Gastrointestinal transit and mucoadhesion of colloidal suspensions of Lycopersicon esculentum L. and Lotus tetragonolobus lectin-PLA microsphere conjugates in rats.

PURPOSE: To investigate in vivo the fate and the behavior of lectin-particle conjugates after oral administration. METHODS: Two plant lectins were selected, namely Lycopersicon esculentum L. and Lotus tetragonolobus lectins, which have been reported to be specific for oligomers of N-acetyl-D-glucosamine and L-fucose, respectively, and conjugated to small poly(lactide) microspheres. Their intestinal transit was investigated in detail using radiolabeled particles. The transport and the distribution of the particles along the intestine, as well as their interactions with the intestinal mucosa, were determined after oral administration in rat. RESULTS: The overall transit of the particles was shown to be strongly delayed when the microspheres were conjugated to the lectins, mainly due to the gastric retention of the particles. A significant fraction of the conjugates adhered to the gastric and intestinal mucosae. No significant differences were observed after a preliminary incubation of lectin-microsphere conjugates with specific sugars. CONCLUSION: Although specific interactions could not be excluded, especially in the stomach, it was likely that adhesion was predominantly due to nonspecific interactions. These results could be attributed both to unfavorable physicochemical characteristics of the conjugates and to premature adsorption of soluble mucin glycoproteins, preventing any further specific adhesion.

Targeting of 3'-azido 3'-deoxythymidine (AZT)-loaded poly(isohexylcyanoacrylate) nanospheres to the gastrointestinal mucosa and associated lymphoid tissues.

PURPOSE: The aim of the studv was to evaluate the capacity of poly(isohexylcyanoacrylate) nanospheres to concentrate 3'-azido 3'-deoxythymidine (AZT) in the intestinal epithelium and associated immunocompetent cells, which are known to be one of the major reservoirs of the human immunodeficiency virus (HIV). METHODS: The tissue concentration of 3H-radiolabeled AZT in the gastrointestinal (GI) tract was obtained 30 and 9() minutes after intragastric administration to rats at a dose of 0.25 mg AZT/100 g of body weight. The distribution along the intestine was determined. AZT concentrations in the lymph were obtained by lymphatic duct cannulation. RESULTS: Unlike the solution. nanoparticles did concentrate AZT very cfficiently in the intestinal mucosa, as well as in the Peyer's patches, and could simultaneously control the release of free AZT. Concentration in Peyer's patches was 4 times higher for nanoparticles, compared with the control solution. The tissue concentration was 30-45 microM, which was much higher than the reported IC50 of AZT (0.06-1.36 microM) and was regularly distributed along the gastrointestinal tract. CONCLUSIONS: Nanoparticles have been shown to be efficient in concentrating AZT in the intestinal epithelium and gut-associated lymphoid tissues, supporting the view that these particles may represent a promising carrier to treat specifically the GI reservoir of HIV.

[Metabolic effects of 3,5-dimethyl-3'-isopropyl-L-thyronine and 3,5,3'-triiodo-L-thyronine in the brain and liver of hypothyroid rats. Similarities and differences]. / Effets métaboliques de la 3,5-diméthyl-3'-isopropyl-L-thyronine (DIMIT) et de la 3,5,3'-triiodo-L-thyronine (T3) dans le cerveau et le foie de rat hypothyroïdien. Analogies et différences.

The metabolic effects of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) on subcellular activities in brain and liver, have been compared to those of T3. Thyroidectomized hypothyroid rats were treated for 10 days with DIMIT (8 micrograms/100 g/day) or T3 (0.25 microgram/100 g/day). In liver mitochondrial oxidative phosphorylation, succinate cytochrome c reductase activities and nuclear RNA polymerases I and II activities were restored to normal level by DIMIT as well as by T3 treatment. In brain T3 treatment normalized both nuclear and mitochondrial activities. On the other hand daily injection of DIMIT restored like T3 nuclear activities whereas that of brain mitochondria were unaffected. We have also examined the early effects of a single injection of T3 (2.5 micrograms/100 g) or DIMIT (80 micrograms/100 g), 20 minutes prior sacrifice. DIMIT is as active as T3 in stimulation of oxidative phosphorylation and succinate cytochrome c reductase activity in liver mitochondria. However DIMIT treatment does not affect the properties of brain mitochondria. On the basis of these observations, it is suggested that there is a tissue specificity of mitochondrial receptors to DIMIT administration as it was shown at the nuclear level.

[Characteristics of the transport of structural analogs of thyroid hormone through hemato-encephalic barrier]. / Caractéristiques du transport des analogues structuraux des hormones thyroïdiennes à travers la barrière hémato-encéphalique.

