholine ratio during the postprandial peak. Chylomicron cholesterol response was linked to fasting LDL cholesterol and low VLDL triglyceride response to fasting insulin.     

Pulmonary deposition of lactose carriers used in inhalation powders

Dry powder dosage forms are generally formulated by mixing the micronized drug particles with the larger carrier particles. Lactose is a commonly used carrier. Carriers enhance the flowability of powder mixtures and therefore enable low dosing of active substances. During inhalation, the drug particles are dispersed from the surface of carrier particles. The aim of this study was to compare how different qualities of 99mTc-labelled lactose carrier systems deposit in the lungs. The sizes of the labelled and unlabelled alpha-lactose monohydrate particles were compared by using a laser diffraction method. Distribution of radiolabel between different particle size fractions was determined using the Andersen cascade impactor. The in vivo depositions of lactose carrier systems were investigated in ten healthy men using the technique of gammascintigraphy. In addition, redispersion of budesonide from the carrier materials was evaluated by using the Andersen cascade impactor. According to the validation data the particle size of the lactose carriers remained unchanged during the labelling process. Low pulmonary deposition varying between 2.5 and 3.3% was detected. Only a small amount of lactose was deposited in the lungs, thus pulmonary deposition is not a limiting factor for lactose selection. According to in vitro redispersion data the fine particle fraction of the delivered dose in the impactor varied between 10.3 and 26.0%. Thus, the redispersion of the budesonide particles can be altered by the properties of the carrier system.     

Nasal delivery systems and their effect on deposition and absorption

Due to nasal anatomy and physiology, with a non-ciliated area in the anterior part of the nasal cavity and a ciliated region in the more posterior part of the nose, the site of deposition is of importance for the nasal mucociliary clearance and retainment of a formulation in the nose. Many drug delivery devices for nasal application of liquid, semisolid and solid formulations were investigated in respect to their deposition in the nasal cavity. The site of deposition and the deposition area depend on several parameters which are related to the delivery device, such as mode of administration, particle size of the formulation and velocity of the delivered particles. Several in vitro and in vivo methods have been used to study distribution and clearance of intranasally delivered therapeutics. The relationship between deposition, absorption and related bioavailability of the nasally applied formulation has been shown.     

Autoantibodies associated with presymptomatic insulin-dependent diabetes mellitus in women

Presymptomatic autoantibody markers of insulin-dependent (Type 1) diabetes mellitus (IDDM) are less well characterized in adults than in children. We quantitated anti-GAD, anti-ICA512 and ICA by titration to endpoint and compared frequencies and levels in 139 Finnish women from whom 390 serum samples had been archived during antecedent pregnancies for 10 years before and up to 1 year after diagnosis of diabetes. Also, we compared the autoantibody status in adults with IDDM with that of children with newly diagnosed IDDM. Of the 35 women seropositive for 1 or more autoantibodies, 77 % developed IDDM, 11 % non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), 9 % gestational diabetes mellitus requiring insulin (GDM-ins) and 3 % GDM controlled by diet. The frequency of antibodies during the 10-year presymptomatic period was 83 % for anti-glutamic acid decarboxylase (GAD), 52 % for anti-ICA512 and 41 % for islet cell antibodies (ICA) for those who developed IDDM, 25 %, 17 %, and 0 % for NIDDM, 12 %, 4 %, and 8 % for GDM-ins and 1 %, 0 %, and 1 % for GDM-diet. Anti-GAD was found most consistently in early samples; 13 of 15 with a single autoantibody at their first test had anti-GAD. Among those who developed IDDM, the frequency of anti-GAD was constant, anti-ICA512 increased threefold, and ICA increased slightly before diagnosis. Levels of the autoantibodies varied between subjects, but were relatively stable in individual subjects. Comparison of tests on the women, and children after diagnosis of IDDM, showed the frequencies and levels to be the same for anti-GAD but lower for anti-ICA512 and ICA in adults. Our observations show in women the long latency of seropositivity before overt IDDM, the predominance of anti-GAD among these three serological markers, and the presence of these markers in NIDDM presumably representing a NIDDM phase of autoimmune insulitis. © 1997 by John Wiley & Sons, Ltd.