Drug design and delivery最新文献

Alkyl cycloalkyl esters of nifedipine (1a) analogues, in which the ortho-nitrophenyl group at position 4 is replaced by pyridinyl (5-19) were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca(2+)-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activity profile for unsymmetrical esters (5-15), which indicated the effect of cycloalkyl ring size on activity, was cyclopentyl > cyclohexyl > cyclobutyl. In addition unsymmetrical esters, possessing one R2-cyclohexyl substituent, exhibited an activity profile dependent upon the nature of the R1-alkyl ester substituent with Me > Et, i-Pr, i-Bu > cyclohexyl > t-Bu. The point of attachment of the C-4 pyridinyl substituent was also a determinant of activity for unsymmetrical compounds (R1 = Me, i-Pr; R2 = cyclohexyl, cyclobutyl) where the relative potency order was 2-pyridinyl > 3-pyridinyl > 4-pyridinyl. In contrast, when the R1 and R2-substituents are larger in size (R1 = R2 = cyclohexyl or R1 = i-Pr, R2 = cyclopentyl) the relative activity profile was 3-pyridinyl = 4-pyridinyl > 2-pyridinyl. The C-3 and C-5 ester substituents therefore appear to provide important interdependent contributions to calcium channel antagonist activity, and hence to interaction with the 1,4-dihydropyridine receptor site.

This study attempted to develop sustained release implantable dosage forms based on PHYCON 6600, a new silicone gel. The solid gel is prepared at ambient temperature by polymerization of two basic components (PHYCON A and PHYCON B solutions) for about 1 h. The application we explored was the use of implantable PHYCON-drug composites in tumor therapy. Carmofur (1-hexylcarbamoyl-5-fluorouracil, HCFU) was chosen as a practical antitumor drug. Using an in vitro dissolution test, near zero-order release rate was observed over a period of about 35 days. The amount of drug released by the 'burst phenomenon' was found to be less than the HCFU toxic dose. In vivo studies of antitumor activity were carried out by measuring the lifespan of lymphoma-inoculated mice (ILS). The increase in lifespan (38.5%) following intraperitoneal administration of the PHYCON formulations was similar to that (36.4%) following injection of the drug alone for 5 days. Our results suggest that the injectable and implantable sustained release formulations of the antitumor drug in PHYCON might be suitable for tumor chemotherapy.

Published c-AMP phosphodiesterase inhibitory activities of 7-substituted-1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazolines are used in a QSAR study to analyse a proposed model of the c-AMP PDE (type IV) active site. Based on the regression equations involving hydrophobic parameters and activities, additional subsites G1 and G2 are identified in the secondary binding region G, and steric hydrophobic tolerance at these subsites is discussed.

Resealed erythrocyte ghosts are potential in vivo carriers of exogenous therapeutic enzymes. In the present work, the effect of administering delta-aminolaevulinate dehydratase (ALA-D) encapsulated in autologous red blood cell ghosts (RBCg) to lead intoxicated and normal mice was investigated. Administration of ALA-D loaded RBCg to intoxicated mice produced an immediate and permanent recovery in erythrocytic ALA-D activity; the effect was also noticeable in liver and spleen and absent in kidney, indicating that the entrapped enzyme was significantly stabilized to allow retention of activity in both circulating and phagocytized cells. Administration of ALA-D loaded ghosts to normal mice did not produce significant changes in ALA-D activity in blood, liver, spleen or kidney. Administration of free exogenous enzyme or blood transfusion during lead intoxication was also ineffective; spontaneous recovery of the poisoned animals was very slow. We show that circulating as well as phagocytized ALA-D entrapped in autologous erythrocyte ghosts can be safe and beneficial in the treatment of lead poisoning. Clinical trial in patients is recommended.

Quantitative structure-activity relationships (QSAR) were studied in a series of chain-modified peptide analogues of the active site of angiotensinogen. The activity of these renin inhibitors was found to be significantly correlated with Kier's first-order valence molecular connectivity index (1 chi v) and with the molecular weight (MW) of the molecules. The activity was less well correlated with the van der Waals volume (Vw), and not at all with the hydrophobic character (log P) of the molecules. These findings suggest that there is a strong dispersion interaction between the inhibitor molecules and the enzyme, and that hydrophobicity plays little part in the interaction.

Seven chemical delivery systems (CDS) based on a dihydropyridine<-->quaternary pyridinium salt type redox system and analogous to the naturally occurring NADH<-->NAD+ coenzyme system were applied in the case of the antidepressant drug desipramine. The pyridine moiety-containing carriers were linked to the amino function of desipramine either as amides or substituted carbamates. Lipophilic properties were expressed in terms of chromatographic Rm values. Oxidative stability of the dihydropyridine forms of the CDSs were determined in vitro. The amide type derivatives were stable toward hydrolysis in buffers and in biological fluids, whereas the carbamates released the parent drug in a very efficient manner. In a behavioral despair test, the CDSs did not show improved activity when compared to desipramine. In vivo distribution studies of one of the CDS did not show more efficient delivery of the desipramine into the rat brain but did show a prolonged presence at a constant level.

We previously evaluated the promoting effects of 2-tert-butylcyclohexanone and its analogues on the percutaneous absorption of indomethacin (IMC), and showed that the 2-position of the cyclohexanone ring plays an important role in drug permeability through the skin. The present study investigates the in vitro penetration enhancement of IMC by five 2-n-alkylcyclohexanone derivatives. 2-n-Octylcyclohexanone was the most effective enhancer, but the other four enhancers also had significant promoting actions on skin permeability of IMC. Maximum absorption enhancement was associated with a defined range of enhancer lipophilicity. We propose that the enhancer penetrates into the stratum corneum and improves skin permeability of a drug by dissolving some of the hard lipid components or modifying the dense lipid stratum corneum.

Neuropeptides and monoamines are found in tissues where immune reactions are initiated such as the skin, gut and respiratory tract. In these tissues they might influence lymphocyte activation in inflammatory diseases. Both stimulatory and inhibitory effects have been described. The inhibitory effects may prove to be of pathophysiological and pharmacological importance. Studies both in vitro and in vivo showing that various neuropeptides and monoamines may inhibit reactions such as T lymphocyte proliferation, Blymphocyte proliferation and antibody synthesis, lymphocyte migration and cytotoxicity, are reviewed.

Some N,N-dialkylderivatives of 6-amino-5,6,7,8-tetrahydroquinoline were synthesized. The affinity of new compounds for dopamine binding sites was measured in a test involving displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) from homogenized rat striatal tissue. While no compound was effective in displacing [3H]SCH 23390, in the binding assays on the D-2 receptor all tetrahydroquinolines displaced [3H]spiperone from specific binding sites, the compounds with a N-n-propyl-N-phenylethylamino group (18) or N,N-di n-propylamino group (16) being the most potent.