The kinetics of competitive inhibition of 125I-T3 transport across the blood-brain barrier by two groups of thyroid hormone analogs (THA) was studied using the carotid injection technique. We confirm previous data that the transport of 125I-T3 was saturable; the Km of T3 transport was 1.2 microM. Our results also indicate that the mechanism of cross inhibition of T3 transport by THA with alanine side chain is competitive inhibition. The replacement of alanine side chain by an acetic acid group greatly reduced the affinity of the transport system. Consequently, the development of THA with selective tissue effects must take into account differential penetration rates of THA in the brain, when correlating biological effects with nuclear binding.

[Effect of thyroidectomy on phosphorylative oxidation and RNA synthesis in various regions of the brain in the adult monkey]. / Effets de la thyroïdectomie sur les oxydations phosphorylatives et la synthèse des ARN dans diverses régions du cerveau de singe adulte.

The subcellular effects of thyroidectomy in selected brain regions of Cynomolgus monkey were analyzed. 20 days after operation the respiratory rates, the activities of succinate cytochrome c reductase, glycerol-3-phosphate dehydrogenase and of oligomycin-sensitive ATPase were decreased in mitochondria isolated from all brain structures. The highest reduction (30%) was found in cerebral cortex and hippocampus. Cerebellar and striatal activities were reduced by about 20%. A smaller decrease (15%) was observed in thalamus. The effects of thyroidectomy on in vitro RNA synthesis were followed in cerebral cortex, cerebellum and thalamus. In the three analyzed regions, the activities of nucleolar and nucleoplasmic RNA polymerases dropped by 40%. Replacement therapy with T4 (2.5 micrograms/kg/day) or T3 (1 microgram/kg/day) administered immediately after thyroidectomy for 20 days, maintained mitochondrial and nuclear activities at normal level.

Comparative effects of thyroid hormone analogs on the activities of brain and liver mitochondria and nuclei in thyroidectomized rats.

Several thyroid hormone analogs have been tested for thyromimetic activity on rat brain and liver subcellular organelles. The compounds were administered immediately after thyroidectomy to 90 g male S-D rats for 10 days, by daily s.c. injection. In cerebral cortex and liver we measured the activities of mitochondrial succinate cytochrome c reductase and alpha-GPD, and nuclear RNA polymerase I. Brain mitochondrial enzymes were unchanged in thyroidectomized (Tx) and in Tx-treated rats, whereas the activities of these enzymes in liver mitochondria were partially restored by the treatments. RNA polymerase I activity in brain and liver dropped significantly 10 days after thyroidectomy and daily injection of thyroid hormones or analogs maintained the nuclear activity at a normal level. Correlation between the structure of thyroid hormone analogs and their subcellular effects is in good agreement with previous binding and in vivo studies. Enzyme activities stimulated by T3 were lowered by replacing the T3 side-chain by an acetic acid group or by substituting the bridged oxygen atom by atom by CO. In contrast, the activity was enhanced by substituting iodine with a 3' isopropyl group. Although less active than iodine, the 3,5-dimethyl substituents may be introduced without a complete loss of nuclear activity.

Effects of short- and long-term thyroidectomy on mitochondrial and nuclear activity in adult rat brain.

We compared subcellular activities in brain and liver at various times after thyroidectomy. Male S.D. rats were used on days 5, 10 or 60 after surgery. Mitochondrial properties were estimated by determining the respective activities of oxidative phosphorylation, succinate oxidase, succinate and beta-hydroxybutyrate cytochrome c reductase and alpha-glycerophosphate dehydrogenase. Nuclear activity was estimated by measuring the RNA polymerase I activity. In brain, RNA polymerase I activity already declined at 5 days after thyroidectomy, whereas mitochondrial respiratory enzymes decreased significantly only after 60 days. In liver, nuclear RNA polymerase I and mitochondrial enzyme activities were observed to drop simultaneously by the 5th day after thyroid removal. On the other hand, daily T3 s.c. injections, 0.25 microgram/100 g B.W., were given for 10 days to rats immediately after thyroidectomy (10 days Tx) or to chronically hypothyroid rats (60 days Hth). Hormonal treatment either maintained or restored subcellular activities to their normal level, both in brain and liver. These data suggest that the metabolic properties of brain mitochondria are sensitive to thyroid hormones, but that the brain needs less iodothyronines than other organs. The fast reduction of RNA polymerase I by thyroidectomy and its subsequent restoration by T3 suggest that the nuclear activity greatly depends on thyroid status.

[Brain mitochondrial and nuclear activity of the thyroidectomized rat]. / Activités mitochondriales et nucléaires cérébrales du rat thyroïdectomisé.

A rapid method of preparation of rat brain mitochondria was described. Oxidative phosphorylation of isolated brain mitochondria was decreased by thyroidectomy. RNA polymerase activity of isolated nuclei was also reduced. Therefore hypothyroidism affects brain subcellular particles as in other tissues.