Drug design and delivery最新文献

A dihydropyridine in equilibrium with pyridinium salt redox system was applied to effect brain delivery of gamma-aminobutyric acid (GABA) derivatives and analogues. The redox system allows the lipophilic dihydropyridine conjugates to penetrate the blood brain barrier, whereas corresponding oxidized pyridinium forms are retained in the brain for an extended period and rapidly eliminated from the periphery. The most promising compound was the GABA benzyl ester-CDS (1a, Scheme I). It had an ED50 of 15.8 mg/kg (i.v.) in protecting mice against maximal electroconvulsive shock-induced tonic hind-leg extension.

Following our previous demonstration that Azone and 2-n-alkylcyclohexanones enhanced the percutaneous absorption of indomethacin, six 1-n-alkylpiperidones were prepared and examined as potential transdermal absorption enhancers. In vitro skin experiments showed that indomethacin absorption enhancement was related to the lipophilicity of the enhancer, and that 1-n-dodecyl piperidone caused the greatest enhancement. The structure of this piperidone is similar to that of Azone, and both compounds had similar lipophilicity and drug absorption enhancement activity. We suggest that they act in the same way by decreasing diffusional resistance in the stratum corneum, and so modifying the hard barrier of the stratum corneum.

A novel series of semisynthetic penicillins was designed and synthesized. The compounds have as an integral part of the molecule a pyridinium <--> dihydropyridine redox system as a substituent at the 6-position. Esters of the dihydropyridine (pro-prodrug) forms of the drugs were expected, because of their pronounced lipophilic character, to easily penetrate biological membranes, including the blood-brain barrier, and to give rise to esters of polar pyridinium ions (prodrug) (via enzymic oxidation of the dihydropyridine moiety). The resulting ions were expected to be rapidly excreted from the periphery, but to be "locked" in the central nervous system; subsequent enzymic cleavage of the ester function was expected to release the free acid-pyridinium salts (drug) in the central nervous system in a sustained manner. The design approach, synthesis, study of some important physicochemical properties, stability determinations and preliminary in vivo distribution and potency evaluations of the novel drugs are described.

Homeostatic regulation of Ca2+ levels within airway smooth muscle cells, and the consequences of changes in intracellular Ca2+ levels are reviewed, and a number of mechanisms are identified as targets for drug action. In the prophylaxis of asthma--by preventing the induction of contraction--the opportunities relate to receptor antagonism, the inhibition of Ca2+ influx, the inhibition of intracellular Ca2+ release, calmodulin antagonism, and the antagonism of contractile proteins. In the symptomatic relief of asthma--by reversal of established contractile responses--the opportunities relate to the inhibition of Ca2+ influx, the inhibition of inositol trisphosphate metabolism, the inhibition of protein kinase C, and the augmentation of Ca2+ removal mechanisms.

The synthesis of a series of bis-daunomycin hydrazones (5a-g)--all moderately stable at 37 degrees C, pH 6.8, with a half-life of approximately 30 h--is reported. Under a pulse exposure of 2 h they exhibited growth inhibition of mouse L1210 cells, and were 2-3 fold more active than daunomycin. Under continuous exposure growth inhibition conditions with human colon cell lines (HT-29 and HCT-8) they hydrolysed to daunomycin and a partially hydrolysed mono-derivative of daunomycin, and there was no apparent increase in activity over that of the parent anthracycline. Their rate of hydrolysis was observed to increase rapidly with decreasing pH.

1-(2-Nitrovinyl) derivatives of nuclear substituted 1,4-dihydropyridines (7a-c), and 1-(N-tert-butyl-formiminyl) derivatives of 1,4-dihydropyridines (9a-c) or 2-pyridones (11a-c) were synthesized for evaluation as cytotoxic agents (see Table I for structures). The in vitro cytotoxic activities, determined in the L1210 assay, indicated that the 4-substituent on a 1,4-dihydropyridine ring system was a determinant of activity in both the 1-(2-nitrovinyl) (7) and 1-(N-tert-butylformiminyl) (9) series, the relative activity order being n-Bu > Ph > Me. In the 1-(N-tert-butylformiminyl) series, the 1,4-dihydropyridine derivatives (9) were generally more cytotoxic than the 2-pyridone derivatives (11). The most active compound was 1-(N-tert-butylformiminyl)-3-(4,4-dimethyloxazolin-2-yl)-4-n -butyl-1,4- dihydropyridine (9b), but it was 2-3 log units less active than the reference standard melphalan.

Swelling and diffusion experiments, performed in vitro with tablets prepared with scleroglucan and several hydrophilic and hydrophobic additives, indicate that it is possible to modulate drug delivery from the matrix by appropriate choice of the nature and amount of the additive. The additives in the formulations may affect the mechanisms (zero order, diffusion, erosion) involved in the release of drugs from the dosage forms.

This article discusses the need for animal behavioural tests in the search for novel anxiolytics and describes in detail those tests that are ethologically-based (the social interaction, elevated plus-maze, light-dark transitions, and rat pup isolation-induced calling tests). The extent to which different animal tests might be sensitive to different types of anxiety is also discussed, with particular reference to possible differences between generalised anxiety and panic disorder.

Tumor, liver, skin and brain explants from tumor-bearing mice were cultured for 6, 12 and 22 hours in the presence of 0.06, 0.1 and 0.2 mM aminolevulinic acid (ALA). It was found that in all organs, synthesis of porphyrins increased with time and ALA concentration. The synthesising activity of tumor was high, of the same order as that of liver, and nearly twice that of skin and brain. The tissue/tumor porphyrin concentration ratios were lower than 0.5 at longer times and higher ALA concentration. In the case of skin/tumor the lowest ratio was about 0.2 and was obtained with 0.2 mM ALA. Chromatographic analysis of individual porphyrins showed that the whole heme pathway was functional in all organs studied, including tumor. Porphyrin synthesis by different organs from tumor bearing and normal mice was comparatively investigated using free and liposome encapsulated ALA. After 22 hours of incubation with 0.4 mM ALA, porphyrin formation was greater when encapsulated ALA was used. Accumulation of porphyrins in tumor was very high. The levels of activity were the same in each pair of organs in either the tumor-bearing mice or the control. These results indicate that free or encapsulated ALA may be used for the detection of tumors and in photodynamic therapy.

Experiments performed in vitro with tablets and capsules indicate that the fungal polysaccharide scleroglucan is suitable for the formulation of sustained-release, oral dosage forms. Delivery of model drugs from the non-disintegrating matrix was studied in solutions buffered at different pH values. The effect on drug release of drug concentration, the physico-chemical properties of the drug, and the compression force used in the preparation of the matrix are reported, and the possible mechanisms of release are discussed.