Drug design and delivery最新文献

Indomethacin-loaded polyisobutylcyanoacrylate nanocapsules were prepared by interfacial polymerization of the alkylcyanoacrylate monomer. Mean particle size of the nanocapsules ranged from 200 to 300 nm. Comparison of the results following intravenous infusion of indomethacin solution and nanocapsules to rats revealed that nanoencapsulation accelerated the extravascular distribution of indomethacin due partly to enhanced uptake of the colloidal carrier by the liver reticuloendothelial system. Following intragastric administration, the oral bioavailability of indomethacin in solution was 90%--indicating complete absorption of this drug from the gastrointestinal tract of the rat. Absorption of indomethacin nanocapsules by this route was more rapid. This was attributed either to an increase in the intensity and/or the duration of contact of the encapsulated drug with the gut wall, or to a more efficient absorption process involving paracellular pathways.

The promoting effect of cyclic monoterpenes present in essential oils on the percutaneous absorption of indomethacin (IMC) from gel ointments was investigated in rats. As compared Azone, drug absorption was markedly enhanced by the addition of d-limonene, which is the main component of orange or lemon oils. Similar activity was observed in the cases of the l- and dl-forms of limonene, p-menthane, alpha-terpinene or terpinolene. On the other hand, no effect was obtained when the additive had hydroxyl or carbonyl groups, or ether oxygen in its chemical structure. The effect of pretreatment of skin with d-limonene on subsequent percutaneous absorption of IMC was investigated in order to estimate the influence of d-limonene on the barrier properties of the skin. No effect was observed suggesting that d-limonene might reversible alter the skin structure as the barrier for the drug transport. The serum concentration of IMC increased proportionally when increasing amounts of ethanol were present in the formulation (gel ointment) containing d-limonene. Therefore, ethanol may act as the accelerating agent for the promoting activity of d-limonene.

The traditional treatment for osteoarthritis is with analgesics, NSAIDs and intra-articular steroids. The development of novel analgesics and the reformulation of steroids to enhance local activity both deserve attention. The disease's slow course makes evaluation of new drugs difficult. More sensitive assessments or perhaps human models of accelerated progression are required. Amongst the drugs that might have fundamental action, hyaluronic acid and the so-called 'chondroprotective' agents have attracted recent interest. Their development highlights the difficulty of reconciling adequate dose-ranging pharmacokinetic studies with investigators' enthusiasm for treating a disease that may be subject to a fluctuant course with spontaneous improvement.

In the present study, two sustained release diclofenac preparations were administered every 12 hours over 4 days to ten human volunteers. Diurnal profiles were recorded on the 1st and 4th days, from which pharmacokinetic parameters were calculated: particular attention was given to cumulation. One, a newly developed sustained release formulation, had a MRT of 5.5 hours, and showed surprisingly small variation coefficients [AUC ss (72-84 hrs) +/- 26%; Cmax ss (72-84 hrs) +/- 19%] after 7 administered doses; accordingly, the maximum concentrations were within a very narrow time window [tmax ss (72-84 hrs) range: 1.5-2.5 hours after administration]. Due to the selected release profiles with this formulation, there was no danger of cumulation in spite of administration every 12 hours [AUC 0-12 hrs, mean value = 1555 ng/ml x h; AUC ss 72-84 hrs, mean value = 1750 ng/ml x h].

We have previously shown that cyclohexanone derivatives exert a promoting effect on the in vivo percutaneous absorption of indomethacin (IMC), and now describe in vitro permeation studies to gain understanding of the mechanism of action. The results of the in vitro experiment were consistent with those of the previous in vivo experiments. 2-tert-Butylcyclohexanone was the most effective of six enhancers examined. The partition coefficient of IMC was determined in a buffer-octanol system containing the cyclohexanone derivatives, and the lipophilicities of these derivatives are discussed using a lipophilic index. We conclude that the cyclohexanone derivatives penetrate into the stratum corneum and alter the skin permeability of IMC by fluidizing or modifying the hard hydrophobic barrier of the corneum.

Nine aminoalkylaminoanthraquinones (I-IX) were evaluated for their cytotoxic potency against normal and malignant mammalian cells. The 1.8-di-(aminopropylamino) derivative (VIII) exhibited significant activity against several tumor cell systems and had some selectivity. The toxicity of this compound was also tested in growing chick embryos.

The Centre for Medicines Research initiated annual lectures in 1986 to provide regular overviews of some of the Centre's major areas of research interest. The 1988 lecture was given on July 6 at the Royal College of Physicians by Dr David Jack, C.B.E., D.Sc., F.R.S.E., who was until recently Research and Development Director of Glaxo Holdings, plc. His comments on drug discovery, based on long and successful research experiences, will we feel be of great interest to our readers. We are grateful to him and the Centre for Medicines Research for this written account of his lecture.

The absorption of gentamicin (GM) from the rectum of rabbits after coadministration of GM (60 mg) and sodium salicylate (SA) or sodium caprylate (CA) as absorption-enhancing agents was investigated. Two types of hollow type suppositories were used--a conventional type (Type I) and a release-restricted type (Type II). Without SA or CA, GM was not absorbed. However, GM absorption was marked when 90 mg of solid SA or CA was added (the bioavailability of GM was 58% with SA, and 59% with CA). The enhancing effect of SA or CA (30 mg) in solid or aqueous solution form on GM absorption was evaluated using the Type I suppository. In the case of SA, the highest plasma GM level (Cmax 15.3 +/- 1.7 micrograms/ml, AUC0-4 27.3 +/- 3.9 h.micrograms/ml) was obtained following coadministration of powdered GM and SA; the plasma GM level (Cmax 1.5 +/- 0.6 micrograms/ml, AUC0-4 3.0 +/- 1.3 h.micrograms/ml) following the administration of a solution of GM and SA was significantly decreased as compared with the results using the powdered form. In the case of CA, the plasma GM level (Cmax 14.8 +/- 4.5 micrograms/ml, AUC0-4 25.4 +/- 8.7 h.micrograms/ml) following administration of the solution form was not significantly decreased in comparison with the results obtained using the powdered form. A marked increase in the enhancing effect of SA on the rectal GM absorption was found following use of Type II suppositories when GM and SA were coadministered in solution form. However, the GM absorption after coadministration of GM and CA using Type II suppositories was not significantly different from the absorption resulting from use of Type I suppositories. Our results suggest that the form and concentration of drug should not be ignored in evaluating the enhancing effects of SA or CA on the rectal absorption of poorly absorbed drugs such as GM.

Homogeneous recombinant human interferon-gamma (IFN-gamma) obtained from Escherichia coli (E. coli) was treated with a protease-containing fraction prepared from mechanically lysed E. coli cells. Polyacrylamide gel electrophoresis of the resulting product revealed two major components of molecular weight less than that of intact IFN-gamma. These were purified by ion exchange chromatography in the presence of 7 M urea and shown to have intact IFN-gamma N-terminal sequences, suggesting that they resulted via C-terminal cleavages of IFN-gamma. Amino acid analysis indicated that 4 C-terminal residues of IFN-gamma were lacking in one, and 15 in the other. The species lacking 4 C-terminal residues had activities virtually indistinguishable from those of IFN-gamma in antiviral and growth inhibitory assays using Encepharomyocarditis-treated HeLa or T98G cells and in a macrophage activation assay using macrophage-like U937 cells. The species lacking 15 C-terminal residues had markedly decreased activities in each of these assays, and had decreased binding affinity for IFN-gamma cell surface receptors. These observations define the C-terminal residues important for IFN-gamma's biological activity--information which should be useful in designing analogs of IFN-gamma with enhanced or altered biological activities.